diff --git a/hbp_knowledge/antalarmin/alderman2018.bel.json b/hbp_knowledge/antalarmin/alderman2018.bel.json
index 8789442ae..73bb38ca8 100644
--- a/hbp_knowledge/antalarmin/alderman2018.bel.json
+++ b/hbp_knowledge/antalarmin/alderman2018.bel.json
@@ -56,6 +56,9 @@
   "links": [
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Species": {
           "7955": true
         }
@@ -79,16 +82,22 @@
       },
       "evidence": "The endogenous response to heat shock was characterized by transient changes in caspase-3 activity and gene expression.",
       "key": "5b4d6e296d0cad179cad195d6b87156b3990139567587bd2aa7ed533e8b3d8148d29494855afd006500651f3d49143dbd516c8b6b8865d8d2becfa9446883013",
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+      "line": 80,
       "object": {
         "modifier": "Activity"
       },
       "relation": "association",
       "source": 2,
-      "target": 4
+      "target": 3
     },
     {
       "annotations": {
+        "CellLine": {
+          "embryonic cell line": true
+        },
+        "Confidence": {
+          "Medium": true
+        },
         "Species": {
           "7955": true
         }
@@ -112,19 +121,22 @@
       },
       "evidence": "For embryos heat shocked at 6 hpf, the induction of caspase-3 activity was dependent on recovery time (interaction of main variables P=0.007), with a significant increase over controls at 7 h and 10 h recovery (Table 1).",
       "key": "7aa8b4d21a477b1c2b6a2e7c2e2ca5c83803fb4d033eb19a3e55ab834b519ea9af39ce1811ce29f4ebee18b959c477dea6ed426d20d72c91f2ff608dbdfee33f",
-      "line": 80,
+      "line": 86,
       "object": {
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       "relation": "increases",
       "source": 2,
-      "target": 4
+      "target": 3
     },
     {
       "annotations": {
         "CellLine": {
           "embryonic cell line": true
         },
+        "Confidence": {
+          "Medium": true
+        },
         "Species": {
           "7955": true
         }
@@ -148,48 +160,18 @@
       },
       "evidence": "In embryos heat shocked at 6 hpf, crf abundance increased relative to controls after 4 h recovery, but there were no differences at 7 h or 10 h recovery (Fig. 1A).",
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+      "line": 95,
       "relation": "increases",
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+      "target": 4
     },
     {
       "annotations": {
         "CellLine": {
           "embryonic cell line": true
         },
-        "Species": {
-          "7955": true
-        }
-      },
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-        "authors": [
-          "Alderman SL",
-          "Bernier NJ",
-          "Fuzzen MLM",
-          "Leishman EM"
-        ],
-        "date": "2018-09-01",
-        "first": "Alderman SL",
-        "last": "Bernier NJ",
-        "name": "General and comparative endocrinology",
-        "pages": "207-213",
-        "reference": "29807032",
-        "title": "Corticotropin-releasing factor regulates caspase-3 and may protect developing zebrafish from stress-induced apoptosis.",
-        "type": "PubMed",
-        "volume": "265"
-      },
-      "evidence": "In embryos heat shocked at 6 hpf, crf abundance increased relative to controls after 4 h recovery, but there were no differences at 7 h or 10 h recovery (Fig. 1A).",
-      "key": "5d0f9448cbd19c85b2ae3568fa9a385a1e6d149d98dd6bdac1c2594d5b9b38e9009fb9186e8ccadc3526475a721cb6b6dffa3740007f922f3e12484c64ace524",
-      "line": 85,
-      "relation": "causesNoChange",
-      "source": 2,
-      "target": 5
-    },
-    {
-      "annotations": {
-        "CellLine": {
-          "embryonic cell line": true
+        "Confidence": {
+          "Medium": true
         },
         "Species": {
           "7955": true
@@ -213,17 +195,20 @@
         "volume": "265"
       },
       "evidence": "The endogenous response to heat shock was also characterized by an increase in crf-bp mRNA levels independent of recovery time (main effect of heat shock P<0.05), and this was true for embryos exposed to the stressor at 6 hpf (Fig. 1C) and at 30 hpf (Fig. 1D).",
-      "key": "b34328d8b6e66e1e36bb71248e4a309e386c1a0673ed8f2bd05b050bc90a1b6adb89dc7bd6a9ea6583169693c869f6c72b6477e081ea7ec7d2ce9c4e435043af",
-      "line": 88,
+      "key": "e0c326eecca8d1a67afb3b4c3a26d095f22f2ba5c2c600017c034065b86027dd2cb56a7ecc9f095fceb15a81f9a0473ae4c9b6943ca16894ca87955090417c3c",
+      "line": 101,
       "relation": "increases",
       "source": 2,
-      "target": 3
+      "target": 6
     },
     {
       "annotations": {
         "CellLine": {
           "embryonic cell line": true
         },
+        "Confidence": {
+          "High": true
+        },
         "Species": {
           "7955": true
         }
@@ -247,16 +232,22 @@
       },
       "evidence": "Heat shock significantly increased embryo mortality relative to non-heat shocked embryos",
       "key": "d4fc40c9cca9e909c2e813b981f011be83cc9f931737079e1282aa7ad5bc561b42d0cd95ffb0a70c2f6c59334daf970bc8742b1f22169d567191e922205e8e16",
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+      "line": 114,
       "relation": "decreases",
       "source": 2,
       "target": 0
     },
     {
       "annotations": {
+        "Cell": {
+          "embryonic cell": true
+        },
         "CellLine": {
           "embryonic cell line": true
         },
+        "Confidence": {
+          "Medium": true
+        },
         "Species": {
           "7955": true
         }
@@ -280,7 +271,7 @@
       },
       "evidence": " Final cumulative mortality (at 10 h recovery) in non-heat shocked embryos was low in both the 0 nM and 10 nM antalarmin groups (4.7% and 8.3%, respectively), and heat shock increased mortality in both groups",
       "key": "30530cfb310904c12a52655c5a17647e99923277111d3ad7f8eb0e359b74fe8c97b5a3bf692ace08bb2ee68302bb94eea2c682fd4c08ec4760a4caf9b16d8e94",
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+      "line": 129,
       "relation": "decreases",
       "source": 2,
       "target": 0
@@ -290,6 +281,9 @@
         "CellLine": {
           "embryonic cell line": true
         },
+        "Confidence": {
+          "High": true
+        },
         "Species": {
           "7955": true
         }
@@ -313,13 +307,16 @@
       },
       "evidence": "The greatest heat shock-induced mortality occurred during the first 1 h of recovery and plateaued after 5 h recovery (main effect of time P<0.001; n=3; Fig. 3B), but the presence of antalarmin did not influence this response.",
       "key": "a27db20a5e10a3857b68be9bb92a5f24830b304e190cf6d733ed73be71b2da5674a14fc87f82c3bba8ec8e812810cd1411beec50feb6c5d83a91d6f7fe11c22d",
-      "line": 105,
+      "line": 135,
       "relation": "decreases",
       "source": 2,
       "target": 0
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Species": {
           "7955": true
         }
@@ -343,9 +340,9 @@
       },
       "evidence": "The endogenous response to heat shock was characterized by transient changes in caspase-3 activity and gene expression.",
       "key": "d91c78c5f870028166b7b23b0be282af23936fb4ff8667f2d53a45d6dbced6984f3ed36e5cefa89d7e22be763a8af08d9c111bc20995a7ec62a38bc6e3f01a26",
-      "line": 77,
+      "line": 80,
       "relation": "association",
-      "source": 4,
+      "source": 3,
       "subject": {
         "modifier": "Activity"
       },
@@ -353,9 +350,15 @@
     },
     {
       "annotations": {
+        "Cell": {
+          "embryonic cell": true
+        },
         "CellLine": {
           "embryonic cell line": true
         },
+        "Confidence": {
+          "Medium": true
+        },
         "Species": {
           "7955": true
         }
@@ -379,19 +382,22 @@
       },
       "evidence": "CRF overexpression by mRNA microinjection reduced heat shock-induced caspase-3 activity by approximately 2-fold relative to control-injected embryos",
       "key": "f32fb5d58d0c51089cd2ae475083abfdb9e0848bc53d9696e7a8b888894a44391b49cde0d500e3600fba6b900962b3d711c6d8dcc51e276b9db0bc63b2870694",
-      "line": 92,
+      "line": 108,
       "object": {
         "modifier": "Activity"
       },
       "relation": "decreases",
-      "source": 5,
-      "target": 4
+      "source": 4,
+      "target": 3
     },
     {
       "annotations": {
         "CellLine": {
           "embryonic cell line": true
         },
+        "Confidence": {
+          "Medium": true
+        },
         "Species": {
           "7955": true
         }
@@ -414,17 +420,23 @@
         "volume": "265"
       },
       "evidence": "The endogenous response to heat shock was also characterized by an increase in crf-bp mRNA levels independent of recovery time (main effect of heat shock P<0.05), and this was true for embryos exposed to the stressor at 6 hpf (Fig. 1C) and at 30 hpf (Fig. 1D).",
-      "key": "81e0a4f7400f1c5b3eacd00decc0936e2f62f0749b695fb3905e6079ce6d7d6ce5af46d0a40cee8508572ba30dffc10c0ded6914ab0298b4ce4e919690abc218",
-      "line": 89,
+      "key": "d6ef7eab1c9ed3773b14a1d19f34fc625d23f00d2f0f1b2f9dc0c5c1c012d630edb45f1f09a50707bd03947a0b9121d691a1d233d192416ca31cd33b14a9732c",
+      "line": 102,
       "relation": "increases",
-      "source": 6,
-      "target": 3
+      "source": 5,
+      "target": 6
     },
     {
       "annotations": {
+        "Cell": {
+          "embryonic cell": true
+        },
         "CellLine": {
           "embryonic cell line": true
         },
+        "Confidence": {
+          "Medium": true
+        },
         "Species": {
           "7955": true
         }
@@ -448,16 +460,22 @@
       },
       "evidence": "However, embryos that recovered from heat shock in the presence of the CRF-R1 antagonist, antalarmin, experienced a greater increase in caspase-3 activity than embryos not given the antagonist",
       "key": "d8ca0bd00ac398bf2f630f7eb44365b12c3157386715bfab3f03672368767b762252ac7c37668adf3ba8a4a9d6a96d376e0c7489e17d917b7a2a9e160d4ffc5e",
-      "line": 98,
+      "line": 120,
       "relation": "decreases",
       "source": 1,
       "target": 2
     },
     {
       "annotations": {
+        "Cell": {
+          "embryonic cell": true
+        },
         "CellLine": {
           "embryonic cell line": true
         },
+        "Confidence": {
+          "Medium": true
+        },
         "Species": {
           "7955": true
         }
@@ -481,19 +499,61 @@
       },
       "evidence": "However, embryos that recovered from heat shock in the presence of the CRF-R1 antagonist, antalarmin, experienced a greater increase in caspase-3 activity than embryos not given the antagonist",
       "key": "9494f4001106a82bb6dc1a194c55b04f7c12f7a94893d1e57127a59cf3c1d72e985d4f7414b17c200e0bf1f1c1b31ba035844d3a953cfb46ff1f3752502ed541",
-      "line": 99,
+      "line": 121,
       "object": {
         "modifier": "Activity"
       },
       "relation": "increases",
       "source": 1,
-      "target": 4
+      "target": 3
+    },
+    {
+      "annotations": {
+        "Cell": {
+          "embryonic cell": true
+        },
+        "CellLine": {
+          "embryonic cell line": true
+        },
+        "Confidence": {
+          "Medium": true
+        },
+        "Species": {
+          "7955": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Alderman SL",
+          "Bernier NJ",
+          "Fuzzen MLM",
+          "Leishman EM"
+        ],
+        "date": "2018-09-01",
+        "first": "Alderman SL",
+        "last": "Bernier NJ",
+        "name": "General and comparative endocrinology",
+        "pages": "207-213",
+        "reference": "29807032",
+        "title": "Corticotropin-releasing factor regulates caspase-3 and may protect developing zebrafish from stress-induced apoptosis.",
+        "type": "PubMed",
+        "volume": "265"
+      },
+      "evidence": " Final cumulative mortality (at 10 h recovery) in non-heat shocked embryos was low in both the 0 nM and 10 nM antalarmin groups (4.7% and 8.3%, respectively), and heat shock increased mortality in both groups",
+      "key": "d20743f9b6d54ec99c5fd0c757621168874919a2f9ff0cf809c58fed037009ddb37b634bcb6b8db021d88622fb401bf3c616ed9d3b880f61771262ec3850c354",
+      "line": 128,
+      "relation": "causesNoChange",
+      "source": 1,
+      "target": 0
     },
     {
       "annotations": {
         "CellLine": {
           "embryonic cell line": true
         },
+        "Confidence": {
+          "High": true
+        },
         "Species": {
           "7955": true
         }
@@ -517,7 +577,7 @@
       },
       "evidence": "The greatest heat shock-induced mortality occurred during the first 1 h of recovery and plateaued after 5 h recovery (main effect of time P<0.001; n=3; Fig. 3B), but the presence of antalarmin did not influence this response.",
       "key": "b59d7c803593c93f87031492725b8b71bc332700c90482a6e25100ec6561989de7834709ab1dda7d383efbc9566a310ef687470da090df2cfe050a68c3210610",
-      "line": 106,
+      "line": 136,
       "relation": "causesNoChange",
       "source": 1,
       "target": 0
@@ -546,13 +606,6 @@
       "name": "Heat-Shock Response",
       "namespace": "MESH"
     },
-    {
-      "bel": "p(MESH:\"corticotropin releasing factor-binding protein\")",
-      "function": "Protein",
-      "id": "3c4aba0d002c21647cc6f629d36bb4241b21dd5d6c9c896a453fdcd70befe8138016758dea4ccea306d80bef936a89d810319b56be5967278582a65e80a920f7",
-      "name": "corticotropin releasing factor-binding protein",
-      "namespace": "MESH"
-    },
     {
       "bel": "p(NCBIGENE:140621)",
       "function": "Protein",
@@ -573,6 +626,13 @@
       "id": "d0789ea931281879b41dea11607a53a5278698fe85ec7943937d9c13f6b852190facf2821f8841fdb20b797a224ade3388118d05fb3b9d0ce7df19990170b082",
       "name": "Stress Disorders, Traumatic",
       "namespace": "MESH"
+    },
+    {
+      "bel": "r(MESH:\"corticotropin releasing factor-binding protein\")",
+      "function": "RNA",
+      "id": "b0bf1a5106f78274130522d61baf2e2dc716acabae957fab16142a3446b830c44514131efe46cc3e9d1a25a4151af7dca6c624eeac76ba65b3e4781794e49e20",
+      "name": "corticotropin releasing factor-binding protein",
+      "namespace": "MESH"
     }
   ]
 }
\ No newline at end of file
diff --git a/hbp_knowledge/antalarmin/lewis1996.bel.json b/hbp_knowledge/antalarmin/lewis1996.bel.json
index a2d04ddb9..8afbcc050 100644
--- a/hbp_knowledge/antalarmin/lewis1996.bel.json
+++ b/hbp_knowledge/antalarmin/lewis1996.bel.json
@@ -67,6 +67,12 @@
   "links": [
     {
       "annotations": {
+        "Anatomy": {
+          "hypothalamus": true
+        },
+        "Confidence": {
+          "Medium": true
+        },
         "Species": {
           "10116": true
         }
@@ -91,10 +97,10 @@
         "volume": "137"
       },
       "evidence": "Corticotropin-releasing hormone (CRH) secreted from the hypothalamus is the major regulator of pituitary ACTH release and consequent glucocorticoid secretion. CRH secreted in the periphery also acts as a proinflammatory modulator.",
-      "key": "530e2b124518f599ab9adfcbfec36061805a001cc49a77bbac352a410d2df3d25665d1306aff075c24dce3797ce2be55552804c2497073a3cbebe2d8f2e5c24c",
-      "line": 78,
-      "relation": "positiveCorrelation",
-      "source": 2,
+      "key": "30c806c9625631a300e27d1704595f3ee23e12fcc9adbcae8ddb903580486ae767206c1949e2eecbaa4bce1c02007b230ff5a1ce61abb30a6eab9807dd792c14",
+      "line": 82,
+      "relation": "regulates",
+      "source": 4,
       "subject": {
         "modifier": "Activity"
       },
@@ -102,6 +108,12 @@
     },
     {
       "annotations": {
+        "Anatomy": {
+          "hypothalamus": true
+        },
+        "Confidence": {
+          "Medium": true
+        },
         "Species": {
           "10116": true
         }
@@ -126,8 +138,8 @@
         "volume": "137"
       },
       "evidence": "Corticotropin-releasing hormone (CRH) secreted from the hypothalamus is the major regulator of pituitary ACTH release and consequent glucocorticoid secretion. CRH secreted in the periphery also acts as a proinflammatory modulator.",
-      "key": "b01819c4cf1f287077b957b8ff920cda22d8a3bae6d6d899a979ff9ee10f376e09dd60e1da3f7ac49b36c45a8ba298fed64c1a918d512d8187ce221e5abb2432",
-      "line": 79,
+      "key": "feeec5f81a6c25cd7bc019e16dc15c12c5bc646b9a278a1fed5538102f153692334212a93aaccae7e4ccf1bd70213275fbc3748b6c1deda3617bfa585c59cb17",
+      "line": 83,
       "object": {
         "effect": {
           "fromLoc": {
@@ -141,12 +153,53 @@
         },
         "modifier": "Translocation"
       },
-      "relation": "regulates",
-      "source": 2,
+      "relation": "increases",
+      "source": 4,
       "subject": {
         "modifier": "Activity"
       },
-      "target": 4
+      "target": 2
+    },
+    {
+      "annotations": {
+        "Anatomy": {
+          "hypothalamus": true
+        },
+        "Confidence": {
+          "Medium": true
+        },
+        "Species": {
+          "10116": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Chrousos GP",
+          "Lewis DB",
+          "Rice KC",
+          "Torpy DJ",
+          "Webster EL",
+          "Zachman EK"
+        ],
+        "date": "1996-12-01",
+        "first": "Webster EL",
+        "last": "Chrousos GP",
+        "name": "Endocrinology",
+        "pages": "5747-50",
+        "reference": "8940412",
+        "title": "In vivo and in vitro characterization of antalarmin, a nonpeptide corticotropin-releasing hormone (CRH) receptor antagonist: suppression of pituitary ACTH release and peripheral inflammation.",
+        "type": "PubMed",
+        "volume": "137"
+      },
+      "evidence": "Corticotropin-releasing hormone (CRH) secreted from the hypothalamus is the major regulator of pituitary ACTH release and consequent glucocorticoid secretion. CRH secreted in the periphery also acts as a proinflammatory modulator.",
+      "key": "530e2b124518f599ab9adfcbfec36061805a001cc49a77bbac352a410d2df3d25665d1306aff075c24dce3797ce2be55552804c2497073a3cbebe2d8f2e5c24c",
+      "line": 84,
+      "relation": "positiveCorrelation",
+      "source": 4,
+      "subject": {
+        "modifier": "Activity"
+      },
+      "target": 3
     },
     {
       "annotations": {
@@ -156,6 +209,9 @@
         "AssayType": {
           "B": true
         },
+        "Confidence": {
+          "Medium": true
+        },
         "MeasurementRelation": {
           "=": true
         },
@@ -193,19 +249,25 @@
       },
       "evidence": "Antalarmin potently displaced 1251-oCRH binding, exhibiting respectively Ki values of 1. 9 f 0.9,. 1.3 f .4, and 1.4 f .6 nM (mean f SEM) in pituitary, cerebellum, and frontal cortex homogenates.Antalarmin, by effectively displacing IoCRH binding in tissues predominately expressing CRHRl but not in tissues expressing CRHR2, appears to be a specific CRHRl receptor antagonist.",
       "key": "40a04dbabe438b8b8fafdfdc7bd04708f737b6736872da95889695d708e494d3cfc3126236b9304b4a8d0a9762dd91fc6ae16addbcbc4b19e65753f46ca79cb1",
-      "line": 91,
+      "line": 100,
       "object": {
         "modifier": "Activity"
       },
       "relation": "directlyIncreases",
-      "source": 2,
+      "source": 4,
       "subject": {
         "modifier": "Activity"
       },
-      "target": 3
+      "target": 5
     },
     {
       "annotations": {
+        "Anatomy": {
+          "hypothalamus": true
+        },
+        "Confidence": {
+          "Medium": true
+        },
         "Species": {
           "10116": true
         }
@@ -231,16 +293,19 @@
       },
       "evidence": "Corticotropin-releasing hormone (CRH) secreted from the hypothalamus is the major regulator of pituitary ACTH release and consequent glucocorticoid secretion. CRH secreted in the periphery also acts as a proinflammatory modulator.",
       "key": "0dcc3379615f5232a3fba98e915705dee2430979d68309bf900dc1e0a32fb0760202258b17b3d8fa37fec9eb563c5163707e3bef2b6aad3c4576675f26f3575e",
-      "line": 78,
+      "line": 84,
       "object": {
         "modifier": "Activity"
       },
       "relation": "positiveCorrelation",
-      "source": 1,
-      "target": 2
+      "source": 3,
+      "target": 4
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Species": {
           "10116": true
         }
@@ -266,9 +331,9 @@
       },
       "evidence": "These results raise the possibility that pyrrolopyrimidine compounds, such as antalarmin, which antagonize CRH at the level of its own receptor, have therapeutic potential in some forms of inflammation.",
       "key": "e4b30e052332aa2e3a46c7499d492da0ea5606dbeb371da05994d7ee0160bd3a7c1df587500016b50ad7c7741053141c026969986cf73f62c0017c5e785406a3",
-      "line": 118,
+      "line": 129,
       "relation": "negativeCorrelation",
-      "source": 1,
+      "source": 3,
       "target": 0
     },
     {
@@ -279,6 +344,9 @@
         "AssayType": {
           "B": true
         },
+        "Confidence": {
+          "Medium": true
+        },
         "MeasurementRelation": {
           "=": true
         },
@@ -316,13 +384,61 @@
       },
       "evidence": "Antalarmin potently displaced 1251-oCRH binding, exhibiting respectively Ki values of 1. 9 f 0.9,. 1.3 f .4, and 1.4 f .6 nM (mean f SEM) in pituitary, cerebellum, and frontal cortex homogenates.Antalarmin, by effectively displacing IoCRH binding in tissues predominately expressing CRHRl but not in tissues expressing CRHR2, appears to be a specific CRHRl receptor antagonist.",
       "key": "1d22d26c4f1fff94b2cf854e6398ca4615577c51747a04939e8fdec58ea987cf7fdbb028bfe3bc3268872d27e8d7f6a1772a598ad29992755114b358cd572cc8",
-      "line": 90,
+      "line": 99,
       "object": {
         "modifier": "Activity"
       },
       "relation": "directlyDecreases",
       "source": 0,
-      "target": 2
+      "target": 4
+    },
+    {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "Species": {
+          "10116": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Chrousos GP",
+          "Lewis DB",
+          "Rice KC",
+          "Torpy DJ",
+          "Webster EL",
+          "Zachman EK"
+        ],
+        "date": "1996-12-01",
+        "first": "Webster EL",
+        "last": "Chrousos GP",
+        "name": "Endocrinology",
+        "pages": "5747-50",
+        "reference": "8940412",
+        "title": "In vivo and in vitro characterization of antalarmin, a nonpeptide corticotropin-releasing hormone (CRH) receptor antagonist: suppression of pituitary ACTH release and peripheral inflammation.",
+        "type": "PubMed",
+        "volume": "137"
+      },
+      "evidence": "Indeed, the compound significantly suppressed (XI-l-induced ACTH secretion to approximately the same extent as neutralizing polyclonal anti-CRH.",
+      "key": "d9203bbc9f15ca3f0805ec00cef4f5365685c66b9346aee5b76c143695364a4a5dd6423a3a688b7eef3c5379f1dbcbf863c349f04d281e6d017f533ced050f66",
+      "line": 136,
+      "object": {
+        "effect": {
+          "fromLoc": {
+            "name": "intracellular",
+            "namespace": "bel"
+          },
+          "toLoc": {
+            "name": "extracellular space",
+            "namespace": "bel"
+          }
+        },
+        "modifier": "Translocation"
+      },
+      "relation": "decreases",
+      "source": 0,
+      "target": 4
     },
     {
       "annotations": {
@@ -332,6 +448,9 @@
         "AssayType": {
           "B": true
         },
+        "Confidence": {
+          "Medium": true
+        },
         "MeasurementRelation": {
           "=": true
         },
@@ -369,16 +488,19 @@
       },
       "evidence": "Antalarmin potently displaced 1251-oCRH binding, exhibiting respectively Ki values of 1. 9 f 0.9,. 1.3 f .4, and 1.4 f .6 nM (mean f SEM) in pituitary, cerebellum, and frontal cortex homogenates.Antalarmin, by effectively displacing IoCRH binding in tissues predominately expressing CRHRl but not in tissues expressing CRHR2, appears to be a specific CRHRl receptor antagonist.",
       "key": "3f8dfcae335a7949fe86a4766cc69ba2dda3f8fc6fc0462731d2a07f69cb3bb41255bb00584cb62d1337b8e5003b350d01ee7cbf0f3d9a8d683922c35d776e7c",
-      "line": 92,
+      "line": 101,
       "object": {
         "modifier": "Activity"
       },
       "relation": "directlyDecreases",
       "source": 0,
-      "target": 3
+      "target": 5
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Species": {
           "10116": true
         }
@@ -404,13 +526,31 @@
       },
       "evidence": "These results raise the possibility that pyrrolopyrimidine compounds, such as antalarmin, which antagonize CRH at the level of its own receptor, have therapeutic potential in some forms of inflammation.",
       "key": "8bd32354bc87fa37ddeed0483100685d15a9543f75ef82c7a915e54c3d868407a05d94a7a1909ea76810e6822dc382a677c87725e0df0fd59da319ed59aaaa28",
-      "line": 118,
+      "line": 129,
       "relation": "negativeCorrelation",
       "source": 0,
-      "target": 1
+      "target": 3
     },
     {
       "annotations": {
+        "Anatomy": {
+          "frontal cortex": true
+        },
+        "AssayType": {
+          "B": true
+        },
+        "Confidence": {
+          "Medium": true
+        },
+        "MeasurementRelation": {
+          "=": true
+        },
+        "MeasurementType": {
+          "Ki": true
+        },
+        "MeasurementUnits": {
+          "nM": true
+        },
         "Species": {
           "10116": true
         }
@@ -434,25 +574,18 @@
         "type": "PubMed",
         "volume": "137"
       },
-      "evidence": "Indeed, the compound significantly suppressed (XI-l-induced ACTH secretion to approximately the same extent as neutralizing polyclonal anti-CRH.",
-      "key": "a60c2d040e5283be39019e3254cb583b64ef33a0425ed25838991ce5737ed50ef9fbc4a8f24bd535280250345dfb6380154eac4b53978b36edabc50b65278ce6",
-      "line": 123,
+      "evidence": "Antalarmin potently displaced 1251-oCRH binding, exhibiting respectively Ki values of 1. 9 f 0.9,. 1.3 f .4, and 1.4 f .6 nM (mean f SEM) in pituitary, cerebellum, and frontal cortex homogenates.Antalarmin, by effectively displacing IoCRH binding in tissues predominately expressing CRHRl but not in tissues expressing CRHR2, appears to be a specific CRHRl receptor antagonist.",
+      "key": "4d7a8169711c6811ec5d29226fb8602474a3ae5b8a1295e09d65efb2adc2a231c0449e6f448eb62bb6e8d204f754279805f50944edc9f744996d35535894c11a",
+      "line": 117,
       "object": {
-        "effect": {
-          "fromLoc": {
-            "name": "intracellular",
-            "namespace": "bel"
-          },
-          "toLoc": {
-            "name": "extracellular space",
-            "namespace": "bel"
-          }
-        },
-        "modifier": "Translocation"
+        "modifier": "Activity"
       },
       "relation": "decreases",
-      "source": 0,
-      "target": 4
+      "source": 6,
+      "subject": {
+        "modifier": "Activity"
+      },
+      "target": 5
     }
   ],
   "multigraph": true,
@@ -464,6 +597,20 @@
       "name": "antalarmin",
       "namespace": "CHEBI"
     },
+    {
+      "bel": "a(MESH:\"Adrenocorticotropic Hormone\")",
+      "function": "Abundance",
+      "id": "cf288cf6a749a597d4cfbcac32847b7708bef0b64df47cdaf894dacc36f6089e3a00098a906596159e357b902b46650d7ddc70681b9845c08add7f727c45effe",
+      "name": "Adrenocorticotropic Hormone",
+      "namespace": "MESH"
+    },
+    {
+      "bel": "a(MESH:Glucocorticoids)",
+      "function": "Abundance",
+      "id": "abcbf36a76bd1cbe9767c48e56070ed109d78639742058342073bacbeebb78f939b84f3681d4ba456b5cf88d5a42546d4585c4f49018edd879895b9a027b0c52",
+      "name": "Glucocorticoids",
+      "namespace": "MESH"
+    },
     {
       "bel": "bp(GO:\"inflammatory response\")",
       "function": "BiologicalProcess",
@@ -486,10 +633,10 @@
       "namespace": "RGD"
     },
     {
-      "bel": "p(RGD:Pomc)",
+      "bel": "p(RGD:Crhr2)",
       "function": "Protein",
-      "id": "d257157819e1bc033beeefdb183bc15f0ddfd4378f631158a4388b8ff59c3aaadb3c5a2d05af1026d2587a1849f30bb3cacbcde20d17fc3afc218804d1ca06ba",
-      "name": "Pomc",
+      "id": "f6f5b44c97267ad892c218b490edd04190a42bb9f48d34e46628687fb50fa974edf824165d30ca8ce603bca949290f57ec4d0a5b14552d9782b491e944d708a0",
+      "name": "Crhr2",
       "namespace": "RGD"
     }
   ]
diff --git a/hbp_knowledge/app/morsy2018.bel.json b/hbp_knowledge/app/morsy2018.bel.json
index a518f74ff..0b63edb1b 100644
--- a/hbp_knowledge/app/morsy2018.bel.json
+++ b/hbp_knowledge/app/morsy2018.bel.json
@@ -57,6 +57,9 @@
   "links": [
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -76,12 +79,17 @@
       },
       "evidence": "Only five drugs (Figure 1) have been approved by the U. S. Food and Drug Administration (FDA), four of which are cholinesterase inhibitors (tacrine, 15  donepezil, 16  rivastigmine 17  and galantamine 18 ) and one of which is a N-methyl-D-aspartate (NMDA) receptor antagonist (memantine 19 ). a N-methyl-D-aspartate (NMDA) receptor antagonist (memantine 19 ). These pharmacological agents have  had  limited  effect  in  improving  the  cognitive  function  of  AD  patients  and  do  not  slow  the progression of the disease. Clinical studies have shown that these agents temporarily stabilize cognitive impairment and help to maintain global function, delaying the need for patient palliative care by only a few month",
       "key": "03322119604890371ecb92c57a322504edcd6b024bd4f17306436fe730e96dff368f1d407228db78d7ff3fbbf9f03d6c99a5bccaeb45aca580b813e26682da89",
-      "line": 90,
+      "line": 91,
       "relation": "increases",
       "source": 11,
-      "target": 33
+      "target": 39
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Morsy A",
@@ -97,16 +105,19 @@
       },
       "evidence": "Only five drugs (Figure 1) have been approved by the U. S. Food and Drug Administration (FDA), four of which are cholinesterase inhibitors (tacrine, 15  donepezil, 16  rivastigmine 17  and galantamine 18 ) and one of which is a N-methyl-D-aspartate (NMDA) receptor antagonist (memantine 19 ). a N-methyl-D-aspartate (NMDA) receptor antagonist (memantine 19 ). These pharmacological agents have  had  limited  effect  in  improving  the  cognitive  function  of  AD  patients  and  do  not  slow  the progression of the disease. Clinical studies have shown that these agents temporarily stabilize cognitive impairment and help to maintain global function, delaying the need for patient palliative care by only a few month",
       "key": "73280a2c882cc8c29043bd75be190c0a37a7c69bba251807a6f63a48d2aaf32bb23f4651ce0e466082409247e2065ffab1ea8f8b2e0531d9369ebc3626a89623",
-      "line": 96,
+      "line": 97,
       "object": {
         "modifier": "Activity"
       },
       "relation": "decreases",
       "source": 11,
-      "target": 46
+      "target": 53
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -126,12 +137,17 @@
       },
       "evidence": "Only five drugs (Figure 1) have been approved by the U. S. Food and Drug Administration (FDA), four of which are cholinesterase inhibitors (tacrine, 15  donepezil, 16  rivastigmine 17  and galantamine 18 ) and one of which is a N-methyl-D-aspartate (NMDA) receptor antagonist (memantine 19 ). a N-methyl-D-aspartate (NMDA) receptor antagonist (memantine 19 ). These pharmacological agents have  had  limited  effect  in  improving  the  cognitive  function  of  AD  patients  and  do  not  slow  the progression of the disease. Clinical studies have shown that these agents temporarily stabilize cognitive impairment and help to maintain global function, delaying the need for patient palliative care by only a few month",
       "key": "098b155404dd7b06fb3c2084bd2bfcf29d7d8c4c00d0c8772f3cbe6415f97f897df9f23d4f6f1fcdd18e19365e082cd0855fe6e3399f1d2be265e4ec62d26d67",
-      "line": 91,
+      "line": 92,
       "relation": "increases",
       "source": 7,
-      "target": 33
+      "target": 39
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Morsy A",
@@ -147,16 +163,19 @@
       },
       "evidence": "Only five drugs (Figure 1) have been approved by the U. S. Food and Drug Administration (FDA), four of which are cholinesterase inhibitors (tacrine, 15  donepezil, 16  rivastigmine 17  and galantamine 18 ) and one of which is a N-methyl-D-aspartate (NMDA) receptor antagonist (memantine 19 ). a N-methyl-D-aspartate (NMDA) receptor antagonist (memantine 19 ). These pharmacological agents have  had  limited  effect  in  improving  the  cognitive  function  of  AD  patients  and  do  not  slow  the progression of the disease. Clinical studies have shown that these agents temporarily stabilize cognitive impairment and help to maintain global function, delaying the need for patient palliative care by only a few month",
       "key": "3e502ddbd2b3774b7d099acc76d4bcdc9a823f4fb9ec20b0623a9c08dada682c223ed26e32d021bb40d0f2c68f7c7da4deafb0a3bab4e5f837b6d3c1b50f3d30",
-      "line": 97,
+      "line": 98,
       "object": {
         "modifier": "Activity"
       },
       "relation": "decreases",
       "source": 7,
-      "target": 46
+      "target": 53
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -176,12 +195,17 @@
       },
       "evidence": "Only five drugs (Figure 1) have been approved by the U. S. Food and Drug Administration (FDA), four of which are cholinesterase inhibitors (tacrine, 15  donepezil, 16  rivastigmine 17  and galantamine 18 ) and one of which is a N-methyl-D-aspartate (NMDA) receptor antagonist (memantine 19 ). a N-methyl-D-aspartate (NMDA) receptor antagonist (memantine 19 ). These pharmacological agents have  had  limited  effect  in  improving  the  cognitive  function  of  AD  patients  and  do  not  slow  the progression of the disease. Clinical studies have shown that these agents temporarily stabilize cognitive impairment and help to maintain global function, delaying the need for patient palliative care by only a few month",
       "key": "0597acb02ef35e7a042a1269728948fb85d2e7ebca2d738560dd49950829832e4b47c843376890276c4de4b3fc42ca595186475ce266c04a345edc06b6c71fb9",
-      "line": 92,
+      "line": 93,
       "relation": "increases",
       "source": 10,
-      "target": 33
+      "target": 39
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Morsy A",
@@ -197,16 +221,19 @@
       },
       "evidence": "Only five drugs (Figure 1) have been approved by the U. S. Food and Drug Administration (FDA), four of which are cholinesterase inhibitors (tacrine, 15  donepezil, 16  rivastigmine 17  and galantamine 18 ) and one of which is a N-methyl-D-aspartate (NMDA) receptor antagonist (memantine 19 ). a N-methyl-D-aspartate (NMDA) receptor antagonist (memantine 19 ). These pharmacological agents have  had  limited  effect  in  improving  the  cognitive  function  of  AD  patients  and  do  not  slow  the progression of the disease. Clinical studies have shown that these agents temporarily stabilize cognitive impairment and help to maintain global function, delaying the need for patient palliative care by only a few month",
       "key": "42698645a961a0c246a5b63dbe7d5210541788a030e42072096329c50fc7378cf27c33291b51924384dc0e51deb529eaad003360fae964fa01ffadcd4809d0e1",
-      "line": 98,
+      "line": 99,
       "object": {
         "modifier": "Activity"
       },
       "relation": "decreases",
       "source": 10,
-      "target": 46
+      "target": 53
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -226,12 +253,17 @@
       },
       "evidence": "Only five drugs (Figure 1) have been approved by the U. S. Food and Drug Administration (FDA), four of which are cholinesterase inhibitors (tacrine, 15  donepezil, 16  rivastigmine 17  and galantamine 18 ) and one of which is a N-methyl-D-aspartate (NMDA) receptor antagonist (memantine 19 ). a N-methyl-D-aspartate (NMDA) receptor antagonist (memantine 19 ). These pharmacological agents have  had  limited  effect  in  improving  the  cognitive  function  of  AD  patients  and  do  not  slow  the progression of the disease. Clinical studies have shown that these agents temporarily stabilize cognitive impairment and help to maintain global function, delaying the need for patient palliative care by only a few month",
       "key": "2af43f6a388b25d174dca8b95ba4f5366869fdc7c338cbde072ab1e5841627e4a111871120df0cc286f6fc8a5f164185fd858cf2cbb34993d459c2b10c8475d7",
-      "line": 93,
+      "line": 94,
       "relation": "increases",
       "source": 8,
-      "target": 33
+      "target": 39
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Morsy A",
@@ -247,16 +279,19 @@
       },
       "evidence": "Only five drugs (Figure 1) have been approved by the U. S. Food and Drug Administration (FDA), four of which are cholinesterase inhibitors (tacrine, 15  donepezil, 16  rivastigmine 17  and galantamine 18 ) and one of which is a N-methyl-D-aspartate (NMDA) receptor antagonist (memantine 19 ). a N-methyl-D-aspartate (NMDA) receptor antagonist (memantine 19 ). These pharmacological agents have  had  limited  effect  in  improving  the  cognitive  function  of  AD  patients  and  do  not  slow  the progression of the disease. Clinical studies have shown that these agents temporarily stabilize cognitive impairment and help to maintain global function, delaying the need for patient palliative care by only a few month",
       "key": "89799e2180fbe60f5dbf823bb24f92397a7934adce22438139586e76efd0e4972ed706b157b88c2e4518f089cf7859f350238a7819c6cca1cf5cb33f206582aa",
-      "line": 99,
+      "line": 100,
       "object": {
         "modifier": "Activity"
       },
       "relation": "decreases",
       "source": 8,
-      "target": 46
+      "target": 53
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -276,12 +311,17 @@
       },
       "evidence": "Only five drugs (Figure 1) have been approved by the U. S. Food and Drug Administration (FDA), four of which are cholinesterase inhibitors (tacrine, 15  donepezil, 16  rivastigmine 17  and galantamine 18 ) and one of which is a N-methyl-D-aspartate (NMDA) receptor antagonist (memantine 19 ). a N-methyl-D-aspartate (NMDA) receptor antagonist (memantine 19 ). These pharmacological agents have  had  limited  effect  in  improving  the  cognitive  function  of  AD  patients  and  do  not  slow  the progression of the disease. Clinical studies have shown that these agents temporarily stabilize cognitive impairment and help to maintain global function, delaying the need for patient palliative care by only a few month",
       "key": "91db688ca3314013216f2379c230a9a1c2fe2b98ea0bdf7d749bdd3f96c4224d2192a86a3a14930250711196eb276c109f48e48cafcfcf2035f9802f959ca41f",
-      "line": 94,
+      "line": 95,
       "relation": "increases",
       "source": 9,
-      "target": 33
+      "target": 39
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Morsy A",
@@ -297,15 +337,20 @@
       },
       "evidence": "Only five drugs (Figure 1) have been approved by the U. S. Food and Drug Administration (FDA), four of which are cholinesterase inhibitors (tacrine, 15  donepezil, 16  rivastigmine 17  and galantamine 18 ) and one of which is a N-methyl-D-aspartate (NMDA) receptor antagonist (memantine 19 ). a N-methyl-D-aspartate (NMDA) receptor antagonist (memantine 19 ). These pharmacological agents have  had  limited  effect  in  improving  the  cognitive  function  of  AD  patients  and  do  not  slow  the progression of the disease. Clinical studies have shown that these agents temporarily stabilize cognitive impairment and help to maintain global function, delaying the need for patient palliative care by only a few month",
       "key": "706699a1bb638b85034edd4f11479effb2f37440c146e9b3aa1eac9004c4493a33e44b77979fdffe35e2be0b35b8be87019267da632e2d05c809238c5aaf4fe7",
-      "line": 100,
+      "line": 101,
       "object": {
         "modifier": "Activity"
       },
       "relation": "decreases",
       "source": 9,
-      "target": 70
+      "target": 77
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "Morsy A",
@@ -321,12 +366,17 @@
       },
       "evidence": "Genetics have a role to play within AD; patients with a mutation in Amyloid Precursor Protein (APP), which results in overproduction of Aβ, will experience early onset AD. 36  Patients with a mutation in Apolipoprotein E4 (APOE4), which affects the clearance of Aβ, will experience late onset AD.",
       "key": "54692692fdf8a36c8b8dc87ed229b3e3de761fe78602f41c53f03d3d69a646be226c0dde93f3977c072c365c72cbb5d2362d7adc9925e3648f3a259e2a8dd29a",
-      "line": 105,
+      "line": 108,
       "relation": "increases",
-      "source": 39,
-      "target": 72
+      "source": 46,
+      "target": 79
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "Morsy A",
@@ -341,20 +391,23 @@
         "type": "PubMed"
       },
       "evidence": "Genetics have a role to play within AD; patients with a mutation in Amyloid Precursor Protein (APP), which results in overproduction of Aβ, will experience early onset AD. 36  Patients with a mutation in Apolipoprotein E4 (APOE4), which affects the clearance of Aβ, will experience late onset AD.",
-      "key": "4286f5224d4041a137d496e69adeac0fb872a77fed4ca850ecb8d45f58959d8c8a7b5354f12af98a7f5ce87283cb5e2f0ca4fecc23dfef300b2802641343c390",
-      "line": 106,
+      "key": "84698a7c11e120f3c21dbd6cd87bf908d7067e455c233ac4d7286075182413b651168486062970a3b2ad9729c1a63bcc80e3b0163cdc53db586014a9af5c8006",
+      "line": 109,
       "relation": "increases",
-      "source": 39,
-      "target": 63
+      "source": 46,
+      "target": 30
     },
     {
       "key": "f1813f708385bd7ca9d6d7aa2a0e30e78c35478c9e91d7a97338422b4e47578afb15b950ca60c0fed3f910b20817212a5009476f193d0a207a85469d7e62aeca",
       "relation": "hasVariant",
-      "source": 38,
-      "target": 39
+      "source": 45,
+      "target": 46
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Cerebral Cortex": true,
           "Hippocampus": true
@@ -375,15 +428,18 @@
       },
       "evidence": " Binding of Aβ to ABAD has been implicated in the development of AD, recent studies detected elevated ABAD levels in the regions of the hippocampus and cerebral cortex which are generally affected by AD pathology",
       "key": "0d1e3dd7f68fd2eee6f7b876bbaaadbf94e377a50be2633d058332a77be52cde83d1a9c6b7e4173a3457cf6fec03bc192aa51e006c323b4a64ae0f537e6b53dc",
-      "line": 135,
+      "line": 150,
       "relation": "positiveCorrelation",
-      "source": 72,
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@@ -401,18 +457,22 @@
       },
       "evidence": "The first, peroxiredoxin-2 (Prdx-2), functions as an antioxidant and has been shown to  be inactivated  in  AD.",
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@@ -430,15 +490,15 @@
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@@ -456,15 +516,15 @@
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       "evidence": " Inactivation of Prdx-2 is controlled by a kinase that has been shown to be elevated in AD, CDK5, 107, 108  which phosphorylates Thr 89  and results in deactivation of Prdx-2.",
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@@ -515,12 +568,17 @@
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@@ -560,18 +620,23 @@
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       "evidence": " In addition, several other gene mutations have been discovered such as Presenilin-1 and Presenilin-2 mutations, which increase the risk for developing AD. 38  ",
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@@ -587,18 +652,23 @@
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@@ -614,30 +684,35 @@
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       "evidence": "The formation of Aβ starts by a transmembrane protein, APP (695 to 770 amino acids in length), which is sequentially cleaved by the aspartate proteases β- and  γ-secretase,  that  leads  to  the  formation  of  Aβ  peptide  (1-42)  and  a  degenerated  C-terminus. ",
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@@ -674,12 +754,17 @@
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       "evidence": " Mitochondrial  dysfunction  is  the  hallmark  of  Aβ-induced toxicity. 50-52  ",
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@@ -695,56 +780,33 @@
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-        "last": "Trippier PC",
-        "name": "Journal of medicinal chemistry",
-        "reference": "30444369",
-        "title": "Amyloid-Binding Alcohol Dehydrogenase (ABAD) Inhibitors for the Treatment of Alzheimer's Disease.",
-        "type": "PubMed"
-      },
-      "evidence": " Isoforms  of  CK1  are  responsible  for  tau phosphorylation. 129   The  enzyme  can  modulate  the  activity  of  γ-secretase  and  consequently  the production of Aβ.",
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@@ -762,15 +824,20 @@
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       "evidence": "However, it is well established that Aβ binding to ABAD induces a conformational change in the enzyme that  prevents  the  binding  of  NAD + ,  preventing  the  enzyme  performing  its  role  in  the  oxidation  of substrates, leading to changes in mitochondrial membrane permeability, which in turn has deleterious effects  on  mitochondrial  enzymes.",
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@@ -786,13 +853,16 @@
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@@ -812,13 +882,16 @@
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       "evidence": " Neurons from these animals exhibited increased oxidative stress, increased generation of ROS, DNA fragmentation, neuronal apoptosis, and impairment in learning, compared to single-transgenic mAPP mice.",
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@@ -838,15 +911,18 @@
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@@ -864,13 +940,16 @@
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@@ -890,13 +969,16 @@
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       "evidence": " Neurons from these animals exhibited increased oxidative stress, increased generation of ROS, DNA fragmentation, neuronal apoptosis, and impairment in learning, compared to single-transgenic mAPP mice.",
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@@ -916,13 +998,16 @@
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       "evidence": " Neurons from these animals exhibited increased oxidative stress, increased generation of ROS, DNA fragmentation, neuronal apoptosis, and impairment in learning, compared to single-transgenic mAPP mice.",
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@@ -942,15 +1027,18 @@
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       "annotations": {
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+        "Confidence": {
+          "Medium": true
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@@ -1023,15 +1117,66 @@
       },
       "evidence": "In another study, neurons from Tg mAPP/ABAD mice were shown to exhibit decreased activity of cyclooxygenase (COX) enzyme, spontaneous release of ROS, loss of mitochondrial membrane potential, a decrease in ATP production and release of cytochrome c from mitochondria with subsequent induction of caspase-3-like activity followed by apoptotic cell death.",
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       "annotations": {
-        "MeSHAnatomy": {
-          "Neurons": true
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+        },
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+          "Medium": true
+        },
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+        }
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+      "citation": {
+        "authors": [
+          "Morsy A",
+          "Trippier PC"
+        ],
+        "date": "2018-11-30",
+        "first": "Morsy A",
+        "last": "Trippier PC",
+        "name": "Journal of medicinal chemistry",
+        "reference": "30444369",
+        "title": "Amyloid-Binding Alcohol Dehydrogenase (ABAD) Inhibitors for the Treatment of Alzheimer's Disease.",
+        "type": "PubMed"
+      },
+      "evidence": "In another study, neurons from Tg mAPP/ABAD mice were shown to exhibit decreased activity of cyclooxygenase (COX) enzyme, spontaneous release of ROS, loss of mitochondrial membrane potential, a decrease in ATP production and release of cytochrome c from mitochondria with subsequent induction of caspase-3-like activity followed by apoptotic cell death.",
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+            "name": "intracellular",
+            "namespace": "bel"
+          },
+          "toLoc": {
+            "name": "extracellular space",
+            "namespace": "bel"
+          }
+        },
+        "modifier": "Translocation"
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+    },
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@@ -1049,18 +1194,24 @@
       },
       "evidence": "In another study, neurons from Tg mAPP/ABAD mice were shown to exhibit decreased activity of cyclooxygenase (COX) enzyme, spontaneous release of ROS, loss of mitochondrial membrane potential, a decrease in ATP production and release of cytochrome c from mitochondria with subsequent induction of caspase-3-like activity followed by apoptotic cell death.",
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     {
       "annotations": {
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+        },
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@@ -1078,15 +1229,18 @@
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       "evidence": "In another study, neurons from Tg mAPP/ABAD mice were shown to exhibit decreased activity of cyclooxygenase (COX) enzyme, spontaneous release of ROS, loss of mitochondrial membrane potential, a decrease in ATP production and release of cytochrome c from mitochondria with subsequent induction of caspase-3-like activity followed by apoptotic cell death.",
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       "annotations": {
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@@ -1104,13 +1258,16 @@
       },
       "evidence": "However, it is well established that Aβ binding to ABAD induces a conformational change in the enzyme that  prevents  the  binding  of  NAD + ,  preventing  the  enzyme  performing  its  role  in  the  oxidation  of substrates, leading to changes in mitochondrial membrane permeability, which in turn has deleterious effects  on  mitochondrial  enzymes.",
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         "MeSHAnatomy": {
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           "Hippocampus": true
@@ -1131,12 +1288,17 @@
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       "evidence": " Binding of Aβ to ABAD has been implicated in the development of AD, recent studies detected elevated ABAD levels in the regions of the hippocampus and cerebral cortex which are generally affected by AD pathology",
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       "citation": {
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@@ -1152,15 +1314,23 @@
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       "evidence": "The  enzyme  is  also  required  for  the catabolism of isoleucine, in which it catalyzes the conversion of 2-methyl-3-hydroxybutyryl-coA (MHB) to 2-methyl-acetoacetyl-coA. 72  ",
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@@ -1176,15 +1346,20 @@
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       "evidence": "The enzyme catalyzes the third step of mitochondrial oxidation, converting  L -3-hydroxyacyl-CoA in the presence of NAD +  to 3-ketoacyl-CoA, NADH, and H + .",
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@@ -1200,15 +1375,20 @@
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       "evidence": "The  oxidation  of  3-adiol  to  5-dihydrotestosterone  in androgen  metabolism  is  catalyzed  by  ABAD  and  it  converts  17β-estradiol  to  estrone  in  estrogen metabolism.",
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@@ -1224,15 +1404,20 @@
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       "evidence": "The  oxidation  of  3-adiol  to  5-dihydrotestosterone  in androgen  metabolism  is  catalyzed  by  ABAD  and  it  converts  17β-estradiol  to  estrone  in  estrogen metabolism.",
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@@ -1247,82 +1432,87 @@
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@@ -1338,12 +1528,17 @@
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       "evidence": " For example, estradiol can reduce the generation of Aβ by altering the metabolism of APP and disrupting it’s trafficking.",
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           "Morsy A",
@@ -1359,12 +1554,17 @@
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       "evidence": "Moreover,  estradiol  has  been  shown  to  inhibit  tau  hyperphosphorylation  and  can  also  modulate glycogen  synthase  kinase-3β  (GSK-3β)  activity,  a  kinase  that  is  involved  in  tau  phosphorylation. Estradiol  deactivates  GSK-3β  by  inducing  its  phosphorylation,  thereafter  reducing  tau phosphorylation. ",
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           "Morsy A",
@@ -1380,15 +1580,20 @@
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       "evidence": "Moreover,  estradiol  has  been  shown  to  inhibit  tau  hyperphosphorylation  and  can  also  modulate glycogen  synthase  kinase-3β  (GSK-3β)  activity,  a  kinase  that  is  involved  in  tau  phosphorylation. Estradiol  deactivates  GSK-3β  by  inducing  its  phosphorylation,  thereafter  reducing  tau phosphorylation. ",
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       "citation": {
         "authors": [
           "Morsy A",
@@ -1404,15 +1609,18 @@
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       "evidence": "Moreover,  estradiol  has  been  shown  to  inhibit  tau  hyperphosphorylation  and  can  also  modulate glycogen  synthase  kinase-3β  (GSK-3β)  activity,  a  kinase  that  is  involved  in  tau  phosphorylation. Estradiol  deactivates  GSK-3β  by  inducing  its  phosphorylation,  thereafter  reducing  tau phosphorylation. ",
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@@ -1430,15 +1638,18 @@
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       "evidence": "  It  enhances  the  expression  of  anti- apoptotic proteins, such as Bcl-2 and Bcl-xL, and down-regulates the expression of Bim, a pro-apoptotic factor, preventing programmed cell death. 90, 100  Estradiol also activates antioxidant systems to protect neuronal cells from apoptosis by upregulating the expression of manganese superoxide dismutase and glutathione peroxidase. 101  ",
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@@ -1456,15 +1667,18 @@
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       "evidence": "  It  enhances  the  expression  of  anti- apoptotic proteins, such as Bcl-2 and Bcl-xL, and down-regulates the expression of Bim, a pro-apoptotic factor, preventing programmed cell death. 90, 100  Estradiol also activates antioxidant systems to protect neuronal cells from apoptosis by upregulating the expression of manganese superoxide dismutase and glutathione peroxidase. 101  ",
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@@ -1482,15 +1696,18 @@
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       "evidence": "  It  enhances  the  expression  of  anti- apoptotic proteins, such as Bcl-2 and Bcl-xL, and down-regulates the expression of Bim, a pro-apoptotic factor, preventing programmed cell death. 90, 100  Estradiol also activates antioxidant systems to protect neuronal cells from apoptosis by upregulating the expression of manganese superoxide dismutase and glutathione peroxidase. 101  ",
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@@ -1508,15 +1725,18 @@
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       "evidence": "  It  enhances  the  expression  of  anti- apoptotic proteins, such as Bcl-2 and Bcl-xL, and down-regulates the expression of Bim, a pro-apoptotic factor, preventing programmed cell death. 90, 100  Estradiol also activates antioxidant systems to protect neuronal cells from apoptosis by upregulating the expression of manganese superoxide dismutase and glutathione peroxidase. 101  ",
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       "evidence": "  It  enhances  the  expression  of  anti- apoptotic proteins, such as Bcl-2 and Bcl-xL, and down-regulates the expression of Bim, a pro-apoptotic factor, preventing programmed cell death. 90, 100  Estradiol also activates antioxidant systems to protect neuronal cells from apoptosis by upregulating the expression of manganese superoxide dismutase and glutathione peroxidase. 101  ",
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@@ -1554,22 +1779,155 @@
         "type": "PubMed"
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+        "title": "Amyloid-Binding Alcohol Dehydrogenase (ABAD) Inhibitors for the Treatment of Alzheimer's Disease.",
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@@ -1585,15 +1943,20 @@
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       "evidence": "Moreover,  estradiol  has  been  shown  to  inhibit  tau  hyperphosphorylation  and  can  also  modulate glycogen  synthase  kinase-3β  (GSK-3β)  activity,  a  kinase  that  is  involved  in  tau  phosphorylation. Estradiol  deactivates  GSK-3β  by  inducing  its  phosphorylation,  thereafter  reducing  tau phosphorylation. ",
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@@ -1609,12 +1972,17 @@
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       "evidence": " In mechanistic studies, it was proposed that methylene blue inhibits the Aβ-ABAD interaction and decreases mitochondrial dysfunction by decreasing the expression of ABAD levels, in addition to decreasing Aβ levels.",
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@@ -1630,12 +1998,17 @@
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@@ -1698,27 +2076,30 @@
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       "evidence": " This results in the activation of mitogen-activated protein kinase kinase kinase 1 (MAP3K1), 114  which then activates a cascade of kinases that eventually leads to the translocation of JNK to the nucleus or other target sites to phosphorylate downstream effectors,  thereby  affecting  significant  aspects  of  neuronal  function  such  as  neurite  outgrowth, mitochondrial  function,  synaptic  plasticity  and  apoptosis. 1",
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       "evidence": "  It  enhances  the  expression  of  anti- apoptotic proteins, such as Bcl-2 and Bcl-xL, and down-regulates the expression of Bim, a pro-apoptotic factor, preventing programmed cell death. 90, 100  Estradiol also activates antioxidant systems to protect neuronal cells from apoptosis by upregulating the expression of manganese superoxide dismutase and glutathione peroxidase. 101  ",
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@@ -1762,15 +2146,18 @@
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       "evidence": "  It  enhances  the  expression  of  anti- apoptotic proteins, such as Bcl-2 and Bcl-xL, and down-regulates the expression of Bim, a pro-apoptotic factor, preventing programmed cell death. 90, 100  Estradiol also activates antioxidant systems to protect neuronal cells from apoptosis by upregulating the expression of manganese superoxide dismutase and glutathione peroxidase. 101  ",
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@@ -1788,15 +2175,18 @@
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       "evidence": "  It  enhances  the  expression  of  anti- apoptotic proteins, such as Bcl-2 and Bcl-xL, and down-regulates the expression of Bim, a pro-apoptotic factor, preventing programmed cell death. 90, 100  Estradiol also activates antioxidant systems to protect neuronal cells from apoptosis by upregulating the expression of manganese superoxide dismutase and glutathione peroxidase. 101  ",
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@@ -1814,18 +2204,22 @@
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       "evidence": "The first, peroxiredoxin-2 (Prdx-2), functions as an antioxidant and has been shown to  be inactivated  in  AD.",
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@@ -1843,21 +2237,21 @@
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@@ -1875,15 +2269,15 @@
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       "evidence": " Inactivation of Prdx-2 is controlled by a kinase that has been shown to be elevated in AD, CDK5, 107, 108  which phosphorylates Thr 89  and results in deactivation of Prdx-2.",
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@@ -1901,15 +2295,15 @@
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       "evidence": " Inactivation of Prdx-2 is controlled by a kinase that has been shown to be elevated in AD, CDK5, 107, 108  which phosphorylates Thr 89  and results in deactivation of Prdx-2.",
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@@ -1927,18 +2321,18 @@
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       "evidence": " Inactivation of Prdx-2 is controlled by a kinase that has been shown to be elevated in AD, CDK5, 107, 108  which phosphorylates Thr 89  and results in deactivation of Prdx-2.",
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@@ -1956,15 +2350,15 @@
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       "evidence": "The second ABAD-related protein, endophilin-1 (Ep-1), is a member of a family of proteins that are responsible for synaptic vesicle endocytosis, mitochondrial function, and receptor trafficking. 110  This family of proteins has been implicated in a number of neurodegenerative diseases, 111  including in AD where it is overexpressed",
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@@ -1982,15 +2376,15 @@
       },
       "evidence": "The second ABAD-related protein, endophilin-1 (Ep-1), is a member of a family of proteins that are responsible for synaptic vesicle endocytosis, mitochondrial function, and receptor trafficking. 110  This family of proteins has been implicated in a number of neurodegenerative diseases, 111  including in AD where it is overexpressed",
       "key": "3280ba5f27a71c334cfad3606ae09291b9ceddca2a490f471dd7d01da3ce2f8c5b7406cce07c4ec0a854f660df9358159b773f0c27c403ecf0b3a6c282eb3d74",
-      "line": 241,
+      "line": 305,
       "relation": "positiveCorrelation",
-      "source": 68,
-      "target": 72
+      "source": 74,
+      "target": 79
     },
     {
       "annotations": {
-        "MeSHAnatomy": {
-          "Neurons": true
+        "Confidence": {
+          "Medium": true
         }
       },
       "citation": {
@@ -2008,18 +2402,18 @@
       },
       "evidence": " This results in the activation of mitogen-activated protein kinase kinase kinase 1 (MAP3K1), 114  which then activates a cascade of kinases that eventually leads to the translocation of JNK to the nucleus or other target sites to phosphorylate downstream effectors,  thereby  affecting  significant  aspects  of  neuronal  function  such  as  neurite  outgrowth, mitochondrial  function,  synaptic  plasticity  and  apoptosis. 1",
       "key": "7a0a791f743fd21dcceacb18625f279a349cd517ca8627d31024caac816ad14a028b48a9dee41a5224b077c16eff73b84633f1efa52f37eaac4ab40c4bf50f22",
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+      "line": 315,
       "object": {
         "modifier": "Activity"
       },
       "relation": "increases",
-      "source": 68,
-      "target": 62
+      "source": 74,
+      "target": 68
     },
     {
       "annotations": {
-        "MeSHAnatomy": {
-          "Neurons": true
+        "Confidence": {
+          "Medium": true
         }
       },
       "citation": {
@@ -2037,15 +2431,15 @@
       },
       "evidence": " This results in the activation of mitogen-activated protein kinase kinase kinase 1 (MAP3K1), 114  which then activates a cascade of kinases that eventually leads to the translocation of JNK to the nucleus or other target sites to phosphorylate downstream effectors,  thereby  affecting  significant  aspects  of  neuronal  function  such  as  neurite  outgrowth, mitochondrial  function,  synaptic  plasticity  and  apoptosis. 1",
       "key": "3f873edeb02231f3baea97e5b3e99b4e8e7ff9b4540065c9830a2125ebc391ba0aef481a640f29d8a710ef1db0e2ad9e50354e5bf6efae22c69c9d0b4575ece2",
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+      "line": 317,
       "relation": "association",
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-      "target": 28
+      "source": 74,
+      "target": 34
     },
     {
       "annotations": {
-        "MeSHAnatomy": {
-          "Neurons": true
+        "Confidence": {
+          "Medium": true
         }
       },
       "citation": {
@@ -2063,15 +2457,15 @@
       },
       "evidence": " This results in the activation of mitogen-activated protein kinase kinase kinase 1 (MAP3K1), 114  which then activates a cascade of kinases that eventually leads to the translocation of JNK to the nucleus or other target sites to phosphorylate downstream effectors,  thereby  affecting  significant  aspects  of  neuronal  function  such  as  neurite  outgrowth, mitochondrial  function,  synaptic  plasticity  and  apoptosis. 1",
       "key": "c4aab0e5b341daaa3aa2e4b00ace45e612878434aa00e2c6b60fce7def039b0881559019a81f43f5ecaefd3a95deee8ca784ee22d5837a063d2eacb9e7a1a23b",
-      "line": 250,
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       "relation": "association",
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-      "target": 30
+      "source": 74,
+      "target": 36
     },
     {
       "annotations": {
-        "MeSHAnatomy": {
-          "Neurons": true
+        "Confidence": {
+          "Medium": true
         }
       },
       "citation": {
@@ -2089,15 +2483,44 @@
       },
       "evidence": " This results in the activation of mitogen-activated protein kinase kinase kinase 1 (MAP3K1), 114  which then activates a cascade of kinases that eventually leads to the translocation of JNK to the nucleus or other target sites to phosphorylate downstream effectors,  thereby  affecting  significant  aspects  of  neuronal  function  such  as  neurite  outgrowth, mitochondrial  function,  synaptic  plasticity  and  apoptosis. 1",
       "key": "f7be7293ae2fface07c017e2ac172b4f3dcb088d9340fe6a415b3b6414f47cd341f5c77fcb3168219c0c93f4e47f44ae5f0382f5636ebc3ec2504e0e9069b229",
-      "line": 251,
+      "line": 319,
       "relation": "association",
+      "source": 74,
+      "target": 33
+    },
+    {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Morsy A",
+          "Trippier PC"
+        ],
+        "date": "2018-11-30",
+        "first": "Morsy A",
+        "last": "Trippier PC",
+        "name": "Journal of medicinal chemistry",
+        "reference": "30444369",
+        "title": "Amyloid-Binding Alcohol Dehydrogenase (ABAD) Inhibitors for the Treatment of Alzheimer's Disease.",
+        "type": "PubMed"
+      },
+      "evidence": " This results in the activation of mitogen-activated protein kinase kinase kinase 1 (MAP3K1), 114  which then activates a cascade of kinases that eventually leads to the translocation of JNK to the nucleus or other target sites to phosphorylate downstream effectors,  thereby  affecting  significant  aspects  of  neuronal  function  such  as  neurite  outgrowth, mitochondrial  function,  synaptic  plasticity  and  apoptosis. 1",
+      "key": "40432880af7e380f93d50e2b830d032952030d0fa9e5543d38732e63e9f9d3f75fde5d39f099782e0be415fafc16caff5fc216417ccb1b7dd09f0e49bbb797ff",
+      "line": 316,
+      "relation": "increases",
       "source": 68,
-      "target": 27
+      "subject": {
+        "modifier": "Activity"
+      },
+      "target": 28
     },
     {
       "annotations": {
-        "MeSHAnatomy": {
-          "Neurons": true
+        "Confidence": {
+          "Medium": true
         }
       },
       "citation": {
@@ -2115,15 +2538,15 @@
       },
       "evidence": " This results in the activation of mitogen-activated protein kinase kinase kinase 1 (MAP3K1), 114  which then activates a cascade of kinases that eventually leads to the translocation of JNK to the nucleus or other target sites to phosphorylate downstream effectors,  thereby  affecting  significant  aspects  of  neuronal  function  such  as  neurite  outgrowth, mitochondrial  function,  synaptic  plasticity  and  apoptosis. 1",
       "key": "8cdf7cb66805edaba24b0172becc4170e894e1de9e8c6b129cdf9ecb0131e927231e34d8cf89fbb2e290f59b6ab17745a32674a388f3a62833e058e6f38d197d",
-      "line": 249,
+      "line": 317,
       "relation": "association",
-      "source": 28,
-      "target": 68
+      "source": 34,
+      "target": 74
     },
     {
       "annotations": {
-        "MeSHAnatomy": {
-          "Neurons": true
+        "Confidence": {
+          "Medium": true
         }
       },
       "citation": {
@@ -2141,15 +2564,15 @@
       },
       "evidence": " This results in the activation of mitogen-activated protein kinase kinase kinase 1 (MAP3K1), 114  which then activates a cascade of kinases that eventually leads to the translocation of JNK to the nucleus or other target sites to phosphorylate downstream effectors,  thereby  affecting  significant  aspects  of  neuronal  function  such  as  neurite  outgrowth, mitochondrial  function,  synaptic  plasticity  and  apoptosis. 1",
       "key": "7048f216f8459223d8a32c677da76b32ba746a4bce7aeecb69f3aa85c73775e13f36b878afb54b0f7c98b473953cb7079b025806e48448c586e2617cc023e6be",
-      "line": 250,
+      "line": 318,
       "relation": "association",
-      "source": 30,
-      "target": 68
+      "source": 36,
+      "target": 74
     },
     {
       "annotations": {
-        "MeSHAnatomy": {
-          "Neurons": true
+        "Confidence": {
+          "High": true
         }
       },
       "citation": {
@@ -2167,18 +2590,18 @@
       },
       "evidence": "A potent ABAD inhibitor, AG18051 (1), containing a pyrazolo[3,4-d] pyrimidine-4(1H)-thione backbone (IC 50  = 92 nM) has been reported. ",
       "key": "27d1907ee7c474459bb8bda32d4d5652e0a80855395ea157bda8adf6dd2b4fc26c11e4efe641c89d4bd482946362f4288e6f9095a5da5eaf0a4faf74e507b8a3",
-      "line": 257,
+      "line": 328,
       "object": {
         "modifier": "Activity"
       },
       "relation": "decreases",
       "source": 14,
-      "target": 60
+      "target": 66
     },
     {
       "annotations": {
-        "MeSHAnatomy": {
-          "Neurons": true
+        "Confidence": {
+          "High": true
         }
       },
       "citation": {
@@ -2196,7 +2619,7 @@
       },
       "evidence": " Moreover, it has been shown to ameliorate Aβ-induced toxicity at the cellular level. 7",
       "key": "bfd2ba54681063a0d4b09e984d3ee933180509ddb938620634a92892fa9c04ccf75796aecb4b7eaae5c34797a692c018a27b43c73737b9d6b63780cd97e8d115",
-      "line": 261,
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       "object": {
         "modifier": "Activity"
       },
@@ -2206,8 +2629,8 @@
     },
     {
       "annotations": {
-        "MeSHAnatomy": {
-          "Neurons": true
+        "Confidence": {
+          "High": true
         }
       },
       "citation": {
@@ -2225,18 +2648,18 @@
       },
       "evidence": "Interestingly, during the search for inhibitors of 17β-HSD isoforms for the treatment of estrogen- related diseases, 127  Ayan et.al identified the steroidal compound RM-532-46 (8) as a reversible ABAD inhibitor (IC 50  = 0.55 M).",
       "key": "ec1851f5007af86dfd00aa40613690bbac3fe29f42169fcd6f8c8fa6d082d510638b8e9d2fda16b192fad32323cffa7968cf1cfcdf3329287cb72d1b25fdb9bc",
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+      "line": 343,
       "object": {
         "modifier": "Activity"
       },
       "relation": "decreases",
       "source": 12,
-      "target": 60
+      "target": 66
     },
     {
       "annotations": {
-        "MeSHAnatomy": {
-          "Neurons": true
+        "Confidence": {
+          "High": true
         }
       },
       "citation": {
@@ -2254,15 +2677,15 @@
       },
       "evidence": "Frentizole,  an  FDA  approved  immunosuppressant  drug,  was  identified  as  an  Aβ-ABAD interaction  inhibitor  (IC 50  =  200  M)  using  an  ELISA-based  screening  assay.",
       "key": "d75a06f81fc128a54fe84d880f9d76bc0ce72b27ec133942f24db28146c1efa96b49a50d9bef5feff7e69192217fe3d59c3b46896650b3d3d8ecbe606cadd225",
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+      "line": 349,
       "relation": "decreases",
-      "source": 20,
-      "target": 36
+      "source": 22,
+      "target": 42
     },
     {
       "annotations": {
-        "MeSHAnatomy": {
-          "Neurons": true
+        "Confidence": {
+          "High": true
         }
       },
       "citation": {
@@ -2280,18 +2703,18 @@
       },
       "evidence": "Screening previously synthesized frentizole derivatives for their efficiency to inhibit CK1 activity as well as ABAD, identified compound 13 which possessed an ABAD IC 50  = 1.67 µM, the most  potent  inhibitor  of  this  chemotype  identified  to  date.",
       "key": "2d0190ea62d86a2f0d206a9eed63b33f5e412bee007cac10d0310e4a457eaa729cfa972997637b34738ba0a606102359d9f16796aa7d7d223e0c156073e05d4b",
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       "object": {
         "modifier": "Activity"
       },
       "relation": "decreases",
-      "source": 20,
-      "target": 57
+      "source": 22,
+      "target": 63
     },
     {
       "annotations": {
-        "MeSHAnatomy": {
-          "Neurons": true
+        "Confidence": {
+          "Medium": true
         }
       },
       "citation": {
@@ -2309,15 +2732,15 @@
       },
       "evidence": " Isoforms  of  CK1  are  responsible  for  tau phosphorylation. 129   The  enzyme  can  modulate  the  activity  of  γ-secretase  and  consequently  the production of Aβ.",
       "key": "0be3804fede56aeb8b237991efee62a6827d9345e5b009f534e0262c177596c2a2a7b2db4fb3159f34a191fade6f40e54eb6097d084c70a096aa242e5a1f0df7",
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+      "line": 356,
       "relation": "increases",
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-      "target": 65
+      "source": 63,
+      "target": 71
     },
     {
       "annotations": {
-        "MeSHAnatomy": {
-          "Neurons": true
+        "Confidence": {
+          "Medium": true
         }
       },
       "citation": {
@@ -2335,18 +2758,18 @@
       },
       "evidence": " Isoforms  of  CK1  are  responsible  for  tau phosphorylation. 129   The  enzyme  can  modulate  the  activity  of  γ-secretase  and  consequently  the production of Aβ.",
       "key": "6bb6979f05b7c685476c4ee9d442d81010cfceab4e853c01ea89fb7e5690462cea5740beb42e0899dfb9dabbc11ec995a004a831cfabd263159619c79970488e",
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+      "line": 357,
       "object": {
         "modifier": "Activity"
       },
       "relation": "regulates",
-      "source": 57,
-      "target": 44
+      "source": 63,
+      "target": 51
     },
     {
       "annotations": {
-        "MeSHAnatomy": {
-          "Neurons": true
+        "Confidence": {
+          "Medium": true
         }
       },
       "citation": {
@@ -2363,45 +2786,28 @@
         "type": "PubMed"
       },
       "evidence": " Isoforms  of  CK1  are  responsible  for  tau phosphorylation. 129   The  enzyme  can  modulate  the  activity  of  γ-secretase  and  consequently  the production of Aβ.",
-      "key": "4ba51b85b02a272b074ab66ae3ec660dd3a0b019694ed2b2aedc0afdc8756085e180959d09f2de61d3a6277ee13bf0c24857ba453cfd6d3040ec4ad71bd5c229",
-      "line": 278,
-      "relation": "association",
-      "source": 57,
-      "target": 13
+      "key": "79cdcf2fd0b238dea972c28c1ad2c90b813e92093b770047b9a1848f4b351af068403e6a0461fb3f4b8631deb0a2bbbbdcbf7ca011e85168b1fbd4ed0916eda4",
+      "line": 358,
+      "relation": "increases",
+      "source": 63,
+      "target": 30
     },
     {
-      "annotations": {
-        "MeSHAnatomy": {
-          "Neurons": true
-        }
-      },
-      "citation": {
-        "authors": [
-          "Morsy A",
-          "Trippier PC"
-        ],
-        "date": "2018-11-30",
-        "first": "Morsy A",
-        "last": "Trippier PC",
-        "name": "Journal of medicinal chemistry",
-        "reference": "30444369",
-        "title": "Amyloid-Binding Alcohol Dehydrogenase (ABAD) Inhibitors for the Treatment of Alzheimer's Disease.",
-        "type": "PubMed"
-      },
-      "evidence": "The frentizole scaffold has been combined with the known monoamine oxidase inhibitor (MAOI) ladostigil to identify a molecule that has a dual effect; inhibiting both ABAD and MAO. A library of synthesized derivatives demonstrated that the most potent inhibitor for MAO (IC 50  = 6.34 µM) lacked ABAD inhibition activity.",
-      "key": "5863e3706a8350ccf1922381e1a48afb93a54a1d1fed860c15fba529d32388f524e201be88832f527215c871c7b04b71b6ab4ba56c2bc3b7518de6291fe84bf6",
-      "line": 289,
-      "object": {
-        "modifier": "Activity"
-      },
-      "relation": "decreases",
-      "source": 19,
-      "target": 61
+      "key": "6fd78e59f91243437e51f974c0c277bbf64e9866b73338d769fe03d2e64610c23b4c93f479ff740253f01268155b2d0b6b6f605a82233cc7679af884c1659fd9",
+      "relation": "hasComponent",
+      "source": 43,
+      "target": 21
+    },
+    {
+      "key": "a23e14852491c32cc59ae7d1b0392d1f6799c498a4788b2d4ee12d54df0e65809307499768845f939452f60a21bc6e356ca32f1237b14942643952fd93005f70",
+      "relation": "hasComponent",
+      "source": 43,
+      "target": 22
     },
     {
       "annotations": {
-        "MeSHAnatomy": {
-          "Neurons": true
+        "Confidence": {
+          "Medium": true
         }
       },
       "citation": {
@@ -2418,14 +2824,14 @@
         "type": "PubMed"
       },
       "evidence": "The frentizole scaffold has been combined with the known monoamine oxidase inhibitor (MAOI) ladostigil to identify a molecule that has a dual effect; inhibiting both ABAD and MAO. A library of synthesized derivatives demonstrated that the most potent inhibitor for MAO (IC 50  = 6.34 µM) lacked ABAD inhibition activity.",
-      "key": "e344227ec57111bf8e423da81f384cad3c8a8c0df0a40745f06108adeccaf52bb07ba8f0e10fa300fa33a7157bdae1f2cb5425f5142f31e2b99a5a9baabf47c5",
-      "line": 290,
+      "key": "1f73eda3b0fcd19bd5c4a9825df454158a6d087e8c3dbaaae26547734adb917d70910420fc281ead7cf2323bf2a35f08cfbd73cc16effc48a1285a863aa2b8cf",
+      "line": 373,
       "object": {
         "modifier": "Activity"
       },
-      "relation": "causesNoChange",
-      "source": 19,
-      "target": 57
+      "relation": "decreases",
+      "source": 43,
+      "target": 67
     }
   ],
   "multigraph": true,
@@ -2535,6 +2941,13 @@
       "name": "AG18051",
       "namespace": "HBP"
     },
+    {
+      "bel": "a(PUBCHEM:101790)",
+      "function": "Abundance",
+      "id": "5523965481cd4cc83ed157a035f805c7952a453986160bf871b5e20a49391a545b9d4f3e825ec8f0367bdddcb3519523f97a66f2ab526ce7ffad79d55e46f687",
+      "name": "101790",
+      "namespace": "PUBCHEM"
+    },
     {
       "bel": "a(PUBCHEM:1038)",
       "function": "Abundance",
@@ -2556,6 +2969,13 @@
       "name": "15818",
       "namespace": "PUBCHEM"
     },
+    {
+      "bel": "a(PUBCHEM:16057918)",
+      "function": "Abundance",
+      "id": "387c1248b84c212c4de1856f4beec7abd7b101c594ac49e5571089cf5cc5aebab044e3211c41b79d9f806df2f3d3d77dc36792985294632386c6feb4160e1710",
+      "name": "16057918",
+      "namespace": "PUBCHEM"
+    },
     {
       "bel": "a(PUBCHEM:193425)",
       "function": "Abundance",
@@ -2598,6 +3018,13 @@
       "name": "5870",
       "namespace": "PUBCHEM"
     },
+    {
+      "bel": "a(PUBCHEM:92786)",
+      "function": "Abundance",
+      "id": "572a86afe66f67914bad6f89d84eb55416523513d4be13ca772c0a1069ae0f54c7636906cf9c81067051c14a19c1ddc52c8ea589f3a61ed8eb88d69a287ed2b8",
+      "name": "92786",
+      "namespace": "PUBCHEM"
+    },
     {
       "bel": "a(PUBCHEM:9543037)",
       "function": "Abundance",
@@ -2605,6 +3032,27 @@
       "name": "9543037",
       "namespace": "PUBCHEM"
     },
+    {
+      "bel": "bp(GO:\"JNK cascade\")",
+      "function": "BiologicalProcess",
+      "id": "305272e7f9e8536b302e0fe9bd6d7a375e50ca0af75e569c33318738ec78aa86f70dad1b11b29e2e89cb1cf476bf18fc2fbc861054182ef14a1b79617775b6f6",
+      "name": "JNK cascade",
+      "namespace": "GO"
+    },
+    {
+      "bel": "bp(GO:\"amyloid-beta clearance\")",
+      "function": "BiologicalProcess",
+      "id": "a1f9fc93d5ca14e48078a2e7077225059a171eb16dbbab5848c1941e2559d615810e11b5f94f7b586331e105ba1484654d4ab0e74dfe6244fd6359349c79d35f",
+      "name": "amyloid-beta clearance",
+      "namespace": "GO"
+    },
+    {
+      "bel": "bp(GO:\"amyloid-beta formation\")",
+      "function": "BiologicalProcess",
+      "id": "78b3edf87ac63c62c4027270412a8d18bf9cded8d1db6354615c4b7e79930f50560150fde88c2996f8bafaefe2809ece6b1f9300ff1e79f0aad756ba51d9a65e",
+      "name": "amyloid-beta formation",
+      "namespace": "GO"
+    },
     {
       "bel": "bp(GO:\"apoptotic DNA fragmentation\")",
       "function": "BiologicalProcess",
@@ -2717,6 +3165,27 @@
         }
       ]
     },
+    {
+      "bel": "composite(a(PUBCHEM:208907), a(PUBCHEM:33334))",
+      "function": "Composite",
+      "id": "01320b7f34dce38a52705761169a43e9d72924d44f5650db65a33c8d95cd1896d37dbc21af924baf0442bab6d86accf44adc317a698f46a3edc3f31adbba7b88",
+      "members": [
+        {
+          "bel": "a(PUBCHEM:208907)",
+          "function": "Abundance",
+          "id": "98b7716217783c4ee76fffc35661176d7d87e567dd197af6432a292da9669cf9b97e3928135fdfe73a368ce630748f8e295b5ac758b0a1ea0fabaf9868cd6a70",
+          "name": "208907",
+          "namespace": "PUBCHEM"
+        },
+        {
+          "bel": "a(PUBCHEM:33334)",
+          "function": "Abundance",
+          "id": "b369be2cfae6cdaeff08c402b043bb7c6e492c95945f44024729cc9eb6f366265860cf797cd7c326220ef7950ed51ab2b854f94c77bf2184cf115c4fd5d8b2da",
+          "name": "33334",
+          "namespace": "PUBCHEM"
+        }
+      ]
+    },
     {
       "bel": "g(HBP:\"APOE e4\")",
       "function": "Gene",
@@ -2805,13 +3274,6 @@
       "name": "Cholinesterase",
       "namespace": "FPLX"
     },
-    {
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diff --git a/hbp_knowledge/app/mroczko2018.bel.json b/hbp_knowledge/app/mroczko2018.bel.json
index d7337395b..f8129d834 100644
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new file mode 100644
index 000000000..3e426cfc0
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+        "type": "PubMed",
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+        "pages": "2025-39",
+        "reference": "21722302",
+        "title": "Unfolded proteins and endoplasmic reticulum stress in neurodegenerative disorders.",
+        "type": "PubMed",
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+      "evidence": "The presenilin protein is a component of the Gamma-secretase complex, which is widely expressed in the ER and Golgi apparatus [70]. Presenilin mutations are linked with the majority of early onset forms of AD [69] with presenilin 1 (PS1) being more highly expressed than PS2, and mutations in the genes coding for a presenilin protein reduce the average age of onset of AD [71].",
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+          "Gupta S",
+          "Healy SJ",
+          "Kennedy D",
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+        "first": "Doyle KM",
+        "last": "Samali A",
+        "name": "Journal of cellular and molecular medicine",
+        "pages": "2025-39",
+        "reference": "21722302",
+        "title": "Unfolded proteins and endoplasmic reticulum stress in neurodegenerative disorders.",
+        "type": "PubMed",
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+      },
+      "evidence": "Mutant PS1 is also known to bind, and inhibit IRE1, thereby reducing, or delaying, the transcription of ER chaperones such as GRP78 which has consistently been found to be down-regulated in AD [73].",
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+        "first": "Doyle KM",
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+        "name": "Journal of cellular and molecular medicine",
+        "pages": "2025-39",
+        "reference": "21722302",
+        "title": "Unfolded proteins and endoplasmic reticulum stress in neurodegenerative disorders.",
+        "type": "PubMed",
+        "volume": "15"
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+      "evidence": "XBP1 can bind to the promotors of at least one key component of the Gamma-secretase complex, namely UBQLN1 that is a negative regulator of the Gamma-secretase complex. It has been suggested that UBQLN1 may control APP trafficking and thus the generation of Abeta. XBP1 can also bind to the promoter of genes involved in APP trafficking and processing as well as genes involved in AD pathogenesis, thereby implicating XBP1 in AD (Fig. 3A) [75].",
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+        "pages": "2025-39",
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+      "evidence": "AMP-activated protein kinase (AMPK) negatively regulates mTOR via the tuberous sclerosis complex (TSC). AMPK is activated in response to many stresses such as hypoxia, starvation, heat shock, ischaemia and ER stress [43]. During ER stress, Ca2+ flux from the ER lumen to the cytosol can lead to the activation of Ca2+/calmodulindependent protein kinase kinase-beta (CaMKK-beta) [44]. CaMKK-beta activates AMPK, in turn inhibiting mTOR and activating the ATG/ULK induction complex. The inhibition of mTOR during ER stress via AMPK is an important event during ER stress for the induction of autophagy [45].",
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+      "evidence": "AMP-activated protein kinase (AMPK) negatively regulates mTOR via the tuberous sclerosis complex (TSC). AMPK is activated in response to many stresses such as hypoxia, starvation, heat shock, ischaemia and ER stress [43]. During ER stress, Ca2+ flux from the ER lumen to the cytosol can lead to the activation of Ca2+/calmodulindependent protein kinase kinase-beta (CaMKK-beta) [44]. CaMKK-beta activates AMPK, in turn inhibiting mTOR and activating the ATG/ULK induction complex. The inhibition of mTOR during ER stress via AMPK is an important event during ER stress for the induction of autophagy [45].",
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+      "evidence": "Overall, it is thought that the apoptotic signals generated from excessive activation of the UPR converge on the mitochondria resulting in opening of the permeability transmembrane pore (PTP) and loss of mitochondrial membrane potential (delta psi m) with consequent release of pro-apoptotic factors, including cytochrome c (Fig. 2).",
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+      "evidence": "CHOP, also known as growth arrest and DNA damage-inducible gene 153 (GADD153), is a member of the C/EBP family that heterodimerizes with other members of the C/EBP transcription factor family. This 29 kD factor is expressed at low levels in unstressed cells and is strongly induced in response to ER stress [33]. It can be induced by all three arms of the UPR. It has been shown that mouse embryonic fibroblasts derived from CHOP-/- animals exhibited significantly less cell death when challenged with ER stress–inducing agents compared to wild type [33].",
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+      "evidence": "Missense mutations in the gene coding for alpha-synuclein cause dominant familial PD. The A53T mutation is associated with UPR activation as evidenced by increased expression of CHOP and GRP78 and increased phosphorylation of eIF2alpha, suggesting the UPR is active in these cells (Fig. 3B) [80].Inhibition of phosphorylation of eIF2alpha protected the A53T alpha- synuclein-overexpressing cells from cell death, suggesting that the activated UPR was shifting the balance towards apoptosis [80].",
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+        "title": "Unfolded proteins and endoplasmic reticulum stress in neurodegenerative disorders.",
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+      "evidence": "Alpha-Synuclein is expressed in synaptic vesicles and on cell membranes in nervous tissue. Post-translational modification of alpha-synuclein such as phosphorylation and nitrosylation can cause misfolding and subsequent deposition of the protein [78]. There is a suggestion that alpha-synuclein, although normally contained within cells, may be released upon cell death [78].",
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+        "type": "PubMed",
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+      "function": "Protein",
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+      "name": "Presenilin",
+      "namespace": "PFAM",
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+          "identifier": "?",
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+        }
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+      "namespace": "DOID"
+    },
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+      "bel": "path(DOID:\"autosomal recessive Parkinson's disease 14\")",
+      "function": "Pathology",
+      "id": "082119b24e5387b1db812e56355498e6c9e893e9e7e93d627474074993f165af3ee693a8afc829993a76dc64d82eff98945874b18d8a41d9a190c1a7a0649593",
+      "name": "autosomal recessive Parkinson's disease 14",
+      "namespace": "DOID"
+    },
+    {
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+      "name": "neurodegenerative disease",
+      "namespace": "DOID"
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+      "name": "prion disease",
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+      "namespace": "HBP"
+    },
+    {
+      "bel": "path(HBP:\"mitochondrial dysfunction\")",
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+      "namespace": "HBP"
+    },
+    {
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+      "function": "Pathology",
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+      "name": "Excitotoxicity",
+      "namespace": "HBP"
+    },
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+      "bel": "path(HBP:Neurodegeneration)",
+      "function": "Pathology",
+      "id": "1e32e61de82d42fab0a4abcd15d32d3fa5b2f65883b2d99c828d4019591a465f11cd017eefe918bc5d066b7f3cef9d21f4e0988e5c23cc2c135313815478263a",
+      "name": "Neurodegeneration",
+      "namespace": "HBP"
+    },
+    {
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+      "function": "Pathology",
+      "id": "70b5c945e50c584c02ecfbe670bc07db497f895abed0158cdd8344da543183c466225a3d894cd2db475c6100df48e5eb180c82125550a36cfcf99aec5ad797fa",
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+      "namespace": "HP"
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+      "function": "Pathology",
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+      "namespace": "HP"
+    },
+    {
+      "bel": "path(HP:\"Senile plaques\")",
+      "function": "Pathology",
+      "id": "8c030650553f0e58ae5a9b7f633c17d807afc8ee7ad927e0477dc5618fe0658ba0a0d186a1da3d25d422881449b27ffe186b5e46ee22379f60cb5b6eba2e9cf6",
+      "name": "Senile plaques",
+      "namespace": "HP"
+    },
+    {
+      "bel": "path(HP:Dyskinesia)",
+      "function": "Pathology",
+      "id": "bfb57b1904baa5f680868df326ab3bd67305411e2b91d972ea0aeca3394dab293edfdc62fc60dad5a24ea3521559cba71d53577f16219454f3a3cd2d7f5c1942",
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+      "namespace": "HP"
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+      "namespace": "MESH"
+    },
+    {
+      "bel": "path(MESH:\"Brain Injuries, Traumatic\")",
+      "function": "Pathology",
+      "id": "045bae6eea134b42537774fcd702c7450a66a9f19fedd90aed63fed01468978b1449afeb8e68a5bf609df87bb9d2bc4613280f3a7225911fb029ca78ab2f02d7",
+      "name": "Brain Injuries, Traumatic",
+      "namespace": "MESH"
+    },
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+      "function": "Pathology",
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+    },
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+      "name": "Neurodegenerative Diseases",
+      "namespace": "MESH"
+    },
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+      "namespace": "MESH"
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+      "function": "Pathology",
+      "id": "fc2c9bedd0c62ffbd4fb1303ba3bf063881eb2b4ec7e3e9cab410ced5b1025f1624066dbb0c9b1d2de6db576f66367b9956407baf3ec647fbb60fd953b149949",
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+    },
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+      "function": "Pathology",
+      "id": "def4b2b2f8f12ec04a5a7ada344d57efed9547211133e8ca8673d264f9d8eaded37af479e4a7853c17aabc6bc66fd425d9591ed363c00a3ba326f695341b6533",
+      "name": "Starvation",
+      "namespace": "MESH"
+    },
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+      "function": "RNA",
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+      "name": "BCL2",
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+      "name": "XBP1",
+      "namespace": "HGNC"
+    },
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+      "function": "RNA",
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+      "name": "molecular chaperone GRP78",
+      "namespace": "MESH"
+    },
+    {
+      "bel": "rxn(reactants(p(HGNC:APP)), products(a(CHEBI:\"amyloid-beta\")))",
+      "function": "Reaction",
+      "id": "7eca0f9cd8cd1456dd9c3029892469af1e745a2c5c36052692b1b6032ceacfba1b5710017947cd215daa0831b0d48a6340d3f52164b6468a45f68669191ee569",
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+          "bel": "a(CHEBI:\"amyloid-beta\")",
+          "function": "Abundance",
+          "id": "a9487b29439483c6840095610dd3e496e3ca9cccc3a8d71e0385a39b570f3c0a26965ac06d83265e1c08deaae7998272d4f4c21ec0534f8be3fd8e4e57dbb3a2",
+          "name": "amyloid-beta",
+          "namespace": "CHEBI"
+        }
+      ],
+      "reactants": [
+        {
+          "bel": "p(HGNC:APP)",
+          "function": "Protein",
+          "id": "ed1d45f3255226e4210017e6c179950e0e04a300727326d7fea6a9659868e8818ff64fd5e8a2a92a703fb1566b3f48323750ac6c28e7adb40843053d276710bc",
+          "name": "APP",
+          "namespace": "HGNC"
+        }
+      ]
+    }
+  ]
+}
\ No newline at end of file
diff --git a/hbp_knowledge/huntington/goh2018.bel.json b/hbp_knowledge/huntington/goh2018.bel.json
new file mode 100644
index 000000000..49a02dbe3
--- /dev/null
+++ b/hbp_knowledge/huntington/goh2018.bel.json
@@ -0,0 +1,1467 @@
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+  "graph": {
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+    },
+    "annotation_url": {
+      "Cell": "https://arty.scai.fraunhofer.de/artifactory/bel/annotation/cell/cell-20170511.belanno",
+      "MeSHAnatomy": "https://arty.scai.fraunhofer.de/artifactory/bel/annotation/mesh-anatomy/mesh-anatomy-20170511.belanno"
+    },
+    "document_metadata": {
+      "authors": "Esther Wollert",
+      "contact": "charles.hoyt@scai.fraunhofer.de",
+      "copyright": "Copyright © 2019 Fraunhofer Institute SCAI, All rights reserved.",
+      "description": "",
+      "licenses": "CC BY 4.0",
+      "name": "Huntington's disease: Neuropsychiatric manifestations of Huntington's disease",
+      "version": "1.0.0"
+    },
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+    "namespace_url": {
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+    },
+    "namespaces_uncached": [],
+    "path": "huntington/goh2018.bel",
+    "pybel_version": "0.13.3-dev"
+  },
+  "links": [
+    {
+      "annotations": {
+        "MeSHAnatomy": {
+          "Corpus Striatum": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Goh AM",
+          "Loi SM",
+          "Looi JC",
+          "Velakoulis D",
+          "Walterfang M",
+          "Wibawa P"
+        ],
+        "date": "2018-08-01",
+        "first": "Goh AM",
+        "last": "Looi JC",
+        "name": "Australasian psychiatry : bulletin of Royal Australian and New Zealand College of Psychiatrists",
+        "pages": "366-375",
+        "reference": "30012004",
+        "title": "Huntington's disease: Neuropsychiatric manifestations of Huntington's disease.",
+        "type": "PubMed",
+        "volume": "26"
+      },
+      "evidence": "Gradual atrophy of the striatum (caudate and putamen) due to neuronal loss is the neuropathological and neuro- radiological  hallmark  of  HD.",
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+      "relation": "increases",
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+      "target": 19
+    },
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+        }
+      },
+      "citation": {
+        "authors": [
+          "Goh AM",
+          "Loi SM",
+          "Looi JC",
+          "Velakoulis D",
+          "Walterfang M",
+          "Wibawa P"
+        ],
+        "date": "2018-08-01",
+        "first": "Goh AM",
+        "last": "Looi JC",
+        "name": "Australasian psychiatry : bulletin of Royal Australian and New Zealand College of Psychiatrists",
+        "pages": "366-375",
+        "reference": "30012004",
+        "title": "Huntington's disease: Neuropsychiatric manifestations of Huntington's disease.",
+        "type": "PubMed",
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+      },
+      "evidence": "Gradual atrophy of the striatum (caudate and putamen) due to neuronal loss is the neuropathological and neuro- radiological  hallmark  of  HD.",
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+      "relation": "positiveCorrelation",
+      "source": 8,
+      "target": 17
+    },
+    {
+      "annotations": {
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+        },
+        "MeSHAnatomy": {
+          "Neostriatum": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Goh AM",
+          "Loi SM",
+          "Looi JC",
+          "Velakoulis D",
+          "Walterfang M",
+          "Wibawa P"
+        ],
+        "date": "2018-08-01",
+        "first": "Goh AM",
+        "last": "Looi JC",
+        "name": "Australasian psychiatry : bulletin of Royal Australian and New Zealand College of Psychiatrists",
+        "pages": "366-375",
+        "reference": "30012004",
+        "title": "Huntington's disease: Neuropsychiatric manifestations of Huntington's disease.",
+        "type": "PubMed",
+        "volume": "26"
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+          "Goh AM",
+          "Loi SM",
+          "Looi JC",
+          "Velakoulis D",
+          "Walterfang M",
+          "Wibawa P"
+        ],
+        "date": "2018-08-01",
+        "first": "Goh AM",
+        "last": "Looi JC",
+        "name": "Australasian psychiatry : bulletin of Royal Australian and New Zealand College of Psychiatrists",
+        "pages": "366-375",
+        "reference": "30012004",
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+        "type": "PubMed",
+        "volume": "26"
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diff --git a/hbp_knowledge/huntington/loi2018.bel.json b/hbp_knowledge/huntington/loi2018.bel.json
new file mode 100644
index 000000000..238befe99
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+      "id": "181472b7f9a4b32696b87492619020f88bad9e24f439e97158614801e3fb1dda434c97b95c252baa65a43ba7d78eecfca26f91f6a5295d37b21e6873f04a73f6",
+      "name": "motor behavior",
+      "namespace": "GO"
+    },
+    {
+      "bel": "bp(GO:behavior)",
+      "function": "BiologicalProcess",
+      "id": "9a101ba3d87b5d6d86780d7ab27c7ab65e2d60e8abbe894683aa3ad6755eb311c595c8a088174655a14224a317985b6ec4db3d3c829671b156af6e3f4d6cae36",
+      "name": "behavior",
+      "namespace": "GO"
+    },
+    {
+      "bel": "p(HGNCGENEFAMILY:\"Glutamate ionotropic receptor NMDA type subunits\")",
+      "function": "Protein",
+      "id": "04fcb6dc2a3a7372aafa9bcd0a67ae080105125c80681cd13f078d8204e354557b8a3cb1bfac030ca24c27787cd42c4ee35ef15010057fba33439f6190647fd7",
+      "name": "Glutamate ionotropic receptor NMDA type subunits",
+      "namespace": "HGNCGENEFAMILY"
+    },
+    {
+      "bel": "path(MESH:\"Cognitive Dysfunction\")",
+      "function": "Pathology",
+      "id": "bd78fa3131dd9ef6067a5fe3ee8689c946c79d0da1bedb054d1f4400b9ad0d3ae041837faa0fbacee0af5a57a4cd343d11e73fd53fd05269e3558803a56df69c",
+      "name": "Cognitive Dysfunction",
+      "namespace": "MESH"
+    },
+    {
+      "bel": "path(MESH:\"Executive Function\")",
+      "function": "Pathology",
+      "id": "49eccc7c6474d853d3f7d9f266a96b278d78b96c15d0f1691b4c116f7c58d193008d088b30c310c4af65bda65369134dc12957dfb47cb73fc2eecaeeead3efe2",
+      "name": "Executive Function",
+      "namespace": "MESH"
+    },
+    {
+      "bel": "path(MESH:\"Huntington Disease\")",
+      "function": "Pathology",
+      "id": "1879e0f73bb6f3f680c5793e5c3b9370792a52545c46d4ee9f41a8ef46edd5ba61400e77effb39bd0d1e7f3de6470e091c5d8e6c5beed8d780456b6740a4406c",
+      "name": "Huntington Disease",
+      "namespace": "MESH"
+    },
+    {
+      "bel": "path(MESH:\"Irritable Mood\")",
+      "function": "Pathology",
+      "id": "dc32a53f051746432afab52fac575e8aa4e99d2cdd367c7191e349adc6121926797504d078531450781cc1fbc5b6d9e6adc02060cedb821fa7e01971e764cb0b",
+      "name": "Irritable Mood",
+      "namespace": "MESH"
+    },
+    {
+      "bel": "path(MESH:\"Motor Disorders\")",
+      "function": "Pathology",
+      "id": "de533e6c384fbd82a035846f8bacbfe0b05a1669df76ade1b87351c17ffc233fc4a2b5b33af6e10b173aa257f030e2f8527a86d5ddbc2655b306c1253498558f",
+      "name": "Motor Disorders",
+      "namespace": "MESH"
+    },
+    {
+      "bel": "path(MESH:\"Neural Pathways\")",
+      "function": "Pathology",
+      "id": "e63c4698a558235340c07558ab0a97a666652d32f4d92ba6bc097d2dc94dab5c480fdfe0254bf415a4090b3b7a08ee571da5ffaf0e0337974a0ce4b65806b6a1",
+      "name": "Neural Pathways",
+      "namespace": "MESH"
+    },
+    {
+      "bel": "path(MESH:\"Neurocognitive Disorders\")",
+      "function": "Pathology",
+      "id": "d3d5ea522d64cf4692e545e3196ba8cec0782cc17665d25e239f114eb2d8fb51563674a7e71fee360f1b87d5a3e240f8e2560417178af514803d6e331ec80f66",
+      "name": "Neurocognitive Disorders",
+      "namespace": "MESH"
+    },
+    {
+      "bel": "path(MESH:\"Neurodegenerative Diseases\")",
+      "function": "Pathology",
+      "id": "95863a6d11beb3bd993523e1c8c7e210d281b0c092553f6a4cf27dd3ecf2fa51b49c5056b8aed6f7ac7c82f99101c34bc9fc0afc3dce117fe011d159ba9e4c89",
+      "name": "Neurodegenerative Diseases",
+      "namespace": "MESH"
+    },
+    {
+      "bel": "path(MESH:\"Obsessive-Compulsive Disorder\")",
+      "function": "Pathology",
+      "id": "416439c93738dd6e4ea529e2ffebdcd0af4d47de3a98f92ae19ad224db65b554ef5530ac40174df80bc63978bd3926b0589ca8f747f12ee7b6de2e9108b5936c",
+      "name": "Obsessive-Compulsive Disorder",
+      "namespace": "MESH"
+    },
+    {
+      "bel": "path(MESH:\"Schizophrenia, Disorganized\")",
+      "function": "Pathology",
+      "id": "de2cfd897525c77f8768631b62fe26e647d2558849058933225b8f21158a82ab7d59966a12967fdda74e239a67ff6a336fd1f4f579edab8857ed77e7223f96c5",
+      "name": "Schizophrenia, Disorganized",
+      "namespace": "MESH"
+    },
+    {
+      "bel": "path(MESH:\"Stereotypic Movement Disorder\")",
+      "function": "Pathology",
+      "id": "34a33d12b815172cadec5aee6c083a25fd7471f53eb675e0957dde5d98223a5dce24576330fc4b720b9259341d5d61f6f31f4ea4f3e5d751a9fb96420c794223",
+      "name": "Stereotypic Movement Disorder",
+      "namespace": "MESH"
+    },
+    {
+      "bel": "path(MESH:Aggression)",
+      "function": "Pathology",
+      "id": "3baeef036ebf13d97eca7c5edfc7cc5122a6600f1a2268e272b2854e3605dd8bfb4d55a0539aec790d0cecd4977770e57a9961252552e9add740de8bfe2c276e",
+      "name": "Aggression",
+      "namespace": "MESH"
+    },
+    {
+      "bel": "path(MESH:Chorea)",
+      "function": "Pathology",
+      "id": "2b4d35982bd7b14a015899b0fbf69581027fc723a4b49eac9a96024415efd458c2f401874bc224607f5388e6b218e0ead9ef7e566137fde8d79910ab3df79c9f",
+      "name": "Chorea",
+      "namespace": "MESH"
+    },
+    {
+      "bel": "path(MESH:Cognition)",
+      "function": "Pathology",
+      "id": "d8ff6334a72a605de87a6f1c577433b40d5732bc0387acd31217452afe3e60a4d5928028b8b819ce892d4784459379ebea852781c6e1c96bc81d3270f4a06b5a",
+      "name": "Cognition",
+      "namespace": "MESH"
+    },
+    {
+      "bel": "path(MESH:Depression)",
+      "function": "Pathology",
+      "id": "1db8d744eac9b5ac408852b1889bb0b09e0054ea091932f1aa44aeeab0ea1b3825912c55c72fb2d25d5848e77d62b1c6a1df2063a2f25ae03e5ca30085922799",
+      "name": "Depression",
+      "namespace": "MESH"
+    },
+    {
+      "bel": "path(MESH:Dystonia)",
+      "function": "Pathology",
+      "id": "aec7e80d4f48a5c0b4e1a6770a1a988548fffc07736ec8abff2d0bcbab97790ec012a79a9f9d0148c7c8009a0acf385010e5f95ffc770fab760ee63d7bbbc00c",
+      "name": "Dystonia",
+      "namespace": "MESH"
+    },
+    {
+      "bel": "path(MESH:Memory)",
+      "function": "Pathology",
+      "id": "458f0dcf7b803807dba1023338bdb4a2f225d390c38b33a8972f9ff63b677d58adabbb4ad1bd00d2986334b90861fc40c133593b338b3873bf033d5e09af1322",
+      "name": "Memory",
+      "namespace": "MESH"
+    },
+    {
+      "bel": "path(MESH:Movement)",
+      "function": "Pathology",
+      "id": "f5a025ce3c8ecad0b34f2bc22c0c2b824a22580b7fe76e17344bc0360f71136cc13b0eb1b3ce13aff810d9654f2bdf8b9ee3481ee2f36837d890002a0891fc89",
+      "name": "Movement",
+      "namespace": "MESH"
+    },
+    {
+      "bel": "path(MESH:Thinking)",
+      "function": "Pathology",
+      "id": "247be1419fd72a3011b27cb437ca5b5b89844c8975199e87b4b15fe2d23f2d238f7214927c567dbbc59b28de50a96de0f4f988f102ce33ba5632d0ee15aebd76",
+      "name": "Thinking",
+      "namespace": "MESH"
+    }
+  ]
+}
\ No newline at end of file
diff --git a/hbp_knowledge/proteostasis/yu2014.bel.json b/hbp_knowledge/proteostasis/yu2014.bel.json
index cc9265839..e80e7e8bb 100644
--- a/hbp_knowledge/proteostasis/yu2014.bel.json
+++ b/hbp_knowledge/proteostasis/yu2014.bel.json
@@ -56,6 +56,11 @@
   },
   "links": [
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Calamini B",
@@ -77,7 +82,7 @@
       },
       "evidence": " It has been proposed that such an imbalance may trigger the onset of many neurodegenerative diseases (10, 26), and recent studies report that polyglutamine (polyQ)-based aggregates can se- quester and inhibit the function of a low-abundance cochaper- one, Sis1p/DNAJB1, in protein degradation (27).",
       "key": "8e06fd0545bf0522388c89a85abf10f241badc79e432906c90284250e1be40bec4a69933f96055f4e4299e3d81bfd739cf282848bd32be915b487690bdda9941",
-      "line": 87,
+      "line": 88,
       "object": {
         "modifier": "Activity"
       },
@@ -89,6 +94,9 @@
       "annotations": {
         "CellLine": {
           "HEK293": true
+        },
+        "Confidence": {
+          "High": true
         }
       },
       "citation": {
@@ -112,12 +120,17 @@
       },
       "evidence": "Previous studies have shown that ag- gregation of expanded polyQ negatively affects endocytosis in yeast and in human HEK 293 cells (34).",
       "key": "17aa5522418e4061327c59e2b0dc2b1a9ecfdd0bfafa8493bc8d95c405bd893c32c781ed7f0d1a68d452f12f775d7f12c6c028e053a2dfc57f1a1d7b7df8db35",
-      "line": 111,
+      "line": 120,
       "relation": "decreases",
       "source": 2,
       "target": 6
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Calamini B",
@@ -139,7 +152,7 @@
       },
       "evidence": "Here, we show that diverse disease-associated aggregates se- quester the highly abundant major chaperone heat shock cognate protein 70 (HSC70) to the point of functional collapse of an essential cellular process, clathrin-mediated endocytosis (CME).",
       "key": "3d18ad4e4ac07c040b17424eef871f436fa5aae6d292d1259ad08a5cd8c8fd61a9a866e741e55dbecf92380ee883d4fd4ea1ad4fdd9763404883886e2432d72e",
-      "line": 93,
+      "line": 96,
       "object": {
         "modifier": "Activity"
       },
@@ -148,6 +161,11 @@
       "target": 9
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Calamini B",
@@ -169,12 +187,17 @@
       },
       "evidence": "Here, we show that diverse disease-associated aggregates se- quester the highly abundant major chaperone heat shock cognate protein 70 (HSC70) to the point of functional collapse of an essential cellular process, clathrin-mediated endocytosis (CME).",
       "key": "ecdcc28c10e3d238590c8f55e8a9051c2351d38bbfc0c7279ed3ec297624ecb20c8f8a5433414db07f0f6f3df387f736287a1741b964fe8ec618763aef42d89a",
-      "line": 94,
+      "line": 97,
       "relation": "decreases",
       "source": 12,
       "target": 5
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Calamini B",
@@ -196,12 +219,17 @@
       },
       "evidence": "Importantly, aggregate-driven CME inhibition is reversible and can be rescued by nominally increasing HSC70 levels.",
       "key": "9b6dac97ff4716f5e254ecff088184467b8fd88a87f710ffab28f3a748666402ac7745d3ba1d18d9b5aa11bd8a397e05e46f25d31214c8dfc308594f83f869a9",
-      "line": 98,
+      "line": 103,
       "relation": "increases",
       "source": 9,
       "target": 5
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Calamini B",
@@ -223,12 +251,17 @@
       },
       "evidence": "Although internalized transferrin levels remained un- changed in cells with near-normal amounts of HSC70, cells with over a 50% reduction in HSC70 expression had significant CME inhibition (compare Fig. 2 E and D ), with a 51 ± 17% decrease in internalized transferrin fluorescence compared with nondepleted cells.",
       "key": "fb68aeca51736d59db010af52ce18758bdb934663ddd935abee162e6552c997e6aa1a473574a37cd84b1410b3b5623373bc9c0a45fa9fdc6b46d34f048a9daf4",
-      "line": 146,
+      "line": 167,
       "relation": "increases",
       "source": 9,
       "target": 5
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Calamini B",
@@ -250,12 +283,17 @@
       },
       "evidence": ". Be- yond maintaining the general solubility of the CME machinery, HSC70 is specifically required for both the disassembly of the clathrin coat from endocytosed vesicles (20, 29 – 31) and in the recycling of coat components back to the plasma membrane.",
       "key": "331147db27893b513ec1580a4b5d6459e880810300383b8a62efe2c2f958a9f491247351efa6a0736fc766ab6ed1a8f88e9db349bb1317fe98639cc8044c79e5",
-      "line": 105,
+      "line": 112,
       "relation": "increases",
       "source": 9,
       "target": 4
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Calamini B",
@@ -277,12 +315,20 @@
       },
       "evidence": "However, CME was substantially reduced in cells con- taining Q82 aggregates (Fig. 1 B , arrows), with quantification of internalized transferrin fluorescence showing a 63 ± 11% reduction in aggregate-containing cells compared with cells expressing soluble Q19 or Q82 (Fig. 1 C ).",
       "key": "0ae5d46d7af5020311120ce7ffb7e46acf1e8d734fa6d0dd1870fc14dcf3be5f2937e9511d797f56de8299b5c8e65554e596f7449747cd202240645f1b868559",
-      "line": 119,
+      "line": 130,
       "relation": "decreases",
       "source": 0,
       "target": 5
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHDisease": {
+          "Huntington Disease": true
+        }
+      },
       "citation": {
         "authors": [
           "Calamini B",
@@ -304,7 +350,7 @@
       },
       "evidence": "CME inhibition was also observed in cells containing aggregated forms of polyQ- expanded Htt exon 1 (Htt Q53); these cells exhibited 50 ± 15% reduced levels of internalized transferrin compared with cells with soluble Htt Q23 or Htt Q53 protein (Fig. S2 A–C ).",
       "key": "9ca8cf360c2c85788689702de5d676e25e8e32cbfd8648dd15d44176a598d0ee784e97820c37dca7706e96d17196d37594017390a8ab23e20eee8c79aea53efc",
-      "line": 126,
+      "line": 140,
       "relation": "decreases",
       "source": 1,
       "target": 5
@@ -314,6 +360,9 @@
         "Cell": {
           "neuron": true
         },
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Huntington Disease": true
         }
@@ -339,12 +388,17 @@
       },
       "evidence": "In contrast, there was a marked reduction in CME in neurons containing mutant Htt exon 1 Q73-CFP aggregates compared with nonexpressing cells (Fig. 5 B , Center ; quantification in Fig. 5 D );",
       "key": "0670ebbcf71fa9e3c64133a6fcb259ca3020dca305c9678a2cd5f253e73b8d7b575f765a8bc15d70b8073eb32a425b87ee3394b002330d40633e3750c309c714",
-      "line": 154,
+      "line": 177,
       "relation": "decreases",
       "source": 1,
       "target": 5
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Calamini B",
@@ -366,7 +420,7 @@
       },
       "evidence": "Down- regulation of CME was not limited to polyQ-induced aggre- gation; cells with aggregated mutant SOD1 A4V also exhibited a 50 ± 10% decrease in levels of internalized transferrin com- pared with cells expressing the soluble WT or mutant protein (Fig. 1 E–G ).",
       "key": "de513d81c5b778b6fcd34cf5cd3f6dc8157cd4b587c38929481f2230d84cf6845ad6eacd9c8446d1321a4e50a96a97dc24b02a9d082e7f82c2d9ac1955139977",
-      "line": 134,
+      "line": 151,
       "relation": "decreases",
       "source": 11,
       "target": 5
@@ -390,6 +444,11 @@
       "target": 9
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Calamini B",
@@ -411,7 +470,7 @@
       },
       "evidence": "Nevertheless, HSC70-ag- gregate colocalization reliably predicted CME inhibition.",
       "key": "2c6e5f7f861c8036d2b817432cad1884a4edc2c547744ed68a7d091ba27131d48e819fe1c2953b07fffd23478694c22326f5fa0722ebacc7fbbd5269cfede822",
-      "line": 138,
+      "line": 157,
       "relation": "decreases",
       "source": 7,
       "target": 5
diff --git a/hbp_knowledge/receptors/albuquerque2009.bel.json b/hbp_knowledge/receptors/albuquerque2009.bel.json
index 7993e7fd8..e34a5ef49 100644
--- a/hbp_knowledge/receptors/albuquerque2009.bel.json
+++ b/hbp_knowledge/receptors/albuquerque2009.bel.json
@@ -56,6 +56,9 @@
   "links": [
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -85,10 +88,13 @@
       },
       "relation": "increases",
       "source": 19,
-      "target": 207
+      "target": 210
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -118,10 +124,13 @@
       },
       "relation": "increases",
       "source": 19,
-      "target": 208
+      "target": 211
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -144,14 +153,17 @@
         "volume": "89"
       },
       "evidence": "From the time of its discovery in 1914 by Henry H. Dale (109) and Otto Loewi (283) (the two shared the Nobel Prize in Physiology and Medicine in 1936) as an agent that decreases heart rate, ACh was recognized as an endogenous signaling compound, synthesized from choline and acetyl-CoA, through the action of choline acetyltransferase, that alters cell function.",
-      "key": "127eea25dbb23b9d56beffc326ca3b528e8f0c96f5c26da94995fdcc41d71d750ff0b032f7f0e53e89c9f68209379353e1c5e184b4748c81de521bff30206eac",
-      "line": 151,
+      "key": "f7141dd523d0737832e9541d5b50a1cea689b66c2a6c917910bd29f8efd9e09bc42f407409f995384d0e7f43bcdd576f8aaf2f42aaf0ca1b077aedcfc8d538c0",
+      "line": 160,
       "relation": "decreases",
       "source": 19,
-      "target": 228
+      "target": 119
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -175,13 +187,16 @@
       },
       "evidence": "From the time of its discovery in 1914 by Henry H. Dale (109) and Otto Loewi (283) (the two shared the Nobel Prize in Physiology and Medicine in 1936) as an agent that decreases heart rate, ACh was recognized as an endogenous signaling compound, synthesized from choline and acetyl-CoA, through the action of choline acetyltransferase, that alters cell function.",
       "key": "fe137b366fed4fb21134a2f0d0f0f52b2882664a13a3159d005cf5c76887c5334e81727af77155cac79c2a20b8da3d966e10d10bce9f12dacffaf57a96e714aa",
-      "line": 152,
+      "line": 162,
       "relation": "association",
       "source": 19,
       "target": 116
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -205,16 +220,19 @@
       },
       "evidence": "The metabotropic receptors are second messenger, G protein-coupled seven-transmembrane proteins. They are classically defined as being activated by muscarine, a toxin from the mushroom Amanita muscaria, and inhibited by atropine, a toxin from Atropa belladonna, a member of the nightshade family. Both toxins cross the blood-brain barrier poorly and were discovered primarily from their influences on postganglionic parasympathetic nervous system functions. Activation of muscarinic AChRs is relatively slow (milliseconds to seconds) and, depending on the subtypes present (M1- M5), they directly alter cellular homeostasis of phospholipase C, inositol trisphosphate, cAMP, and free calcium.",
       "key": "34f67b5cae8450d12d39dee94a365514851bd000192a8165d86f66b4703ddb59b4d3b38dd3166c8cf6046e9ff4fe309dcf1cf8e787de32a12c389a77b895a515",
-      "line": 112,
+      "line": 116,
       "relation": "regulates",
-      "source": 207,
+      "source": 210,
       "subject": {
         "modifier": "Activity"
       },
-      "target": 165
+      "target": 169
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -238,9 +256,9 @@
       },
       "evidence": "The metabotropic receptors are second messenger, G protein-coupled seven-transmembrane proteins. They are classically defined as being activated by muscarine, a toxin from the mushroom Amanita muscaria, and inhibited by atropine, a toxin from Atropa belladonna, a member of the nightshade family. Both toxins cross the blood-brain barrier poorly and were discovered primarily from their influences on postganglionic parasympathetic nervous system functions. Activation of muscarinic AChRs is relatively slow (milliseconds to seconds) and, depending on the subtypes present (M1- M5), they directly alter cellular homeostasis of phospholipase C, inositol trisphosphate, cAMP, and free calcium.",
       "key": "242d41d738365bf7bcdbe5d03e6d6d32a5981b8af9e55aacfb2481eaf6a51ca6823d93ef88057d35d47c6f7431d382c010b83cd73e11a4f8d75310c90a4fbd6f",
-      "line": 113,
+      "line": 117,
       "relation": "regulates",
-      "source": 207,
+      "source": 210,
       "subject": {
         "modifier": "Activity"
       },
@@ -248,6 +266,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -271,9 +292,9 @@
       },
       "evidence": "The metabotropic receptors are second messenger, G protein-coupled seven-transmembrane proteins. They are classically defined as being activated by muscarine, a toxin from the mushroom Amanita muscaria, and inhibited by atropine, a toxin from Atropa belladonna, a member of the nightshade family. Both toxins cross the blood-brain barrier poorly and were discovered primarily from their influences on postganglionic parasympathetic nervous system functions. Activation of muscarinic AChRs is relatively slow (milliseconds to seconds) and, depending on the subtypes present (M1- M5), they directly alter cellular homeostasis of phospholipase C, inositol trisphosphate, cAMP, and free calcium.",
       "key": "c98ac7c40f304d5b09238910f783d4dfe4ebfd683c94d38cde4e3a945012eebb66cac0cd8eb5d5c197001f402228767dee9040bd2ac3c377a891e896436c2e71",
-      "line": 114,
+      "line": 118,
       "relation": "regulates",
-      "source": 207,
+      "source": 210,
       "subject": {
         "modifier": "Activity"
       },
@@ -281,6 +302,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -304,9 +328,9 @@
       },
       "evidence": "The metabotropic receptors are second messenger, G protein-coupled seven-transmembrane proteins. They are classically defined as being activated by muscarine, a toxin from the mushroom Amanita muscaria, and inhibited by atropine, a toxin from Atropa belladonna, a member of the nightshade family. Both toxins cross the blood-brain barrier poorly and were discovered primarily from their influences on postganglionic parasympathetic nervous system functions. Activation of muscarinic AChRs is relatively slow (milliseconds to seconds) and, depending on the subtypes present (M1- M5), they directly alter cellular homeostasis of phospholipase C, inositol trisphosphate, cAMP, and free calcium.",
       "key": "f7654eeefea3c27d6d4d2bbba799b4183e52d87f5778a08f9c8ecc492667ac794a5a0580e644f44c366b845743ad7e23d48c6a6aab36042fa338bf79e8ee41a0",
-      "line": 115,
+      "line": 119,
       "relation": "regulates",
-      "source": 207,
+      "source": 210,
       "subject": {
         "modifier": "Activity"
       },
@@ -314,6 +338,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -337,76 +364,22 @@
       },
       "evidence": "The first was the finding that the electric organ of a fish that produces an electric pulse to stun its prey, such as Torpedo, expresses nAChRs at densities that approach a crystalline array (245, 438). This provided an unprecedented source of starting material for receptor purification since nAChRs comprise 40% of the protein from this organ.",
       "key": "c6b5ecfe66b1b2f6a5a2ff8cab89e54fea6004ecaa4b4b47ba324c593d89191a843f9861becdff882c9552de255aff187ebf2db57d67c9463342df5f3e70b160",
-      "line": 133,
+      "line": 140,
       "relation": "association",
-      "source": 208,
+      "source": 211,
       "target": 47
     },
     {
-      "annotations": {
-        "Species": {
-          "7130": true
-        },
-        "TextLocation": {
-          "Review": true
-        }
-      },
-      "citation": {
-        "authors": [
-          "Albuquerque EX",
-          "Alkondon M",
-          "Pereira EF",
-          "Rogers SW"
-        ],
-        "date": "2009-01-01",
-        "first": "Albuquerque EX",
-        "last": "Rogers SW",
-        "name": "Physiological reviews",
-        "pages": "73-120",
-        "reference": "19126755",
-        "title": "Mammalian nicotinic acetylcholine receptors: from structure to function.",
-        "type": "PubMed",
-        "volume": "89"
-      },
-      "evidence": "One insect has escaped the ill effects of nicotine, Manduca sextans or the tobacco horn worm. While nicotine binds the nAChR to activate and subsequently desensitize it, this insect eats the tobacco plant without ill effects. Manduca exhibits two adaptations to tolerate the effects of nicotine. The first is altered nAChR amino acid sequences that limit the affinity of nicotine for the nAChR (136). The second is the development of the functional equivalent to a blood-brain barrier.",
-      "key": "4c46bcff036d3aeff8cbdbc3b7fb8456b36261f198bc6753352d71614525826b7000d42bea7596d798c49966087ef87d1415bbebd54b1acb0cfa166eeb055230",
-      "line": 228,
-      "relation": "decreases",
-      "source": 208,
-      "target": 109
-    },
-    {
-      "annotations": {
-        "TextLocation": {
-          "Review": true
-        }
-      },
-      "citation": {
-        "authors": [
-          "Albuquerque EX",
-          "Alkondon M",
-          "Pereira EF",
-          "Rogers SW"
-        ],
-        "date": "2009-01-01",
-        "first": "Albuquerque EX",
-        "last": "Rogers SW",
-        "name": "Physiological reviews",
-        "pages": "73-120",
-        "reference": "19126755",
-        "title": "Mammalian nicotinic acetylcholine receptors: from structure to function.",
-        "type": "PubMed",
-        "volume": "89"
-      },
-      "evidence": "Not surprisingly, the Cys-loop is required for proper domain folding and receptor expression (131, 485). This might also be conditional, since reducing agents such as dithiothreitol (176) can disrupt the role of this structure in receptor assembly and expression.",
-      "key": "40a1f5c73ea571478c79dcada4cb385b30fd08168c3aadecf17ea6993905803fe5be6a4084fe6deff1a0e605a99139043ae900b054f546b11a3def71a3c92e84",
-      "line": 612,
-      "relation": "isA",
-      "source": 208,
-      "target": 213
+      "key": "2afcfe8e2e157deb81bc791a2d94f92f02314e1a9d9ceec689f8e0c2f9ad211fc08fab1cf759fb836f1705a83bb46382fd7d6199834b4b2c97b1231f90d98910",
+      "relation": "hasVariant",
+      "source": 211,
+      "target": 212
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -430,7 +403,7 @@
       },
       "evidence": "Third, nAChR-mediated GABA release can cause neuronal hyperpolarization, which in turn affects neuronal function via several mechanisms, including removal of inactivation of inward currents (89).",
       "key": "f06e5367e5a461ceb35f54969e0e67709b01911a7fc276f32e988ba05627d384a0bbb8497194e911a231445a6d8fb3d91aa94686a4f80e82728bd9c80318a944",
-      "line": 779,
+      "line": 852,
       "object": {
         "effect": {
           "fromLoc": {
@@ -445,11 +418,14 @@
         "modifier": "Translocation"
       },
       "relation": "increases",
-      "source": 208,
+      "source": 211,
       "target": 10
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Basal Ganglia": true
         },
@@ -476,9 +452,9 @@
       },
       "evidence": "In the basal ganglia, for instance, dopaminergic transmission is ultimately regulated by the activity of specific nAChR subtypes in different neurons and neuronal compartments (Fig. 5). Thus evidence exists that in the VTA,alpha6- andalpha4-containing nAChRs are mainly located on dopaminergic nerve terminals, whereas alpha7 nAChRs are primarily expressed on the soma of dopaminergic neurons (Fig. 5).",
       "key": "19a631d7aef441dd1e1204d89c143f69befa7712f24910e2e3345355a16a4585db67016cb7beb2a75a0883de26995b4881e33fe06ac6a57cd4b13af57f269eea",
-      "line": 847,
+      "line": 926,
       "relation": "regulates",
-      "source": 208,
+      "source": 211,
       "subject": {
         "modifier": "Activity"
       },
@@ -486,6 +462,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -509,16 +488,19 @@
       },
       "evidence": "Reduced nAChR function/expression in the brain has been associated with the pathophysiology of catastrophic disorders, including AD and schizophrenia (discussed in later sections, and see Refs. 277, 432).",
       "key": "22b1ebaf31b2c85aef2044b2ca3a0509bfdddba75e06e7ed5710912f8b71b0b89082870b88aadff657e2007282c6c5698948ba594ffc99b0bc3b8e90c08a19f8",
-      "line": 985,
+      "line": 1077,
       "relation": "negativeCorrelation",
-      "source": 208,
+      "source": 211,
       "subject": {
         "modifier": "Activity"
       },
-      "target": 220
+      "target": 225
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -542,13 +524,16 @@
       },
       "evidence": "However, loss of brain nAChRs precedes that of muscarinic receptors during normal aging, and it is often much more extensive in human brains afflicted with AD relative to age-matched controls (236, 308, 373, 374, 416, 519). In fact, alpha4 nAChR expression can decrease by >80% in the AD brain (306, 374).",
       "key": "a758030642c1ae6bb231210ff169c85bda2771618924ada5dd7476412f0d96fb38979b3a4638369949fd2cf36d8e1bdf0564f066216e622e463b588dbc55514f",
-      "line": 1614,
+      "line": 1758,
       "relation": "negativeCorrelation",
-      "source": 208,
-      "target": 220
+      "source": 211,
+      "target": 225
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Astrocytes": true
         },
@@ -575,13 +560,16 @@
       },
       "evidence": "It is noteworthy that nAChR expression by astrocytes in brains afflicted with AD is increased (463, 518), and astrocytes in general have been reported to be more plentiful in the hippocampus of some rat strains with age (35, 284).",
       "key": "3f32ba50641455897484f2bc6c844c891d8cb8d445dea820a24e945a2abd7c42de865b0c003b0634e3cc71fe799bb083fc509e27971b28bed00bc864de073706",
-      "line": 1665,
+      "line": 1813,
       "relation": "positiveCorrelation",
-      "source": 208,
-      "target": 220
+      "source": 211,
+      "target": 225
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -605,16 +593,19 @@
       },
       "evidence": "Reduced nAChR function/expression in the brain has been associated with the pathophysiology of catastrophic disorders, including AD and schizophrenia (discussed in later sections, and see Refs. 277, 432).",
       "key": "aa9e724594b19d67ae956120b97a99d5431189d24896461673d1dad45e5391aef5d1bfd856b235fd0f5663e56a035b694a92ff6715a927cd3f104890f8e82cb7",
-      "line": 986,
+      "line": 1078,
       "relation": "negativeCorrelation",
-      "source": 208,
+      "source": 211,
       "subject": {
         "modifier": "Activity"
       },
-      "target": 251
+      "target": 255
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -638,9 +629,9 @@
       },
       "evidence": "Of note is that in both of these catastrophic disorders, reduced nAChR activity/expression is accompanied by increased levels of kynurenic acid (KYNA), a tryptophan metabolite that in the brain is primarily produced and released by astrocytes (244, 419).",
       "key": "e58f40adaf0a68cc5da8d10d9dc749859fd70485416da14a092dc6ed27677b25840d11458ce852d13aa1b382a3759777ccf21d5f1c6b2206b6eb4bd80de13973",
-      "line": 1021,
+      "line": 1119,
       "relation": "negativeCorrelation",
-      "source": 208,
+      "source": 211,
       "subject": {
         "modifier": "Activity"
       },
@@ -648,6 +639,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -671,9 +665,9 @@
       },
       "evidence": "Other endogenous ligands that impact on the activity of nAChRs noncompetitively and voltage independently include the amyloid beta peptide 1-42 (Abeta1-42; Refs. 123, 376) and the canabinoid anandamide (356, 442).",
       "key": "c44c87d0a17547b203c997f71afacd7995205e0da189c6058fde3241d36209fdea51d5cd7d8fdcfa6b59d1073169c7a245bd9a1c8afe0959a6af1916428c2545",
-      "line": 1215,
+      "line": 1330,
       "relation": "association",
-      "source": 208,
+      "source": 211,
       "subject": {
         "modifier": "Activity"
       },
@@ -681,6 +675,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -704,9 +701,9 @@
       },
       "evidence": "Other endogenous ligands that impact on the activity of nAChRs noncompetitively and voltage independently include the amyloid beta peptide 1-42 (Abeta1-42; Refs. 123, 376) and the canabinoid anandamide (356, 442).",
       "key": "c6ce39cd90c5e8e3c1b0797d89753d7a605a2a02e338a4079b1aa40e7457182c0d7cb6577c772fbb28f0d3236f0c2727806fa1d1240a7e901827773d3eb15c6d",
-      "line": 1216,
+      "line": 1331,
       "relation": "association",
-      "source": 208,
+      "source": 211,
       "subject": {
         "modifier": "Activity"
       },
@@ -714,6 +711,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -737,13 +737,16 @@
       },
       "evidence": "Anandamide, a compound originally isolated from porcine brain extracts, is known to interact with canabinoid receptors 1 and 2 in the brain (120, 159). However, anandamide interacts with numerous other receptors, including voltage-gated Ca2+ channels (357), voltage-gated K+ channels (293), 5-HT3 receptors (358), kainate receptors (3), and nAChRs (356). At nanomolar concentrations, anandamine blocks noncompetitively and voltage independently the activation of alpha7 nAChRs ectopically expressed in Xenopus oocytes (356). It also inhibits the activity of alpha4beta2 nAChRs expressed in SH-EP1 cells (443).",
       "key": "6eec45fb1671ae471a3bfe7e2ec7e8e2fbd8be84e170957dcd040ae62368c2737ec7d98ed43f1b0ce4b7633492b02aecb4e640324f6864c78a61fb42452e245f",
-      "line": 1291,
+      "line": 1411,
       "relation": "association",
-      "source": 208,
+      "source": 211,
       "target": 20
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -767,16 +770,19 @@
       },
       "evidence": "It has long been recognized that nAChR activation in mammalian sympathetic neurons induces the opening of a nonselective cation channel that leads to Na+ influx, membrane depolarization, and consequently activation of voltage-gated Ca2+ channels (92, 119).",
       "key": "847104be62152ba7af370a2620585f4ed9e0d6c83541f61e3f10034e2872e8566485b990d13ebb8268da10fa103d99348aa46250620d9d4387c627e3e030aed3",
-      "line": 1336,
+      "line": 1459,
       "relation": "increases",
-      "source": 208,
+      "source": 211,
       "subject": {
         "modifier": "Activity"
       },
-      "target": 88
+      "target": 87
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -800,7 +806,7 @@
       },
       "evidence": "It has long been recognized that nAChR activation in mammalian sympathetic neurons induces the opening of a nonselective cation channel that leads to Na+ influx, membrane depolarization, and consequently activation of voltage-gated Ca2+ channels (92, 119).",
       "key": "b74cde7ea4eadd1de5a901502a35adbeda64c036e92cfe71e600d127f3eef87b520d22c303191fe36aa9419cf39e81a979ca098f51f46318360c35ab68daeebb",
-      "line": 1337,
+      "line": 1460,
       "object": {
         "location": {
           "name": "intracellular",
@@ -808,7 +814,7 @@
         }
       },
       "relation": "increases",
-      "source": 208,
+      "source": 211,
       "subject": {
         "modifier": "Activity"
       },
@@ -816,6 +822,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -839,16 +848,19 @@
       },
       "evidence": "It has long been recognized that nAChR activation in mammalian sympathetic neurons induces the opening of a nonselective cation channel that leads to Na+ influx, membrane depolarization, and consequently activation of voltage-gated Ca2+ channels (92, 119).",
       "key": "fbf361444a27bfee33e1c4d3aa8f1acc71f0cba8425a5b77580e70f81279a72f6f87a67f6985bbc9f9ea4a94702fe7cfbe3eb740ee141a25dd5a9dcdc9ea961f",
-      "line": 1338,
+      "line": 1461,
       "relation": "increases",
-      "source": 208,
+      "source": 211,
       "subject": {
         "modifier": "Activity"
       },
-      "target": 101
+      "target": 100
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -872,16 +884,19 @@
       },
       "evidence": "It has long been recognized that nAChR activation in mammalian sympathetic neurons induces the opening of a nonselective cation channel that leads to Na+ influx, membrane depolarization, and consequently activation of voltage-gated Ca2+ channels (92, 119).",
       "key": "9e5a5b982334345c7875dad34a13f83eb45a2ed5b7a3ca21fa81e9e509213af7c119862c626b5d7700d35a21d6fc23f9a729c6759c72d67675c131ec50c9a1b6",
-      "line": 1339,
+      "line": 1462,
       "relation": "increases",
-      "source": 208,
+      "source": 211,
       "subject": {
         "modifier": "Activity"
       },
-      "target": 107
+      "target": 106
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Muscles": true,
           "PC12 Cells": true,
@@ -910,7 +925,7 @@
       },
       "evidence": "Long before the identification of the high Ca2+ permeability of alpha7 nAChR channels, different studies reported significant Ca2+ influx through nAChRs in muscle, parasympathetic neurons, pheochromocytoma cells, and human neuroblastoma cells (115, 321, 347, 407, 411, 459, 468).",
       "key": "88b70c1e7cb864092506354c2cec0e8df59e265c4c3d0351608796e14c9a62d8498906f771d92c66d6f8ddafc58abe537c0dc07846129d66d9ab2425baaa492a",
-      "line": 1352,
+      "line": 1476,
       "object": {
         "location": {
           "name": "intracellular",
@@ -918,7 +933,7 @@
         }
       },
       "relation": "increases",
-      "source": 208,
+      "source": 211,
       "subject": {
         "modifier": "Activity"
       },
@@ -926,6 +941,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Skin": true
         },
@@ -952,13 +970,16 @@
       },
       "evidence": "There is current evidence that nAChRs present in skin cells modulate the responses triggered by inflammatory stimuli applied to the skin (354). Smoking is a welldefined risk factor in delayed wound healing and possibly the development of premature facial wrinkling (226).",
       "key": "27e23d065003f651cca11017c9c2e8b07dd12dc04a80237f6d29d30b1fec3576fd031ae186d941cc360b4473a1aa82ff83883de5f0692d582c80a67c605cc450",
-      "line": 1495,
+      "line": 1627,
       "relation": "regulates",
-      "source": 208,
-      "target": 98
+      "source": 211,
+      "target": 97
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Keratinocytes": true
         },
@@ -985,16 +1006,19 @@
       },
       "evidence": "Mechanistically, nicotine, acting through nAChRs, decreases keratinocyte migration (188, 189) and modifies the activity of PI3K/Akt, ERK, MEK, and JAK signaling pathways.",
       "key": "78438a82ae3ddc989e6f8642ebfd723aa0be215d388469a8716d54b54a5c6129da356bcc026e748efeef727ab4b08bc6a8c1fe706e730572e54467531439511a",
-      "line": 1509,
+      "line": 1642,
       "relation": "decreases",
-      "source": 208,
+      "source": 211,
       "subject": {
         "modifier": "Activity"
       },
-      "target": 99
+      "target": 98
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Keratinocytes": true
         },
@@ -1021,16 +1045,19 @@
       },
       "evidence": "Mechanistically, nicotine, acting through nAChRs, decreases keratinocyte migration (188, 189) and modifies the activity of PI3K/Akt, ERK, MEK, and JAK signaling pathways.",
       "key": "b2a81c7db2dcdf68f847f822e23cc202dc2f204c0fb2d01beeca427b6243da20c0efecbf40fffd056ddbcf24cfc520b571732b27e5c409fcbfa7b48aeff4bba8",
-      "line": 1510,
+      "line": 1643,
       "relation": "regulates",
-      "source": 208,
+      "source": 211,
       "subject": {
         "modifier": "Activity"
       },
-      "target": 106
+      "target": 105
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Keratinocytes": true
         },
@@ -1057,16 +1084,19 @@
       },
       "evidence": "Mechanistically, nicotine, acting through nAChRs, decreases keratinocyte migration (188, 189) and modifies the activity of PI3K/Akt, ERK, MEK, and JAK signaling pathways.",
       "key": "d8341a7d723423252bd98920458ed89208b3ac4f4db767421881102032f01ee03b0f719dc8eccf2f003ccb90075d7293ae257dec4490494a53b6956731d82b7e",
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       "subject": {
         "modifier": "Activity"
       },
-      "target": 83
+      "target": 82
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Keratinocytes": true
         },
@@ -1093,9 +1123,9 @@
       },
       "evidence": "Mechanistically, nicotine, acting through nAChRs, decreases keratinocyte migration (188, 189) and modifies the activity of PI3K/Akt, ERK, MEK, and JAK signaling pathways.",
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       "subject": {
         "modifier": "Activity"
       },
@@ -1103,6 +1133,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Cerebellum": true,
           "Corpus Striatum": true,
@@ -1135,13 +1168,16 @@
       },
       "evidence": "For instance, substantial strain-specific variability in nAChR expression has been observed in the striatum (34), retina (227), cerebellum (471), and dorsal hippocampus (164, 165, 167, 169) of mice.",
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       "relation": "association",
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       "target": 53
     },
     {
       "annotations": {
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         "TextLocation": {
           "Review": true
         }
@@ -1165,13 +1201,16 @@
       },
       "evidence": "These results suggest that mouse strains of different genetic backgrounds undergo dissimilar age-related changes in the expression of nAChR subunits.",
       "key": "1d1f60e22cfd2a90137642ab1d902d92b14f4a4c66a399bd847747ec962c5588ef32d2b79b9558951a2f8183abf6ff5a398bc02a5fcc85f7c8c2023435c154c9",
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       "relation": "association",
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       "target": 53
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Brain": true
         },
@@ -1201,13 +1240,16 @@
       },
       "evidence": "Strain-dependent variations in nAChR density in regions of the rat brain have also been reported. ",
       "key": "3a5c8dc0ddc2b960319f8d6f144e8df4704ec6d3e39c78c12b28ebb338aac6d6bbd8a1a57c4915b45174e87ca24f026914026e6081daafc017b6d39f9952609c",
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       "relation": "association",
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       "target": 57
     },
     {
       "annotations": {
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         "TextLocation": {
           "Review": true
         }
@@ -1231,43 +1273,19 @@
       },
       "evidence": "However, loss of brain nAChRs precedes that of muscarinic receptors during normal aging, and it is often much more extensive in human brains afflicted with AD relative to age-matched controls (236, 308, 373, 374, 416, 519). In fact, alpha4 nAChR expression can decrease by >80% in the AD brain (306, 374).",
       "key": "45b98b0f951d216408ddc10e41599bdb41c035d325c763f748f3348cb509383504038bec875b0045f614eae5f7ee08346c9ce81f7c071bfab61cc467f3722fe3",
-      "line": 1613,
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       "relation": "negativeCorrelation",
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-    {
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-        }
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-          "Albuquerque EX",
-          "Alkondon M",
-          "Pereira EF",
-          "Rogers SW"
-        ],
-        "date": "2009-01-01",
-        "first": "Albuquerque EX",
-        "last": "Rogers SW",
-        "name": "Physiological reviews",
-        "pages": "73-120",
-        "reference": "19126755",
-        "title": "Mammalian nicotinic acetylcholine receptors: from structure to function.",
-        "type": "PubMed",
-        "volume": "89"
-      },
-      "evidence": "The metabotropic receptors are second messenger, G protein-coupled seven-transmembrane proteins. They are classically defined as being activated by muscarine, a toxin from the mushroom Amanita muscaria, and inhibited by atropine, a toxin from Atropa belladonna, a member of the nightshade family. Both toxins cross the blood-brain barrier poorly and were discovered primarily from their influences on postganglionic parasympathetic nervous system functions. Activation of muscarinic AChRs is relatively slow (milliseconds to seconds) and, depending on the subtypes present (M1- M5), they directly alter cellular homeostasis of phospholipase C, inositol trisphosphate, cAMP, and free calcium.",
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-      "line": 108,
-      "relation": "increases",
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-      "target": 18
+      "source": 211,
+      "target": 248
     },
     {
       "annotations": {
+        "Confidence": {
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@@ -1291,46 +1309,22 @@
       },
       "evidence": "The metabotropic receptors are second messenger, G protein-coupled seven-transmembrane proteins. They are classically defined as being activated by muscarine, a toxin from the mushroom Amanita muscaria, and inhibited by atropine, a toxin from Atropa belladonna, a member of the nightshade family. Both toxins cross the blood-brain barrier poorly and were discovered primarily from their influences on postganglionic parasympathetic nervous system functions. Activation of muscarinic AChRs is relatively slow (milliseconds to seconds) and, depending on the subtypes present (M1- M5), they directly alter cellular homeostasis of phospholipase C, inositol trisphosphate, cAMP, and free calcium.",
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       "object": {
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       "source": 18,
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-          "Alkondon M",
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-        "first": "Albuquerque EX",
-        "last": "Rogers SW",
-        "name": "Physiological reviews",
-        "pages": "73-120",
-        "reference": "19126755",
-        "title": "Mammalian nicotinic acetylcholine receptors: from structure to function.",
-        "type": "PubMed",
-        "volume": "89"
-      },
-      "evidence": "The metabotropic receptors are second messenger, G protein-coupled seven-transmembrane proteins. They are classically defined as being activated by muscarine, a toxin from the mushroom Amanita muscaria, and inhibited by atropine, a toxin from Atropa belladonna, a member of the nightshade family. Both toxins cross the blood-brain barrier poorly and were discovered primarily from their influences on postganglionic parasympathetic nervous system functions. Activation of muscarinic AChRs is relatively slow (milliseconds to seconds) and, depending on the subtypes present (M1- M5), they directly alter cellular homeostasis of phospholipase C, inositol trisphosphate, cAMP, and free calcium.",
-      "key": "474d999459a3902570b87f50ec5b8264cccee7db0aac18aa7332fd7a050bad4c62edac5863987f158d9fd1f05e6105ba31cd3f1f6d1426ddd06102fe65216113",
-      "line": 110,
-      "relation": "increases",
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-      "target": 21
+      "target": 210
     },
     {
       "annotations": {
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         }
@@ -1354,16 +1348,19 @@
       },
       "evidence": "The metabotropic receptors are second messenger, G protein-coupled seven-transmembrane proteins. They are classically defined as being activated by muscarine, a toxin from the mushroom Amanita muscaria, and inhibited by atropine, a toxin from Atropa belladonna, a member of the nightshade family. Both toxins cross the blood-brain barrier poorly and were discovered primarily from their influences on postganglionic parasympathetic nervous system functions. Activation of muscarinic AChRs is relatively slow (milliseconds to seconds) and, depending on the subtypes present (M1- M5), they directly alter cellular homeostasis of phospholipase C, inositol trisphosphate, cAMP, and free calcium.",
       "key": "685738076a3d404fc3d3217b2cefb70b3f4e53c503833db7407cae2c17a2463ee4d1d3965f86528a43b1d23f7135319e0cb2737be7476f5155be16df50263214",
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       "relation": "decreases",
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-      "target": 207
+      "target": 210
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "MeSHAnatomy": {
           "Keratinocytes": true
         },
@@ -1390,16 +1387,19 @@
       },
       "evidence": "Furthermore, pharmacological dissection of nicotine’s influence on cell cycle progression, apoptosis, and differentiation (43) indicate that alpha7 nAChRs expressed in keratynocytes are important. Other receptors are clearly involved in this process, since atropine, a muscarinic and sometimes nAChR inhibitor (531, 532), reduces cell adhesion through decreasing desmoligein expression.",
       "key": "7c9ada0f6ed5e3a9e60badb73255ed66f7e483034d473f85f1548eaa0987ecbf612d3659b2a0cde7ffc88ebf9cd0d9f14c046c48a3e55513adb460cbfe094477",
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       "relation": "decreases",
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-      "target": 207
+      "target": 210
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "MeSHAnatomy": {
           "Keratinocytes": true
         },
@@ -1426,13 +1426,16 @@
       },
       "evidence": "Furthermore, pharmacological dissection of nicotine’s influence on cell cycle progression, apoptosis, and differentiation (43) indicate that alpha7 nAChRs expressed in keratynocytes are important. Other receptors are clearly involved in this process, since atropine, a muscarinic and sometimes nAChR inhibitor (531, 532), reduces cell adhesion through decreasing desmoligein expression.",
       "key": "a5d5253e795217f44f2bf155aca60489e53375f07cb92058ff0cacd3466c285e8df349cee848cccfdf446a09625ea64097d431e798075eb8f7ea13fad8f29c02",
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       "relation": "decreases",
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     },
     {
       "annotations": {
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+        },
         "TextLocation": {
           "Review": true
         }
@@ -1456,16 +1459,19 @@
       },
       "evidence": "The other subtype of AChR is the fast ionotropic cationic nicotinic receptor channel (nAChR). These receptors are sensitive to activation by nicotine and have ion channels whose activity is induced in the micro- to submicrosecond range.",
       "key": "e3419cac6f6d222b167ee791f3adb4310948c36884ec579eb9177b0825c09f04e3c94377342dccb68a0c882c0ad3ad9ec4c82434e7e186df4a03e026ed7748ba",
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       "relation": "increases",
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-      "target": 208
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     },
     {
       "annotations": {
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           "Review": true
         }
@@ -1489,7 +1495,7 @@
       },
       "evidence": "Also, the continuous exposure of cells to nicotine increases nAChR surface expression by reducing degradation of the intracellular pool of receptors (367, 394).",
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       "object": {
         "location": {
           "name": "endoplasmic reticulum",
@@ -1499,10 +1505,13 @@
       },
       "relation": "decreases",
       "source": 30,
-      "target": 208
+      "target": 211
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -1526,13 +1535,16 @@
       },
       "evidence": "In the smoker’s brain, upregulation can increase high-affinity nicotine binding by nearly fourfold relative to age- and gender-matched controls that have not been exposed to nicotine (373, 421). The mechanism by which nicotine increases the total number of high-affinity nAChRs, though poorly defined, is highly conserved among species.",
       "key": "a29737cec19543da78c6fe9ecd0e2a789880388bfcdfcbd5c267f26a6fbf71bc5b049be56ca44732880c893a21b985afb2753337e360979c0501179362d65a15",
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       "relation": "increases",
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-      "target": 208
+      "target": 211
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Keratinocytes": true
         },
@@ -1559,16 +1571,19 @@
       },
       "evidence": "Mechanistically, nicotine, acting through nAChRs, decreases keratinocyte migration (188, 189) and modifies the activity of PI3K/Akt, ERK, MEK, and JAK signaling pathways.",
       "key": "7edf1769cdd36c6efc9c0464be6e9b8552f9ca2c9815d3ff3c2cfe239422d1682c6cc6b0f3974ba9eaf17cdf95172670513aeba0a331d207571292083f70af80",
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       "relation": "increases",
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-      "target": 208
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     },
     {
       "annotations": {
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         "TextLocation": {
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         }
@@ -1592,13 +1607,16 @@
       },
       "evidence": "First, age-related nAChR subunit expression decline was observed in both strains, and this was dominated by diminished alpha4 nAChR expression. Second, long-term (12 mo) oral nicotine failed to reduce the age-related decline in the number of neurons expressing alpha4 nAChR subunits, although the neurons that remained exhibited larger processes with more varicosities than age-matched controls (165, 396). Acute nicotine treatment (alpha6 wk of oral nicotine) of aged mice had no measurable influence on nAChR expression, neuronal viability, or dendritic complexity (e.g., Ref. 396)",
       "key": "77dbb687444eb90a2e7debca7849b2b675e5a570bbb4a2edff663456a39b9096da4118070132127c372dfde2d027edcd5355f80c7917c6dcb24fb9e3b8f1bb74",
-      "line": 1655,
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       "relation": "causesNoChange",
       "source": 30,
-      "target": 208
+      "target": 211
     },
     {
       "annotations": {
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         }
@@ -1622,13 +1640,16 @@
       },
       "evidence": "Nicotine is perhaps the most addictive drug that is widely used; 95% or more of its users with a strong desire to stop using it relapse within 1 yr (47, 203). Chronic nicotine use and the phenotypes of addiction are closely associated in humans and other animals with concurrent physiological changes in nAChR function and expression",
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       "relation": "regulates",
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-      "target": 208
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     },
     {
       "annotations": {
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+        },
         "TextLocation": {
           "Review": true
         }
@@ -1652,16 +1673,19 @@
       },
       "evidence": "Nicotine is perhaps the most addictive drug that is widely used; 95% or more of its users with a strong desire to stop using it relapse within 1 yr (47, 203). Chronic nicotine use and the phenotypes of addiction are closely associated in humans and other animals with concurrent physiological changes in nAChR function and expression",
       "key": "c3ba0889836bb735a9fc37f129e4a5d1e33fd9d51f259b1d083e8fa34e118f563a9fd1483b2e00e49135ba164977a9adcacd2acccf0f7874c53e0d0b0b063653",
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       "relation": "regulates",
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-      "target": 208
+      "target": 211
     },
     {
       "annotations": {
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         "TextLocation": {
           "Review": true
         }
@@ -1685,13 +1709,16 @@
       },
       "evidence": "One insect has escaped the ill effects of nicotine, Manduca sextans or the tobacco horn worm. While nicotine binds the nAChR to activate and subsequently desensitize it, this insect eats the tobacco plant without ill effects. Manduca exhibits two adaptations to tolerate the effects of nicotine. The first is altered nAChR amino acid sequences that limit the affinity of nicotine for the nAChR (136). The second is the development of the functional equivalent to a blood-brain barrier.",
       "key": "5722440da30529f45ab62cab27cb22acf369a68fcc5b894bf617807754944433fa0804b4b6ff8c0942732e65111e8fa69d2fd66fd085737b20b6b35c77cfdba5",
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+      "line": 243,
       "relation": "causesNoChange",
       "source": 30,
       "target": 70
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -1715,13 +1742,16 @@
       },
       "evidence": "Metabolic degradation of nicotine and rapid clearance is a mechanism that protects neurons from greater nicotine concentrations, since nicotine readily crosses the mammalian blood-brain barrier and accumulates in the lipophilic brain environment to concentrations that may exceed plasma concentrations by one order of magnitude. Nevertheless, neurotoxicity to nicotine is not uncommon, as attested to by the recent increase in hospital emergency room visits by smokers who concurrently use the transdermal nicotine patch (503).",
       "key": "12f678c6ba18f7ab369214312e200b14fa30eb7610e6646f3ae32fc0ebd57302ce65fdb678b0d99d1848b53cbe79e3cc4317687738fabb4bff7b6072f890b75e",
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       "relation": "association",
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-      "target": 219
+      "target": 224
     },
     {
       "annotations": {
+        "Confidence": {
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+        },
         "TextLocation": {
           "Review": true
         }
@@ -1745,13 +1775,16 @@
       },
       "evidence": "The receptor that exhibits the greatest upregulation when exposed to nicotine is the alpha4beta2 nAChR. Receptors assembled from this subunit combination form the highaffinity nicotine binding site (151, 215) and account for the vast majority of upregulated sites in the brain of smokers (55).",
       "key": "1242ab1ebab07922de709922f2ed098aa7fd29d4d94ec8b96da7fe210027924e13007748f973bc850082ab080540688d0b77faa8c6e89cb759c6e22202691627",
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       "relation": "increases",
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-      "target": 168
+      "target": 171
     },
     {
       "annotations": {
+        "Confidence": {
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+        },
         "TextLocation": {
           "Review": true
         }
@@ -1775,13 +1808,16 @@
       },
       "evidence": "transfection of cells with the beta4 and alpha2 nAChR subunits or expression of these in Xenopus oocytes leads to high-affinity nicotine-binding receptors that upregulate in response to prolonged exposure to nicotine (113, 184, 215).",
       "key": "11690486fe254cb8a8647d511351459edb289e4ddeea1d97dc9919ae06e8edbd4a43a6b26ca49764d2deb901438e4cf6f7963796bfa9c0fe04c85bc31abb30a6",
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       "relation": "increases",
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-      "target": 168
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     },
     {
       "annotations": {
+        "Confidence": {
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+        },
         "TextLocation": {
           "Review": true
         }
@@ -1805,13 +1841,16 @@
       },
       "evidence": "In particular, repeated self-administration produces the upregulation of high-affinity (alpha4beta2) nAChR expression, reduces receptor function due to desensitization and, in most cases, imparts developmental tolerance. Additional changes imposed by nicotine abuse range from reinforcement to physical discomfort associated with withdrawal including craving, anxiety, and a multitude of other less than desirable sensations of autonomic dysfunction when use is stopped.",
       "key": "190b3098fa9c23f63dca72dfad88791ae6689f93d279424cf70d4145fe0e710767086417b03b0cd7b59ea3522bfc885db480d6346ec6143505f31cb74bfb387f",
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       "relation": "increases",
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-      "target": 168
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     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -1835,16 +1874,19 @@
       },
       "evidence": "In particular, repeated self-administration produces the upregulation of high-affinity (alpha4beta2) nAChR expression, reduces receptor function due to desensitization and, in most cases, imparts developmental tolerance. Additional changes imposed by nicotine abuse range from reinforcement to physical discomfort associated with withdrawal including craving, anxiety, and a multitude of other less than desirable sensations of autonomic dysfunction when use is stopped.",
       "key": "442840984dad3781f8d14322d0f487b54d269e67e7cece42777a6cc07f80363ff2d21527fc51fcfcbd4e30675750b8baa56a9795a9c0f9dfd44b46672d12b60d",
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       "object": {
         "modifier": "Activity"
       },
       "relation": "decreases",
       "source": 30,
-      "target": 168
+      "target": 171
     },
     {
       "annotations": {
+        "Confidence": {
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+        },
         "TextLocation": {
           "Review": true
         }
@@ -1868,16 +1910,19 @@
       },
       "evidence": "The receptor that exhibits the greatest upregulation when exposed to nicotine is the alpha4beta2 nAChR. Receptors assembled from this subunit combination form the highaffinity nicotine binding site (151, 215) and account for the vast majority of upregulated sites in the brain of smokers (55).",
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       "relation": "increases",
       "source": 30,
-      "target": 124
+      "target": 127
     },
     {
       "annotations": {
         "CellLine": {
           "HEK293": true
         },
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -1901,7 +1946,7 @@
       },
       "evidence": "For instance, prolonged exposure of HEK293 cells to saturating nicotine concentrations increased by 6- and 1.5-fold, respectively, the expression of alpha3beta2 and alpha3beta4 nAChRs.Similarly, while alpha4beta2 nAChRs upregulate strongly, alpha4beta4 nAChRs upregulate poorly in response to continuous exposure to nicotine.",
       "key": "9d9a0e8374ba7539fca542a677da8b0f99edf785946a20cabad1ab8b9e540f0894252b3c89a644f489620a02b3229467b1aa39f5dcb284348fe530c9385d67cb",
-      "line": 721,
+      "line": 785,
       "relation": "increases",
       "source": 30,
       "target": 34
@@ -1911,6 +1956,9 @@
         "CellLine": {
           "HEK293": true
         },
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -1934,13 +1982,16 @@
       },
       "evidence": "For instance, prolonged exposure of HEK293 cells to saturating nicotine concentrations increased by 6- and 1.5-fold, respectively, the expression of alpha3beta2 and alpha3beta4 nAChRs.Similarly, while alpha4beta2 nAChRs upregulate strongly, alpha4beta4 nAChRs upregulate poorly in response to continuous exposure to nicotine.",
       "key": "36811b36ac18c77f4132fe67bf52417f6d53ff2595a7106445dd3bf66597178ee38de6594bc4465a691571ea31acb8af5949c91111d6fd28f1da30c0769523e8",
-      "line": 722,
+      "line": 786,
       "relation": "increases",
       "source": 30,
       "target": 35
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "MeSHAnatomy": {
           "Brain": true
         },
@@ -1971,13 +2022,16 @@
       },
       "evidence": "Prolonged treatment of rodents and monkeys with nicotine downregulates the expression of alpha6beta3-containing nAChRs in the brain (257, 311, 332). However, in heterologous culture systems, nicotine appears to upregulate the expression of receptors assembled from alpha4/alpha6/beta2/beta3 input cDNA (363), and this may depend on numerous factors including ligand concentrations (483).",
       "key": "a1489f41719c186076d044653b3a0cb82a063fa6fb92b4bb21559e3aa1a61d3f24a1a4f331710f5879675735074570c44c13f5f81f1fd3d040eb731a2fe4a46e",
-      "line": 738,
+      "line": 803,
       "relation": "decreases",
       "source": 30,
-      "target": 142
+      "target": 145
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Central Nervous System": true,
           "Parasympathetic Nervous System": true
@@ -2005,16 +2059,19 @@
       },
       "evidence": "An ever-growing body of evidence indicates that in CNS and parasympathetic nervous system neurons and in heterologous systems expressing specific nAChR subtypes, nicotine stimulates several Ca2+-dependent kinases, including PI3K, protein kinase C (PKC), protein kinase A (PKA), calmodulin-dependent protein kinase II (CAM kinase II), and extracellular signal-regulated kinases (ERKs; Refs. 108, 112, 146, 318, 469).",
       "key": "e732865b3c475f4cf4d6c34cd191a7c6893c483eee016a8b0af000a1a097f276d366560037fee69a6ef87ae47651748693934aa10f9f4d62c630d85fe50d4565",
-      "line": 1378,
+      "line": 1504,
       "object": {
         "modifier": "Activity"
       },
       "relation": "increases",
       "source": 30,
-      "target": 162
+      "target": 166
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Central Nervous System": true,
           "Parasympathetic Nervous System": true
@@ -2042,16 +2099,19 @@
       },
       "evidence": "An ever-growing body of evidence indicates that in CNS and parasympathetic nervous system neurons and in heterologous systems expressing specific nAChR subtypes, nicotine stimulates several Ca2+-dependent kinases, including PI3K, protein kinase C (PKC), protein kinase A (PKA), calmodulin-dependent protein kinase II (CAM kinase II), and extracellular signal-regulated kinases (ERKs; Refs. 108, 112, 146, 318, 469).",
       "key": "a4b1f3c518035a109281d0c106d8f280f05eef079bbe0b4b65fd9a43eded0e60f4a4d5ef210176526d7d9b17ff0d83b6af55e0af9be7a2c1a5c65b56ebc6f91e",
-      "line": 1379,
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       "object": {
         "modifier": "Activity"
       },
       "relation": "increases",
       "source": 30,
-      "target": 163
+      "target": 167
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Central Nervous System": true,
           "Parasympathetic Nervous System": true
@@ -2079,16 +2139,19 @@
       },
       "evidence": "An ever-growing body of evidence indicates that in CNS and parasympathetic nervous system neurons and in heterologous systems expressing specific nAChR subtypes, nicotine stimulates several Ca2+-dependent kinases, including PI3K, protein kinase C (PKC), protein kinase A (PKA), calmodulin-dependent protein kinase II (CAM kinase II), and extracellular signal-regulated kinases (ERKs; Refs. 108, 112, 146, 318, 469).",
       "key": "f69760c1d6b7a6a6aa3e5e30b21f78e6384ac3dc170bcb4afd8e3df4fc6b81a9f6e457caf7490f83add36e64d5fd86bc18fe450a3559b141d84aeba35d2e27d4",
-      "line": 1380,
+      "line": 1506,
       "object": {
         "modifier": "Activity"
       },
       "relation": "increases",
       "source": 30,
-      "target": 164
+      "target": 168
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Central Nervous System": true,
           "Parasympathetic Nervous System": true
@@ -2116,16 +2179,19 @@
       },
       "evidence": "An ever-growing body of evidence indicates that in CNS and parasympathetic nervous system neurons and in heterologous systems expressing specific nAChR subtypes, nicotine stimulates several Ca2+-dependent kinases, including PI3K, protein kinase C (PKC), protein kinase A (PKA), calmodulin-dependent protein kinase II (CAM kinase II), and extracellular signal-regulated kinases (ERKs; Refs. 108, 112, 146, 318, 469).",
       "key": "9ac0e3d863d40f86f4a38b90dd836b4401cc9b877a73296803e82514113165fafda550aa1b8a715d24d184807e0e938ef118dc33238410d0de3cd5e5f91229b3",
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       "object": {
         "modifier": "Activity"
       },
       "relation": "increases",
       "source": 30,
-      "target": 160
+      "target": 164
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "MeSHAnatomy": {
           "PC12 Cells": true
         },
@@ -2151,9 +2217,13 @@
         "volume": "89"
       },
       "evidence": "Downstream from the nicotine-stimulated kinases, a number of transcription factors have been shown to be activated. Among these factors are the cAMP response element binding protein (CREB) and the activating transcription factor 2 (ATF-2) in PC12 cells (211, 337, 460), the Ets-like transcription factor Elk-1 in the rat hippocampus (349), and the signal transducer and activator of transcription (STAT3) in macrophages and skin cells (114, 354).",
-      "key": "cd86a1c89ae5c28c1a9d8bc353c447ab7d4c0e8342360ddd22e1db9590be49cdef37a8dc5803bccb847ccccfb8cda69b306ea51632f0818bc3d135029a98abd6",
-      "line": 1397,
+      "key": "e3801bc8a59512f2fa312bcc141abf94f58e32a1c7a1dc653d21f6747b712bcf4e456c0d886575ab3af2a7fac08eb31cd43c728800dde33fbe6be80d20966556",
+      "line": 1524,
       "object": {
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+          "name": "tscript",
+          "namespace": "bel"
+        },
         "modifier": "Activity"
       },
       "relation": "increases",
@@ -2161,10 +2231,13 @@
       "subject": {
         "modifier": "Activity"
       },
-      "target": 161
+      "target": 165
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "MeSHAnatomy": {
           "PC12 Cells": true
         },
@@ -2190,9 +2263,13 @@
         "volume": "89"
       },
       "evidence": "Downstream from the nicotine-stimulated kinases, a number of transcription factors have been shown to be activated. Among these factors are the cAMP response element binding protein (CREB) and the activating transcription factor 2 (ATF-2) in PC12 cells (211, 337, 460), the Ets-like transcription factor Elk-1 in the rat hippocampus (349), and the signal transducer and activator of transcription (STAT3) in macrophages and skin cells (114, 354).",
-      "key": "6d5b9c118ed45979556a51cec7f1dd70fceb8ec37c995f3f74b1db278a43a9205a4a6fd8ab6b534b7a1751eaeb038291913cbf4a8240c69c7ec77dc192625a47",
-      "line": 1398,
+      "key": "bea67ad5dd2dbd5d9527d7b0cd4d5d039a85f0d71cd87f7aae62af66dda4feaa147f2cac609191b899a091bea3a6c22a05932b29f5e189e9ced4a21f0d838012",
+      "line": 1525,
       "object": {
+        "effect": {
+          "name": "tscript",
+          "namespace": "bel"
+        },
         "modifier": "Activity"
       },
       "relation": "increases",
@@ -2200,10 +2277,13 @@
       "subject": {
         "modifier": "Activity"
       },
-      "target": 176
+      "target": 179
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "MeSHAnatomy": {
           "Hippocampus": true
         },
@@ -2232,9 +2312,13 @@
         "volume": "89"
       },
       "evidence": "Downstream from the nicotine-stimulated kinases, a number of transcription factors have been shown to be activated. Among these factors are the cAMP response element binding protein (CREB) and the activating transcription factor 2 (ATF-2) in PC12 cells (211, 337, 460), the Ets-like transcription factor Elk-1 in the rat hippocampus (349), and the signal transducer and activator of transcription (STAT3) in macrophages and skin cells (114, 354).",
-      "key": "c59b5ad95fe3bc8e8e2877d98834f604798ed0e86acbd2b692400d92c8478fd4315ff26e52172136333ffc8a46a09f57da28755702f65e9a1f17467627743f2c",
-      "line": 1405,
+      "key": "f8049c1baf4db024bc0911396ca0e9627997ac5e053a7f985083f334f35881ae79ba75c896da54422cf737af6f87353e0eee31c6737a6ea8628708c97bdc58de",
+      "line": 1532,
       "object": {
+        "effect": {
+          "name": "tscript",
+          "namespace": "bel"
+        },
         "modifier": "Activity"
       },
       "relation": "increases",
@@ -2242,10 +2326,13 @@
       "subject": {
         "modifier": "Activity"
       },
-      "target": 217
+      "target": 222
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "MeSHAnatomy": {
           "Macrophages": true,
           "Skin": true
@@ -2272,9 +2359,13 @@
         "volume": "89"
       },
       "evidence": "Downstream from the nicotine-stimulated kinases, a number of transcription factors have been shown to be activated. Among these factors are the cAMP response element binding protein (CREB) and the activating transcription factor 2 (ATF-2) in PC12 cells (211, 337, 460), the Ets-like transcription factor Elk-1 in the rat hippocampus (349), and the signal transducer and activator of transcription (STAT3) in macrophages and skin cells (114, 354).",
-      "key": "781d07729c17705b7b240104ad0d9d0e7321566bf5e80540e0e8f0f3f7ae4aaaadb8bb4263b992612366c873b27286c47f9eaa7b0d9a66910d46a89ae984e0fd",
-      "line": 1412,
+      "key": "f6eac2c8e58a86f136895c0baabf882255f3037a4eedd2c2f290c68dea89f271f0dd1ff12bcf25e3fe2414caaea3b442b39f0be4fa1285dc768be652ff07135a",
+      "line": 1539,
       "object": {
+        "effect": {
+          "name": "tscript",
+          "namespace": "bel"
+        },
         "modifier": "Activity"
       },
       "relation": "increases",
@@ -2282,10 +2373,13 @@
       "subject": {
         "modifier": "Activity"
       },
-      "target": 205
+      "target": 208
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Skin": true
         },
@@ -2312,7 +2406,7 @@
       },
       "evidence": "Recent studies have supported a role for ERK and CREB activity in neural plasticity associated with nicotine addiction (71, 381, 484). It has also been proposed that the ERK and JAK-2/STAT-3 signaling pathways contribute to the toxic effects of nicotine in skin cells (42), and other pathways contribute to the effects of nicotine and other nicotinic ligands on inflammatory responses as described below.",
       "key": "6e2207204b48da5b39848323db135ce339df06b6000e03f6ea664a8c44816f5aa2b707ae27dcfd89df6507ed499044c217dae5063e6b7bada5da8a6dd3105c25",
-      "line": 1434,
+      "line": 1562,
       "relation": "association",
       "source": 30,
       "subject": {
@@ -2322,6 +2416,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Intestines": true
         },
@@ -2348,16 +2445,19 @@
       },
       "evidence": "Modulation by nicotine of inflammatory responses in the intestines is much better reported. Early studies found that patients with ulcerative colitis who stopped smoking tobacco developed the disease or exhibited more severe disease progression, which was ameliorated by either returning to smoking (58, 401, 466), or, in some cases, administering nicotine through transdermal patches (313).In contrast, patients with Crohn’s disease experience much more severe disease when smoking (401).",
       "key": "5fa0c099ac65176f9deda39ea7142b2acda0be9f42a0cdd62851518d57f9cbfee624fdfbc5dbe4727bdcacd1dc8c99f262f99b3d54970958e35981f80bccb2c3",
-      "line": 1463,
+      "line": 1593,
       "relation": "regulates",
       "source": 30,
       "subject": {
         "modifier": "Activity"
       },
-      "target": 98
+      "target": 97
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Intestines": true
         },
@@ -2384,13 +2484,16 @@
       },
       "evidence": "Modulation by nicotine of inflammatory responses in the intestines is much better reported. Early studies found that patients with ulcerative colitis who stopped smoking tobacco developed the disease or exhibited more severe disease progression, which was ameliorated by either returning to smoking (58, 401, 466), or, in some cases, administering nicotine through transdermal patches (313).In contrast, patients with Crohn’s disease experience much more severe disease when smoking (401).",
       "key": "70ba0dc08e0dbd1bf0c7bc93dbe85b11d50376cbda343fc208c150eccd6023ae1ccdeaaef2525ba392d56c4eb5b8c274e957b263911b2fd529d4112473a66b00",
-      "line": 1465,
+      "line": 1595,
       "relation": "decreases",
       "source": 30,
-      "target": 223
+      "target": 228
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Species": {
           "10090": true
         },
@@ -2417,13 +2520,16 @@
       },
       "evidence": "Notably, mice with a null mutation in the gene that encodes the alpha5 nAChR subunit exhibit enhanced sensitivity to induction of inflammatory bowel disease relative to controls (353). Despite increased sensitivity to disease initiation, administration of transdermal nicotine remains effective in attenuating the disease process. Therefore, again nicotine appears to impact on inflammatory processes with considerable specificity and tissue dependency.",
       "key": "7a1d9430f8dda12dbe8377e9180ae532b91f425250cfdf579b1aa9ecc25e53e2cf88706e7e339d41e1a6c9c2b9787339c09b6818224a579c400685dbaee56495",
-      "line": 1483,
+      "line": 1614,
       "relation": "decreases",
       "source": 30,
-      "target": 229
+      "target": 233
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Adipocytes": true
         },
@@ -2453,7 +2559,7 @@
       },
       "evidence": "Notably, nicotine pretreatment of rat adipocytes (279) reduces the release of TNF-alpha as well as free fatty acids and the adipokine adiponectin (whose function is not known, although its levels change in metabolic syndrome).",
       "key": "f62176a0bd591915286d034997cea5927b5781bd5d3dd7d81e97bdb6e5bd7174def4cf95783ce00705d79797adafa3f093a467067fc5f857512ec357517ef44e",
-      "line": 1551,
+      "line": 1690,
       "object": {
         "effect": {
           "fromLoc": {
@@ -2469,10 +2575,13 @@
       },
       "relation": "decreases",
       "source": 30,
-      "target": 206
+      "target": 209
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Species": {
           "10090": true
         },
@@ -2499,16 +2608,19 @@
       },
       "evidence": "Mice are particularly well-defined for their strain-specific complex genetic traits related to the effects of nicotine (105, 302) and morphological variations in the brain (e.g., Refs. 166, 167, 169).",
       "key": "df38e72ec5a5ab8b5b1cde7b9c723938b8818e32cc7ff7e3c9141ef098883c4c2bc1c19959e9dc75e46d98c6303a46119efa6fccaab365820af08523b449e6ca",
-      "line": 1563,
+      "line": 1703,
       "relation": "association",
       "source": 30,
       "subject": {
         "modifier": "Activity"
       },
-      "target": 227
+      "target": 232
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -2532,13 +2644,16 @@
       },
       "evidence": "In human trials, nicotine showed little efficacy in ameliorating AD symptoms (437). However, treatment was initiated after diagnosis of symptoms, and there is both epidemiological data and direct evidence from animal models that this is too late (106, 346, 396).",
       "key": "88045d78f07d726adb62e167cbf6326c3fe59abe953950164665a5866d99365e8608ed252df9cbc3e209116ee6ca0ecbd431d2cd9a5960bd976e11958a902514",
-      "line": 1638,
+      "line": 1784,
       "relation": "causesNoChange",
       "source": 30,
-      "target": 220
+      "target": 225
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -2562,13 +2677,16 @@
       },
       "evidence": "First, age-related nAChR subunit expression decline was observed in both strains, and this was dominated by diminished alpha4 nAChR expression. Second, long-term (12 mo) oral nicotine failed to reduce the age-related decline in the number of neurons expressing alpha4 nAChR subunits, although the neurons that remained exhibited larger processes with more varicosities than age-matched controls (165, 396). Acute nicotine treatment (alpha6 wk of oral nicotine) of aged mice had no measurable influence on nAChR expression, neuronal viability, or dendritic complexity (e.g., Ref. 396)",
       "key": "f985b42981cc93472adb494fb57027df4c715cae3ebb44d66c8b84ba2925a0fd6ec321ae1da313ec0ab0ca719f1b5ac06d659222278fbe64df8d47deea6b0ad6",
-      "line": 1654,
+      "line": 1801,
       "relation": "causesNoChange",
       "source": 30,
-      "target": 214
+      "target": 219
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -2592,7 +2710,7 @@
       },
       "evidence": "A link between alpha4 nAChRs and Cox2 was suggested by the observation that interneurons in the hippocampus coexpress both proteins (165). A mechanistic connection was inferred when long-term treatment of aged animals with NS398 promoted retention of alpha4 nAChR expression in the brain, an effect that was antagonized by the coadministration of nicotine.",
       "key": "eb2ac3d61786c0d56308cbb197fc5d08a9f437e6c4e4b1bfbbb157907553d7fb351f57f8a8eccabbc65d3c285add6c81b8ec265a8705db21a559880c469705e3",
-      "line": 1732,
+      "line": 1887,
       "object": {
         "modifier": "Activity"
       },
@@ -2602,6 +2720,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Parkinson Disease": true
         },
@@ -2628,13 +2749,16 @@
       },
       "evidence": "More direct evidence of the protective effects of nicotine in this disease process comes from studies in primates, where oral nicotine reduces the nigrostriatal neuronal loss observed in chemically induced PD (384, 385).",
       "key": "a8394b012a3fe5b7829eee1540c09ed906ea3a40566315c1a32f109ad24683bdf8534e83d1f6c21dc5b35752235ac13f2f5f1d86d05556ba77b227db264d8187",
-      "line": 1764,
+      "line": 1922,
       "relation": "decreases",
       "source": 30,
-      "target": 102
+      "target": 101
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Corpus Striatum": true
         },
@@ -2661,13 +2785,16 @@
       },
       "evidence": "However, in rodent and nonprimate animal models, nicotine has been shown to enhance striatal dopamine release and to prevent toxin-induced degeneration of dopaminergic neurons (384, 385).",
       "key": "b61db4d6c4677cf1f4dbc5c77841f17d2554ef71dbc771f5a77b811ccfd11dcaf9705081906a9fb17966a41795ac2a34f1af5656251dc3d92a4ef2adc1e03c1e",
-      "line": 1776,
+      "line": 1935,
       "relation": "decreases",
       "source": 30,
-      "target": 102
+      "target": 101
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Corpus Striatum": true
         },
@@ -2694,7 +2821,7 @@
       },
       "evidence": "However, in rodent and nonprimate animal models, nicotine has been shown to enhance striatal dopamine release and to prevent toxin-induced degeneration of dopaminergic neurons (384, 385).",
       "key": "0ed4e2ebaa9afb43daf1a0832108823b530f8f1eaed813e23a409e8e2d9097e12ded2f862b4c4ddd3d9952e76e94ca524255ad7317bfbdce8418cfbefea5eb7e",
-      "line": 1775,
+      "line": 1934,
       "object": {
         "effect": {
           "fromLoc": {
@@ -2714,6 +2841,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -2737,13 +2867,16 @@
       },
       "evidence": "Nicotine is perhaps the most addictive drug that is widely used; 95% or more of its users with a strong desire to stop using it relapse within 1 yr (47, 203). Chronic nicotine use and the phenotypes of addiction are closely associated in humans and other animals with concurrent physiological changes in nAChR function and expression",
       "key": "c0538a95f9a7cbb42beaf872c13ea6b284fb67a50054138e50b00df91dbb2f3107a7cafa6ff5552268c2206eb15725f547d51dadf19cc516d2d136dbcc1525c6",
-      "line": 1787,
+      "line": 1947,
       "relation": "increases",
       "source": 30,
-      "target": 221
+      "target": 226
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -2767,13 +2900,16 @@
       },
       "evidence": "In particular, repeated self-administration produces the upregulation of high-affinity (alpha4beta2) nAChR expression, reduces receptor function due to desensitization and, in most cases, imparts developmental tolerance. Additional changes imposed by nicotine abuse range from reinforcement to physical discomfort associated with withdrawal including craving, anxiety, and a multitude of other less than desirable sensations of autonomic dysfunction when use is stopped.",
       "key": "c50e178faf47a089d15eb146a95fdc190e3c4f37278e2f0508e550cab9403aeeff32711a03cbdad307d9611b3f9bc5ce2d651909cdf3cf146b30631c863a14ae",
-      "line": 1803,
+      "line": 1964,
       "relation": "increases",
       "source": 30,
-      "target": 246
+      "target": 250
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -2797,13 +2933,16 @@
       },
       "evidence": "In particular, repeated self-administration produces the upregulation of high-affinity (alpha4beta2) nAChR expression, reduces receptor function due to desensitization and, in most cases, imparts developmental tolerance. Additional changes imposed by nicotine abuse range from reinforcement to physical discomfort associated with withdrawal including craving, anxiety, and a multitude of other less than desirable sensations of autonomic dysfunction when use is stopped.",
       "key": "aebedbdd9c97dd8396cc48fd9ed4fba1979ed2230739c831f1513db150b3e32aed969eefd25907fa31e1203b67b5d163078aabb3fdd8885433485ed0b5511621",
-      "line": 1804,
+      "line": 1965,
       "relation": "increases",
       "source": 30,
-      "target": 245
+      "target": 249
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Seizures": true
         },
@@ -2830,16 +2969,19 @@
       },
       "evidence": "A principle component of genetic analysis of the contribution of alpha7 and alpha4beta2 nAChRs to the effects of nicotine was reported 15 years ago. The number of alpha-BGT binding sites (presumably alpha7 nAChRs) was shown to be highly correlated with sensitivity to nicotinic-induced seizures (105, 301, 303).",
       "key": "041a319a999f835bf0f889eb536264dedd2013238b210d7d5415ee60e09aec12ea59f1f959e59455117fab32955efe00878d57c737851581245c72f8cfc8b0c4",
-      "line": 1815,
+      "line": 1977,
       "object": {
         "modifier": "Activity"
       },
       "relation": "association",
       "source": 30,
-      "target": 186
+      "target": 189
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -2863,13 +3005,16 @@
       },
       "evidence": "The concept that beta2-containing nAChRs are involved in the reinforcing effects of nicotine was supported by the findings that these mice lacked the high-affinity nicotine binding site, exhibited poor nicotine self-administration, and failed to develop behaviors related to reinforcement (378). The demonstration that these mice developed symptoms of the nicotine withdrawal syndrome similar to those observed in wild-type mice led to the conclusion that beta2-containing nAChRs do not contribute to the physical dependence on nicotine (57).",
       "key": "2dc535ff2785469ab0091b0559020b0afa459b7ca8811c7aca985042eea67a84db7ebacfef2081750fc58cf89bb5fb0653f1cb99e97bdd24a7be1623b058b1f9",
-      "line": 1831,
+      "line": 1994,
       "relation": "association",
       "source": 30,
       "target": 40
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -2893,13 +3038,16 @@
       },
       "evidence": "The first was the finding that the electric organ of a fish that produces an electric pulse to stun its prey, such as Torpedo, expresses nAChRs at densities that approach a crystalline array (245, 438). This provided an unprecedented source of starting material for receptor purification since nAChRs comprise 40% of the protein from this organ.",
       "key": "c7bd5871e2e7ab3925066cd77c3dcc1c116d15496135776ae1b61182db2ac40be6374b49ca1ed24e545d299b0be41ad8f259261f3b817c3f6e34288ce367da41",
-      "line": 133,
+      "line": 140,
       "relation": "association",
       "source": 47,
-      "target": 208
+      "target": 211
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -2923,16 +3071,19 @@
       },
       "evidence": "The second was the discovery of alpha-bungarotoxin (alpha-BGT), a component of krait snake venom that binds muscle-type nAChRs with near covalent affinity to inhibit their function and promote debilitating paralysis at the neuromuscular junction (6, 50, 149, 264).",
       "key": "f58df4858ad3715296f54e7a7f913cee8fb0d1772f17aea000f6b3661842cea8a6ce3eb8c325165012525622292803a69a1ecbab55f3bd73bcfffab72702b923",
-      "line": 141,
+      "line": 149,
       "object": {
         "modifier": "Activity"
       },
       "relation": "decreases",
       "source": 38,
-      "target": 208
+      "target": 211
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -2956,13 +3107,16 @@
       },
       "evidence": "The most valuable of these toxins to researchers proved to be alpha-BGT from the snake Bungarus multicinctus. Because this toxin binds to the muscle nAChR with great specificity and a near-covalent affinity, it was an invaluable tool in the purification of the first nAChRs (discussed above).",
       "key": "088d1ba47a570ce1c34dcf03a5073e2dbcf0de3e8c66e8fe5d9c407434141c42533e1f22ae3cdc516bcf192321b7c0aa890988ecc09a74caee993517d9f9e4a1",
-      "line": 254,
+      "line": 278,
       "relation": "increases",
       "source": 38,
-      "target": 125
+      "target": 128
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Corpus Striatum": true
         },
@@ -2992,7 +3146,7 @@
       },
       "evidence": "Activation of alpha7 nAChRs is known to contribute to the regulation of extracellular dopamine levels in the rat striatum (81). Application via microdialysis of KYNA or alpha-BGT to the rat striatum significantly reduces the extracellular levels of dopamine, and the magnitude of the effect of either antagonist alone is comparable to that of both antagonists together (285).",
       "key": "11350ab414eebc8c5c7bd095641eb63382fa1705d72ff0eb21c0c8f2839423ac24457d0f97afbb65892009ac39d87a42819516eea33241e74303b1154be54e3f",
-      "line": 1151,
+      "line": 1259,
       "object": {
         "location": {
           "name": "extracellular region",
@@ -3005,6 +3159,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -3028,13 +3185,16 @@
       },
       "evidence": "From the time of its discovery in 1914 by Henry H. Dale (109) and Otto Loewi (283) (the two shared the Nobel Prize in Physiology and Medicine in 1936) as an agent that decreases heart rate, ACh was recognized as an endogenous signaling compound, synthesized from choline and acetyl-CoA, through the action of choline acetyltransferase, that alters cell function.",
       "key": "0c3af58959fb2f81f4b15864b0376865f1baa90451e1c4be226c8ab66ea1580fe1653c0398c9b72359e70b63186d0d0069666fc68f586a473a53f27ab85d8959",
-      "line": 152,
+      "line": 162,
       "relation": "association",
       "source": 116,
       "target": 19
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -3058,34 +3218,37 @@
       },
       "evidence": "From the time of its discovery in 1914 by Henry H. Dale (109) and Otto Loewi (283) (the two shared the Nobel Prize in Physiology and Medicine in 1936) as an agent that decreases heart rate, ACh was recognized as an endogenous signaling compound, synthesized from choline and acetyl-CoA, through the action of choline acetyltransferase, that alters cell function.",
       "key": "42bbe1a8ec2ee015b5b9ae2b440c88b5331eef9b6547fb680cbfacd31c74fbb58798aaf9e88f9cb917b2c5d3fbdc459e1429ca63740808212aa13a0af25cd2a8",
-      "line": 153,
+      "line": 163,
       "relation": "directlyIncreases",
-      "source": 178,
+      "source": 181,
       "subject": {
         "modifier": "Activity"
       },
-      "target": 266
+      "target": 271
     },
     {
       "key": "b7a4038970fcc90b38a886ddfc984321f4602a9d4e8ea04407efe739116a29dbbf69e25e6a86466da85ff080d45a78e87339f82d93511faecc27812ee2b24f56",
       "relation": "hasReactant",
-      "source": 266,
+      "source": 271,
       "target": 5
     },
     {
       "key": "0dfcd2b8ee4ab08b59dfb48bdf0dde698ada7e0c914debad30a5142030ab1f39b23aadaee50f095bce2454d169da52c511557f5d3ba368c0926911eb51cd78cf",
       "relation": "hasReactant",
-      "source": 266,
+      "source": 271,
       "target": 23
     },
     {
       "key": "648351a9cc77a8bc75462b2eeb17d36f2a93437a782f4899e188773b46b6e2475a9047a343b6c6d1db928666d1c661358ffa6cf67feaa5a372fe7d53a87ea260",
       "relation": "hasProduct",
-      "source": 266,
+      "source": 271,
       "target": 19
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -3109,13 +3272,16 @@
       },
       "evidence": "However, loss of brain nAChRs precedes that of muscarinic receptors during normal aging, and it is often much more extensive in human brains afflicted with AD relative to age-matched controls (236, 308, 373, 374, 416, 519). In fact, alpha4 nAChR expression can decrease by >80% in the AD brain (306, 374).",
       "key": "aeb02ee83182188df674de6aff4eb9f768ebefb0f5d0052c1575bd50900b4b545af14f704390ae737d3c2cf41d93d3da58a11a308f77c8c87ba6de7d075014a1",
-      "line": 1615,
+      "line": 1759,
       "relation": "negativeCorrelation",
-      "source": 183,
-      "target": 220
+      "source": 186,
+      "target": 225
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -3139,13 +3305,52 @@
       },
       "evidence": "A link between alpha4 nAChRs and Cox2 was suggested by the observation that interneurons in the hippocampus coexpress both proteins (165). A mechanistic connection was inferred when long-term treatment of aged animals with NS398 promoted retention of alpha4 nAChR expression in the brain, an effect that was antagonized by the coadministration of nicotine.",
       "key": "26cb751e0529b71a3a8fa2cf189c9a5894feb674b950a675486029dc9d82db429a0eb301171c8668dfac463ea2d58a1d62b8db133e62e234d7fbd3e82d26c082",
-      "line": 1730,
+      "line": 1884,
       "relation": "association",
-      "source": 183,
-      "target": 202
+      "source": 186,
+      "target": 205
+    },
+    {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "TextLocation": {
+          "Review": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Albuquerque EX",
+          "Alkondon M",
+          "Pereira EF",
+          "Rogers SW"
+        ],
+        "date": "2009-01-01",
+        "first": "Albuquerque EX",
+        "last": "Rogers SW",
+        "name": "Physiological reviews",
+        "pages": "73-120",
+        "reference": "19126755",
+        "title": "Mammalian nicotinic acetylcholine receptors: from structure to function.",
+        "type": "PubMed",
+        "volume": "89"
+      },
+      "evidence": "In receptors harboring the gamma subunit, agonist-induced receptor activation results in a long-lasting open channel time. The large agonist-induced current in turn leads to local intermittent depolarization and adjustments to protein-protein interactions that favor receptor clustering. As the depolarization increases, transcription of the epsilon subunit is increased dramatically (183).",
+      "key": "27fe503c640e9278f5fc3e3074065f05de55ce013f66848f80878860347618990d3e556a8242cc090f6c53644e19b1a322738a5b90f27f9146b3c8a8dd76574c",
+      "line": 523,
+      "relation": "increases",
+      "source": 198,
+      "subject": {
+        "modifier": "Activity"
+      },
+      "target": 99
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Species": {
           "10090": true
         },
@@ -3172,13 +3377,16 @@
       },
       "evidence": "Notably, mice with a null mutation in the gene that encodes the alpha5 nAChR subunit exhibit enhanced sensitivity to induction of inflammatory bowel disease relative to controls (353). Despite increased sensitivity to disease initiation, administration of transdermal nicotine remains effective in attenuating the disease process. Therefore, again nicotine appears to impact on inflammatory processes with considerable specificity and tissue dependency.",
       "key": "5fdfd32d04196f3c99ece0ed557600d92ff1ed7bb094d8a762526b50eceaa78a11d70e5f4d70a48fda4a9a2ed4cf45a3dab2f622502f69fbfb33e47098e76585",
-      "line": 1482,
+      "line": 1613,
       "relation": "decreases",
-      "source": 184,
-      "target": 229
+      "source": 187,
+      "target": 233
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -3202,13 +3410,16 @@
       },
       "evidence": "For example, while the alpha7 nAChR is primarily a homomeric receptor in neurons (127), combinations of alpha7 nAChR subunits with alpha5, beta2, or beta3 nAChR subunits have been reported to form functional heteromeric receptors in some systems (240, 360, 515).",
       "key": "484d0094112ec47e82b2a42f5d2c160644d663a2829d5c06437ef8e5ba02c94c7d79815d1f68e751598b319fc4e2f3520170a9d442cb8e129803b212a5b3e0d0",
-      "line": 444,
+      "line": 484,
       "relation": "association",
-      "source": 186,
+      "source": 189,
       "target": 73
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -3232,13 +3443,16 @@
       },
       "evidence": "For example, while the alpha7 nAChR is primarily a homomeric receptor in neurons (127), combinations of alpha7 nAChR subunits with alpha5, beta2, or beta3 nAChR subunits have been reported to form functional heteromeric receptors in some systems (240, 360, 515).",
       "key": "6b4a76cdd2519eca3c7ba882b746b652898c897ec80986e07970ce41e420174d12c3818701d530ee9cbb288774433bb6315714798559aa55703b34c4f8df2aac",
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       "relation": "association",
-      "source": 186,
-      "target": 141
+      "source": 189,
+      "target": 144
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -3262,13 +3476,16 @@
       },
       "evidence": "For example, while the alpha7 nAChR is primarily a homomeric receptor in neurons (127), combinations of alpha7 nAChR subunits with alpha5, beta2, or beta3 nAChR subunits have been reported to form functional heteromeric receptors in some systems (240, 360, 515).",
       "key": "2ddf5a5367652fc171a2ce8d18a4acff8b3828160fcf61ea582ace972d5dcc6ea287130b8e4b95208fab49e353e154dff635d66fa46f7d959065631dc2b181ed",
-      "line": 446,
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       "relation": "association",
-      "source": 186,
-      "target": 144
+      "source": 189,
+      "target": 147
     },
     {
       "annotations": {
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+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -3292,22 +3509,25 @@
       },
       "evidence": "For example, while the alpha7 nAChR is primarily a homomeric receptor in neurons (127), combinations of alpha7 nAChR subunits with alpha5, beta2, or beta3 nAChR subunits have been reported to form functional heteromeric receptors in some systems (240, 360, 515).",
       "key": "545934880d5c7c6e3910605ca279773e20c33edc7383117399a28cb5645ed4c1be2804acba525c2504acfacf019deb4325ecfb5173805231c3fe34d4553670df",
-      "line": 447,
+      "line": 487,
       "relation": "association",
-      "source": 186,
-      "target": 145
+      "source": 189,
+      "target": 148
     },
     {
       "key": "2b5be611b1206001744e3f6cd49b08d7bfbd1c8fd986e47536fcce3f4455252487d1f449cdd5047147ff71ca4f493c5f7f8440c3c846e6512379f7de18345c6d",
       "relation": "hasVariant",
-      "source": 186,
-      "target": 187
+      "source": 189,
+      "target": 190
     },
     {
       "annotations": {
         "Anatomy": {
           "hippocampus stratum lacunosum moleculare": true
         },
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -3331,16 +3551,19 @@
       },
       "evidence": "It is noteworthy that, via such mechanisms, alpha7 nAChR activation could trigger rebound burst firing in SLM interneurons even in the absence of excitation (256). Burst firing in SLM interneurons suppresses spikes in pyramidal neurons evoked by stimulation of Schaffer collaterals (134), and, thereby allows selective activation of the pyramidal cells via the perforant pathway.",
       "key": "7739203d7aa85acc0accb3629e4178d6b222ab35827c98716203f14a45e9030d337115bb339831ac894b52c87c90c244607e1fbee248814afb311f71496a8319",
-      "line": 792,
+      "line": 866,
       "relation": "increases",
-      "source": 186,
+      "source": 189,
       "subject": {
         "modifier": "Activity"
       },
-      "target": 85
+      "target": 84
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "CA1 Region, Hippocampal": true,
           "CA3 Region, Hippocampal": true,
@@ -3369,9 +3592,9 @@
       },
       "evidence": "In CA1 and CA3 pyramidal neurons of the developed hippocampus, alpha7 nAChRs are expressed primarily on axon terminals whereby their activation modulates the efficacy of glutamate synaptic transmission.",
       "key": "c5c69d382fedf3d9e8a09e598b6ea21221053fc8f00f8e6c6a9a808b45b13a0afa34d3c364adb16708fe4a4c2f3c194815a9f318a714f5703ac8e6838330f3ce",
-      "line": 804,
+      "line": 879,
       "relation": "regulates",
-      "source": 186,
+      "source": 189,
       "subject": {
         "location": {
           "name": "axon terminus",
@@ -3383,6 +3606,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -3406,7 +3632,7 @@
       },
       "evidence": "For example, during a low degree of activation of alpha7 and alpha3beta4 nAChRs, Ca2+ can enter the cells through nAChRs or NMDA receptors and favor activation (i.e., phosphorylation) of the transcription factor CREB, which in turn modifies gene expression (82).",
       "key": "c0db2de4981e3e4b0968b2b3cf09959a988f1191405b86e494f8572444cd9a1ca7814438161f628945d3eafa2c9fd34893615c6cbd4a6cfc7292dd4f1a4a28d3",
-      "line": 815,
+      "line": 891,
       "object": {
         "location": {
           "name": "intracellular",
@@ -3414,7 +3640,7 @@
         }
       },
       "relation": "increases",
-      "source": 186,
+      "source": 189,
       "subject": {
         "modifier": "Activity"
       },
@@ -3422,6 +3648,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -3445,7 +3674,7 @@
       },
       "evidence": "Long before the identification of the high Ca2+ permeability of alpha7 nAChR channels, different studies reported significant Ca2+ influx through nAChRs in muscle, parasympathetic neurons, pheochromocytoma cells, and human neuroblastoma cells (115, 321, 347, 407, 411, 459, 468).",
       "key": "6a4fe4e144decf0a359db6ba16c6d4994033597d5024c13768ab5e1a852ec599a86cee3c98629c5b43662c6d9d709cd59e67e8174b007dcf741841db641da93c",
-      "line": 1348,
+      "line": 1472,
       "object": {
         "location": {
           "name": "intracellular",
@@ -3453,7 +3682,7 @@
         }
       },
       "relation": "increases",
-      "source": 186,
+      "source": 189,
       "subject": {
         "modifier": "Activity"
       },
@@ -3461,6 +3690,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -3484,16 +3716,19 @@
       },
       "evidence": "Activation of somatodendritic alpha7 nAChRs increases the action potential-dependent release of dopamine, while activation of presynaptic alpha6 and/or alpha4 nAChRs increases action potential-independent dopamine release.",
       "key": "ce419275ee2914e2aa438a0ec4c09e5d3dce61cecccb7a6a8562cfe4b54abf867f892eff5518136aa07c56f0135b1b60ecc8158222ebff5ebd7af87710bea580",
-      "line": 864,
+      "line": 944,
       "relation": "increases",
-      "source": 186,
+      "source": 189,
       "subject": {
         "modifier": "Activity"
       },
-      "target": 105
+      "target": 104
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -3517,9 +3752,9 @@
       },
       "evidence": "Other levels of regulation of dopaminergic transmission arise from alpha7 nAChRs located on cortical glutamatergic terminals; activation of these receptors increases glutamate release onto dopaminergic neurons in the VTA and, consequently, increases the their firing (344).",
       "key": "e1f46a544d2b9b3266a6b9dde355a19a639335c3a8a704fcdb676902ed97e6a438c1a3f447d5d8a9600f643ff3498416c2c55e60045e3c5b387f4cc2424f4ab3",
-      "line": 876,
+      "line": 957,
       "relation": "regulates",
-      "source": 186,
+      "source": 189,
       "subject": {
         "location": {
           "name": "glutamatergic synapse",
@@ -3531,6 +3766,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -3554,7 +3792,7 @@
       },
       "evidence": "Other levels of regulation of dopaminergic transmission arise from alpha7 nAChRs located on cortical glutamatergic terminals; activation of these receptors increases glutamate release onto dopaminergic neurons in the VTA and, consequently, increases the their firing (344).",
       "key": "623dc82e0b9c72faf7ed8e8d299a7af9f1edb299c8cd4435869c449474f929019cd2be553167e6149c7f0e69886b38b37f76f386148954d4bcaa619f9b5ed642",
-      "line": 877,
+      "line": 958,
       "object": {
         "location": {
           "name": "Dopaminergic Neurons",
@@ -3562,7 +3800,7 @@
         }
       },
       "relation": "increases",
-      "source": 186,
+      "source": 189,
       "subject": {
         "location": {
           "name": "glutamatergic synapse",
@@ -3574,6 +3812,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "CA1 Region, Hippocampal": true
         },
@@ -3600,7 +3841,7 @@
       },
       "evidence": "Activation of alpha7 nAChRs in somatodendritic and preterminal/ terminal areas of interneurons in various strata of the CA1 region and in the dentate gyrus facilitates spontaneous quantal release of GABA (14, 25). Glutamate release from mossy fibers onto CA3 pyramidal neurons is also modulated by alpha7 nAChRs present in the mossy fiber terminals (190).",
       "key": "1552ab8c1c7240d3b7ce96e42e8d1cb8c6a41ba2f670402718774f628a0177de5f2febd568200ab840b022f737641cdc1866502cb5be19c46771edb7fd22eae0",
-      "line": 1134,
+      "line": 1241,
       "object": {
         "location": {
           "name": "Pyramidal Cells",
@@ -3608,7 +3849,7 @@
         }
       },
       "relation": "regulates",
-      "source": 186,
+      "source": 189,
       "subject": {
         "location": {
           "name": "Mossy Fibers, Hippocampal",
@@ -3619,6 +3860,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -3642,13 +3886,16 @@
       },
       "evidence": "In particular, the association of the alpha7 nAChR gene with a sensory gating deficit that is similar to attention deficits in patients with schizophrenia (157), and the degree of alpha4beta2 nAChR loss and altered alpha7 expresson correlate well with the magnitude of progressive cognitive decline in mild-to-moderate AD patients (46).",
       "key": "e0295d000e2ec5fc5a12c2404cdfb5447935c51d56db739fe9d3516ba07a10a415d1b70d9df8b58265e4ba54827de072008bd519ce40f437de578d396a398212",
-      "line": 1000,
+      "line": 1093,
       "relation": "positiveCorrelation",
-      "source": 186,
+      "source": 189,
       "target": 115
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Hippocampus": true
         },
@@ -3675,9 +3922,9 @@
       },
       "evidence": "Chronic alpha7 nAChR inhibition in the hippocampus by elevated levels of KYNA can contribute to auditory gating deficits, which appear to be associated with the development of schizophrenia (156). It is also feasible that KYNAinduced inhibition of alpha7 nAChRs contributes to the cognitive impairment observed in patients with AD and schizophrenia (273).",
       "key": "41886a0b5c8a194468436173978333c62e6bea0dfb34e37bae56a11dfca4c166489d6fc9b31d3d8c5b9338a9ddefb66a5f507f734e0ec5b05991b29de0759aaf",
-      "line": 1197,
+      "line": 1308,
       "relation": "association",
-      "source": 186,
+      "source": 189,
       "subject": {
         "modifier": "Activity"
       },
@@ -3685,6 +3932,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -3708,13 +3958,16 @@
       },
       "evidence": "In particular, the association of the alpha7 nAChR gene with a sensory gating deficit that is similar to attention deficits in patients with schizophrenia (157), and the degree of alpha4beta2 nAChR loss and altered alpha7 expresson correlate well with the magnitude of progressive cognitive decline in mild-to-moderate AD patients (46).",
       "key": "67c01f6fc262ba807305015257df1149236df0ba48e978e9fe6ad460d482e652a62acaeb037d0b4fae2a9f09a67da4c18235829fb59845c4e04c47945101debc",
-      "line": 1001,
+      "line": 1094,
       "relation": "negativeCorrelation",
-      "source": 186,
-      "target": 220
+      "source": 189,
+      "target": 225
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "CA1 Region, Hippocampal": true
         },
@@ -3741,7 +3994,7 @@
       },
       "evidence": "Activation of alpha7 nAChRs in somatodendritic and preterminal/ terminal areas of interneurons in various strata of the CA1 region and in the dentate gyrus facilitates spontaneous quantal release of GABA (14, 25). Glutamate release from mossy fibers onto CA3 pyramidal neurons is also modulated by alpha7 nAChRs present in the mossy fiber terminals (190).",
       "key": "ef181a41a4dfc7d1771f64303820a4bc8e75d0cf40b7c2894b13c290dbdc3fbbb2a214b15a06fea2989ebd9d9cba3040c1748bd3247051ffd35f080bf015bbfa",
-      "line": 1132,
+      "line": 1239,
       "object": {
         "effect": {
           "fromLoc": {
@@ -3756,7 +4009,7 @@
         "modifier": "Translocation"
       },
       "relation": "increases",
-      "source": 186,
+      "source": 189,
       "subject": {
         "modifier": "Activity"
       },
@@ -3764,6 +4017,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Corpus Striatum": true
         },
@@ -3793,7 +4049,7 @@
       },
       "evidence": "Activation of alpha7 nAChRs is known to contribute to the regulation of extracellular dopamine levels in the rat striatum (81). Application via microdialysis of KYNA or alpha-BGT to the rat striatum significantly reduces the extracellular levels of dopamine, and the magnitude of the effect of either antagonist alone is comparable to that of both antagonists together (285).",
       "key": "6579afaf2570a8665c5ae0009e0cfd92d88a1e31960ef98ad3b38c1a089c73e762ba7d47cc2612dacfc86ac29c02d134771f9da589b1b202b1799cdb5b032d01",
-      "line": 1149,
+      "line": 1257,
       "object": {
         "location": {
           "name": "extracellular region",
@@ -3801,7 +4057,7 @@
         }
       },
       "relation": "regulates",
-      "source": 186,
+      "source": 189,
       "subject": {
         "modifier": "Activity"
       },
@@ -3809,6 +4065,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Dopaminergic Neurons": true
         },
@@ -3835,7 +4094,7 @@
       },
       "evidence": "As illustrated in Figure 8, KYNA-induced reduction of extracellular dopamine levels can be explained by the inhibition of tonically active alpha7 nAChRs in the dopaminergic neurons within the VTA and/or in cortical glutamatergic terminals that synapse onto striatal neurons. VTA dopaminergic neurons represent the major dopaminergic input to the nucleus accumbens.",
       "key": "65f0d82de7b8e5d5ca693ec37f43081c2b87ff2d8a7b7ede219bda9793cc12264541018917ed9827f67596fb218275620e3013cd3f4935797b89a47c4cc2348e",
-      "line": 1179,
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       "object": {
         "location": {
           "name": "extracellular region",
@@ -3843,7 +4102,7 @@
         }
       },
       "relation": "increases",
-      "source": 186,
+      "source": 189,
       "subject": {
         "modifier": "Activity"
       },
@@ -3851,6 +4110,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Hippocampus": true
         },
@@ -3877,16 +4139,19 @@
       },
       "evidence": "Chronic alpha7 nAChR inhibition in the hippocampus by elevated levels of KYNA can contribute to auditory gating deficits, which appear to be associated with the development of schizophrenia (156). It is also feasible that KYNAinduced inhibition of alpha7 nAChRs contributes to the cognitive impairment observed in patients with AD and schizophrenia (273).",
       "key": "516ef8cf9eded498afd35dbfbf4e8a87156252366ef0c68cdc52b6b6fd17d8582b8fe2f285d3b349b130f36b379ff8f99e4fe4eff91ae693d3f908315d17966f",
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       "relation": "association",
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+      "source": 189,
       "subject": {
         "modifier": "Activity"
       },
-      "target": 237
+      "target": 241
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Neurons": true
         },
@@ -3913,7 +4178,7 @@
       },
       "evidence": "It is noteworthy that the alpha7 nAChR activity increases intracellular accumulation of Abeta in neurons (336), and Abeta peptides, in addition to modulating nAChR activity, downregulate the expression of nAChRs (197).",
       "key": "f55b19695827902d1554f01bba3de118a2656adbc04c674064c0110dcd56245dc51e664cff8ab3c36991ac18485d70836d51ba53af8218a26a33e8a3a3b430c3",
-      "line": 1267,
+      "line": 1386,
       "object": {
         "location": {
           "name": "intracellular",
@@ -3921,7 +4186,7 @@
         }
       },
       "relation": "increases",
-      "source": 186,
+      "source": 189,
       "subject": {
         "modifier": "Activity"
       },
@@ -3929,6 +4194,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Neurons": true
         },
@@ -3955,9 +4223,9 @@
       },
       "evidence": "There is evidence that anandamide is produced by postsynaptic neurons in response to elevated intracellular Ca2+ levels. For instance, concomitant activation of alpha7 nAChRs and NMDA receptors triggers the production of anandamine in postsynaptic neurons (448). Anandamine, then, functions as a retrograde messenger and regulates synaptic transmission by interacting with specific receptors in the presynaptic neurons/terminals (498).",
       "key": "3e6bfba0d36b18373d9b062487490c2b4327b3d90dd658b11642305f50ef39b2a278a7f8e4427c02486f79d27423cf1b4bd77e0fb012a654507e1a19bb79fc61",
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       "relation": "increases",
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+      "source": 189,
       "subject": {
         "modifier": "Activity"
       },
@@ -3965,6 +4233,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "MeSHAnatomy": {
           "Keratinocytes": true
         },
@@ -3991,15 +4262,18 @@
       },
       "evidence": "Furthermore, pharmacological dissection of nicotine’s influence on cell cycle progression, apoptosis, and differentiation (43) indicate that alpha7 nAChRs expressed in keratynocytes are important. Other receptors are clearly involved in this process, since atropine, a muscarinic and sometimes nAChR inhibitor (531, 532), reduces cell adhesion through decreasing desmoligein expression.",
       "key": "014b6128a6f7df7c8dfd4c5d109de90b6f98da24d355930fa1133cc296d7c2db768d8a2e32fc77c76257538a18240931bcaaefeaf52e4303d50b28df8b23c489",
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       "relation": "regulates",
-      "source": 186,
-      "target": 90
+      "source": 189,
+      "target": 89
     },
     {
       "annotations": {
-        "MeSHDisease": {
-          "Seizures": true
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Keratinocytes": true
         },
         "TextLocation": {
           "Review": true
@@ -4022,18 +4296,21 @@
         "type": "PubMed",
         "volume": "89"
       },
-      "evidence": "A principle component of genetic analysis of the contribution of alpha7 and alpha4beta2 nAChRs to the effects of nicotine was reported 15 years ago. The number of alpha-BGT binding sites (presumably alpha7 nAChRs) was shown to be highly correlated with sensitivity to nicotinic-induced seizures (105, 301, 303).",
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-      "line": 1815,
-      "relation": "association",
-      "source": 186,
-      "subject": {
-        "modifier": "Activity"
-      },
-      "target": 30
+      "evidence": "Furthermore, pharmacological dissection of nicotine’s influence on cell cycle progression, apoptosis, and differentiation (43) indicate that alpha7 nAChRs expressed in keratynocytes are important. Other receptors are clearly involved in this process, since atropine, a muscarinic and sometimes nAChR inhibitor (531, 532), reduces cell adhesion through decreasing desmoligein expression.",
+      "key": "fc49493d779f608e4d63804ee75cb59372790103fe202793bdda0bfebcef316012911bc0456652c01567394fe4c93347896e6ff247b590eb34cd599387ba273f",
+      "line": 1662,
+      "relation": "regulates",
+      "source": 189,
+      "target": 121
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Keratinocytes": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -4055,15 +4332,57 @@
         "type": "PubMed",
         "volume": "89"
       },
-      "evidence": "Several possibilities exist for the identity of the nAChR important to tolerance development. The strong positive correlation between alpha-BGT site number and sensitivity to nicotine-induced seizures among multiple mouse strains led to the suggestion that alpha7 nAChRs are critical to limit oral nicotine self-administration in mice (105, 301).",
-      "key": "2a660ab23c07ffc54fe3b0fe78d5c312c4b13dd01aae0b19dcb5b88c8e7a86f2c8bb5c0f5a04e4fa90e81deedade55607010d10dc9cde6e0969efec1e9c3508e",
-      "line": 1842,
+      "evidence": "Furthermore, pharmacological dissection of nicotine’s influence on cell cycle progression, apoptosis, and differentiation (43) indicate that alpha7 nAChRs expressed in keratynocytes are important. Other receptors are clearly involved in this process, since atropine, a muscarinic and sometimes nAChR inhibitor (531, 532), reduces cell adhesion through decreasing desmoligein expression.",
+      "key": "9dd3dcd4877f0025317a4eb8ddd6008362b3a45002215eb38f6e296aa1fd44aeb613b1890840fba5c3af67a9fbcfbfff2756225b00a7eddc569d0d5b023055b7",
+      "line": 1663,
       "relation": "regulates",
-      "source": 186,
+      "source": 189,
+      "target": 118
+    },
+    {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        },
+        "MeSHDisease": {
+          "Seizures": true
+        },
+        "TextLocation": {
+          "Review": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Albuquerque EX",
+          "Alkondon M",
+          "Pereira EF",
+          "Rogers SW"
+        ],
+        "date": "2009-01-01",
+        "first": "Albuquerque EX",
+        "last": "Rogers SW",
+        "name": "Physiological reviews",
+        "pages": "73-120",
+        "reference": "19126755",
+        "title": "Mammalian nicotinic acetylcholine receptors: from structure to function.",
+        "type": "PubMed",
+        "volume": "89"
+      },
+      "evidence": "A principle component of genetic analysis of the contribution of alpha7 and alpha4beta2 nAChRs to the effects of nicotine was reported 15 years ago. The number of alpha-BGT binding sites (presumably alpha7 nAChRs) was shown to be highly correlated with sensitivity to nicotinic-induced seizures (105, 301, 303).",
+      "key": "63981f8c05bb526e33fac747585a2c47110b9341746760e9d465fc35edad65d7bcc268bb4046f38ac134f10323ac600532b054644331ed973f7a252a04c87e1b",
+      "line": 1977,
+      "relation": "association",
+      "source": 189,
+      "subject": {
+        "modifier": "Activity"
+      },
       "target": 30
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -4085,15 +4404,18 @@
         "type": "PubMed",
         "volume": "89"
       },
-      "evidence": "While development of tolerance does not seem to be regulated by alpha7 nAChRs, a recent study of alpha7 nAChR-null mice indicates that these receptors control the severity of the nicotine withdrawal syndrome (402).",
-      "key": "5308147034af8f881f6f1ab9a75b4cdabe675315f66b3975898f28ec0e060baa0c5aa63eef0b26c3ce9ac4fd404b07669e573944c19f294adbd4054bcb703d65",
-      "line": 1849,
+      "evidence": "Several possibilities exist for the identity of the nAChR important to tolerance development. The strong positive correlation between alpha-BGT site number and sensitivity to nicotine-induced seizures among multiple mouse strains led to the suggestion that alpha7 nAChRs are critical to limit oral nicotine self-administration in mice (105, 301).",
+      "key": "2a660ab23c07ffc54fe3b0fe78d5c312c4b13dd01aae0b19dcb5b88c8e7a86f2c8bb5c0f5a04e4fa90e81deedade55607010d10dc9cde6e0969efec1e9c3508e",
+      "line": 2006,
       "relation": "regulates",
-      "source": 186,
-      "target": 240
+      "source": 189,
+      "target": 30
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -4115,15 +4437,18 @@
         "type": "PubMed",
         "volume": "89"
       },
-      "evidence": "In summary, while nicotine-induced upregulation requires at least the beta2 nAChR subunit, development of tolerance to nicotine requires neither the beta2 nor the alpha7 nAChR subunit; instead, it appears to be modulated by a beta4-containing nAChR and to require an alpha4-containing nAChR.",
-      "key": "12171d5de9e7c26f50599ff86d643d9894a929b5ae7206abb095b5a2db3b8a4d2e0f83a3bd6b24c9f663a9ae97a6ce6120baa629b8df2982090f4cf6e33608f1",
-      "line": 1858,
-      "relation": "association",
-      "source": 192,
-      "target": 226
+      "evidence": "While development of tolerance does not seem to be regulated by alpha7 nAChRs, a recent study of alpha7 nAChR-null mice indicates that these receptors control the severity of the nicotine withdrawal syndrome (402).",
+      "key": "5308147034af8f881f6f1ab9a75b4cdabe675315f66b3975898f28ec0e060baa0c5aa63eef0b26c3ce9ac4fd404b07669e573944c19f294adbd4054bcb703d65",
+      "line": 2014,
+      "relation": "regulates",
+      "source": 189,
+      "target": 244
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -4145,15 +4470,18 @@
         "type": "PubMed",
         "volume": "89"
       },
-      "evidence": "Furthermore, TNF-alpha strongly promotes ligand-mediated upregulation of alpha4beta2 nAChRs through a mechanism that requires p38 mitogen-activated protein kinase (MAPK) signaling (163).",
-      "key": "bb006908610c1571958fcb2f522924bbc8d6cd9c308687635f357a2afa47370b54e8368cdd15996db1f1cb54860489cd47191e1cd8416f0d42e62dfcfeb35f95",
-      "line": 188,
-      "relation": "increases",
-      "source": 206,
-      "target": 84
+      "evidence": "In summary, while nicotine-induced upregulation requires at least the beta2 nAChR subunit, development of tolerance to nicotine requires neither the beta2 nor the alpha7 nAChR subunit; instead, it appears to be modulated by a beta4-containing nAChR and to require an alpha4-containing nAChR.",
+      "key": "12171d5de9e7c26f50599ff86d643d9894a929b5ae7206abb095b5a2db3b8a4d2e0f83a3bd6b24c9f663a9ae97a6ce6120baa629b8df2982090f4cf6e33608f1",
+      "line": 2024,
+      "relation": "association",
+      "source": 195,
+      "target": 231
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -4176,17 +4504,17 @@
         "volume": "89"
       },
       "evidence": "Furthermore, TNF-alpha strongly promotes ligand-mediated upregulation of alpha4beta2 nAChRs through a mechanism that requires p38 mitogen-activated protein kinase (MAPK) signaling (163).",
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-      "line": 189,
-      "object": {
-        "modifier": "Activity"
-      },
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       "relation": "increases",
-      "source": 84,
-      "target": 168
+      "source": 209,
+      "target": 83
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -4208,15 +4536,21 @@
         "type": "PubMed",
         "volume": "89"
       },
-      "evidence": "In cell lines, this interaction of trans-activating components is also under the regulation of the Ras-dependent MAPK and pathways related to phosphoinositide-3-kinase (PI3K) and MEK activation whose response to trophic factors such as nerve growth factor (NGF) contributes to regulating transcript initiation.",
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-      "line": 397,
-      "relation": "regulates",
-      "source": 84,
-      "target": 265
+      "evidence": "Furthermore, TNF-alpha strongly promotes ligand-mediated upregulation of alpha4beta2 nAChRs through a mechanism that requires p38 mitogen-activated protein kinase (MAPK) signaling (163).",
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+      "line": 205,
+      "object": {
+        "modifier": "Activity"
+      },
+      "relation": "increases",
+      "source": 83,
+      "target": 171
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -4238,15 +4572,18 @@
         "type": "PubMed",
         "volume": "89"
       },
-      "evidence": "As will be returned to below, it is also the first nAChR subtype to exhibit measurable decline in expression in the aged mammalian brain and especially in neurodegenerative disorders such as AD (236, 374).",
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-      "line": 693,
-      "relation": "negativeCorrelation",
-      "source": 168,
-      "target": 244
+      "evidence": "In cell lines, this interaction of trans-activating components is also under the regulation of the Ras-dependent MAPK and pathways related to phosphoinositide-3-kinase (PI3K) and MEK activation whose response to trophic factors such as nerve growth factor (NGF) contributes to regulating transcript initiation.",
+      "key": "4cdd3725044ce36678987733dd3414043c3ec68c568386a6675e795ae5718893a043a00555e36a54114beb5e09f26219e743fb2a61279e189c21840330629c42",
+      "line": 432,
+      "relation": "regulates",
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+      "target": 270
     },
     {
       "annotations": {
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+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -4269,14 +4606,17 @@
         "volume": "89"
       },
       "evidence": "As will be returned to below, it is also the first nAChR subtype to exhibit measurable decline in expression in the aged mammalian brain and especially in neurodegenerative disorders such as AD (236, 374).",
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-      "target": 220
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+      "target": 248
     },
     {
       "annotations": {
+        "Confidence": {
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         "TextLocation": {
           "Review": true
         }
@@ -4298,15 +4638,18 @@
         "type": "PubMed",
         "volume": "89"
       },
-      "evidence": "In particular, the association of the alpha7 nAChR gene with a sensory gating deficit that is similar to attention deficits in patients with schizophrenia (157), and the degree of alpha4beta2 nAChR loss and altered alpha7 expresson correlate well with the magnitude of progressive cognitive decline in mild-to-moderate AD patients (46).",
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-      "line": 999,
+      "evidence": "As will be returned to below, it is also the first nAChR subtype to exhibit measurable decline in expression in the aged mammalian brain and especially in neurodegenerative disorders such as AD (236, 374).",
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+      "line": 765,
       "relation": "negativeCorrelation",
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-      "target": 220
+      "source": 171,
+      "target": 225
     },
     {
       "annotations": {
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         "TextLocation": {
           "Review": true
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@@ -4328,15 +4671,18 @@
         "type": "PubMed",
         "volume": "89"
       },
-      "evidence": "Genetic deletion of the alpha4 or the alpha2 nAChR subunit abolishes essentially all high-affinity nicotine binding to brain tissue and upregulation in response to chronic exposure to nicotine (151, 311).",
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-      "line": 701,
-      "relation": "increases",
-      "source": 168,
-      "target": 124
+      "evidence": "In particular, the association of the alpha7 nAChR gene with a sensory gating deficit that is similar to attention deficits in patients with schizophrenia (157), and the degree of alpha4beta2 nAChR loss and altered alpha7 expresson correlate well with the magnitude of progressive cognitive decline in mild-to-moderate AD patients (46).",
+      "key": "a574ad357fe0031d1a745504e8733e40c560e6f855d90b42b74a43f2753c9a3942c931e38d8006bb1a7d15983d9f8c89210de4f7a934a4272aaa1467e3c2bc15",
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+      "relation": "negativeCorrelation",
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     },
     {
       "annotations": {
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         "TextLocation": {
           "Review": true
         }
@@ -4360,9 +4706,9 @@
       },
       "evidence": "A concurrent activation of preterminal alpha4beta2 nAChRs would hyperpolarize the neuron via GABAergic inhibition and prevent activation of the VGCC.",
       "key": "251e21228739a6abbf1fd2f1f864c4dfbec53b0847d1f10c5189ae3578661e33ca82efbedd577762b1dfd155d7004759056e38462bf8040dac22238b6a971f97",
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       "relation": "decreases",
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+      "source": 171,
       "subject": {
         "modifier": "Activity"
       },
@@ -4370,6 +4716,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
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@@ -4393,19 +4742,22 @@
       },
       "evidence": "A concurrent activation of preterminal alpha4beta2 nAChRs would hyperpolarize the neuron via GABAergic inhibition and prevent activation of the VGCC.",
       "key": "f2d71547683702dd7d2b7279b2d3e94069910c17b81943cc16fc35bc9bce70e2b09ca30e362a09403e5c2922011b4ab64c88789ecc35f14c3d395d6cedb41876",
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       "relation": "decreases",
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       "subject": {
         "modifier": "Activity"
       },
-      "target": 119
+      "target": 122
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Ventral Tegmental Area": true
         },
@@ -4432,12 +4784,12 @@
       },
       "evidence": "Activation of alpha4beta2 nAChRs on GABAergic interneurons in the VTA relieves the inhibitory control they exert on dopaminergic neurons (295, 380).",
       "key": "fdb0146962fc767a14d304ad45f8b4b3c8165683b757b42aeeacb7b12c4b6156982df44be871516ce75dff1abbd21723226ef112a516e703a10d0e6f364dcc36",
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       "relation": "increases",
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+      "source": 171,
       "subject": {
         "location": {
           "name": "GABAergic Neurons",
@@ -4449,6 +4801,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -4472,13 +4827,16 @@
       },
       "evidence": "In particular, the association of the alpha7 nAChR gene with a sensory gating deficit that is similar to attention deficits in patients with schizophrenia (157), and the degree of alpha4beta2 nAChR loss and altered alpha7 expresson correlate well with the magnitude of progressive cognitive decline in mild-to-moderate AD patients (46).",
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       "relation": "positiveCorrelation",
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+      "source": 171,
       "target": 115
     },
     {
       "annotations": {
+        "Confidence": {
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         "TextLocation": {
           "Review": true
         }
@@ -4502,19 +4860,22 @@
       },
       "evidence": "In the basal ganglia, including the ventral tegmental area (VTA) and substantia nigra, the alpha6 and possibly the beta3 nAChR subunits are included in alpha4beta2 nAChR complexes to generate highaffinity receptors. At present, this is the only brain area identified where alpha6 and beta3 are coexpressed with alpha4 and beta2 nAChR subunits. This finding is highly relevant for Parkinson’s disease (385, 386).",
       "key": "a67e36d742d12740d4779ec6285d276fb74d23c74d7c1b94aab2926aaefd83ce0081e562a449d450017dba646589c5e12e2f0a5cbc69c95db3c19a00d877c615",
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       "relation": "association",
-      "source": 170,
+      "source": 173,
       "subject": {
         "location": {
           "name": "Basal Ganglia",
           "namespace": "MESH"
         }
       },
-      "target": 235
+      "target": 239
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -4538,7 +4899,7 @@
       },
       "evidence": "In the basal ganglia, including the ventral tegmental area (VTA) and substantia nigra, the alpha6 and possibly the beta3 nAChR subunits are included in alpha4beta2 nAChR complexes to generate highaffinity receptors. At present, this is the only brain area identified where alpha6 and beta3 are coexpressed with alpha4 and beta2 nAChR subunits. This finding is highly relevant for Parkinson’s disease (385, 386).",
       "key": "a6be8adde4149552730f67329a4d4460459b4cbc2614efd566f0d290a67ae59c771071851a78473e117f9cd0db4069cfc9b7c014cb6992c6fe6fab8164d7df76",
-      "line": 200,
+      "line": 217,
       "object": {
         "location": {
           "name": "Basal Ganglia",
@@ -4546,11 +4907,14 @@
         }
       },
       "relation": "association",
-      "source": 235,
-      "target": 170
+      "source": 239,
+      "target": 173
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Dopaminergic Neurons": true
         },
@@ -4577,13 +4941,16 @@
       },
       "evidence": "Parkinson’s disease (PD) is characterized by selective damage to dopaminergic nigrostriatal neurons and is clinically revealed by motor deficits, including rigidity, tremor, and bradykinesia. Dopamine replacement therapy (usually with L-dopa) is the most common treatment, although this drug loses efficacy over time.",
       "key": "a2f46af18b7da0e1c471c166c573d508210242315455b75579e855258f80126bca7a634a9361744af0456343671f2dddb1483b3f43a2e5f7d6e211c9d1e7c8b6",
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       "relation": "positiveCorrelation",
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-      "target": 252
+      "source": 239,
+      "target": 256
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Dopaminergic Neurons": true
         },
@@ -4610,13 +4977,16 @@
       },
       "evidence": "Parkinson’s disease (PD) is characterized by selective damage to dopaminergic nigrostriatal neurons and is clinically revealed by motor deficits, including rigidity, tremor, and bradykinesia. Dopamine replacement therapy (usually with L-dopa) is the most common treatment, although this drug loses efficacy over time.",
       "key": "ef8efe1d0db31572f068ead081f843c6a808cc4415a21784a06f6963b9fd99f49f425e35b18a475e73bbc255d92ef7b87969a2df975a630863e7f0adbfccfcf7",
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+      "line": 1900,
       "relation": "positiveCorrelation",
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-      "target": 248
+      "source": 239,
+      "target": 252
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Dopaminergic Neurons": true
         },
@@ -4643,13 +5013,16 @@
       },
       "evidence": "Parkinson’s disease (PD) is characterized by selective damage to dopaminergic nigrostriatal neurons and is clinically revealed by motor deficits, including rigidity, tremor, and bradykinesia. Dopamine replacement therapy (usually with L-dopa) is the most common treatment, although this drug loses efficacy over time.",
       "key": "f360602721d91fd6ddab5e0edcf1d5ad7e0b323215a35424b9a917adeedd04e7fd56f40af51e84f5fa798eee93a44c695ad5bd6e3289430af12e93389d948ad7",
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+      "line": 1901,
       "relation": "positiveCorrelation",
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-      "target": 231
+      "source": 239,
+      "target": 235
     },
     {
       "annotations": {
+        "Confidence": {
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+        },
         "TextLocation": {
           "Review": true
         }
@@ -4673,13 +5046,16 @@
       },
       "evidence": "However, epidemiological studies have reported that heavy smokers are less likely to experience PD (see reviews in Refs. 384, 385).",
       "key": "5f7f377951cf614019daa1ba5935eaa43b082926877ff3022540634a714d86d4cfefd4932fa432fe8ec7090486e104d0b56d7e610bf75c1a8a684ac218fd7a17",
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       "relation": "negativeCorrelation",
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-      "target": 241
+      "source": 239,
+      "target": 245
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -4703,13 +5079,16 @@
       },
       "evidence": "Receptors composed of alpha7 subunits are known to desensitize rapidly and to have a high Ca2+:Na+ permeability ratio that exceeds that of the glutamate NMDA receptor, and the 3-4:1 ratio of most other nAChRs (8, 68, 78, 387). As a result, quite distinctly from other nAChRs and even other ligand-activated ion channels, the opening of alpha7 nAChR channels can impact on several Ca2+-dependent mechanisms, including activation of second messenger pathways (328, 456).",
       "key": "b7f1d64573f390b463039a48bd8d32b0885207fc83c846f223af815e4285911cca4757b9bf5ed326c9d7b1d83553ba3c69fe3d6b6e82ab9cfd6e7cd5d0646df6",
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       "relation": "increases",
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-      "target": 87
+      "source": 175,
+      "target": 86
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "Species": {
           "7130": true
         },
@@ -4736,13 +5115,16 @@
       },
       "evidence": "One insect has escaped the ill effects of nicotine, Manduca sextans or the tobacco horn worm. While nicotine binds the nAChR to activate and subsequently desensitize it, this insect eats the tobacco plant without ill effects. Manduca exhibits two adaptations to tolerate the effects of nicotine. The first is altered nAChR amino acid sequences that limit the affinity of nicotine for the nAChR (136). The second is the development of the functional equivalent to a blood-brain barrier.",
       "key": "2aadf044e387b9a5b5c4d2f97d7449c0b300dbee949db10b094c732df57db2712d1350b2919700c5188269c93719550e3736928ea72638ac748efcf676136c5b",
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       "relation": "association",
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-      "target": 95
+      "target": 94
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "Species": {
           "7130": true
         },
@@ -4768,14 +5150,20 @@
         "volume": "89"
       },
       "evidence": "One insect has escaped the ill effects of nicotine, Manduca sextans or the tobacco horn worm. While nicotine binds the nAChR to activate and subsequently desensitize it, this insect eats the tobacco plant without ill effects. Manduca exhibits two adaptations to tolerate the effects of nicotine. The first is altered nAChR amino acid sequences that limit the affinity of nicotine for the nAChR (136). The second is the development of the functional equivalent to a blood-brain barrier.",
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-      "relation": "association",
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+      "relation": "decreases",
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+      "target": 109
     },
     {
       "annotations": {
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+        "Species": {
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           "Review": true
         }
@@ -4797,18 +5185,18 @@
         "type": "PubMed",
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-      "evidence": "Metabolic degradation of nicotine and rapid clearance is a mechanism that protects neurons from greater nicotine concentrations, since nicotine readily crosses the mammalian blood-brain barrier and accumulates in the lipophilic brain environment to concentrations that may exceed plasma concentrations by one order of magnitude. Nevertheless, neurotoxicity to nicotine is not uncommon, as attested to by the recent increase in hospital emergency room visits by smokers who concurrently use the transdermal nicotine patch (503).",
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-      "object": {
-        "modifier": "Degradation"
-      },
-      "relation": "increases",
-      "source": 73,
-      "target": 30
+      "evidence": "One insect has escaped the ill effects of nicotine, Manduca sextans or the tobacco horn worm. While nicotine binds the nAChR to activate and subsequently desensitize it, this insect eats the tobacco plant without ill effects. Manduca exhibits two adaptations to tolerate the effects of nicotine. The first is altered nAChR amino acid sequences that limit the affinity of nicotine for the nAChR (136). The second is the development of the functional equivalent to a blood-brain barrier.",
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     },
     {
       "annotations": {
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         "TextLocation": {
           "Review": true
         }
@@ -4830,15 +5218,21 @@
         "type": "PubMed",
         "volume": "89"
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-      "evidence": "For instance, the alpha3 nAChR transcript generally dominates in the prenatal brain or in injured neurons, whereas its expression tends to be downregulated in the adult or healthy neuron, and alpha4 transcription is increased.",
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-      "line": 376,
-      "relation": "decreases",
+      "evidence": "Metabolic degradation of nicotine and rapid clearance is a mechanism that protects neurons from greater nicotine concentrations, since nicotine readily crosses the mammalian blood-brain barrier and accumulates in the lipophilic brain environment to concentrations that may exceed plasma concentrations by one order of magnitude. Nevertheless, neurotoxicity to nicotine is not uncommon, as attested to by the recent increase in hospital emergency room visits by smokers who concurrently use the transdermal nicotine patch (503).",
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+      "object": {
+        "modifier": "Degradation"
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+      "relation": "increases",
       "source": 73,
-      "target": 254
+      "target": 30
     },
     {
       "annotations": {
+        "Confidence": {
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           "Review": true
         }
@@ -4860,15 +5254,18 @@
         "type": "PubMed",
         "volume": "89"
       },
-      "evidence": "For instance, the alpha3 nAChR transcript generally dominates in the prenatal brain or in injured neurons, whereas its expression tends to be downregulated in the adult or healthy neuron, and alpha4 transcription is increased.",
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-      "line": 377,
-      "relation": "increases",
+      "evidence": "For example, while the alpha7 nAChR is primarily a homomeric receptor in neurons (127), combinations of alpha7 nAChR subunits with alpha5, beta2, or beta3 nAChR subunits have been reported to form functional heteromeric receptors in some systems (240, 360, 515).",
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     {
       "annotations": {
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           "Review": true
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@@ -4890,15 +5287,18 @@
         "type": "PubMed",
         "volume": "89"
       },
-      "evidence": "For example, while the alpha7 nAChR is primarily a homomeric receptor in neurons (127), combinations of alpha7 nAChR subunits with alpha5, beta2, or beta3 nAChR subunits have been reported to form functional heteromeric receptors in some systems (240, 360, 515).",
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-      "line": 444,
-      "relation": "association",
+      "evidence": "Interestingly, astrocytic KYNA production is regulated by neuronal activity (187) and cellular energy metabolism (213). This dependence of extracellular KYNA concentrations on the functional interplay between neurons and astrocytes is in line with the postulated neuromodulatory role of KYNA (418) and adds to the complexity of the neurochemical networks in the brain.",
+      "key": "328016bc0745352e134b53188fadbaef0d991f44cba38cd7bddae7b1ea84b4daee2ef06f6c013440410cdb63fe0e333fd66af518139860bdd618aa3fb77cb54e",
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-      "target": 186
+      "target": 12
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
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         "TextLocation": {
           "Review": true
         }
@@ -4920,15 +5320,18 @@
         "type": "PubMed",
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         "type": "PubMed",
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@@ -5006,28 +5412,31 @@
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@@ -5051,16 +5460,19 @@
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       "evidence": "Such toxins are not limited to the muscle receptor as seen in the Taiwanese krate snake. This snake produces “neuronal bungarotoxin” (also referred to as 3.1 toxin or kappa-bungarotoxin; Ref. 286), which preferentially binds to and inactivates neuronal nAChRs that contain the alpha3 and beta4 subunits. In this case, the specificity of the toxin appears to in part be controlled by the subtype of beta nAChR subunit; beta2-containing nAChRs are less sensitive than beta4-containing nAChRs to inhibition by neuronal BGT.",
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@@ -5084,7 +5496,7 @@
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@@ -5092,7 +5504,7 @@
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@@ -5135,16 +5550,19 @@
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       "evidence": "Such toxins are not limited to the muscle receptor as seen in the Taiwanese krate snake. This snake produces “neuronal bungarotoxin” (also referred to as 3.1 toxin or kappa-bungarotoxin; Ref. 286), which preferentially binds to and inactivates neuronal nAChRs that contain the alpha3 and beta4 subunits. In this case, the specificity of the toxin appears to in part be controlled by the subtype of beta nAChR subunit; beta2-containing nAChRs are less sensitive than beta4-containing nAChRs to inhibition by neuronal BGT.",
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@@ -5168,16 +5586,19 @@
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       "evidence": "Not unlike snake toxins, conotoxins can disrupt multiple components of neurotransmission including voltage-gated Na+ and K+ channels in addition to nAChRs (132, 351).",
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@@ -5201,16 +5622,19 @@
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@@ -5233,17 +5657,20 @@
         "volume": "89"
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@@ -5267,13 +5694,16 @@
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       "evidence": "Anandamide, a compound originally isolated from porcine brain extracts, is known to interact with canabinoid receptors 1 and 2 in the brain (120, 159). However, anandamide interacts with numerous other receptors, including voltage-gated Ca2+ channels (357), voltage-gated K+ channels (293), 5-HT3 receptors (358), kainate receptors (3), and nAChRs (356). At nanomolar concentrations, anandamine blocks noncompetitively and voltage independently the activation of alpha7 nAChRs ectopically expressed in Xenopus oocytes (356). It also inhibits the activity of alpha4beta2 nAChRs expressed in SH-EP1 cells (443).",
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@@ -5297,7 +5727,7 @@
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       "evidence": "In addition to nicotine, an nAChR agonist of considerable commercial importance is anatoxin-a (Fig. 3). This toxin is a product of the blue-green algae, Anabaena, and can reach high concentrations during algal blooms common to ponds that serve as the summer water source of livestock. While this toxin exerts much of its effect through targeting muscle nAChRs, it was recognized over two decades ago to also interact with nAChRs expressed by ganglionic receptors (38). Its ability to activate in central nervous system (CNS) neurons nicotinic currents sensitive to alpha-BGT was among the first indicators that functional alpha7 nAChRs could be distinguished from other nAChRs in neurons of the mammalian brain (38).",
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@@ -5305,17 +5735,20 @@
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       "annotations": {
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         "MeSHAnatomy": {
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           "Ganglia": true,
@@ -5344,16 +5777,19 @@
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       "evidence": "In addition to nicotine, an nAChR agonist of considerable commercial importance is anatoxin-a (Fig. 3). This toxin is a product of the blue-green algae, Anabaena, and can reach high concentrations during algal blooms common to ponds that serve as the summer water source of livestock. While this toxin exerts much of its effect through targeting muscle nAChRs, it was recognized over two decades ago to also interact with nAChRs expressed by ganglionic receptors (38). Its ability to activate in central nervous system (CNS) neurons nicotinic currents sensitive to alpha-BGT was among the first indicators that functional alpha7 nAChRs could be distinguished from other nAChRs in neurons of the mammalian brain (38).",
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@@ -5377,25 +5813,28 @@
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       "evidence": "More recently, epibatidine, an alkaloid from the skin of the Ecuadorain tree frog Epipedobates tricolor, revealed another example of how a nicotinic agonist can produce toxic effects (111, 130). In addition to being a potent analgesic, when injected into mice at a relatively low dose (0.4 microg/mouse), this compound produced straub tail reaction. The major target of epibatidine is the alpha4beta2 high-affinity nAChR, although other nAChRs are targeted with various affinities (e.g., Ref. 507).",
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@@ -5419,28 +5858,31 @@
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       "evidence": "More recently, epibatidine, an alkaloid from the skin of the Ecuadorain tree frog Epipedobates tricolor, revealed another example of how a nicotinic agonist can produce toxic effects (111, 130). In addition to being a potent analgesic, when injected into mice at a relatively low dose (0.4 microg/mouse), this compound produced straub tail reaction. The major target of epibatidine is the alpha4beta2 high-affinity nAChR, although other nAChRs are targeted with various affinities (e.g., Ref. 507).",
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@@ -5464,28 +5906,31 @@
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@@ -5509,7 +5954,7 @@
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       "evidence": "Finally, the alkaloid methyllycaconitine (MLA) emerged as a potent and specific competitive antagonist that inhibits muscle, alpha7-, alpha6-, and alpha3-containing nAChRs (30, 326, 445). The alkaloid is derived from the larkspur (genus Delphinium), which is of great economic interest since estimates of its cost to ranchers in poisoned livestock exceeds many millions of dollars annually. Similar to most nAChR poisons, MLA binds to the receptor agonistbinding site (Fig. 3) in a manner similar to that of alpha-BGT to block agonist binding and receptor activation.",
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@@ -5518,23 +5963,26 @@
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@@ -5558,7 +6006,7 @@
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@@ -5567,23 +6015,26 @@
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@@ -5607,7 +6058,7 @@
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@@ -5616,11 +6067,14 @@
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@@ -5644,13 +6098,16 @@
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@@ -5674,13 +6131,16 @@
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@@ -5704,7 +6164,7 @@
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@@ -5713,10 +6173,13 @@
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@@ -5740,7 +6203,7 @@
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@@ -5748,11 +6211,14 @@
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@@ -5775,14 +6241,23 @@
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@@ -5805,32 +6280,41 @@
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@@ -5854,13 +6338,16 @@
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@@ -5887,13 +6374,16 @@
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@@ -5917,16 +6407,19 @@
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@@ -5950,16 +6443,19 @@
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@@ -5983,25 +6479,28 @@
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@@ -6025,9 +6524,9 @@
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@@ -6035,10 +6534,13 @@
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@@ -6062,28 +6564,31 @@
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       "evidence": "Also central to restricting (or at least limiting) the expression of these transcripts to predominantly neuronal-like cell lines (Neuro2A and NGF-treated PC12) are interactions among other factors including SCIP/Tst- 1/Oct-6 and transactivation by Sox10 (66, 268, 317, 513).",
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         "MeSHAnatomy": {
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@@ -6110,13 +6615,16 @@
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       "evidence": "For example, in the original PC12 line (194), NGF is a potent inducer of beta4 transcription (217), but in PC12 lines that are defective in the expression of functional alpha7 nAChRs, NGF decreases beta4 nAChR subunit transcription (60, 397).",
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@@ -6140,13 +6648,16 @@
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@@ -6170,25 +6681,28 @@
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@@ -6212,19 +6726,22 @@
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       "evidence": "For example, while the alpha7 nAChR is primarily a homomeric receptor in neurons (127), combinations of alpha7 nAChR subunits with alpha5, beta2, or beta3 nAChR subunits have been reported to form functional heteromeric receptors in some systems (240, 360, 515).",
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@@ -6248,25 +6765,28 @@
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@@ -7192,14 +7745,17 @@
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@@ -7223,13 +7779,16 @@
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@@ -7253,13 +7812,16 @@
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@@ -7282,14 +7844,17 @@
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@@ -7313,28 +7878,67 @@
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+        "authors": [
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+          "Alkondon M",
+          "Pereira EF",
+          "Rogers SW"
+        ],
+        "date": "2009-01-01",
+        "first": "Albuquerque EX",
+        "last": "Rogers SW",
+        "name": "Physiological reviews",
+        "pages": "73-120",
+        "reference": "19126755",
+        "title": "Mammalian nicotinic acetylcholine receptors: from structure to function.",
+        "type": "PubMed",
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+      "evidence": "Upon transfection of the cDNA encoding alpha7 nAChR subunits, HEK293 cells reportedly express the corresponding transcripts and even make considerable protein. Yet, the number of functional receptors expressed on the cell surface was low and could vary by three orders of magnitude.",
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@@ -7358,19 +7962,22 @@
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@@ -7394,13 +8001,16 @@
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@@ -7424,13 +8034,16 @@
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       "evidence": "In particular, the association of the alpha7 nAChR gene with a sensory gating deficit that is similar to attention deficits in patients with schizophrenia (157), and the degree of alpha4beta2 nAChR loss and altered alpha7 expresson correlate well with the magnitude of progressive cognitive decline in mild-to-moderate AD patients (46).",
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@@ -7454,13 +8067,16 @@
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       "evidence": "For example, Loring and colleagues (458) compared the relative expression of alpah4beta2 versus alpha7 nAChRs transfected into five different cell lines (GH4C1, SH-EP1, CV1, SN-56, and CHOCAR). Each cell line expressed appropriate mRNAs (indicating successful transfection); however, the relative levels of expression of each receptor subtype varied significantly among the various cell lines.",
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@@ -7484,28 +8100,31 @@
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       "evidence": "All cell lines appeared to produce alpha4beta2 nAChRs, although at considerably variable levels relative to each other. Therefore, cell and receptor identity combine to collectively determine the efficiency of nAChR expression on the cell surface.",
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     {
       "annotations": {
         "CellLine": {
           "GH4-C1 cell": true
         },
+        "Confidence": {
+          "High": true
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         "TextLocation": {
           "Review": true
         }
@@ -7529,25 +8148,28 @@
       },
       "evidence": "Only two of these cell lines expressed alpha7 nAChRs: GH4C1 cells expressed substantially greater numbers of surface receptors than did SH-EP1 cells, which exhibited poor assembly efficiency.",
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           "Review": true
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@@ -7571,19 +8193,55 @@
       },
       "evidence": "Studies of recombinant chimeric subunits containing sequences of the NH2-terminal domains of the alpha7 and the alpha3 (M1-S232) nAChR subunits indicated that a 23- amino acid region (glycine-23 to asparagine-46) contained residues required for correct association of the alpha7 subunit into a homopentameric receptor.",
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       "relation": "increases",
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       "relation": "hasComponent",
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+          "Medium": true
+        },
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+          "Review": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Albuquerque EX",
+          "Alkondon M",
+          "Pereira EF",
+          "Rogers SW"
+        ],
+        "date": "2009-01-01",
+        "first": "Albuquerque EX",
+        "last": "Rogers SW",
+        "name": "Physiological reviews",
+        "pages": "73-120",
+        "reference": "19126755",
+        "title": "Mammalian nicotinic acetylcholine receptors: from structure to function.",
+        "type": "PubMed",
+        "volume": "89"
+      },
+      "evidence": "Not surprisingly, the Cys-loop is required for proper domain folding and receptor expression (131, 485). This might also be conditional, since reducing agents such as dithiothreitol (176) can disrupt the role of this structure in receptor assembly and expression.",
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     {
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         "TextLocation": {
           "Review": true
         }
@@ -7607,13 +8265,16 @@
       },
       "evidence": "Another significant assembly checkpoint to ensure only correctly assembled nAChRs are transported to the cell surface is the endoplasmic reticulum. Most nAChRs are not constitutively sent to lysosomes. Instead, they are retained in intracellular pools that range from 65 to 85% of the total receptor number in a cell (147, 359, 397, 496).",
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     {
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           "Review": true
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@@ -7635,15 +8296,18 @@
         "type": "PubMed",
         "volume": "89"
       },
-      "evidence": "In fact, 80% of the synthesized subunits appear to improperly assemble or never leave the endoplasmic reticulum where they are then degraded (485). The process of retaining subunits and possibly fully assembled receptors and then degrading them may be an important component of regulating receptor number.",
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-      "line": 633,
+      "evidence": "In fact, 80% of the synthesized subunits appear to improperly assemble or never leave the endoplasmic reticulum where they are then degraded (485). The process of retaining subunits and possibly fully assembled receptors and then degrading them may be an important component of regulating receptor number'.",
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       "annotations": {
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@@ -7665,9 +8329,9 @@
         "type": "PubMed",
         "volume": "89"
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-      "evidence": "In fact, 80% of the synthesized subunits appear to improperly assemble or never leave the endoplasmic reticulum where they are then degraded (485). The process of retaining subunits and possibly fully assembled receptors and then degrading them may be an important component of regulating receptor number.",
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-      "line": 634,
+      "evidence": "In fact, 80% of the synthesized subunits appear to improperly assemble or never leave the endoplasmic reticulum where they are then degraded (485). The process of retaining subunits and possibly fully assembled receptors and then degrading them may be an important component of regulating receptor number'.",
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           "name": "endoplasmic reticulum",
@@ -7677,10 +8341,13 @@
       },
       "relation": "increases",
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-      "target": 208
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     },
     {
       "annotations": {
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         "Species": {
           "8355": true
         },
@@ -7707,7 +8374,7 @@
       },
       "evidence": "When cRNAs encoding specific nAChR subunits are introduced into Xenopus oocytes, simple (alpha3beta4) as well as more complex (muscle alpha1beta1deltagamma) heteromeric receptors are assembled and expressed on the cell surface (341). In Xenopus oocytes, these heteromeric nAChRs are assembled and expressed with almost equivalent efficiencies as the homomeric 5HT3A receptor (341).",
       "key": "71e854248ba95e35eab536d5b69d6591a9a8464f3fab2540033dcd2dca8da88bc7bb10a645d310b5ed76a09b2a9e56512de5497b2ecb08ecb6a68464d9d96105",
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@@ -7716,10 +8383,13 @@
       },
       "relation": "increases",
       "source": 117,
-      "target": 167
+      "target": 170
     },
     {
       "annotations": {
+        "Confidence": {
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+        },
         "Species": {
           "8355": true
         },
@@ -7746,7 +8416,7 @@
       },
       "evidence": "When cRNAs encoding specific nAChR subunits are introduced into Xenopus oocytes, simple (alpha3beta4) as well as more complex (muscle alpha1beta1deltagamma) heteromeric receptors are assembled and expressed on the cell surface (341). In Xenopus oocytes, these heteromeric nAChRs are assembled and expressed with almost equivalent efficiencies as the homomeric 5HT3A receptor (341).",
       "key": "1955316d7e2171cb42c95f494407f1bd18c13108db781fc48fd00b33d4efef7464c465e28ec6bc8b9bad10903368ab95a04cf190771d60f729af2a0662c53780",
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@@ -7755,10 +8425,13 @@
       },
       "relation": "increases",
       "source": 117,
-      "target": 135
+      "target": 137
     },
     {
       "annotations": {
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+        },
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           "Review": true
         }
@@ -7782,7 +8455,7 @@
       },
       "evidence": "Thus inhibitors of proteasome function block endoplasmic reticulum-associated degradation of unassembled AChR subunits, which in turn increases the availability of subunits for assembly into mature receptors that are trafficked to the cell surface.",
       "key": "2f0ee7af4175a28cf2437c1c4d59bc257bf190adc02274f6582d2251632b4bf5affd638b2a1e536968eee5cd34358aca22c210629917b910f97801c2501b3266",
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       "object": {
         "location": {
           "name": "endoplasmic reticulum",
@@ -7792,22 +8465,58 @@
       },
       "relation": "decreases",
       "source": 16,
-      "target": 208
+      "target": 211
+    },
+    {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
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+          "Review": true
+        }
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+      "citation": {
+        "authors": [
+          "Albuquerque EX",
+          "Alkondon M",
+          "Pereira EF",
+          "Rogers SW"
+        ],
+        "date": "2009-01-01",
+        "first": "Albuquerque EX",
+        "last": "Rogers SW",
+        "name": "Physiological reviews",
+        "pages": "73-120",
+        "reference": "19126755",
+        "title": "Mammalian nicotinic acetylcholine receptors: from structure to function.",
+        "type": "PubMed",
+        "volume": "89"
+      },
+      "evidence": "Thus inhibitors of proteasome function block endoplasmic reticulum-associated degradation of unassembled AChR subunits, which in turn increases the availability of subunits for assembly into mature receptors that are trafficked to the cell surface.",
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     {
       "annotations": {
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+        },
         "TextLocation": {
           "Review": true
         }
@@ -7831,13 +8540,16 @@
       },
       "evidence": "As will be returned to below, it is also the first nAChR subtype to exhibit measurable decline in expression in the aged mammalian brain and especially in neurodegenerative disorders such as AD (236, 374).",
       "key": "6e9bf4f0bc1c42e7da3dcc3617130ea4305a10700273d6d2a68c42d5b4c2c94e690b2a0a9f60c689bb93d5fd26348c1e77b8b933fb583bb0630c72ea3ef88c21",
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     },
     {
       "annotations": {
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           "Review": true
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@@ -7861,13 +8573,16 @@
       },
       "evidence": "However, loss of brain nAChRs precedes that of muscarinic receptors during normal aging, and it is often much more extensive in human brains afflicted with AD relative to age-matched controls (236, 308, 373, 374, 416, 519). In fact, alpha4 nAChR expression can decrease by >80% in the AD brain (306, 374).",
       "key": "a3837e0be1c37183c827fe25fc75504f9522fce4f4c2011458d7fa3187a3f226cd5ffb5e05b3c0f4705aaf6fd8c325efce2dd04efab8140ae6cfaed0fb540ea8",
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-      "target": 208
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     {
       "annotations": {
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           "Review": true
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@@ -7891,13 +8606,16 @@
       },
       "evidence": "First, age-related nAChR subunit expression decline was observed in both strains, and this was dominated by diminished alpha4 nAChR expression. Second, long-term (12 mo) oral nicotine failed to reduce the age-related decline in the number of neurons expressing alpha4 nAChR subunits, although the neurons that remained exhibited larger processes with more varicosities than age-matched controls (165, 396). Acute nicotine treatment (alpha6 wk of oral nicotine) of aged mice had no measurable influence on nAChR expression, neuronal viability, or dendritic complexity (e.g., Ref. 396)",
       "key": "4a43f624bb65b98607129f196c59721d9aa011dc4776b2d5335473df0f9550016aacf141ac95adfb64efe19ef131eb7bbdd3182f235e63ac255e7129ea260983",
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       "relation": "decreases",
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-      "target": 208
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+      "target": 211
     },
     {
       "annotations": {
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+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -7921,13 +8639,16 @@
       },
       "evidence": "First, age-related nAChR subunit expression decline was observed in both strains, and this was dominated by diminished alpha4 nAChR expression. Second, long-term (12 mo) oral nicotine failed to reduce the age-related decline in the number of neurons expressing alpha4 nAChR subunits, although the neurons that remained exhibited larger processes with more varicosities than age-matched controls (165, 396). Acute nicotine treatment (alpha6 wk of oral nicotine) of aged mice had no measurable influence on nAChR expression, neuronal viability, or dendritic complexity (e.g., Ref. 396)",
       "key": "61c6dba37e8775f1a59114031b4cfa6731399c77acf15381b6bc1bc8b5beb85b968a153f4ab25c50de3c3c04d8bcc8ada349643ddda883a81789db2b9ac7bdfa",
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-      "target": 214
+      "source": 248,
+      "target": 219
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Hippocampus": true
         },
@@ -7957,13 +8678,16 @@
       },
       "evidence": "Mouse strains, like humans, also exhibit a striking age-related decline in nAChR expression. For instance, in the hippocampus of aged CBA and B6 mice, expression of alpha4 and alpha7 nAChR subunits decreases with age (166). ",
       "key": "8ff36920c9a3b913cafcc29b90ace536d4ba9e67d5daac7a64706c4c1be605b42cd070cb3cfb53d3fa22a05d8c6983a39d8750d7cbab1d6105102dae66398048",
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-      "target": 214
+      "source": 248,
+      "target": 219
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Hippocampus": true
         },
@@ -7993,13 +8717,16 @@
       },
       "evidence": "Mouse strains, like humans, also exhibit a striking age-related decline in nAChR expression. For instance, in the hippocampus of aged CBA and B6 mice, expression of alpha4 and alpha7 nAChR subunits decreases with age (166). ",
       "key": "c253db78e7638142d967d5b3f990cd79b09c6619db62c60db95ba3aec56a35bec96936f12069e5c6b98e9a70474bfa7d51af47055dcd7a4a11785b780f3d706f",
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-      "target": 215
+      "source": 248,
+      "target": 220
     },
     {
       "annotations": {
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+        },
         "TextLocation": {
           "Review": true
         }
@@ -8023,13 +8750,16 @@
       },
       "evidence": "As will be returned to below, it is also the first nAChR subtype to exhibit measurable decline in expression in the aged mammalian brain and especially in neurodegenerative disorders such as AD (236, 374).",
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-      "target": 168
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     },
     {
       "annotations": {
+        "Confidence": {
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+        },
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           "Review": true
         }
@@ -8053,13 +8783,16 @@
       },
       "evidence": "In particular, the association of the alpha7 nAChR gene with a sensory gating deficit that is similar to attention deficits in patients with schizophrenia (157), and the degree of alpha4beta2 nAChR loss and altered alpha7 expresson correlate well with the magnitude of progressive cognitive decline in mild-to-moderate AD patients (46).",
       "key": "c72b2a18e228b687d9cb722df2ea8ea1fb2703810443dc4fd97127cdf529ed2fb65ca923c593a956a7c2c1e7c692c0ffb5656dc68a2133cb13130b0b01de3f7c",
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-      "target": 168
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+      "target": 171
     },
     {
       "annotations": {
+        "Confidence": {
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+        },
         "TextLocation": {
           "Review": true
         }
@@ -8083,16 +8816,19 @@
       },
       "evidence": "Reduced nAChR function/expression in the brain has been associated with the pathophysiology of catastrophic disorders, including AD and schizophrenia (discussed in later sections, and see Refs. 277, 432).",
       "key": "a7561777b90da0a246c71d9440db00bb9a0c8b8eeaa9823a33051fe79f88f837a89a8d6287913dcdbf02dd433c24e4629343f723c1bdfd54fa8d10cbe8ed2eba",
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       "object": {
         "modifier": "Activity"
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       "relation": "negativeCorrelation",
-      "source": 220,
-      "target": 208
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+      "target": 211
     },
     {
       "annotations": {
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+        },
         "TextLocation": {
           "Review": true
         }
@@ -8116,13 +8852,16 @@
       },
       "evidence": "However, loss of brain nAChRs precedes that of muscarinic receptors during normal aging, and it is often much more extensive in human brains afflicted with AD relative to age-matched controls (236, 308, 373, 374, 416, 519). In fact, alpha4 nAChR expression can decrease by >80% in the AD brain (306, 374).",
       "key": "b5e41ab945359ff9b4bf2658bd10c78982289fb7c277194761b5aa76415c8c03eb18b7d1cc17e0d775835cfc3e5280f443acb89179856fb829dfa2a622d33ace",
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       "relation": "negativeCorrelation",
-      "source": 220,
-      "target": 208
+      "source": 225,
+      "target": 211
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Astrocytes": true
         },
@@ -8149,13 +8888,16 @@
       },
       "evidence": "It is noteworthy that nAChR expression by astrocytes in brains afflicted with AD is increased (463, 518), and astrocytes in general have been reported to be more plentiful in the hippocampus of some rat strains with age (35, 284).",
       "key": "aa0e5a2562a227b9780fa6ccad8cfe35d92e1eb5c4f1b1ed39cd6f3c2fe29212976b19adcc97faef9d41cfaa165484a1828634def72290e77799abdaeb2ef077",
-      "line": 1665,
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       "relation": "positiveCorrelation",
-      "source": 220,
-      "target": 208
+      "source": 225,
+      "target": 211
     },
     {
       "annotations": {
+        "Confidence": {
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       "evidence": "In particular, the association of the alpha7 nAChR gene with a sensory gating deficit that is similar to attention deficits in patients with schizophrenia (157), and the degree of alpha4beta2 nAChR loss and altered alpha7 expresson correlate well with the magnitude of progressive cognitive decline in mild-to-moderate AD patients (46).",
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     {
       "annotations": {
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         "MeSHAnatomy": {
           "Hippocampus": true
         },
@@ -8212,13 +8957,16 @@
       },
       "evidence": "Chronic alpha7 nAChR inhibition in the hippocampus by elevated levels of KYNA can contribute to auditory gating deficits, which appear to be associated with the development of schizophrenia (156). It is also feasible that KYNAinduced inhibition of alpha7 nAChRs contributes to the cognitive impairment observed in patients with AD and schizophrenia (273).",
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@@ -8272,13 +9023,16 @@
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@@ -8463,41 +9256,110 @@
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+        "pages": "73-120",
+        "reference": "19126755",
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+        "type": "PubMed",
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+      "evidence": "Prolonged treatment of rodents and monkeys with nicotine downregulates the expression of alpha6beta3-containing nAChRs in the brain (257, 311, 332). However, in heterologous culture systems, nicotine appears to upregulate the expression of receptors assembled from alpha4/alpha6/beta2/beta3 input cDNA (363), and this may depend on numerous factors including ligand concentrations (483).",
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     {
       "annotations": {
         "Anatomy": {
           "hippocampus stratum lacunosum moleculare": true
         },
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@@ -8521,7 +9383,7 @@
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       "evidence": "On the other hand, when alpha4beta2 nAChRs are activated, both SR and SLM interneurons are inhibited, resulting in disinhibition of dendritic areas innervated by both neuron types.",
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@@ -8534,6 +9396,9 @@
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@@ -8557,7 +9422,7 @@
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       "evidence": "Third, nAChR-mediated GABA release can cause neuronal hyperpolarization, which in turn affects neuronal function via several mechanisms, including removal of inactivation of inward currents (89).",
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@@ -8573,13 +9438,16 @@
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     {
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           "hippocampus stratum lacunosum moleculare": true
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@@ -8603,7 +9471,7 @@
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       "evidence": "It is noteworthy that, via such mechanisms, alpha7 nAChR activation could trigger rebound burst firing in SLM interneurons even in the absence of excitation (256). Burst firing in SLM interneurons suppresses spikes in pyramidal neurons evoked by stimulation of Schaffer collaterals (134), and, thereby allows selective activation of the pyramidal cells via the perforant pathway.",
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@@ -8611,7 +9479,7 @@
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@@ -8619,6 +9487,9 @@
         "Anatomy": {
           "hippocampus stratum lacunosum moleculare": true
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@@ -8642,16 +9513,19 @@
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       "evidence": "It is noteworthy that, via such mechanisms, alpha7 nAChR activation could trigger rebound burst firing in SLM interneurons even in the absence of excitation (256). Burst firing in SLM interneurons suppresses spikes in pyramidal neurons evoked by stimulation of Schaffer collaterals (134), and, thereby allows selective activation of the pyramidal cells via the perforant pathway.",
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@@ -8675,7 +9549,7 @@
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       "evidence": "For example, during a low degree of activation of alpha7 and alpha3beta4 nAChRs, Ca2+ can enter the cells through nAChRs or NMDA receptors and favor activation (i.e., phosphorylation) of the transcription factor CREB, which in turn modifies gene expression (82).",
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@@ -8691,10 +9565,13 @@
           "namespace": "GO"
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     {
       "annotations": {
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         "MeSHAnatomy": {
           "Neurons": true
         },
@@ -8721,7 +9598,7 @@
       },
       "evidence": "There is evidence that anandamide is produced by postsynaptic neurons in response to elevated intracellular Ca2+ levels. For instance, concomitant activation of alpha7 nAChRs and NMDA receptors triggers the production of anandamine in postsynaptic neurons (448). Anandamine, then, functions as a retrograde messenger and regulates synaptic transmission by interacting with specific receptors in the presynaptic neurons/terminals (498).",
       "key": "b7521ee60cdb2937a8125d771a518f5c6719ddcefd7799f61c3c6d1d717277036d73f832f42d284b0581a79f21b97f843dbcb84f530fcc74dd13870e6263310d",
-      "line": 1306,
+      "line": 1427,
       "relation": "increases",
       "source": 9,
       "subject": {
@@ -8734,6 +9611,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -8757,7 +9637,7 @@
       },
       "evidence": "It was then recognized that Ca2+ flux directly through nAChR channels or indirectly via voltage-gated Ca2+ channels is relevant for nicotinic modulation of transmitter release, synaptic plasticity, as well as neuronal viability, differentiation, and migration.",
       "key": "024db609a2642fe6dbc56bcbf4bf6b1d4adbf7ad9782637407c32f6ab890e8f3c81733e9f04619f5479e70943a14d4c7c06e3219b5649569c6966f6f532fbc1e",
-      "line": 1362,
+      "line": 1487,
       "relation": "regulates",
       "source": 9,
       "subject": {
@@ -8770,6 +9650,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -8793,7 +9676,7 @@
       },
       "evidence": "It was then recognized that Ca2+ flux directly through nAChR channels or indirectly via voltage-gated Ca2+ channels is relevant for nicotinic modulation of transmitter release, synaptic plasticity, as well as neuronal viability, differentiation, and migration.",
       "key": "8f00c8867acebdf4a7842bd16aa260946af8a3db594e3c4e60c5015af92f71e2ada88b0a38a5d82def6361c61f810cc4d933ac37c820e46a3020d17f22336311",
-      "line": 1363,
+      "line": 1488,
       "relation": "regulates",
       "source": 9,
       "subject": {
@@ -8802,10 +9685,13 @@
           "namespace": "GO"
         }
       },
-      "target": 118
+      "target": 120
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -8829,7 +9715,7 @@
       },
       "evidence": "It was then recognized that Ca2+ flux directly through nAChR channels or indirectly via voltage-gated Ca2+ channels is relevant for nicotinic modulation of transmitter release, synaptic plasticity, as well as neuronal viability, differentiation, and migration.",
       "key": "f8b391859937d1155b95a318ac3a963a25fb44655b8cf7a5fc7cb8a27548d99f762a2aeface3b78ce337b6dc04000f78ee9ef132bed717d4ee0eb28bf679214e",
-      "line": 1364,
+      "line": 1489,
       "relation": "regulates",
       "source": 9,
       "subject": {
@@ -8838,10 +9724,13 @@
           "namespace": "GO"
         }
       },
-      "target": 104
+      "target": 103
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -8865,7 +9754,7 @@
       },
       "evidence": "It was then recognized that Ca2+ flux directly through nAChR channels or indirectly via voltage-gated Ca2+ channels is relevant for nicotinic modulation of transmitter release, synaptic plasticity, as well as neuronal viability, differentiation, and migration.",
       "key": "70e298180cb23ecf5b67e69b32f122f2cb67e9d9a2bb6c145ac2dbf6f4b264340c6801d012e02329e7c9f0a032a906af1ec16cfe4bce224965865b7c2c43be31",
-      "line": 1365,
+      "line": 1490,
       "relation": "regulates",
       "source": 9,
       "subject": {
@@ -8874,10 +9763,13 @@
           "namespace": "GO"
         }
       },
-      "target": 103
+      "target": 102
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -8901,9 +9793,9 @@
       },
       "evidence": "For example, during a low degree of activation of alpha7 and alpha3beta4 nAChRs, Ca2+ can enter the cells through nAChRs or NMDA receptors and favor activation (i.e., phosphorylation) of the transcription factor CREB, which in turn modifies gene expression (82).",
       "key": "0f7c3343522562e90a8a5664c92e59083609880945d79bce561049d6b534ddffae4efbfd03f3dd7b74e688dd3db5269b46fd446f3538b4dc02f1f5d075d1c498",
-      "line": 818,
+      "line": 894,
       "relation": "regulates",
-      "source": 161,
+      "source": 165,
       "subject": {
         "effect": {
           "name": "tscript",
@@ -8911,10 +9803,13 @@
         },
         "modifier": "Activity"
       },
-      "target": 96
+      "target": 95
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -8938,16 +9833,19 @@
       },
       "evidence": "Recent studies have supported a role for ERK and CREB activity in neural plasticity associated with nicotine addiction (71, 381, 484). It has also been proposed that the ERK and JAK-2/STAT-3 signaling pathways contribute to the toxic effects of nicotine in skin cells (42), and other pathways contribute to the effects of nicotine and other nicotinic ligands on inflammatory responses as described below.",
       "key": "8d84365a54f7c53f65d14084eb1960c034527908439643a8ff97005cac4150d96f49d12be0dc565f08cc05c8b9e9227e0216d7c7c402637033650fce0ea388de",
-      "line": 1425,
+      "line": 1553,
       "relation": "association",
-      "source": 161,
+      "source": 165,
       "subject": {
         "modifier": "Activity"
       },
-      "target": 118
+      "target": 120
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -8971,16 +9869,19 @@
       },
       "evidence": "Recent studies have supported a role for ERK and CREB activity in neural plasticity associated with nicotine addiction (71, 381, 484). It has also been proposed that the ERK and JAK-2/STAT-3 signaling pathways contribute to the toxic effects of nicotine in skin cells (42), and other pathways contribute to the effects of nicotine and other nicotinic ligands on inflammatory responses as described below.",
       "key": "34874cacfed305d7f5efff120d0d8aad9931d970c80e5a1d840f18a2da6ef19b057d8b8b9f6fceb6df2aa7793295d42f67f9a005e5a494d14e42d8307f88cfa1",
-      "line": 1428,
+      "line": 1556,
       "relation": "association",
-      "source": 161,
+      "source": 165,
       "subject": {
         "modifier": "Activity"
       },
-      "target": 241
+      "target": 245
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -9004,16 +9905,19 @@
       },
       "evidence": "If there is intense stimulation of all three nAChRs, the resulting depolarization can trigger activation of voltage- gated Ca2+ channels (VGCC), which in turn would activate the calcineurin pathway and prevent CREB activation.",
       "key": "cb318a46c1ff92f054865dcb3d5e92f8ce3557a20cb7f5413c902a4d013beaf6f958a48d82369171d8ae257799f9f56bb3aef2f7a45debd4223c5e9a353f9e7c",
-      "line": 826,
+      "line": 903,
       "relation": "increases",
-      "source": 119,
+      "source": 122,
       "subject": {
         "modifier": "Activity"
       },
-      "target": 86
+      "target": 85
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -9037,7 +9941,7 @@
       },
       "evidence": "If there is intense stimulation of all three nAChRs, the resulting depolarization can trigger activation of voltage- gated Ca2+ channels (VGCC), which in turn would activate the calcineurin pathway and prevent CREB activation.",
       "key": "8750dc2f217b338b40edee802ce51db7fa5dcf7248ba0f32ebeae995052d735c4c3a0de8c7e9d3deab0fb9f081e560b6e21704cfc33f4c88ea4bfb7caace06a1",
-      "line": 827,
+      "line": 904,
       "object": {
         "effect": {
           "name": "tscript",
@@ -9046,14 +9950,17 @@
         "modifier": "Activity"
       },
       "relation": "decreases",
-      "source": 119,
+      "source": 122,
       "subject": {
         "modifier": "Activity"
       },
-      "target": 161
+      "target": 165
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -9077,13 +9984,16 @@
       },
       "evidence": "Anandamide, a compound originally isolated from porcine brain extracts, is known to interact with canabinoid receptors 1 and 2 in the brain (120, 159). However, anandamide interacts with numerous other receptors, including voltage-gated Ca2+ channels (357), voltage-gated K+ channels (293), 5-HT3 receptors (358), kainate receptors (3), and nAChRs (356). At nanomolar concentrations, anandamine blocks noncompetitively and voltage independently the activation of alpha7 nAChRs ectopically expressed in Xenopus oocytes (356). It also inhibits the activity of alpha4beta2 nAChRs expressed in SH-EP1 cells (443).",
       "key": "e25d7f5d6da3c4632f7074ad96f6cf06beed21918a5828c4a258afab43b0666346e6aab87ecc8ff98696d35678a018615871d9756dfdc2ebf0cc10154a1029d3",
-      "line": 1287,
+      "line": 1407,
       "relation": "association",
-      "source": 119,
+      "source": 122,
       "target": 20
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -9107,7 +10017,7 @@
       },
       "evidence": "Activation of somatodendritic alpha7 nAChRs increases the action potential-dependent release of dopamine, while activation of presynaptic alpha6 and/or alpha4 nAChRs increases action potential-independent dopamine release.",
       "key": "ae2a7661dacfe1c68be8835a6dc499ff0a76b1b9f2b946900cb8fa172e4dde2a1ac42a6ff713901acc48e174575d65971db95732790a8c5200909ab5915a2bad",
-      "line": 866,
+      "line": 946,
       "object": {
         "effect": {
           "fromLoc": {
@@ -9122,11 +10032,14 @@
         "modifier": "Translocation"
       },
       "relation": "increases",
-      "source": 169,
+      "source": 172,
       "target": 26
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -9150,7 +10063,7 @@
       },
       "evidence": "Activation of somatodendritic alpha7 nAChRs increases the action potential-dependent release of dopamine, while activation of presynaptic alpha6 and/or alpha4 nAChRs increases action potential-independent dopamine release.",
       "key": "367b70c017555621607bb1dc319eedf5d920a055418d2ba9710ad687572ddf4b1fb650b322a3aafe289e708e1452b3fe4326cc96247e2ce80a13f0debe798160",
-      "line": 867,
+      "line": 947,
       "object": {
         "effect": {
           "fromLoc": {
@@ -9165,11 +10078,14 @@
         "modifier": "Translocation"
       },
       "relation": "increases",
-      "source": 171,
+      "source": 174,
       "target": 26
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -9193,7 +10109,7 @@
       },
       "evidence": "Activation of somatodendritic alpha7 nAChRs increases the action potential-dependent release of dopamine, while activation of presynaptic alpha6 and/or alpha4 nAChRs increases action potential-independent dopamine release.",
       "key": "fce4a51dbef8568ff157339384dcaf6c7dc9829caf4f41f87cc40e0c7421781c6504b3ee724f7ba70be53118489114a93756802e642d64659298e8d2677b89c6",
-      "line": 865,
+      "line": 945,
       "object": {
         "effect": {
           "fromLoc": {
@@ -9208,11 +10124,14 @@
         "modifier": "Translocation"
       },
       "relation": "increases",
-      "source": 105,
+      "source": 104,
       "target": 26
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Dopaminergic Neurons": true
         },
@@ -9239,13 +10158,16 @@
       },
       "evidence": "Parkinson’s disease (PD) is characterized by selective damage to dopaminergic nigrostriatal neurons and is clinically revealed by motor deficits, including rigidity, tremor, and bradykinesia. Dopamine replacement therapy (usually with L-dopa) is the most common treatment, although this drug loses efficacy over time.",
       "key": "00aa148e3ba8d79eb81310c1c44c22ac50361643752a66c7c9b3a016d1ffe1d1a07658510f04ca5abb094de4fc306c387b2c251014f57a01ff97e040688643f9",
-      "line": 1746,
+      "line": 1902,
       "relation": "decreases",
       "source": 26,
-      "target": 235
+      "target": 239
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -9269,7 +10191,7 @@
       },
       "evidence": "Other levels of regulation of dopaminergic transmission arise from alpha7 nAChRs located on cortical glutamatergic terminals; activation of these receptors increases glutamate release onto dopaminergic neurons in the VTA and, consequently, increases the their firing (344).",
       "key": "d82b8c48a46c050dce3880a054b6c78a304c5cca4f03a7c693a60e54501153c8b83b66d5b490b1b5931ff721d5848962898afc69aac6c46202ac46392a59a828",
-      "line": 878,
+      "line": 959,
       "relation": "increases",
       "source": 11,
       "subject": {
@@ -9282,6 +10204,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -9305,13 +10230,16 @@
       },
       "evidence": "Neuronal nAChRs are not expressed exclusively in neurons. Instead, they are expressed by multiple cell types of diverse origins and functions including glia (165, 167, 425), keratinocytes (44, 86, 95, 426), endothelial cells (290, 495), and multiple cell types of the digestive system, lungs, and immune system (e.g., Refs. 95, 309, 492, 495).",
       "key": "a3b08a46a00a464b4828ad1cae8b2042b603335f82852b8686996864a4db830d17dc49988545dba364b70ff9df9239f62fb94f35ac443aef2e4db7249da06627",
-      "line": 897,
+      "line": 980,
       "relation": "increases",
       "source": 72,
-      "target": 208
+      "target": 211
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -9335,13 +10263,16 @@
       },
       "evidence": "Neuronal nAChRs are not expressed exclusively in neurons. Instead, they are expressed by multiple cell types of diverse origins and functions including glia (165, 167, 425), keratinocytes (44, 86, 95, 426), endothelial cells (290, 495), and multiple cell types of the digestive system, lungs, and immune system (e.g., Refs. 95, 309, 492, 495).",
       "key": "c32080ebca04e0c5db6435108eb0b93186bdfd3f433eb33f95e8588e5413a8cdc152909ab96427963eb490bfbab6568b475d6668d9978fef5fff3f19e89e682a",
-      "line": 898,
+      "line": 981,
       "relation": "increases",
       "source": 69,
-      "target": 208
+      "target": 211
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -9365,13 +10296,16 @@
       },
       "evidence": "Neuronal nAChRs are not expressed exclusively in neurons. Instead, they are expressed by multiple cell types of diverse origins and functions including glia (165, 167, 425), keratinocytes (44, 86, 95, 426), endothelial cells (290, 495), and multiple cell types of the digestive system, lungs, and immune system (e.g., Refs. 95, 309, 492, 495).",
       "key": "c0fd505f0a0fc0ebe7d40b2f49c2fce8f2c1f7be156a982919db2c98585dc6facb8e0350ea5fd3e66e278f9f8a302dbf0190dc9ac4b73d0a4f5abdab03e2cee3",
-      "line": 899,
+      "line": 982,
       "relation": "increases",
       "source": 50,
-      "target": 208
+      "target": 211
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Neuromuscular Junction": true
         },
@@ -9398,16 +10332,55 @@
       },
       "evidence": "At the neuromuscular junction, nicotinic function is enhanced by inhibition of acetylcholinesterase (AChE), the enzyme that metabolizes the endogenous neurotransmitter ACh.",
       "key": "1164b4236586393b7d1c56cb9fc6b818a7b62dfdae852055312bf855e5724314c52495605e7da9dc47bbe242e33ba047a34e7b5db44b99dbbd894a84cab46aed",
-      "line": 908,
+      "line": 992,
       "object": {
         "modifier": "Activity"
       },
       "relation": "decreases",
-      "source": 175,
+      "source": 178,
       "target": 30
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "TextLocation": {
+          "Review": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Albuquerque EX",
+          "Alkondon M",
+          "Pereira EF",
+          "Rogers SW"
+        ],
+        "date": "2009-01-01",
+        "first": "Albuquerque EX",
+        "last": "Rogers SW",
+        "name": "Physiological reviews",
+        "pages": "73-120",
+        "reference": "19126755",
+        "title": "Mammalian nicotinic acetylcholine receptors: from structure to function.",
+        "type": "PubMed",
+        "volume": "89"
+      },
+      "evidence": "Drugs currently approved to treat mild-to-moderate AD, including galantamine, donepezil, and rivastigmine, all inhibit AChE, the enzyme that hydrolyzes ACh (462).",
+      "key": "abfd4f8768bb6502b129fcdddd9dbc64a315dbb9cb6b08fb3f7260f090fdb3e9d9d5600bf82386f6c3c98cd4d429ac7065dae045f2bdcde972d502daa571a01f",
+      "line": 1321,
+      "relation": "decreases",
+      "source": 178,
+      "subject": {
+        "modifier": "Activity"
+      },
+      "target": 60
+    },
+    {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -9431,16 +10404,19 @@
       },
       "evidence": "In fact, as described above, AChE inhibitors do not affect alpha7 nAChR-mediated synaptic transmission evoked by low-frequency stimulation of cholinergic fibers in chick ciliary ganglia (522).",
       "key": "52522ffb4afa13038aa4181a3ca385c5a84297a236779580d63b60ec2dcf813fd6ff2dee235fa720e9216a3306d755397051ab2027983a1ff94bbd9f06be1ad4",
-      "line": 917,
+      "line": 1002,
       "object": {
         "modifier": "Activity"
       },
       "relation": "causesNoChange",
       "source": 45,
-      "target": 186
+      "target": 189
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -9464,16 +10440,19 @@
       },
       "evidence": "An alternative means to increase nicotinic functions in the brain is to sensitize the nAChRs to activation by the endogenous agonist(s) using the so-called nicotinic allosteric potentiating ligands (APLs), which include drugs such as physostigmine and galantamine, a drug currently approved for the treatment of AD.",
       "key": "93db6a86f87c194138b30b8975bc8832a11f28d15d942db7f2293aea12e74241f3c9fc3d9cce234a216d1d5097b18048bd421a45c248efbc681a5ac42bc4a228",
-      "line": 926,
+      "line": 1012,
       "object": {
         "modifier": "Activity"
       },
       "relation": "increases",
       "source": 31,
-      "target": 208
+      "target": 211
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Species": {
           "8342": true
         },
@@ -9500,7 +10479,7 @@
       },
       "evidence": "Studies from the early 1980s provided evidence that the cholinesterase (ChE) inhibitor physostigmine could interact directly with nAChRs at the frog neuromuscular junction and induce nicotinic single-channel currents (428, 429).",
       "key": "3bba0b6ad5b8490c51c48059964a95b852bf27e87c4dcd329ef607a903143cbc4b9a73b0319d61493b1520bb52e907ba5c9c8323f4a6a74059dffba0478fe1ba",
-      "line": 937,
+      "line": 1024,
       "object": {
         "location": {
           "name": "Neuromuscular Junction",
@@ -9510,10 +10489,13 @@
       },
       "relation": "increases",
       "source": 31,
-      "target": 208
+      "target": 211
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -9537,16 +10519,19 @@
       },
       "evidence": "Surprisingly, however, activation of nAChRs by galantamine or physostigmine was insensitive to blockade by competitive nAChR antagonists, was detected even when the receptors were desensitized by high agonist concentrations, and was inhibited by the monoclonal antibody FK1 (350, 370, 372, 413, 428, 429).",
       "key": "4061f0b8864c4e9000f96a6a4119fa0e82b1d1cd2ac9f63d780c38bd933942fdf735986281f9b4e992656732721f302aac665ce20e475c0d33516a3b38879eb3",
-      "line": 959,
+      "line": 1048,
       "object": {
         "modifier": "Activity"
       },
       "relation": "increases",
       "source": 31,
-      "target": 208
+      "target": 211
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -9570,16 +10555,19 @@
       },
       "evidence": "An alternative means to increase nicotinic functions in the brain is to sensitize the nAChRs to activation by the endogenous agonist(s) using the so-called nicotinic allosteric potentiating ligands (APLs), which include drugs such as physostigmine and galantamine, a drug currently approved for the treatment of AD.",
       "key": "cf20e168da265537091cd5605229db1a01abe9c44cf0f5cc3fff6b52a6399c6131b872126547e4905ba4c3149476332d5784e5877268886b61bc839f8e36583a",
-      "line": 927,
+      "line": 1013,
       "object": {
         "modifier": "Activity"
       },
       "relation": "increases",
       "source": 28,
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@@ -9636,16 +10627,19 @@
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@@ -9669,16 +10663,19 @@
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@@ -9702,13 +10699,16 @@
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@@ -9732,13 +10732,16 @@
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       "evidence": "The nicotinic APL action of galantamine appears to be an important determinant of its clinical effectiveness (reviewed in Refs. 98, 291, 371). Acting primarily as a nicotinic APL, galantamine improves synaptic transmission and decreases neurodegeneration, two effects essential for its cognitive-enhancing properties (40, 108, 241, 409, 521).",
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@@ -9762,13 +10765,16 @@
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       "evidence": "Drugs currently approved to treat mild-to-moderate AD, including galantamine, donepezil, and rivastigmine, all inhibit AChE, the enzyme that hydrolyzes ACh (462).",
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@@ -9792,7 +10798,7 @@
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       "evidence": "Surprisingly, however, activation of nAChRs by galantamine or physostigmine was insensitive to blockade by competitive nAChR antagonists, was detected even when the receptors were desensitized by high agonist concentrations, and was inhibited by the monoclonal antibody FK1 (350, 370, 372, 413, 428, 429).",
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@@ -9802,6 +10808,9 @@
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@@ -9825,7 +10834,7 @@
       },
       "evidence": "Surprisingly, however, activation of nAChRs by galantamine or physostigmine was insensitive to blockade by competitive nAChR antagonists, was detected even when the receptors were desensitized by high agonist concentrations, and was inhibited by the monoclonal antibody FK1 (350, 370, 372, 413, 428, 429).",
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@@ -9835,6 +10844,45 @@
     },
     {
       "annotations": {
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+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "PC12 Cells": true
+        },
+        "TextLocation": {
+          "Review": true
+        }
+      },
+      "citation": {
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+          "Albuquerque EX",
+          "Alkondon M",
+          "Pereira EF",
+          "Rogers SW"
+        ],
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+        "pages": "73-120",
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+        "volume": "89"
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@@ -9858,7 +10906,7 @@
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       "evidence": "Surprisingly, however, activation of nAChRs by galantamine or physostigmine was insensitive to blockade by competitive nAChR antagonists, was detected even when the receptors were desensitized by high agonist concentrations, and was inhibited by the monoclonal antibody FK1 (350, 370, 372, 413, 428, 429).",
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@@ -9868,6 +10916,9 @@
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@@ -9891,7 +10942,7 @@
       },
       "evidence": "Surprisingly, however, activation of nAChRs by galantamine or physostigmine was insensitive to blockade by competitive nAChR antagonists, was detected even when the receptors were desensitized by high agonist concentrations, and was inhibited by the monoclonal antibody FK1 (350, 370, 372, 413, 428, 429).",
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@@ -9901,6 +10952,9 @@
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         "MeSHAnatomy": {
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@@ -9927,13 +10981,16 @@
       },
       "evidence": "For instance, studies carried out in PC12 cells demonstrated that codeine, a drug with no significant effect on ChE, can activate nicotinic single-channel currents and that this nicotinic agonist effect is sensitive to inhibition by FK1 while unaffected by classical nAChR antagonists (450).",
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@@ -9960,13 +11017,16 @@
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       "evidence": "For instance, studies carried out in PC12 cells demonstrated that codeine, a drug with no significant effect on ChE, can activate nicotinic single-channel currents and that this nicotinic agonist effect is sensitive to inhibition by FK1 while unaffected by classical nAChR antagonists (450).",
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@@ -9993,16 +11053,19 @@
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       "evidence": "For instance, studies carried out in PC12 cells demonstrated that codeine, a drug with no significant effect on ChE, can activate nicotinic single-channel currents and that this nicotinic agonist effect is sensitive to inhibition by FK1 while unaffected by classical nAChR antagonists (450).",
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@@ -10026,16 +11089,19 @@
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       "evidence": "Reduced nAChR function/expression in the brain has been associated with the pathophysiology of catastrophic disorders, including AD and schizophrenia (discussed in later sections, and see Refs. 277, 432).",
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@@ -10059,13 +11125,16 @@
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       "evidence": "In particular, the association of the alpha7 nAChR gene with a sensory gating deficit that is similar to attention deficits in patients with schizophrenia (157), and the degree of alpha4beta2 nAChR loss and altered alpha7 expresson correlate well with the magnitude of progressive cognitive decline in mild-to-moderate AD patients (46).",
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@@ -10092,13 +11161,16 @@
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       "evidence": "Chronic alpha7 nAChR inhibition in the hippocampus by elevated levels of KYNA can contribute to auditory gating deficits, which appear to be associated with the development of schizophrenia (156). It is also feasible that KYNAinduced inhibition of alpha7 nAChRs contributes to the cognitive impairment observed in patients with AD and schizophrenia (273).",
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@@ -10122,13 +11194,16 @@
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       "evidence": "In particular, the association of the alpha7 nAChR gene with a sensory gating deficit that is similar to attention deficits in patients with schizophrenia (157), and the degree of alpha4beta2 nAChR loss and altered alpha7 expresson correlate well with the magnitude of progressive cognitive decline in mild-to-moderate AD patients (46).",
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@@ -10152,13 +11227,16 @@
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       "evidence": "In particular, the association of the alpha7 nAChR gene with a sensory gating deficit that is similar to attention deficits in patients with schizophrenia (157), and the degree of alpha4beta2 nAChR loss and altered alpha7 expresson correlate well with the magnitude of progressive cognitive decline in mild-to-moderate AD patients (46).",
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       "annotations": {
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         "MeSHAnatomy": {
           "Hippocampus": true
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@@ -10185,13 +11263,16 @@
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       "evidence": "Chronic alpha7 nAChR inhibition in the hippocampus by elevated levels of KYNA can contribute to auditory gating deficits, which appear to be associated with the development of schizophrenia (156). It is also feasible that KYNAinduced inhibition of alpha7 nAChRs contributes to the cognitive impairment observed in patients with AD and schizophrenia (273).",
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@@ -10218,16 +11299,19 @@
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       "evidence": "Chronic alpha7 nAChR inhibition in the hippocampus by elevated levels of KYNA can contribute to auditory gating deficits, which appear to be associated with the development of schizophrenia (156). It is also feasible that KYNAinduced inhibition of alpha7 nAChRs contributes to the cognitive impairment observed in patients with AD and schizophrenia (273).",
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@@ -10251,13 +11335,16 @@
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       "evidence": "In particular, the association of the alpha7 nAChR gene with a sensory gating deficit that is similar to attention deficits in patients with schizophrenia (157), and the degree of alpha4beta2 nAChR loss and altered alpha7 expresson correlate well with the magnitude of progressive cognitive decline in mild-to-moderate AD patients (46).",
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@@ -10281,13 +11368,16 @@
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       "evidence": "In particular, the association of the alpha7 nAChR gene with a sensory gating deficit that is similar to attention deficits in patients with schizophrenia (157), and the degree of alpha4beta2 nAChR loss and altered alpha7 expresson correlate well with the magnitude of progressive cognitive decline in mild-to-moderate AD patients (46).",
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       "annotations": {
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@@ -10314,16 +11404,19 @@
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       "evidence": "Chronic alpha7 nAChR inhibition in the hippocampus by elevated levels of KYNA can contribute to auditory gating deficits, which appear to be associated with the development of schizophrenia (156). It is also feasible that KYNAinduced inhibition of alpha7 nAChRs contributes to the cognitive impairment observed in patients with AD and schizophrenia (273).",
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         "MeSHAnatomy": {
           "Hippocampus": true
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@@ -10350,13 +11443,49 @@
       },
       "evidence": "Chronic alpha7 nAChR inhibition in the hippocampus by elevated levels of KYNA can contribute to auditory gating deficits, which appear to be associated with the development of schizophrenia (156). It is also feasible that KYNAinduced inhibition of alpha7 nAChRs contributes to the cognitive impairment observed in patients with AD and schizophrenia (273).",
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+        }
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+        "authors": [
+          "Albuquerque EX",
+          "Alkondon M",
+          "Pereira EF",
+          "Rogers SW"
+        ],
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+        "first": "Albuquerque EX",
+        "last": "Rogers SW",
+        "name": "Physiological reviews",
+        "pages": "73-120",
+        "reference": "19126755",
+        "title": "Mammalian nicotinic acetylcholine receptors: from structure to function.",
+        "type": "PubMed",
+        "volume": "89"
+      },
+      "evidence": "The nicotinic APL action of galantamine appears to be an important determinant of its clinical effectiveness (reviewed in Refs. 98, 291, 371). Acting primarily as a nicotinic APL, galantamine improves synaptic transmission and decreases neurodegeneration, two effects essential for its cognitive-enhancing properties (40, 108, 241, 409, 521).",
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     {
       "annotations": {
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         "Species": {
           "10090": true
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@@ -10383,13 +11512,49 @@
       },
       "evidence": "The importance of retaining the high-affinity nicotine binding sites to brain integrity has been demonstrated in studies of mice with a null mutation in the gene that encodes the beta2 nAChR subunit, a structural subunit of the high-affinity nicotine binding site (150, 184, 215, 311); these mice experience early onset neurodegeneration (528).",
       "key": "0bc357a1b53a19406647003428428e50b9336c97fd82b9f236b2701445e98104cef9ee514247845e54ff11d63214cab45ddfe5ff2496fcaa25fcae7b396a36ec",
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       "relation": "negativeCorrelation",
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-      "target": 216
+      "source": 223,
+      "target": 221
+    },
+    {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "TextLocation": {
+          "Review": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Albuquerque EX",
+          "Alkondon M",
+          "Pereira EF",
+          "Rogers SW"
+        ],
+        "date": "2009-01-01",
+        "first": "Albuquerque EX",
+        "last": "Rogers SW",
+        "name": "Physiological reviews",
+        "pages": "73-120",
+        "reference": "19126755",
+        "title": "Mammalian nicotinic acetylcholine receptors: from structure to function.",
+        "type": "PubMed",
+        "volume": "89"
+      },
+      "evidence": "The nicotinic APL action of galantamine appears to be an important determinant of its clinical effectiveness (reviewed in Refs. 98, 291, 371). Acting primarily as a nicotinic APL, galantamine improves synaptic transmission and decreases neurodegeneration, two effects essential for its cognitive-enhancing properties (40, 108, 241, 409, 521).",
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+      "relation": "increases",
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+      "target": 115
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -10413,13 +11578,16 @@
       },
       "evidence": "AD is the most common form of dementia in the elderly population. The histopathology of this disease is well known to have at least four components: 1) loss of cholinergic neurotransmission, 2) deposition of extracellular Abeta peptides into plaques, 3) hyperphosphorylation of the tau protein that leads to excessive formation of neurofibrillar tangles, and 4) increased local inflammation.",
       "key": "c6885d4b3859970496259d931ff9d355e469c602d06bc934a45f3d7d09c24eae2cea0b0c481bf4aee9d31d02610a47e6135d7695a49bfa990953e30d906d83ae",
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       "relation": "negativeCorrelation",
       "source": 112,
-      "target": 220
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     },
     {
       "annotations": {
+        "Confidence": {
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+        },
         "TextLocation": {
           "Review": true
         }
@@ -10443,16 +11611,19 @@
       },
       "evidence": "Of note is that in both of these catastrophic disorders, reduced nAChR activity/expression is accompanied by increased levels of kynurenic acid (KYNA), a tryptophan metabolite that in the brain is primarily produced and released by astrocytes (244, 419).",
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       "relation": "negativeCorrelation",
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     {
       "annotations": {
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           "Review": true
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@@ -10476,16 +11647,19 @@
       },
       "evidence": "The neuroactive properties of KYNA have long been attributed to the inhibition of NMDA receptors (329). Electrophysiological studies, however, have demonstrated that physiologically relevant concentrations of KYNA block alpha7 nAChR activity noncompetitively and voltage independently (210).",
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       "relation": "decreases",
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     {
       "annotations": {
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           "Review": true
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@@ -10509,16 +11683,19 @@
       },
       "evidence": "The neuroactive properties of KYNA have long been attributed to the inhibition of NMDA receptors (329). Electrophysiological studies, however, have demonstrated that physiologically relevant concentrations of KYNA block alpha7 nAChR activity noncompetitively and voltage independently (210).",
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       "relation": "decreases",
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-      "target": 186
+      "target": 189
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Hippocampus": true
         },
@@ -10545,16 +11722,19 @@
       },
       "evidence": "This constituted the first evidence that in the hippocampus endogenous levels of KYNA are sufficient to directly modulate the activity of alpha7 nAChRs, but not that of NMDA receptors (31).",
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     {
       "annotations": {
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@@ -10578,16 +11758,19 @@
       },
       "evidence": "Acting as an endogenous regulator of the alpha7 nAChR activity, astrocyte-derived KYNA can modulate synaptic transmission, synaptic plasticity, neuronal viability, and neuronal connectivity in different areas of the brain (Fig. 8).",
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       "relation": "regulates",
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     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Dopaminergic Neurons": true
         },
@@ -10614,16 +11797,19 @@
       },
       "evidence": "As illustrated in Figure 8, KYNA-induced reduction of extracellular dopamine levels can be explained by the inhibition of tonically active alpha7 nAChRs in the dopaminergic neurons within the VTA and/or in cortical glutamatergic terminals that synapse onto striatal neurons. VTA dopaminergic neurons represent the major dopaminergic input to the nucleus accumbens.",
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     },
     {
       "annotations": {
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+          "High": true
+        },
         "MeSHAnatomy": {
           "Hippocampus": true
         },
@@ -10650,16 +11836,19 @@
       },
       "evidence": "Chronic alpha7 nAChR inhibition in the hippocampus by elevated levels of KYNA can contribute to auditory gating deficits, which appear to be associated with the development of schizophrenia (156). It is also feasible that KYNAinduced inhibition of alpha7 nAChRs contributes to the cognitive impairment observed in patients with AD and schizophrenia (273).",
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+      "target": 189
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "CA1 Region, Hippocampal": true
         },
@@ -10689,7 +11878,7 @@
       },
       "evidence": "Mice with a null mutation in the gene that encodes KAT II became a unique tool to resolve this issue (31, 410, 516). Low levels of KYNA in these mutant mice lead to alpha7 nAChR disinhibition in hippocampal CA1 SR interneurons, thereby increasing the activity of GABAergic interneurons impinging onto CA1 pyramidal neurons (31)",
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       "object": {
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           "name": "Interneurons",
@@ -10699,10 +11888,13 @@
       },
       "relation": "decreases",
       "source": 12,
-      "target": 215
+      "target": 220
     },
     {
       "annotations": {
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         "TextLocation": {
           "Review": true
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@@ -10726,13 +11918,16 @@
       },
       "evidence": "Acting as an endogenous regulator of the alpha7 nAChR activity, astrocyte-derived KYNA can modulate synaptic transmission, synaptic plasticity, neuronal viability, and neuronal connectivity in different areas of the brain (Fig. 8).",
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     {
       "annotations": {
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@@ -10756,13 +11951,16 @@
       },
       "evidence": "Acting as an endogenous regulator of the alpha7 nAChR activity, astrocyte-derived KYNA can modulate synaptic transmission, synaptic plasticity, neuronal viability, and neuronal connectivity in different areas of the brain (Fig. 8).",
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       "relation": "regulates",
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       "target": 112
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     {
       "annotations": {
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@@ -10786,13 +11984,16 @@
       },
       "evidence": "Acting as an endogenous regulator of the alpha7 nAChR activity, astrocyte-derived KYNA can modulate synaptic transmission, synaptic plasticity, neuronal viability, and neuronal connectivity in different areas of the brain (Fig. 8).",
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       "relation": "regulates",
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-      "target": 222
+      "target": 227
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Corpus Striatum": true
         },
@@ -10822,7 +12023,7 @@
       },
       "evidence": "Activation of alpha7 nAChRs is known to contribute to the regulation of extracellular dopamine levels in the rat striatum (81). Application via microdialysis of KYNA or alpha-BGT to the rat striatum significantly reduces the extracellular levels of dopamine, and the magnitude of the effect of either antagonist alone is comparable to that of both antagonists together (285).",
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       "object": {
         "location": {
           "name": "extracellular region",
@@ -10835,6 +12036,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -10858,13 +12062,16 @@
       },
       "evidence": "Of note is that in both of these catastrophic disorders, reduced nAChR activity/expression is accompanied by increased levels of kynurenic acid (KYNA), a tryptophan metabolite that in the brain is primarily produced and released by astrocytes (244, 419).",
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       "relation": "increases",
       "source": 62,
       "target": 12
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Neurons": true
         },
@@ -10891,9 +12098,9 @@
       },
       "evidence": "There is evidence that anandamide is produced by postsynaptic neurons in response to elevated intracellular Ca2+ levels. For instance, concomitant activation of alpha7 nAChRs and NMDA receptors triggers the production of anandamine in postsynaptic neurons (448). Anandamine, then, functions as a retrograde messenger and regulates synaptic transmission by interacting with specific receptors in the presynaptic neurons/terminals (498).",
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       "relation": "increases",
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       "subject": {
         "modifier": "Activity"
       },
@@ -10901,6 +12108,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Astrocytes": true
         },
@@ -10927,13 +12137,16 @@
       },
       "evidence": "KYNA is formed enzymatically by the irreversible transamination of L-kynurenine, a major peripheral tryptophan metabolite with ready access to the brain. Immunohistochemical and lesion studies demonstrated that cerebral KYNA synthesis takes place almost exclusively in astrocytes (129, 187, 199).",
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       "target": 12
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     {
       "annotations": {
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@@ -10957,13 +12170,16 @@
       },
       "evidence": "Because of the absence of reuptake or degradation mechanisms, subsequent KYNA removal is accomplished exclusively by probenecid-sensitive brain efflux (330, 473).",
       "key": "aae433775726bd983fb4f650ece9e563b8eed5c5f23e22c131667e264dc1553701c95beee70e6697fb92753785dcc96ef0120826265e0f2ad9a23358057842f7",
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       "relation": "decreases",
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       "target": 12
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     {
       "annotations": {
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         "TextLocation": {
           "Review": true
         }
@@ -10987,13 +12203,16 @@
       },
       "evidence": "Interestingly, astrocytic KYNA production is regulated by neuronal activity (187) and cellular energy metabolism (213). This dependence of extracellular KYNA concentrations on the functional interplay between neurons and astrocytes is in line with the postulated neuromodulatory role of KYNA (418) and adds to the complexity of the neurochemical networks in the brain.",
       "key": "31cc2a90976360349fcdff64d27378bb769c9de12eb7007f97403320721d95fd289fff4165abb997a20e7152163cd321e6ec723233109a690148e4fffbb7a87e",
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       "relation": "regulates",
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+      "source": 93,
       "target": 12
     },
     {
       "annotations": {
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         "TextLocation": {
           "Review": true
         }
@@ -11017,9 +12236,9 @@
       },
       "evidence": "In the normal brain, \u000470% of KYNA formation is catalyzed by KAT II, one of the three cerebral KATs (199, 200). Systemic treatment of rats and mice with kynurenine leads to an elevation of brain levels of several neuroactive intermediates, including KYNA, the free radical generator 3-hydroxykynurenine, and the excitotoxic quinolinic acid (419).",
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       "relation": "increases",
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+      "source": 177,
       "subject": {
         "effect": {
           "name": "cat",
@@ -11031,6 +12250,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Species": {
           "10090": true,
           "10116": true
@@ -11058,13 +12280,16 @@
       },
       "evidence": "In the normal brain, \u000470% of KYNA formation is catalyzed by KAT II, one of the three cerebral KATs (199, 200). Systemic treatment of rats and mice with kynurenine leads to an elevation of brain levels of several neuroactive intermediates, including KYNA, the free radical generator 3-hydroxykynurenine, and the excitotoxic quinolinic acid (419).",
       "key": "98c16bb6a6b9a059d58d5585b970ae96878e94c8c710a0c8c129c5e345dfab06700810e4e0d702c5f6a88275bd4794d471a777d84e65271fea6d54a655d38363",
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       "relation": "increases",
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       "target": 12
     },
     {
       "annotations": {
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+          "High": true
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         "Species": {
           "10090": true,
           "10116": true
@@ -11092,13 +12317,16 @@
       },
       "evidence": "In the normal brain, \u000470% of KYNA formation is catalyzed by KAT II, one of the three cerebral KATs (199, 200). Systemic treatment of rats and mice with kynurenine leads to an elevation of brain levels of several neuroactive intermediates, including KYNA, the free radical generator 3-hydroxykynurenine, and the excitotoxic quinolinic acid (419).",
       "key": "6c865b9a7318c954e895a7a991de0e6265907c66cf4a787cb645f13408690385dd2a8cc088fa499913c58b81f9e2333a0df5aa3fa193d0a08e957bc0fcb2b060",
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       "relation": "increases",
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       "target": 1
     },
     {
       "annotations": {
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+          "High": true
+        },
         "Species": {
           "10090": true,
           "10116": true
@@ -11126,13 +12354,16 @@
       },
       "evidence": "In the normal brain, \u000470% of KYNA formation is catalyzed by KAT II, one of the three cerebral KATs (199, 200). Systemic treatment of rats and mice with kynurenine leads to an elevation of brain levels of several neuroactive intermediates, including KYNA, the free radical generator 3-hydroxykynurenine, and the excitotoxic quinolinic acid (419).",
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       "relation": "increases",
       "source": 29,
       "target": 17
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "CA1 Region, Hippocampal": true
         },
@@ -11162,12 +12393,12 @@
       },
       "evidence": "Mice with a null mutation in the gene that encodes KAT II became a unique tool to resolve this issue (31, 410, 516). Low levels of KYNA in these mutant mice lead to alpha7 nAChR disinhibition in hippocampal CA1 SR interneurons, thereby increasing the activity of GABAergic interneurons impinging onto CA1 pyramidal neurons (31)",
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+      "source": 220,
       "subject": {
         "location": {
           "name": "Interneurons",
@@ -11179,6 +12410,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Hippocampus": true
         },
@@ -11208,13 +12442,16 @@
       },
       "evidence": "Mouse strains, like humans, also exhibit a striking age-related decline in nAChR expression. For instance, in the hippocampus of aged CBA and B6 mice, expression of alpha4 and alpha7 nAChR subunits decreases with age (166). ",
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       "relation": "negativeCorrelation",
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-      "target": 244
+      "source": 220,
+      "target": 248
     },
     {
       "annotations": {
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+        },
         "TextLocation": {
           "Review": true
         }
@@ -11238,16 +12475,19 @@
       },
       "evidence": "Recent studies have supported a role for ERK and CREB activity in neural plasticity associated with nicotine addiction (71, 381, 484). It has also been proposed that the ERK and JAK-2/STAT-3 signaling pathways contribute to the toxic effects of nicotine in skin cells (42), and other pathways contribute to the effects of nicotine and other nicotinic ligands on inflammatory responses as described below.",
       "key": "c16b6e6294b4d52de0c6f9bf448d2d561b97d40cd6d1d35065bb4041cbdf891ea8c0d57ce2fa344b4c4b679f1388b8e2a7e305a48daddca1b8afa80357fedcc2",
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       "object": {
         "modifier": "Activity"
       },
       "relation": "association",
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-      "target": 161
+      "source": 120,
+      "target": 165
     },
     {
       "annotations": {
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+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -11271,16 +12511,19 @@
       },
       "evidence": "Recent studies have supported a role for ERK and CREB activity in neural plasticity associated with nicotine addiction (71, 381, 484). It has also been proposed that the ERK and JAK-2/STAT-3 signaling pathways contribute to the toxic effects of nicotine in skin cells (42), and other pathways contribute to the effects of nicotine and other nicotinic ligands on inflammatory responses as described below.",
       "key": "f08cb26bbb1881a0486ac4bac29a51fae08e69d7983897f1de80dfbbf6fa0b22c55d2400a8f19a5725e2a8120f591aa9d21860651ad9b9f702001505b0f58aa0",
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       "object": {
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       "relation": "association",
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-      "target": 199
+      "source": 120,
+      "target": 202
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "CA1 Region, Hippocampal": true
         },
@@ -11307,7 +12550,7 @@
       },
       "evidence": "Activation of alpha7 nAChRs in somatodendritic and preterminal/ terminal areas of interneurons in various strata of the CA1 region and in the dentate gyrus facilitates spontaneous quantal release of GABA (14, 25). Glutamate release from mossy fibers onto CA3 pyramidal neurons is also modulated by alpha7 nAChRs present in the mossy fiber terminals (190).",
       "key": "05c8094c08cd4a6a43dd1dd7b16dc228d7a91263d10542451c96fa5e36297b2f02f15eb6fc925d981fcf2a9a020fa12d16f0f202616c318a1e69cc49afadfb99",
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       "object": {
         "location": {
           "name": "Pyramidal Cells",
@@ -11320,6 +12563,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Corpus Striatum": true
         },
@@ -11349,7 +12595,7 @@
       },
       "evidence": "In contrast, the NMDA receptor antagonist 7-chloro-KYNA has no significant ef- fect on the extracellular levels of dopamine in the rat striatum (391). ",
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       "object": {
         "location": {
           "name": "extracellular region",
@@ -11362,6 +12608,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -11385,13 +12634,16 @@
       },
       "evidence": "Drugs currently approved to treat mild-to-moderate AD, including galantamine, donepezil, and rivastigmine, all inhibit AChE, the enzyme that hydrolyzes ACh (462).",
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       "relation": "decreases",
       "source": 25,
-      "target": 175
+      "target": 178
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "TextLocation": {
           "Review": true
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@@ -11415,13 +12667,16 @@
       },
       "evidence": "Drugs currently approved to treat mild-to-moderate AD, including galantamine, donepezil, and rivastigmine, all inhibit AChE, the enzyme that hydrolyzes ACh (462).",
       "key": "c6423707b577a9f305eb48f13e5544c34c6852a993f4d68a2c6077c9ffa34c7779d28cffbe20ed1862afbada44beea4def29a15278fb6a6b8043373c340a8d80",
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       "relation": "decreases",
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-      "target": 175
+      "target": 178
     },
     {
       "annotations": {
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+        },
         "TextLocation": {
           "Review": true
         }
@@ -11445,16 +12700,19 @@
       },
       "evidence": "Other endogenous ligands that impact on the activity of nAChRs noncompetitively and voltage independently include the amyloid beta peptide 1-42 (Abeta1-42; Refs. 123, 376) and the canabinoid anandamide (356, 442).",
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       "relation": "association",
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-      "target": 208
+      "target": 211
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Neurons": true
         },
@@ -11481,16 +12739,19 @@
       },
       "evidence": "It is noteworthy that the alpha7 nAChR activity increases intracellular accumulation of Abeta in neurons (336), and Abeta peptides, in addition to modulating nAChR activity, downregulate the expression of nAChRs (197).",
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       "object": {
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       "relation": "regulates",
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-      "target": 208
+      "target": 211
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Brain": true
         },
@@ -11520,13 +12781,16 @@
       },
       "evidence": "The Abeta1-42 peptide is one of the breakdown products of the proteolytic cleavage of the amyloid precursor protein by beta- and gamma-secretases. In biopsy samples of human brain tissue obtained from AD patients and in ectopic systems overexpressing either alpha7 nAChRs or APP, Abeta1-42 coimmunoprecipitates with alpha7 nAChRs (490). The Abeta1-42 peptide also displaces binding of [3H]MLA from alpha7 nAChRs in cerebral cortical and hippocampal synaptosomes (490).",
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       "relation": "increases",
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-      "target": 121
+      "target": 124
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Brain": true
         },
@@ -11556,13 +12820,16 @@
       },
       "evidence": "The Abeta1-42 peptide is one of the breakdown products of the proteolytic cleavage of the amyloid precursor protein by beta- and gamma-secretases. In biopsy samples of human brain tissue obtained from AD patients and in ectopic systems overexpressing either alpha7 nAChRs or APP, Abeta1-42 coimmunoprecipitates with alpha7 nAChRs (490). The Abeta1-42 peptide also displaces binding of [3H]MLA from alpha7 nAChRs in cerebral cortical and hippocampal synaptosomes (490).",
       "key": "d322d92aa897f6467f2da0cf3d760006ab8b4a41b36cc50eb77e0c0578ae7481e87f3c078ca0d5366b147f91bf8066afab765d51469a619d57d92670e1a6486b",
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       "relation": "decreases",
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     {
       "annotations": {
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           "Review": true
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@@ -11586,16 +12853,19 @@
       },
       "evidence": "More functional studies reported that while at picomolar concentrations Abeta1-42 activates alpha7 nAChRs ectopically expressed in Xenopus oocytes (123, 126), at nanomolar concentrations it inhibits alpha7 nAChRs present in different preparations (278, 376). The alpha7 nAChR inhibition by Abeta1-42 is noncompetitive with respect to the agonist, is voltage independent, and is therefore likely to be mediated by the interaction of the peptide with a site different from that for ACh on the nAChRs.",
       "key": "6a67fa9100b3bf41397a80446f5f8b84b2b8a400b5ca62fea0c0ed41366b9dbd8f3a248f2647c7e2e8920b947eefa40fa36e909ca290cd59e56f1d818f991c45",
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     },
     {
       "annotations": {
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         "TextLocation": {
           "Review": true
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@@ -11619,16 +12889,19 @@
       },
       "evidence": "Other studies have reported that alpha4beta2 nAChRs are more sensitive than alpha7 nAChRs to inhibition by nanomolar concentrations of Abeta1-42 (506). ",
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-      "target": 168
+      "target": 171
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Neurons": true
         },
@@ -11655,13 +12928,16 @@
       },
       "evidence": "It is noteworthy that the alpha7 nAChR activity increases intracellular accumulation of Abeta in neurons (336), and Abeta peptides, in addition to modulating nAChR activity, downregulate the expression of nAChRs (197).",
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       "relation": "decreases",
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     {
       "annotations": {
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           "Review": true
         }
@@ -11685,16 +12961,19 @@
       },
       "evidence": "Other endogenous ligands that impact on the activity of nAChRs noncompetitively and voltage independently include the amyloid beta peptide 1-42 (Abeta1-42; Refs. 123, 376) and the canabinoid anandamide (356, 442).",
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     {
       "annotations": {
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@@ -11718,13 +12997,16 @@
       },
       "evidence": "Anandamide, a compound originally isolated from porcine brain extracts, is known to interact with canabinoid receptors 1 and 2 in the brain (120, 159). However, anandamide interacts with numerous other receptors, including voltage-gated Ca2+ channels (357), voltage-gated K+ channels (293), 5-HT3 receptors (358), kainate receptors (3), and nAChRs (356). At nanomolar concentrations, anandamine blocks noncompetitively and voltage independently the activation of alpha7 nAChRs ectopically expressed in Xenopus oocytes (356). It also inhibits the activity of alpha4beta2 nAChRs expressed in SH-EP1 cells (443).",
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     {
       "annotations": {
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@@ -11748,13 +13030,16 @@
       },
       "evidence": "Anandamide, a compound originally isolated from porcine brain extracts, is known to interact with canabinoid receptors 1 and 2 in the brain (120, 159). However, anandamide interacts with numerous other receptors, including voltage-gated Ca2+ channels (357), voltage-gated K+ channels (293), 5-HT3 receptors (358), kainate receptors (3), and nAChRs (356). At nanomolar concentrations, anandamine blocks noncompetitively and voltage independently the activation of alpha7 nAChRs ectopically expressed in Xenopus oocytes (356). It also inhibits the activity of alpha4beta2 nAChRs expressed in SH-EP1 cells (443).",
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     {
       "annotations": {
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@@ -11778,13 +13063,16 @@
       },
       "evidence": "Anandamide, a compound originally isolated from porcine brain extracts, is known to interact with canabinoid receptors 1 and 2 in the brain (120, 159). However, anandamide interacts with numerous other receptors, including voltage-gated Ca2+ channels (357), voltage-gated K+ channels (293), 5-HT3 receptors (358), kainate receptors (3), and nAChRs (356). At nanomolar concentrations, anandamine blocks noncompetitively and voltage independently the activation of alpha7 nAChRs ectopically expressed in Xenopus oocytes (356). It also inhibits the activity of alpha4beta2 nAChRs expressed in SH-EP1 cells (443).",
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     {
       "annotations": {
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@@ -11808,13 +13096,16 @@
       },
       "evidence": "Anandamide, a compound originally isolated from porcine brain extracts, is known to interact with canabinoid receptors 1 and 2 in the brain (120, 159). However, anandamide interacts with numerous other receptors, including voltage-gated Ca2+ channels (357), voltage-gated K+ channels (293), 5-HT3 receptors (358), kainate receptors (3), and nAChRs (356). At nanomolar concentrations, anandamine blocks noncompetitively and voltage independently the activation of alpha7 nAChRs ectopically expressed in Xenopus oocytes (356). It also inhibits the activity of alpha4beta2 nAChRs expressed in SH-EP1 cells (443).",
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       "relation": "association",
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     },
     {
       "annotations": {
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         "TextLocation": {
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@@ -11838,13 +13129,16 @@
       },
       "evidence": "Anandamide, a compound originally isolated from porcine brain extracts, is known to interact with canabinoid receptors 1 and 2 in the brain (120, 159). However, anandamide interacts with numerous other receptors, including voltage-gated Ca2+ channels (357), voltage-gated K+ channels (293), 5-HT3 receptors (358), kainate receptors (3), and nAChRs (356). At nanomolar concentrations, anandamine blocks noncompetitively and voltage independently the activation of alpha7 nAChRs ectopically expressed in Xenopus oocytes (356). It also inhibits the activity of alpha4beta2 nAChRs expressed in SH-EP1 cells (443).",
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       "relation": "association",
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     },
     {
       "annotations": {
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@@ -11868,13 +13162,16 @@
       },
       "evidence": "Anandamide, a compound originally isolated from porcine brain extracts, is known to interact with canabinoid receptors 1 and 2 in the brain (120, 159). However, anandamide interacts with numerous other receptors, including voltage-gated Ca2+ channels (357), voltage-gated K+ channels (293), 5-HT3 receptors (358), kainate receptors (3), and nAChRs (356). At nanomolar concentrations, anandamine blocks noncompetitively and voltage independently the activation of alpha7 nAChRs ectopically expressed in Xenopus oocytes (356). It also inhibits the activity of alpha4beta2 nAChRs expressed in SH-EP1 cells (443).",
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       "relation": "association",
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       "target": 58
     },
     {
       "annotations": {
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         "TextLocation": {
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@@ -11898,13 +13195,16 @@
       },
       "evidence": "Anandamide, a compound originally isolated from porcine brain extracts, is known to interact with canabinoid receptors 1 and 2 in the brain (120, 159). However, anandamide interacts with numerous other receptors, including voltage-gated Ca2+ channels (357), voltage-gated K+ channels (293), 5-HT3 receptors (358), kainate receptors (3), and nAChRs (356). At nanomolar concentrations, anandamine blocks noncompetitively and voltage independently the activation of alpha7 nAChRs ectopically expressed in Xenopus oocytes (356). It also inhibits the activity of alpha4beta2 nAChRs expressed in SH-EP1 cells (443).",
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     },
     {
       "annotations": {
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@@ -11928,16 +13228,19 @@
       },
       "evidence": "Anandamide, a compound originally isolated from porcine brain extracts, is known to interact with canabinoid receptors 1 and 2 in the brain (120, 159). However, anandamide interacts with numerous other receptors, including voltage-gated Ca2+ channels (357), voltage-gated K+ channels (293), 5-HT3 receptors (358), kainate receptors (3), and nAChRs (356). At nanomolar concentrations, anandamine blocks noncompetitively and voltage independently the activation of alpha7 nAChRs ectopically expressed in Xenopus oocytes (356). It also inhibits the activity of alpha4beta2 nAChRs expressed in SH-EP1 cells (443).",
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+      "target": 189
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     {
       "annotations": {
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@@ -11961,16 +13264,19 @@
       },
       "evidence": "Anandamide, a compound originally isolated from porcine brain extracts, is known to interact with canabinoid receptors 1 and 2 in the brain (120, 159). However, anandamide interacts with numerous other receptors, including voltage-gated Ca2+ channels (357), voltage-gated K+ channels (293), 5-HT3 receptors (358), kainate receptors (3), and nAChRs (356). At nanomolar concentrations, anandamine blocks noncompetitively and voltage independently the activation of alpha7 nAChRs ectopically expressed in Xenopus oocytes (356). It also inhibits the activity of alpha4beta2 nAChRs expressed in SH-EP1 cells (443).",
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-      "target": 168
+      "target": 171
     },
     {
       "annotations": {
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+        },
         "MeSHAnatomy": {
           "Neurons": true
         },
@@ -11997,13 +13303,16 @@
       },
       "evidence": "There is evidence that anandamide is produced by postsynaptic neurons in response to elevated intracellular Ca2+ levels. For instance, concomitant activation of alpha7 nAChRs and NMDA receptors triggers the production of anandamine in postsynaptic neurons (448). Anandamine, then, functions as a retrograde messenger and regulates synaptic transmission by interacting with specific receptors in the presynaptic neurons/terminals (498).",
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     {
       "annotations": {
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           "Review": true
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@@ -12027,13 +13336,16 @@
       },
       "evidence": "The Abeta1-42 peptide is one of the breakdown products of the proteolytic cleavage of the amyloid precursor protein by beta- and gamma-secretases. In biopsy samples of human brain tissue obtained from AD patients and in ectopic systems overexpressing either alpha7 nAChRs or APP, Abeta1-42 coimmunoprecipitates with alpha7 nAChRs (490). The Abeta1-42 peptide also displaces binding of [3H]MLA from alpha7 nAChRs in cerebral cortical and hippocampal synaptosomes (490).",
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       "relation": "increases",
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+      "source": 176,
       "target": 6
     },
     {
       "annotations": {
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         "TextLocation": {
           "Review": true
         }
@@ -12057,25 +13369,28 @@
       },
       "evidence": "The Abeta1-42 peptide is one of the breakdown products of the proteolytic cleavage of the amyloid precursor protein by beta- and gamma-secretases. In biopsy samples of human brain tissue obtained from AD patients and in ectopic systems overexpressing either alpha7 nAChRs or APP, Abeta1-42 coimmunoprecipitates with alpha7 nAChRs (490). The Abeta1-42 peptide also displaces binding of [3H]MLA from alpha7 nAChRs in cerebral cortical and hippocampal synaptosomes (490).",
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@@ -12099,13 +13414,16 @@
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       "evidence": "Anandamide, a compound originally isolated from porcine brain extracts, is known to interact with canabinoid receptors 1 and 2 in the brain (120, 159). However, anandamide interacts with numerous other receptors, including voltage-gated Ca2+ channels (357), voltage-gated K+ channels (293), 5-HT3 receptors (358), kainate receptors (3), and nAChRs (356). At nanomolar concentrations, anandamine blocks noncompetitively and voltage independently the activation of alpha7 nAChRs ectopically expressed in Xenopus oocytes (356). It also inhibits the activity of alpha4beta2 nAChRs expressed in SH-EP1 cells (443).",
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@@ -12129,13 +13447,16 @@
       },
       "evidence": "Anandamide, a compound originally isolated from porcine brain extracts, is known to interact with canabinoid receptors 1 and 2 in the brain (120, 159). However, anandamide interacts with numerous other receptors, including voltage-gated Ca2+ channels (357), voltage-gated K+ channels (293), 5-HT3 receptors (358), kainate receptors (3), and nAChRs (356). At nanomolar concentrations, anandamine blocks noncompetitively and voltage independently the activation of alpha7 nAChRs ectopically expressed in Xenopus oocytes (356). It also inhibits the activity of alpha4beta2 nAChRs expressed in SH-EP1 cells (443).",
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@@ -12159,13 +13480,16 @@
       },
       "evidence": "Anandamide, a compound originally isolated from porcine brain extracts, is known to interact with canabinoid receptors 1 and 2 in the brain (120, 159). However, anandamide interacts with numerous other receptors, including voltage-gated Ca2+ channels (357), voltage-gated K+ channels (293), 5-HT3 receptors (358), kainate receptors (3), and nAChRs (356). At nanomolar concentrations, anandamine blocks noncompetitively and voltage independently the activation of alpha7 nAChRs ectopically expressed in Xenopus oocytes (356). It also inhibits the activity of alpha4beta2 nAChRs expressed in SH-EP1 cells (443).",
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@@ -12189,13 +13513,16 @@
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       "evidence": "Anandamide, a compound originally isolated from porcine brain extracts, is known to interact with canabinoid receptors 1 and 2 in the brain (120, 159). However, anandamide interacts with numerous other receptors, including voltage-gated Ca2+ channels (357), voltage-gated K+ channels (293), 5-HT3 receptors (358), kainate receptors (3), and nAChRs (356). At nanomolar concentrations, anandamine blocks noncompetitively and voltage independently the activation of alpha7 nAChRs ectopically expressed in Xenopus oocytes (356). It also inhibits the activity of alpha4beta2 nAChRs expressed in SH-EP1 cells (443).",
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@@ -12219,16 +13546,19 @@
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       "evidence": "Finally, bupropion (16, 294, 433) and UCI-30002 (514) are examples of synthetic compounds that act as noncompetitive inhibitors of different nAChRs, including those made up of the subunits alpha7, alpha4beta2, or alpha3beta4. Both compounds effectively decrease nicotine self-administration in rats (280, 514). Bupropion is presently approved as an adjunct therapy for smoking cessation.",
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@@ -12252,16 +13582,19 @@
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       "evidence": "Finally, bupropion (16, 294, 433) and UCI-30002 (514) are examples of synthetic compounds that act as noncompetitive inhibitors of different nAChRs, including those made up of the subunits alpha7, alpha4beta2, or alpha3beta4. Both compounds effectively decrease nicotine self-administration in rats (280, 514). Bupropion is presently approved as an adjunct therapy for smoking cessation.",
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@@ -12285,16 +13618,19 @@
       },
       "evidence": "Finally, bupropion (16, 294, 433) and UCI-30002 (514) are examples of synthetic compounds that act as noncompetitive inhibitors of different nAChRs, including those made up of the subunits alpha7, alpha4beta2, or alpha3beta4. Both compounds effectively decrease nicotine self-administration in rats (280, 514). Bupropion is presently approved as an adjunct therapy for smoking cessation.",
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@@ -12318,13 +13654,16 @@
       },
       "evidence": "Finally, bupropion (16, 294, 433) and UCI-30002 (514) are examples of synthetic compounds that act as noncompetitive inhibitors of different nAChRs, including those made up of the subunits alpha7, alpha4beta2, or alpha3beta4. Both compounds effectively decrease nicotine self-administration in rats (280, 514). Bupropion is presently approved as an adjunct therapy for smoking cessation.",
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@@ -12348,16 +13687,19 @@
       },
       "evidence": "Finally, bupropion (16, 294, 433) and UCI-30002 (514) are examples of synthetic compounds that act as noncompetitive inhibitors of different nAChRs, including those made up of the subunits alpha7, alpha4beta2, or alpha3beta4. Both compounds effectively decrease nicotine self-administration in rats (280, 514). Bupropion is presently approved as an adjunct therapy for smoking cessation.",
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@@ -12381,16 +13723,19 @@
       },
       "evidence": "Finally, bupropion (16, 294, 433) and UCI-30002 (514) are examples of synthetic compounds that act as noncompetitive inhibitors of different nAChRs, including those made up of the subunits alpha7, alpha4beta2, or alpha3beta4. Both compounds effectively decrease nicotine self-administration in rats (280, 514). Bupropion is presently approved as an adjunct therapy for smoking cessation.",
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@@ -12414,16 +13759,19 @@
       },
       "evidence": "Finally, bupropion (16, 294, 433) and UCI-30002 (514) are examples of synthetic compounds that act as noncompetitive inhibitors of different nAChRs, including those made up of the subunits alpha7, alpha4beta2, or alpha3beta4. Both compounds effectively decrease nicotine self-administration in rats (280, 514). Bupropion is presently approved as an adjunct therapy for smoking cessation.",
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@@ -12447,13 +13795,16 @@
       },
       "evidence": "Finally, bupropion (16, 294, 433) and UCI-30002 (514) are examples of synthetic compounds that act as noncompetitive inhibitors of different nAChRs, including those made up of the subunits alpha7, alpha4beta2, or alpha3beta4. Both compounds effectively decrease nicotine self-administration in rats (280, 514). Bupropion is presently approved as an adjunct therapy for smoking cessation.",
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@@ -12477,16 +13828,19 @@
       },
       "evidence": "Recent studies have supported a role for ERK and CREB activity in neural plasticity associated with nicotine addiction (71, 381, 484). It has also been proposed that the ERK and JAK-2/STAT-3 signaling pathways contribute to the toxic effects of nicotine in skin cells (42), and other pathways contribute to the effects of nicotine and other nicotinic ligands on inflammatory responses as described below.",
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@@ -12510,16 +13864,19 @@
       },
       "evidence": "Recent studies have supported a role for ERK and CREB activity in neural plasticity associated with nicotine addiction (71, 381, 484). It has also been proposed that the ERK and JAK-2/STAT-3 signaling pathways contribute to the toxic effects of nicotine in skin cells (42), and other pathways contribute to the effects of nicotine and other nicotinic ligands on inflammatory responses as described below.",
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@@ -12543,16 +13900,19 @@
       },
       "evidence": "Recent studies have supported a role for ERK and CREB activity in neural plasticity associated with nicotine addiction (71, 381, 484). It has also been proposed that the ERK and JAK-2/STAT-3 signaling pathways contribute to the toxic effects of nicotine in skin cells (42), and other pathways contribute to the effects of nicotine and other nicotinic ligands on inflammatory responses as described below.",
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@@ -12576,16 +13936,19 @@
       },
       "evidence": "Recent studies have supported a role for ERK and CREB activity in neural plasticity associated with nicotine addiction (71, 381, 484). It has also been proposed that the ERK and JAK-2/STAT-3 signaling pathways contribute to the toxic effects of nicotine in skin cells (42), and other pathways contribute to the effects of nicotine and other nicotinic ligands on inflammatory responses as described below.",
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@@ -12609,13 +13972,16 @@
       },
       "evidence": "In fact, the relationship between tobacco abuse (including smokeless) and difficulty in healing, increased susceptibility to infection (especially oral), enhanced expression of indicators of skin aging, and increased cancer risk are all well-documented (383, 452).",
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     {
       "annotations": {
+        "Confidence": {
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         "MeSHAnatomy": {
           "Skin": true
         },
@@ -12642,13 +14008,16 @@
       },
       "evidence": "There is current evidence that nAChRs present in skin cells modulate the responses triggered by inflammatory stimuli applied to the skin (354). Smoking is a welldefined risk factor in delayed wound healing and possibly the development of premature facial wrinkling (226).",
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@@ -12672,13 +14041,16 @@
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       "evidence": "In fact, the relationship between tobacco abuse (including smokeless) and difficulty in healing, increased susceptibility to infection (especially oral), enhanced expression of indicators of skin aging, and increased cancer risk are all well-documented (383, 452).",
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@@ -12702,13 +14074,16 @@
       },
       "evidence": "In fact, the relationship between tobacco abuse (including smokeless) and difficulty in healing, increased susceptibility to infection (especially oral), enhanced expression of indicators of skin aging, and increased cancer risk are all well-documented (383, 452).",
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     },
     {
       "annotations": {
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         "MeSHAnatomy": {
           "Skin": true
         },
@@ -12735,13 +14110,16 @@
       },
       "evidence": "There is current evidence that nAChRs present in skin cells modulate the responses triggered by inflammatory stimuli applied to the skin (354). Smoking is a welldefined risk factor in delayed wound healing and possibly the development of premature facial wrinkling (226).",
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@@ -12765,13 +14143,16 @@
       },
       "evidence": "In fact, the relationship between tobacco abuse (including smokeless) and difficulty in healing, increased susceptibility to infection (especially oral), enhanced expression of indicators of skin aging, and increased cancer risk are all well-documented (383, 452).",
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     },
     {
       "annotations": {
+        "Confidence": {
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         "MeSHAnatomy": {
           "Intestines": true
         },
@@ -12798,13 +14179,16 @@
       },
       "evidence": "Modulation by nicotine of inflammatory responses in the intestines is much better reported. Early studies found that patients with ulcerative colitis who stopped smoking tobacco developed the disease or exhibited more severe disease progression, which was ameliorated by either returning to smoking (58, 401, 466), or, in some cases, administering nicotine through transdermal patches (313).In contrast, patients with Crohn’s disease experience much more severe disease when smoking (401).",
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     },
     {
       "annotations": {
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+          "High": true
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         "MeSHAnatomy": {
           "Intestines": true
         },
@@ -12831,13 +14215,16 @@
       },
       "evidence": "Modulation by nicotine of inflammatory responses in the intestines is much better reported. Early studies found that patients with ulcerative colitis who stopped smoking tobacco developed the disease or exhibited more severe disease progression, which was ameliorated by either returning to smoking (58, 401, 466), or, in some cases, administering nicotine through transdermal patches (313).In contrast, patients with Crohn’s disease experience much more severe disease when smoking (401).",
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     {
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@@ -12861,13 +14248,16 @@
       },
       "evidence": "It has long been known that smokers tend to be leaner, and yet approximately four times more likely to become insulin resistant and develop type I diabetes (497), a condition that is more commonly observed in obese patients.",
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@@ -12891,13 +14281,16 @@
       },
       "evidence": "However, epidemiological studies have reported that heavy smokers are less likely to experience PD (see reviews in Refs. 384, 385).",
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     {
       "annotations": {
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         "MeSHAnatomy": {
           "Skin": true
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@@ -12924,7 +14317,7 @@
       },
       "evidence": "Recent studies have supported a role for ERK and CREB activity in neural plasticity associated with nicotine addiction (71, 381, 484). It has also been proposed that the ERK and JAK-2/STAT-3 signaling pathways contribute to the toxic effects of nicotine in skin cells (42), and other pathways contribute to the effects of nicotine and other nicotinic ligands on inflammatory responses as described below.",
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@@ -12934,6 +14327,9 @@
     },
     {
       "annotations": {
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         "MeSHAnatomy": {
           "Skin": true
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@@ -12960,16 +14356,19 @@
       },
       "evidence": "Recent studies have supported a role for ERK and CREB activity in neural plasticity associated with nicotine addiction (71, 381, 484). It has also been proposed that the ERK and JAK-2/STAT-3 signaling pathways contribute to the toxic effects of nicotine in skin cells (42), and other pathways contribute to the effects of nicotine and other nicotinic ligands on inflammatory responses as described below.",
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       "target": 30
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     {
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@@ -12996,7 +14395,7 @@
       },
       "evidence": "Recent studies have supported a role for ERK and CREB activity in neural plasticity associated with nicotine addiction (71, 381, 484). It has also been proposed that the ERK and JAK-2/STAT-3 signaling pathways contribute to the toxic effects of nicotine in skin cells (42), and other pathways contribute to the effects of nicotine and other nicotinic ligands on inflammatory responses as described below.",
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@@ -13006,6 +14405,9 @@
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@@ -13029,13 +14431,16 @@
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       "evidence": "In fact, the relationship between tobacco abuse (including smokeless) and difficulty in healing, increased susceptibility to infection (especially oral), enhanced expression of indicators of skin aging, and increased cancer risk are all well-documented (383, 452).",
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@@ -13059,13 +14464,16 @@
       },
       "evidence": "In fact, the relationship between tobacco abuse (including smokeless) and difficulty in healing, increased susceptibility to infection (especially oral), enhanced expression of indicators of skin aging, and increased cancer risk are all well-documented (383, 452).",
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@@ -13089,13 +14497,16 @@
       },
       "evidence": "In fact, the relationship between tobacco abuse (including smokeless) and difficulty in healing, increased susceptibility to infection (especially oral), enhanced expression of indicators of skin aging, and increased cancer risk are all well-documented (383, 452).",
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@@ -13119,13 +14530,16 @@
       },
       "evidence": "It has long been known that smokers tend to be leaner, and yet approximately four times more likely to become insulin resistant and develop type I diabetes (497), a condition that is more commonly observed in obese patients.",
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@@ -13149,13 +14563,16 @@
       },
       "evidence": "It has long been known that smokers tend to be leaner, and yet approximately four times more likely to become insulin resistant and develop type I diabetes (497), a condition that is more commonly observed in obese patients.",
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     {
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@@ -13182,16 +14599,19 @@
       },
       "evidence": "Mice are particularly well-defined for their strain-specific complex genetic traits related to the effects of nicotine (105, 302) and morphological variations in the brain (e.g., Refs. 166, 167, 169).",
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     {
       "annotations": {
+        "Confidence": {
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         "MeSHAnatomy": {
           "Cerebellum": true,
           "Corpus Striatum": true,
@@ -13224,13 +14644,16 @@
       },
       "evidence": "For instance, substantial strain-specific variability in nAChR expression has been observed in the striatum (34), retina (227), cerebellum (471), and dorsal hippocampus (164, 165, 167, 169) of mice.",
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@@ -13254,13 +14677,16 @@
       },
       "evidence": "These results suggest that mouse strains of different genetic backgrounds undergo dissimilar age-related changes in the expression of nAChR subunits.",
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     {
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         "MeSHAnatomy": {
           "Brain": true
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@@ -13290,13 +14716,16 @@
       },
       "evidence": "Strain-dependent variations in nAChR density in regions of the rat brain have also been reported. ",
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@@ -13320,13 +14749,16 @@
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       "evidence": "AD is the most common form of dementia in the elderly population. The histopathology of this disease is well known to have at least four components: 1) loss of cholinergic neurotransmission, 2) deposition of extracellular Abeta peptides into plaques, 3) hyperphosphorylation of the tau protein that leads to excessive formation of neurofibrillar tangles, and 4) increased local inflammation.",
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     {
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@@ -13350,13 +14782,16 @@
       },
       "evidence": "AD is the most common form of dementia in the elderly population. The histopathology of this disease is well known to have at least four components: 1) loss of cholinergic neurotransmission, 2) deposition of extracellular Abeta peptides into plaques, 3) hyperphosphorylation of the tau protein that leads to excessive formation of neurofibrillar tangles, and 4) increased local inflammation.",
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@@ -13380,13 +14815,16 @@
       },
       "evidence": "AD is the most common form of dementia in the elderly population. The histopathology of this disease is well known to have at least four components: 1) loss of cholinergic neurotransmission, 2) deposition of extracellular Abeta peptides into plaques, 3) hyperphosphorylation of the tau protein that leads to excessive formation of neurofibrillar tangles, and 4) increased local inflammation.",
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     {
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@@ -13410,13 +14848,16 @@
       },
       "evidence": "AD is the most common form of dementia in the elderly population. The histopathology of this disease is well known to have at least four components: 1) loss of cholinergic neurotransmission, 2) deposition of extracellular Abeta peptides into plaques, 3) hyperphosphorylation of the tau protein that leads to excessive formation of neurofibrillar tangles, and 4) increased local inflammation.",
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     },
     {
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         "Species": {
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@@ -13443,13 +14884,16 @@
       },
       "evidence": "The importance of retaining the high-affinity nicotine binding sites to brain integrity has been demonstrated in studies of mice with a null mutation in the gene that encodes the beta2 nAChR subunit, a structural subunit of the high-affinity nicotine binding site (150, 184, 215, 311); these mice experience early onset neurodegeneration (528).",
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+      "target": 223
     },
     {
       "annotations": {
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+          "High": true
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         "MeSHAnatomy": {
           "Hippocampus": true
         },
@@ -13479,13 +14923,16 @@
       },
       "evidence": "Mouse strains, like humans, also exhibit a striking age-related decline in nAChR expression. For instance, in the hippocampus of aged CBA and B6 mice, expression of alpha4 and alpha7 nAChR subunits decreases with age (166). ",
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     },
     {
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           "Review": true
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@@ -13509,16 +14956,19 @@
       },
       "evidence": "However, this appealing scenario is complicated by recent findings that beta-amyloid peptides directly modify alpha7 nAChR function (242, 278).",
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-      "target": 186
+      "target": 189
     },
     {
       "annotations": {
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@@ -13542,16 +14992,19 @@
       },
       "evidence": "NSAIDs [e.g., drugs such as ibuprofen and NS398 (celecoxib or Celebrex)] antagonize to varying degrees two related cyclooxygenase (Cox) enzymes, Cox1 and Cox2 (also termed, prostaglandin-endoperoxide synthase 2), that are rate-limiting in converting arachidonic acid to prostaglandin H2, a precursor to many additional prostaglandins (for review, see Ref. 436).",
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-      "target": 201
+      "target": 204
     },
     {
       "annotations": {
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           "Review": true
         }
@@ -13575,16 +15028,19 @@
       },
       "evidence": "NSAIDs [e.g., drugs such as ibuprofen and NS398 (celecoxib or Celebrex)] antagonize to varying degrees two related cyclooxygenase (Cox) enzymes, Cox1 and Cox2 (also termed, prostaglandin-endoperoxide synthase 2), that are rate-limiting in converting arachidonic acid to prostaglandin H2, a precursor to many additional prostaglandins (for review, see Ref. 436).",
       "key": "1f02dfde76e5ceb0aded38ea17214a856f678ef2cf1b2ddafa127bfcd0018adf7c0542415aec372ce8443eb9f791971595b218bf97051dcee0d368eaea7e995c",
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-      "target": 202
+      "target": 205
     },
     {
       "annotations": {
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         "TextLocation": {
           "Review": true
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@@ -13608,9 +15064,9 @@
       },
       "evidence": "NSAIDs [e.g., drugs such as ibuprofen and NS398 (celecoxib or Celebrex)] antagonize to varying degrees two related cyclooxygenase (Cox) enzymes, Cox1 and Cox2 (also termed, prostaglandin-endoperoxide synthase 2), that are rate-limiting in converting arachidonic acid to prostaglandin H2, a precursor to many additional prostaglandins (for review, see Ref. 436).",
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       "subject": {
         "modifier": "Activity"
       },
@@ -13618,6 +15074,9 @@
     },
     {
       "annotations": {
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         "TextLocation": {
           "Review": true
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@@ -13641,9 +15100,9 @@
       },
       "evidence": "NSAIDs [e.g., drugs such as ibuprofen and NS398 (celecoxib or Celebrex)] antagonize to varying degrees two related cyclooxygenase (Cox) enzymes, Cox1 and Cox2 (also termed, prostaglandin-endoperoxide synthase 2), that are rate-limiting in converting arachidonic acid to prostaglandin H2, a precursor to many additional prostaglandins (for review, see Ref. 436).",
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       "subject": {
         "modifier": "Activity"
       },
@@ -13651,6 +15110,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Brain": true
         },
@@ -13677,19 +15139,22 @@
       },
       "evidence": "In the brain, however, Cox2 is constitutively expressed by neurons (212, 512), participates in modulating synaptic plasticity (53, 464), and conditionally can either inhibit or promote cell death (74, 85, 237, 322, 451).",
       "key": "c36d4f60a620b282200f7d5bfff943561025f8822484f39973e51552cea0924f6f2bb667b3b371d8cb3d0662d8b0c8ed28702683809bb075c83d93feb96483ba",
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       "subject": {
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           "name": "Neurons",
           "namespace": "MESH"
         }
       },
-      "target": 234
+      "target": 238
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Brain": true
         },
@@ -13716,19 +15181,22 @@
       },
       "evidence": "In the brain, however, Cox2 is constitutively expressed by neurons (212, 512), participates in modulating synaptic plasticity (53, 464), and conditionally can either inhibit or promote cell death (74, 85, 237, 322, 451).",
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           "name": "Neurons",
           "namespace": "MESH"
         }
       },
-      "target": 91
+      "target": 90
     },
     {
       "annotations": {
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         "TextLocation": {
           "Review": true
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@@ -13752,13 +15220,16 @@
       },
       "evidence": "A link between alpha4 nAChRs and Cox2 was suggested by the observation that interneurons in the hippocampus coexpress both proteins (165). A mechanistic connection was inferred when long-term treatment of aged animals with NS398 promoted retention of alpha4 nAChR expression in the brain, an effect that was antagonized by the coadministration of nicotine.",
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       "relation": "association",
-      "source": 202,
-      "target": 183
+      "source": 205,
+      "target": 186
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -13781,14 +15252,17 @@
         "volume": "89"
       },
       "evidence": "A link between alpha4 nAChRs and Cox2 was suggested by the observation that interneurons in the hippocampus coexpress both proteins (165). A mechanistic connection was inferred when long-term treatment of aged animals with NS398 promoted retention of alpha4 nAChR expression in the brain, an effect that was antagonized by the coadministration of nicotine.",
-      "key": "b9353e8c7e4e75c62b7e6134507bb2f508ba51bce6e6b683768bd56bf1a51399b908fc7f2e7f59e7c97a5c9a2297f69bf1ad059afe18290070d2574948330600",
-      "line": 1731,
-      "relation": "decreases",
+      "key": "a31460d8e79d1e71e7f37593ecb10c55cce1273abdab10c797125a2d0e0405b5e39a8a8098422b94d85c4ba773c645ea383e4c2b8364c92716d44ae4e065879a",
+      "line": 1885,
+      "relation": "increases",
       "source": 4,
-      "target": 183
+      "target": 186
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Dopaminergic Neurons": true
         },
@@ -13815,13 +15289,16 @@
       },
       "evidence": "Parkinson’s disease (PD) is characterized by selective damage to dopaminergic nigrostriatal neurons and is clinically revealed by motor deficits, including rigidity, tremor, and bradykinesia. Dopamine replacement therapy (usually with L-dopa) is the most common treatment, although this drug loses efficacy over time.",
       "key": "3ba8cc7bd23228b377e62b35c2301e94086d572eb867542cfc7a825055c7108a0bd19c693629f0ab928861a73feb296d93b0e0cc71ede636cb2d191823319c1f",
-      "line": 1743,
+      "line": 1899,
       "relation": "positiveCorrelation",
-      "source": 252,
-      "target": 235
+      "source": 256,
+      "target": 239
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Dopaminergic Neurons": true
         },
@@ -13848,13 +15325,16 @@
       },
       "evidence": "Parkinson’s disease (PD) is characterized by selective damage to dopaminergic nigrostriatal neurons and is clinically revealed by motor deficits, including rigidity, tremor, and bradykinesia. Dopamine replacement therapy (usually with L-dopa) is the most common treatment, although this drug loses efficacy over time.",
       "key": "256ac01dac8d92ba1e33e261d0977e3cf30ed314c66e239a3fc531b834c40e2951e7ee648c679f7865ec0f81ed13da26eb80d412cd69796dccc2a9c9241b4c4d",
-      "line": 1744,
+      "line": 1900,
       "relation": "positiveCorrelation",
-      "source": 248,
-      "target": 235
+      "source": 252,
+      "target": 239
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Dopaminergic Neurons": true
         },
@@ -13881,13 +15361,16 @@
       },
       "evidence": "Parkinson’s disease (PD) is characterized by selective damage to dopaminergic nigrostriatal neurons and is clinically revealed by motor deficits, including rigidity, tremor, and bradykinesia. Dopamine replacement therapy (usually with L-dopa) is the most common treatment, although this drug loses efficacy over time.",
       "key": "012df55225acd1c441e5900ee3c2931a5dc8102a7748d929dea4b1c328c294df19ba1e29e46072ef285a27fc88610c1f2b045f83761e213237a2ac75d93c5447",
-      "line": 1745,
+      "line": 1901,
       "relation": "positiveCorrelation",
-      "source": 231,
-      "target": 235
+      "source": 235,
+      "target": 239
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -13911,13 +15394,16 @@
       },
       "evidence": "The concept that beta2-containing nAChRs are involved in the reinforcing effects of nicotine was supported by the findings that these mice lacked the high-affinity nicotine binding site, exhibited poor nicotine self-administration, and failed to develop behaviors related to reinforcement (378). The demonstration that these mice developed symptoms of the nicotine withdrawal syndrome similar to those observed in wild-type mice led to the conclusion that beta2-containing nAChRs do not contribute to the physical dependence on nicotine (57).",
       "key": "f6d78603dc846e0441f86384301b274eb17cfa5b98d1de6af8bb22d013a219158a1220117cee62e1b4a14123f855abd23f2d9248e90d34de52c86bbd95bedcd7",
-      "line": 1831,
+      "line": 1994,
       "relation": "association",
       "source": 40,
       "target": 30
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -13941,7 +15427,7 @@
       },
       "evidence": "The concept that beta2-containing nAChRs are involved in the reinforcing effects of nicotine was supported by the findings that these mice lacked the high-affinity nicotine binding site, exhibited poor nicotine self-administration, and failed to develop behaviors related to reinforcement (378). The demonstration that these mice developed symptoms of the nicotine withdrawal syndrome similar to those observed in wild-type mice led to the conclusion that beta2-containing nAChRs do not contribute to the physical dependence on nicotine (57).",
       "key": "a75c32a34bd9fe63c7f902ba811b5408fed81abc6a9fa174fddbe56883ff7fab5fcac189355813a9eb80999d5ac5f29ef72ceb110b5d64f61ba1cc1efbd75bce",
-      "line": 1832,
+      "line": 1995,
       "object": {
         "modifier": "Activity"
       },
@@ -13951,6 +15437,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -13974,13 +15463,16 @@
       },
       "evidence": "In summary, while nicotine-induced upregulation requires at least the beta2 nAChR subunit, development of tolerance to nicotine requires neither the beta2 nor the alpha7 nAChR subunit; instead, it appears to be modulated by a beta4-containing nAChR and to require an alpha4-containing nAChR.",
       "key": "b455be0cec558a45960cbfc5648d995e39d0940b0d717dfd8bf6371983b4030e2464e4ef6654d6c4cbc6d4f488df0eb8ce709abedbb924c066d352f631b4fb4c",
-      "line": 1858,
+      "line": 2024,
       "relation": "association",
-      "source": 226,
-      "target": 192
+      "source": 231,
+      "target": 195
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -14004,13 +15496,16 @@
       },
       "evidence": "In summary, while nicotine-induced upregulation requires at least the beta2 nAChR subunit, development of tolerance to nicotine requires neither the beta2 nor the alpha7 nAChR subunit; instead, it appears to be modulated by a beta4-containing nAChR and to require an alpha4-containing nAChR.",
       "key": "7e7d9abfae281708482f8ffc4e9c1d84c3ef37479f5053c612800c696b758c7e31fbf9e87bea12d8d9c0c24c59e5380e0284e93209aec647e5be9d73e0e73985",
-      "line": 1859,
+      "line": 2025,
       "relation": "association",
-      "source": 226,
+      "source": 231,
       "target": 37
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -14034,10 +15529,10 @@
       },
       "evidence": "In summary, while nicotine-induced upregulation requires at least the beta2 nAChR subunit, development of tolerance to nicotine requires neither the beta2 nor the alpha7 nAChR subunit; instead, it appears to be modulated by a beta4-containing nAChR and to require an alpha4-containing nAChR.",
       "key": "1e3a51317ec1e7aae140dcbb39c843af1278146ee7f3866314fc82100916ac721604f02e344e124d08e86fb6583bc515a53e17246c4618f8163c672b2ebc1874",
-      "line": 1859,
+      "line": 2025,
       "relation": "association",
       "source": 37,
-      "target": 226
+      "target": 231
     }
   ],
   "multigraph": true,
@@ -14456,17 +15951,17 @@
       "namespace": "MESH"
     },
     {
-      "bel": "a(MESH:\"Voltage-Gated Sodium Channels\")",
+      "bel": "a(MESH:\"alpha-cobratoxin\")",
       "function": "Abundance",
-      "id": "622945b24320f0660b930836a39a31f0a277c6a9e7c3805080df7417907379d01793cbb3fcb108c71f383fa8b42f5cee8fe96594824b201e5a6ce4aac6fe252b",
-      "name": "Voltage-Gated Sodium Channels",
+      "id": "37394a9a180f81d95a0bb983463a52277351b1a518d36e0af087e893016b24825e0b76457b4bfc162596ab7a8a019121aea4973cb065a43a380971832cadef65",
+      "name": "alpha-cobratoxin",
       "namespace": "MESH"
     },
     {
-      "bel": "a(MESH:\"alpha-cobratoxin\")",
+      "bel": "a(MESH:Acetylcholine)",
       "function": "Abundance",
-      "id": "37394a9a180f81d95a0bb983463a52277351b1a518d36e0af087e893016b24825e0b76457b4bfc162596ab7a8a019121aea4973cb065a43a380971832cadef65",
-      "name": "alpha-cobratoxin",
+      "id": "9e020dc85a11a30c92b2497436a3887fae49f9424c6b39afca85dc0bec3938998cff2426b2edceaad35239244592cc290dffe5a587823f21da7e012a65241f0f",
+      "name": "Acetylcholine",
       "namespace": "MESH"
     },
     {
@@ -14603,17 +16098,10 @@
       "namespace": "TAXONOMY"
     },
     {
-      "bel": "a(TAXONOMY:33113)",
-      "function": "Abundance",
-      "id": "e83d524192c8d208058ae3933af11bfe332ab41faffb73f143b9e8b9372839f02c6fd85c5cad38a20b250e8094f7a70d34a6d799b90ab4162c47f9afcef0d664",
-      "name": "33113",
-      "namespace": "TAXONOMY"
-    },
-    {
-      "bel": "a(TAXONOMY:41956)",
+      "bel": "a(TAXONOMY:8616)",
       "function": "Abundance",
-      "id": "060ccb75353b7c476e25c2e7d6f93b4cf6aaf1c43fa7e5a8d58d419320ac46f3d71db0e4d0fd24e4adb14c67c9f31192351c72d0c5a558a592ca39af283224fa",
-      "name": "41956",
+      "id": "4854c4cf875eb47849413c643fa6686e6efedd971c32ef48397a28535b570ae4299b3820540ecb835514a530bf351929362bfdd9a29224117c89e625055309eb",
+      "name": "8616",
       "namespace": "TAXONOMY"
     },
     {
@@ -14798,6 +16286,13 @@
       "name": "positive regulation of voltage-gated calcium channel activity",
       "namespace": "GO"
     },
+    {
+      "bel": "bp(GO:\"receptor clustering\")",
+      "function": "BiologicalProcess",
+      "id": "0329322eaa0c495c3b7353c2ec229dc093fb05d82c06006990747a5dbd5c30c695c57d2b63c3d645ea2a1fc0505c414293fc45bcf8a80c69039007b5179ed9b6",
+      "name": "receptor clustering",
+      "namespace": "GO"
+    },
     {
       "bel": "bp(GO:\"receptor signaling pathway via JAK-STAT\")",
       "function": "BiologicalProcess",
@@ -14868,6 +16363,20 @@
       "name": "nAChR assembly",
       "namespace": "HBP"
     },
+    {
+      "bel": "bp(MESH:\"Cell Differentiation\")",
+      "function": "BiologicalProcess",
+      "id": "0b1ac181a5931e4501ee72945608edeb629a92b280e4ddb3a5d75c08b7dbf8fda6c8e3aabd189c9ef32188b893fb7f73568cd9ccab57740084126410de206b6f",
+      "name": "Cell Differentiation",
+      "namespace": "MESH"
+    },
+    {
+      "bel": "bp(MESH:\"Heart Rate\")",
+      "function": "BiologicalProcess",
+      "id": "a9db0d03c176030975fcb0f87e6a8f242bd1abf328344e0117fbe69973c3825a4c57b6c00e4bae20ad8321cde6aa9c2e9eb837688bb1f65ef14ab298e39c1b36",
+      "name": "Heart Rate",
+      "namespace": "MESH"
+    },
     {
       "bel": "bp(MESH:\"Neuronal Plasticity\")",
       "function": "BiologicalProcess",
@@ -14875,6 +16384,13 @@
       "name": "Neuronal Plasticity",
       "namespace": "MESH"
     },
+    {
+      "bel": "bp(MESH:Apoptosis)",
+      "function": "BiologicalProcess",
+      "id": "39c21a5bf990cacd109cd022171f1f8d53f15707601351a2acf509f4f1a1c21650a3be4e5ddc8df4e09a2d236cc4cc03242239c0b4cde5940d3950792f6b9449",
+      "name": "Apoptosis",
+      "namespace": "MESH"
+    },
     {
       "bel": "complex(GO:\"voltage-gated calcium channel complex\")",
       "function": "Complex",
@@ -15218,48 +16734,6 @@
         }
       ]
     },
-    {
-      "bel": "complex(p(HGNC:CHRNA1), p(HGNC:CHRNB1), p(HGNC:CHRNB1), p(HGNC:CHRND), p(HGNC:CHRNG))",
-      "function": "Complex",
-      "id": "108270291950b7272402ddd0d23128b471632579c41a9f91b9fef0a638cca2dbb07957be4ef52b791d414390e3fe88489fcb7ddd6910ff0126c944af2f896a6d",
-      "members": [
-        {
-          "bel": "p(HGNC:CHRNA1)",
-          "function": "Protein",
-          "id": "2c954be76ae672869d04b052482aff81e8668f2b0c084e05a07b56bc45478c32c71764e3875f446be6d7e0117f400a88ca72e5d5fc0029229d0c16c4ae3e8e6f",
-          "name": "CHRNA1",
-          "namespace": "HGNC"
-        },
-        {
-          "bel": "p(HGNC:CHRNB1)",
-          "function": "Protein",
-          "id": "1c047d2b05c2943c0d93829faf7eca2f2847720340809607e7aa7e77cf2565d0ce5534dc0153fcd6d94cf666bef778540900bf0f642be98eb5ca383f7f9e8770",
-          "name": "CHRNB1",
-          "namespace": "HGNC"
-        },
-        {
-          "bel": "p(HGNC:CHRNB1)",
-          "function": "Protein",
-          "id": "1c047d2b05c2943c0d93829faf7eca2f2847720340809607e7aa7e77cf2565d0ce5534dc0153fcd6d94cf666bef778540900bf0f642be98eb5ca383f7f9e8770",
-          "name": "CHRNB1",
-          "namespace": "HGNC"
-        },
-        {
-          "bel": "p(HGNC:CHRND)",
-          "function": "Protein",
-          "id": "0fc12a3743f6213b0a8c9854f102f96f98b6d4ca5f6b93243215c6be9ef59d1071e4a981dfef35497424c052ed7d381aad79e113dad69e8c322a85d581ef69e9",
-          "name": "CHRND",
-          "namespace": "HGNC"
-        },
-        {
-          "bel": "p(HGNC:CHRNG)",
-          "function": "Protein",
-          "id": "fdc2324c7ab13b542120da2e930dae1aa2c84562e3bc9a659ddf97ae7412bf4cd7e8ad8fa72eca411b79eb3b1dc8c21dbdeb575bf3d6015c33aae8e21ca0cdf8",
-          "name": "CHRNG",
-          "namespace": "HGNC"
-        }
-      ]
-    },
     {
       "bel": "complex(p(HGNC:CHRNA1), p(HGNC:CHRNB1), p(HGNC:CHRND), p(HGNC:CHRNG))",
       "function": "Complex",
@@ -15393,6 +16867,34 @@
         }
       ]
     },
+    {
+      "bel": "complex(p(HGNC:CHRNA4), p(HGNC:CHRNA7), p(HGNC:CHRNB2))",
+      "function": "Complex",
+      "id": "cd42bb1096f7f8d0a0aa2e947cdbf33772448c46228176d63733c8651f9ec5d77e51b6ff8177b63c7b4f2c95891c34a2581128d9af17ce88ab9628b13f89b374",
+      "members": [
+        {
+          "bel": "p(HGNC:CHRNA4)",
+          "function": "Protein",
+          "id": "c49a9652cba613af55ca7c03c108df12ef9ea4e37760fcb7b2302e019899a0eaa11f06c1dcd9b9eb143b9baba0daa89737d73dafbfde9d8ddd8dd53b2a8269e0",
+          "name": "CHRNA4",
+          "namespace": "HGNC"
+        },
+        {
+          "bel": "p(HGNC:CHRNA7)",
+          "function": "Protein",
+          "id": "6f517aad2a254d42d4e0bd5118246057049b85324ab857629d0caa2da5e997bfcc08f9a0a2cd83bbb2b536c048ce402c0d521604c43b1b9c720f4e20b4dacd99",
+          "name": "CHRNA7",
+          "namespace": "HGNC"
+        },
+        {
+          "bel": "p(HGNC:CHRNB2)",
+          "function": "Protein",
+          "id": "fe8a0d337c8dfad7d9bbfcd38db3a76bbbfa276ae7af2e39600a1b845049505e52dd605173e1b8a8b67178c31bb8cde3f2669676e398c994800c15170b63033e",
+          "name": "CHRNB2",
+          "namespace": "HGNC"
+        }
+      ]
+    },
     {
       "bel": "complex(p(HGNC:CHRNA4), p(HGNC:CHRNB2))",
       "function": "Complex",
@@ -15541,9 +17043,9 @@
       ]
     },
     {
-      "bel": "composite(a(CHEBI:nicotine), g(HGNC:CHRNA4), g(HGNC:CHRNA6), g(HGNC:CHRNB2), g(HGNC:CHRNB3))",
+      "bel": "composite(a(CHEBI:nicotine), g(HGNC:CHRNA4))",
       "function": "Composite",
-      "id": "74ba7dc22b352707558f33df843ace29281296118daf209d405bfaef52a6b0848aeb24e13eda8f8bc0f7376d8ec87d3e25d81c9cdc03b7bfa362f5508c5172d2",
+      "id": "86a51909cba3b794fdcd079f34ea6520dab7195d67ae4a7a69abac88dfd3d44d3684f1c0bb656c6bad8c4ca51888c6a0dedef8d73f3de4e146f32a0124cc6cd6",
       "members": [
         {
           "bel": "a(CHEBI:nicotine)",
@@ -15558,6 +17060,20 @@
           "id": "e1e479226a67e190a74a68d36e1d14a9e471b87407adee5c90aaf4a844534e333eeb4074503fb6b551bb9309cb995461ea60e6c00e08b5eae96c613bf4ebc413",
           "name": "CHRNA4",
           "namespace": "HGNC"
+        }
+      ]
+    },
+    {
+      "bel": "composite(a(CHEBI:nicotine), g(HGNC:CHRNA6))",
+      "function": "Composite",
+      "id": "4f6c07a5ec61270ce2c3c8f199c6a0349098a3dd88e0a97afb4fa4a9781da625d165890046b02dbd4a2261e728ca330fca2cc64add8938bd655f90f459841c7c",
+      "members": [
+        {
+          "bel": "a(CHEBI:nicotine)",
+          "function": "Abundance",
+          "id": "81813864e07e0e955a0ccf7e9ec2430ce5cdbeae237c18991897f8314b29bdb2d0985dedfa71377ab67541fbcea0567e323d0cf47a5517efc83a67ac442abdb8",
+          "name": "nicotine",
+          "namespace": "CHEBI"
         },
         {
           "bel": "g(HGNC:CHRNA6)",
@@ -15565,6 +17081,20 @@
           "id": "d29630b5de45975040b6d3d7e4417a679d8d23e1a1008d79d7b4896f924ce2df6d764f0a70c574b49357897aa45bf1f9b146d77f26aa2bfdc305b8db2c2f4eb6",
           "name": "CHRNA6",
           "namespace": "HGNC"
+        }
+      ]
+    },
+    {
+      "bel": "composite(a(CHEBI:nicotine), g(HGNC:CHRNB2))",
+      "function": "Composite",
+      "id": "e001ea4f68bc0fb82561e02c5ef5b83da839fe0d338138a38eaf75fd378fb9efface7333513aa397d9d94c9c3ecc896a3ae661d9dab53c3026f6282770a113e2",
+      "members": [
+        {
+          "bel": "a(CHEBI:nicotine)",
+          "function": "Abundance",
+          "id": "81813864e07e0e955a0ccf7e9ec2430ce5cdbeae237c18991897f8314b29bdb2d0985dedfa71377ab67541fbcea0567e323d0cf47a5517efc83a67ac442abdb8",
+          "name": "nicotine",
+          "namespace": "CHEBI"
         },
         {
           "bel": "g(HGNC:CHRNB2)",
@@ -15572,6 +17102,20 @@
           "id": "5622fd830925a6531d48fb668c953c765dffa8a1547f9696b4d8dd7f30e81846ec1c2f6ef31e23bbb62f09f2b3e681e7de84dad6771c741e34cc4518f530b080",
           "name": "CHRNB2",
           "namespace": "HGNC"
+        }
+      ]
+    },
+    {
+      "bel": "composite(a(CHEBI:nicotine), g(HGNC:CHRNB3))",
+      "function": "Composite",
+      "id": "39ff6aba50fb0b3b40e87f7cd9252598b83d558df8a863ff8497b86a1176280a611157e2c0695d4d5a381d328c5cd95660aa6def61fe02947d05ca50d9986545",
+      "members": [
+        {
+          "bel": "a(CHEBI:nicotine)",
+          "function": "Abundance",
+          "id": "81813864e07e0e955a0ccf7e9ec2430ce5cdbeae237c18991897f8314b29bdb2d0985dedfa71377ab67541fbcea0567e323d0cf47a5517efc83a67ac442abdb8",
+          "name": "nicotine",
+          "namespace": "CHEBI"
         },
         {
           "bel": "g(HGNC:CHRNB3)",
@@ -15604,9 +17148,9 @@
       ]
     },
     {
-      "bel": "composite(complex(p(HGNC:CHRNA1), p(HGNC:CHRND)), complex(p(HGNC:CHRNA1), p(HGNC:CHRNG)), p(HGNC:CHRNB1))",
+      "bel": "composite(complex(p(HGNC:CHRNA1), p(HGNC:CHRND)), complex(p(HGNC:CHRNA1), p(HGNC:CHRNG)))",
       "function": "Composite",
-      "id": "416d54bdf3727791d4194a1ef5acb057b6a7ebeeaec556f1454f022e4b7b3350e6512ee0b0436c86ad1084aad5052331782e3a656bee5bba3dc06f4154f9960c",
+      "id": "2a01aae973597077025588032f4e9488ded677248f220ed8a7f5c2c72e379eb3354e016e006751ba934026e08b4fb1eded47af97ed952c46dbb260be30ae6b9a",
       "members": [
         {
           "bel": "complex(p(HGNC:CHRNA1), p(HGNC:CHRND))",
@@ -15649,13 +17193,6 @@
               "namespace": "HGNC"
             }
           ]
-        },
-        {
-          "bel": "p(HGNC:CHRNB1)",
-          "function": "Protein",
-          "id": "1c047d2b05c2943c0d93829faf7eca2f2847720340809607e7aa7e77cf2565d0ce5534dc0153fcd6d94cf666bef778540900bf0f642be98eb5ca383f7f9e8770",
-          "name": "CHRNB1",
-          "namespace": "HGNC"
         }
       ]
     },
@@ -15708,69 +17245,6 @@
         }
       ]
     },
-    {
-      "bel": "composite(p(HGNC:CHRNA4), p(HGNC:CHRNA6), p(HGNC:CHRNB2), p(HGNC:CHRNB3))",
-      "function": "Composite",
-      "id": "9ea0adcf41bfeaf2e1b607bd3e6ff9a9e45e2f4a06d0808f28e0176d3e08f388cfa2648d13e348a996b221aead3235452398efb13e3eca60cc9efffffb6a9a01",
-      "members": [
-        {
-          "bel": "p(HGNC:CHRNA4)",
-          "function": "Protein",
-          "id": "c49a9652cba613af55ca7c03c108df12ef9ea4e37760fcb7b2302e019899a0eaa11f06c1dcd9b9eb143b9baba0daa89737d73dafbfde9d8ddd8dd53b2a8269e0",
-          "name": "CHRNA4",
-          "namespace": "HGNC"
-        },
-        {
-          "bel": "p(HGNC:CHRNA6)",
-          "function": "Protein",
-          "id": "538307ae2a1fc2af82c7e0a0286320b0366e3e9a4e5b9597803273c5c0f3049fadef72ad508f6edec030727aaf62edd6170575aaa6046e40567d53e7322aaabe",
-          "name": "CHRNA6",
-          "namespace": "HGNC"
-        },
-        {
-          "bel": "p(HGNC:CHRNB2)",
-          "function": "Protein",
-          "id": "fe8a0d337c8dfad7d9bbfcd38db3a76bbbfa276ae7af2e39600a1b845049505e52dd605173e1b8a8b67178c31bb8cde3f2669676e398c994800c15170b63033e",
-          "name": "CHRNB2",
-          "namespace": "HGNC"
-        },
-        {
-          "bel": "p(HGNC:CHRNB3)",
-          "function": "Protein",
-          "id": "cab3d2b7a9a4321d552b5fbe2ff10363ec8ef4b6600f91369ec41f7131fc6d427e0b159e6626d5c42f2eea7b9c11390fc4a6b2964471ee70776ea8960135e7ca",
-          "name": "CHRNB3",
-          "namespace": "HGNC"
-        }
-      ]
-    },
-    {
-      "bel": "composite(p(HGNC:CHRNA4), p(HGNC:CHRNA7), p(HGNC:CHRNB2))",
-      "function": "Composite",
-      "id": "4fe57c870f03e01ad0d9462f711e7d23261ec4decdb8a9f8ce715aeb171fed7e157f6eb3fecba5289549a66080bb6634e35c5a4f887d029b47cd95e3aa60f399",
-      "members": [
-        {
-          "bel": "p(HGNC:CHRNA4)",
-          "function": "Protein",
-          "id": "c49a9652cba613af55ca7c03c108df12ef9ea4e37760fcb7b2302e019899a0eaa11f06c1dcd9b9eb143b9baba0daa89737d73dafbfde9d8ddd8dd53b2a8269e0",
-          "name": "CHRNA4",
-          "namespace": "HGNC"
-        },
-        {
-          "bel": "p(HGNC:CHRNA7)",
-          "function": "Protein",
-          "id": "6f517aad2a254d42d4e0bd5118246057049b85324ab857629d0caa2da5e997bfcc08f9a0a2cd83bbb2b536c048ce402c0d521604c43b1b9c720f4e20b4dacd99",
-          "name": "CHRNA7",
-          "namespace": "HGNC"
-        },
-        {
-          "bel": "p(HGNC:CHRNB2)",
-          "function": "Protein",
-          "id": "fe8a0d337c8dfad7d9bbfcd38db3a76bbbfa276ae7af2e39600a1b845049505e52dd605173e1b8a8b67178c31bb8cde3f2669676e398c994800c15170b63033e",
-          "name": "CHRNB2",
-          "namespace": "HGNC"
-        }
-      ]
-    },
     {
       "bel": "composite(p(HGNC:CHRNA7), p(HGNC:NGF))",
       "function": "Composite",
@@ -15869,13 +17343,6 @@
       "name": "PLC",
       "namespace": "FPLX"
     },
-    {
-      "bel": "p(HBP:\"alpha-3 beta-2 nAChR\")",
-      "function": "Protein",
-      "id": "978f090b6df94e1da305071a7247b758036277306095f25ee56a9fdea0e01a8144f11111e9e8ba09998e3f6da8ade003a1ac3b80484e62091ed9bb7ae83bb877",
-      "name": "alpha-3 beta-2 nAChR",
-      "namespace": "HBP"
-    },
     {
       "bel": "p(HBP:\"alpha-3 beta-4 nAChR\")",
       "function": "Protein",
@@ -16177,6 +17644,19 @@
       "name": "Cholinergic receptors nicotinic subunits",
       "namespace": "HGNCGENEFAMILY"
     },
+    {
+      "bel": "p(HGNCGENEFAMILY:\"Cholinergic receptors nicotinic subunits\", var(\"?\"))",
+      "function": "Protein",
+      "id": "ea21977eb87ed21be2b7bd87dfcf8db5bc0ab3c7cd4b26d3c586477fe7ba4ef6240e61b490dfa758da8fa892b4255a74d82aa1e8a5e191ba06a5e5d2539cb625",
+      "name": "Cholinergic receptors nicotinic subunits",
+      "namespace": "HGNCGENEFAMILY",
+      "variants": [
+        {
+          "identifier": "?",
+          "kind": "hgvs"
+        }
+      ]
+    },
     {
       "bel": "p(HGNCGENEFAMILY:\"ETS transcription factor family\")",
       "function": "Protein",
@@ -16212,6 +17692,13 @@
       "name": "Cysteine Loop Ligand-Gated Ion Channel Receptors",
       "namespace": "MESH"
     },
+    {
+      "bel": "p(MESH:\"Voltage-Gated Sodium Channels\")",
+      "function": "Protein",
+      "id": "7dfb84824330a6690b82139953a028b8619f6820cb864078490102bd24d71ca9071023c9786aa5b0a360a256954ad613be196537cc5ef41644a4fc1fccacb676",
+      "name": "Voltage-Gated Sodium Channels",
+      "namespace": "MESH"
+    },
     {
       "bel": "p(MGI:Chrna4)",
       "function": "Protein",
@@ -16310,13 +17797,6 @@
       "name": "Genetic Variation",
       "namespace": "MESH"
     },
-    {
-      "bel": "path(MESH:\"Heart Rate\")",
-      "function": "Pathology",
-      "id": "f8a2fbc9a7fa5b9495c3c7595d8e762469814efa7afa24c44842c575b8dd10f95dd4336251b928f56809d6431d7f72ade379fb9d214e47cc5f8b6d8fd6b5b8cc",
-      "name": "Heart Rate",
-      "namespace": "MESH"
-    },
     {
       "bel": "path(MESH:\"Inflammatory Bowel Diseases\")",
       "function": "Pathology",
@@ -16520,6 +18000,13 @@
       "name": "CHRNA6",
       "namespace": "HGNC"
     },
+    {
+      "bel": "r(HGNC:CHRNA7)",
+      "function": "RNA",
+      "id": "a05aa727d187aba9ed37f09183caad69734432d7986be00a7e4d4c0b221431d56c8ed588073cd0a9e76046cca38bd11b903a3ed354351e9b01094db398835d19",
+      "name": "CHRNA7",
+      "namespace": "HGNC"
+    },
     {
       "bel": "r(HGNC:CHRNB1)",
       "function": "RNA",
diff --git a/hbp_knowledge/receptors/choi2014.bel.json b/hbp_knowledge/receptors/choi2014.bel.json
index 6bb1c7ce0..90b2f3924 100644
--- a/hbp_knowledge/receptors/choi2014.bel.json
+++ b/hbp_knowledge/receptors/choi2014.bel.json
@@ -54,6 +54,9 @@
   "links": [
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Central Nervous System": true
         }
@@ -83,6 +86,11 @@
       "target": 87
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "Choi DL",
@@ -102,12 +110,17 @@
       },
       "evidence": "Conversely, the most commonly associated symptoms of AD are cognitive in nature and include deficits in learning and memory. However, 50%–80% of AD patients display psychotic and behavioral disturbances that are correlated with poor social and functional outcomes",
       "key": "e70a537388ceb7cf95ecc01c41ca219db3b3db3b0a00ff919caca11b33fb2964dea6aaaa5b758e2fcd798e0d030d0e60942bd81c4c41b5c22650a0ea04ee39a6",
-      "line": 105,
+      "line": 108,
       "relation": "association",
       "source": 78,
       "target": 87
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "Choi DL",
@@ -127,13 +140,16 @@
       },
       "evidence": "AD is the most commonly diagnosed form of dementia and currently affects approximately 35 million individuals worldwide.7 AD is a progressive neurodegenerative disease that is characterized by a host of cognitive deficits, including impairments in learning and memory. In addition to the well-documented cognitive impairments, AD patients also display behavioral disturbances, including anxiety, depression, and psychosis",
       "key": "1028c21782f67bfa45887cfab7e993f4fad24422ef2090342d9bcbfa17bff5283e554964b4d8292e8c391a3a77d35314cf0bad8a2f78931627e117751ace5f79",
-      "line": 171,
+      "line": 180,
       "relation": "association",
       "source": 78,
       "target": 87
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Central Nervous System": true
         }
@@ -163,6 +179,11 @@
       "target": 80
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "Choi DL",
@@ -182,12 +203,17 @@
       },
       "evidence": "AD is the most commonly diagnosed form of dementia and currently affects approximately 35 million individuals worldwide.7 AD is a progressive neurodegenerative disease that is characterized by a host of cognitive deficits, including impairments in learning and memory. In addition to the well-documented cognitive impairments, AD patients also display behavioral disturbances, including anxiety, depression, and psychosis",
       "key": "2a246cf2d9f5fce030031667407bcd984f2382480e8f12e832bc899c813c63974fbaeb6328ec1d1f6edbfefc70a9bc6ef5f4d07cc1928ecc8b2b90524635abbf",
-      "line": 166,
+      "line": 173,
       "relation": "association",
       "source": 78,
       "target": 80
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "Choi DL",
@@ -207,12 +233,17 @@
       },
       "evidence": "Conversely, the most commonly associated symptoms of AD are cognitive in nature and include deficits in learning and memory. However, 50%–80% of AD patients display psychotic and behavioral disturbances that are correlated with poor social and functional outcomes",
       "key": "e864d5c9143b2aefa9ba3d8ef32fc7df2e741b194c29cd9f9a26ff3ab08d5491644324aaff4994bdc04a827058712cf7b7cb5f851b76b17da6b7204e763362e8",
-      "line": 102,
+      "line": 104,
       "relation": "association",
       "source": 78,
       "target": 51
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "Choi DL",
@@ -232,12 +263,17 @@
       },
       "evidence": "AD is the most commonly diagnosed form of dementia and currently affects approximately 35 million individuals worldwide.7 AD is a progressive neurodegenerative disease that is characterized by a host of cognitive deficits, including impairments in learning and memory. In addition to the well-documented cognitive impairments, AD patients also display behavioral disturbances, including anxiety, depression, and psychosis",
       "key": "8422b906a27b7ec06e41135363ce09d9929cf3931f005fd13845bf30fb10b6c78048e45f2a803824229a95bc3a27486e1c5a66f8e4b019267bc5114abbeaf9f4",
-      "line": 167,
+      "line": 174,
       "relation": "decreases",
       "source": 78,
       "target": 51
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "Choi DL",
@@ -256,13 +292,18 @@
         "volume": "10"
       },
       "evidence": "Conversely, the most commonly associated symptoms of AD are cognitive in nature and include deficits in learning and memory. However, 50%–80% of AD patients display psychotic and behavioral disturbances that are correlated with poor social and functional outcomes",
-      "key": "28233574c671dbac4921d54839386bdb70dc25f7393560b9253d9d02c321f7579ef56aab099915bf04a0a1ff85b312fdaafe9fc0ed8235d1824906947e1aaa68",
-      "line": 103,
-      "relation": "association",
+      "key": "125fe6ec6f4829eba49f8a43341dd8f3a70944f51d19d46ab107e67b0092e438a668c5544e126d4775d799efdae48c0cb3bf6c49bc8aaea8e8daa131f21bc238",
+      "line": 105,
+      "relation": "decreases",
       "source": 78,
       "target": 52
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "Choi DL",
@@ -282,12 +323,17 @@
       },
       "evidence": "AD is the most commonly diagnosed form of dementia and currently affects approximately 35 million individuals worldwide.7 AD is a progressive neurodegenerative disease that is characterized by a host of cognitive deficits, including impairments in learning and memory. In addition to the well-documented cognitive impairments, AD patients also display behavioral disturbances, including anxiety, depression, and psychosis",
       "key": "814fdafba15e248ef8149e9ac2ee4f2efb9441362c83f586c329f8456c943a73d762a302b0b294babe4715ead893a7c28b1d87e4b3c2fa9dd9e1ae852f11e765",
-      "line": 168,
+      "line": 175,
       "relation": "decreases",
       "source": 78,
       "target": 52
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "Choi DL",
@@ -306,13 +352,48 @@
         "volume": "10"
       },
       "evidence": "Conversely, the most commonly associated symptoms of AD are cognitive in nature and include deficits in learning and memory. However, 50%–80% of AD patients display psychotic and behavioral disturbances that are correlated with poor social and functional outcomes",
-      "key": "877356e3267429402fd029e7d769c6912cc2c2ca8ed08056ac9d18e3dfcd1d96c376a5949bbe111877d24e6eb888174edcbf8708e00b0fb0e74c03c9b532f560",
-      "line": 104,
-      "relation": "association",
+      "key": "34d7b76b9b6caa549a6b1c0ac93685522deabfed0e90b8b952509660a828c67313d6a3dd22a685893090f1ce47ea3023a63d6ff86ba90b8080602de977ffef0c",
+      "line": 106,
+      "relation": "decreases",
       "source": 78,
       "target": 54
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Choi DL",
+          "Conn PJ",
+          "Foster DJ",
+          "Rook JM"
+        ],
+        "date": "2014-01-01",
+        "first": "Foster DJ",
+        "last": "Rook JM",
+        "name": "Neuropsychiatric disease and treatment",
+        "pages": "183-91",
+        "reference": "24511233",
+        "title": "Activation of M1 and M4 muscarinic receptors as potential treatments for Alzheimer's disease and schizophrenia.",
+        "type": "PubMed",
+        "volume": "10"
+      },
+      "evidence": "AD is the most commonly diagnosed form of dementia and currently affects approximately 35 million individuals worldwide.7 AD is a progressive neurodegenerative disease that is characterized by a host of cognitive deficits, including impairments in learning and memory. In addition to the well-documented cognitive impairments, AD patients also display behavioral disturbances, including anxiety, depression, and psychosis",
+      "key": "e2fcb9cf1e3f7aa9a69265d686c0a5dd36df341f0d222437b64a88ef318d6e465aaf6dbc80fe3b4a915f84942e6e538e2e1a5dac74215c04daeca2803997789c",
+      "line": 176,
+      "relation": "decreases",
+      "source": 78,
+      "target": 54
+    },
+    {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Choi DL",
@@ -332,12 +413,17 @@
       },
       "evidence": "Another commonality between AD and SZ is the apparent involvement of dysregulated cholinergic signaling in the brain.",
       "key": "f63be799eef75fee6a5a969bb63b576c2494ac347598b2a1b4a2bd3808d88b0c1c085fea2918a2b912c9c4261dcedce2a46d7729bf081fb9f9f68a267d6451a0",
-      "line": 111,
+      "line": 115,
       "relation": "decreases",
       "source": 78,
       "target": 47
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Choi DL",
@@ -357,12 +443,17 @@
       },
       "evidence": "1 Several lines of evidence suggest that impaired cholinergic signaling plays a key role in mediating both the cognitive and the behavioral impairments observed in AD patients.12 The basal forebrain cholinergic system is disproportionately affected in AD patients, with a robust loss of cholinergic neurons, including those innervating the hippocampus and cortex.",
       "key": "154aa3756540b6b078183444d92d2b34a047ac2c62a9797f1c33b41ad10b4b6f1e05679363ae6c202e22159e3f7f743d68415e2cce55551e192e74bfb04a1942",
-      "line": 216,
+      "line": 229,
       "relation": "decreases",
       "source": 78,
       "target": 47
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "Choi DL",
@@ -382,12 +473,17 @@
       },
       "evidence": "AD is the most commonly diagnosed form of dementia and currently affects approximately 35 million individuals worldwide.7 AD is a progressive neurodegenerative disease that is characterized by a host of cognitive deficits, including impairments in learning and memory. In addition to the well-documented cognitive impairments, AD patients also display behavioral disturbances, including anxiety, depression, and psychosis",
       "key": "3d9fb6548c0918fab494dc094cb7deb56165b6febf0cc6b12a34b091baea5ee5e9b9ca472dbd31e1b40ab51f7dbda65239372ded46e4e6349be55fe57377233e",
-      "line": 164,
+      "line": 171,
       "relation": "association",
       "source": 78,
       "target": 93
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "Choi DL",
@@ -407,12 +503,17 @@
       },
       "evidence": "AD is the most commonly diagnosed form of dementia and currently affects approximately 35 million individuals worldwide.7 AD is a progressive neurodegenerative disease that is characterized by a host of cognitive deficits, including impairments in learning and memory. In addition to the well-documented cognitive impairments, AD patients also display behavioral disturbances, including anxiety, depression, and psychosis",
       "key": "ae88ca4f9c01acbfdd0dbb0d6872e3347dcc0729ebc0bbfce55d726876677c229e09ce487739e75adf7de0f3b619b444b42de0d3e343c208d3341a10888b9de4",
-      "line": 165,
+      "line": 172,
       "relation": "isA",
       "source": 78,
       "target": 84
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "Choi DL",
@@ -432,12 +533,17 @@
       },
       "evidence": "AD is the most commonly diagnosed form of dementia and currently affects approximately 35 million individuals worldwide.7 AD is a progressive neurodegenerative disease that is characterized by a host of cognitive deficits, including impairments in learning and memory. In addition to the well-documented cognitive impairments, AD patients also display behavioral disturbances, including anxiety, depression, and psychosis",
       "key": "482e142f101175a9b985906bdb38fed733ed4b774749861f75f8193b018b2fcbc26cd82c6571941501884d0f60786a79bdf13ba4e87c0e6291b56f7dc1e02de7",
-      "line": 169,
+      "line": 178,
       "relation": "increases",
       "source": 78,
       "target": 94
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "Choi DL",
@@ -457,12 +563,17 @@
       },
       "evidence": "AD is the most commonly diagnosed form of dementia and currently affects approximately 35 million individuals worldwide.7 AD is a progressive neurodegenerative disease that is characterized by a host of cognitive deficits, including impairments in learning and memory. In addition to the well-documented cognitive impairments, AD patients also display behavioral disturbances, including anxiety, depression, and psychosis",
       "key": "beeaa00b584314706c77dc454eed70c7790e9d2d40f0418def1c75e4b497b44f884b73e03941911bc05f1d4eb8688c76367d3caddf09a96cb0c012dd3059f2a5",
-      "line": 170,
+      "line": 179,
       "relation": "increases",
       "source": 78,
       "target": 90
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Choi DL",
@@ -482,13 +593,16 @@
       },
       "evidence": "Age is the primary risk factor for AD, and the disease usually manifests in individuals after the age of 60 years. Due to an aging population, the prevalence of AD is predicted to rise to 66 million people by the year 2030.",
       "key": "16e2220f5e054057f9311988f0e63657fbe45269f42eb8c2ec6c63cf04acfa687ed667a3402a936f095c63fc8a9f3047928fb4ffcbf5cb9dfe9a9aebb23969e7",
-      "line": 178,
+      "line": 188,
       "relation": "association",
       "source": 78,
       "target": 57
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Cerebral Cortex": true,
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       "evidence": "1 Several lines of evidence suggest that impaired cholinergic signaling plays a key role in mediating both the cognitive and the behavioral impairments observed in AD patients.12 The basal forebrain cholinergic system is disproportionately affected in AD patients, with a robust loss of cholinergic neurons, including those innervating the hippocampus and cortex.",
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     {
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         "MeSHAnatomy": {
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     {
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@@ -593,13 +720,16 @@
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@@ -715,6 +856,9 @@
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@@ -745,6 +889,9 @@
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@@ -1224,13 +1459,16 @@
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       "evidence": "The popular amyloid cascade hypothesis posits that the gradual build-up of Abeta plaques leads to neuronal inflammation, dysfunction, and, eventually, cell death. The two brain regions most critically affected by this degeneration are the cortex and hippocampus, both of which are involved in cognition, learning, and memory.",
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@@ -1255,12 +1493,17 @@
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       "evidence": "The popular amyloid cascade hypothesis posits that the gradual build-up of Abeta plaques leads to neuronal inflammation, dysfunction, and, eventually, cell death. The two brain regions most critically affected by this degeneration are the cortex and hippocampus, both of which are involved in cognition, learning, and memory.",
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       "evidence": "1 Several lines of evidence suggest that impaired cholinergic signaling plays a key role in mediating both the cognitive and the behavioral impairments observed in AD patients.12 The basal forebrain cholinergic system is disproportionately affected in AD patients, with a robust loss of cholinergic neurons, including those innervating the hippocampus and cortex.",
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@@ -1312,12 +1558,17 @@
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@@ -1367,12 +1621,17 @@
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       "evidence": "In brain slice electrophysiology studies, BQCA enhanced excitatory postsynaptic currents in medial prefrontal cortical neurons,69 an area critical for higher cognitive, learning, and memory functions.70 In pre-clinical animal studies, BQCA reversed scopolamine-impaired contextual fear conditioning and rescued medial prefrontal cortex-dependent discrimination reversal learning deficits in a transgenic mouse model of AD.",
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     {
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       "evidence": "1 Several lines of evidence suggest that impaired cholinergic signaling plays a key role in mediating both the cognitive and the behavioral impairments observed in AD patients.12 The basal forebrain cholinergic system is disproportionately affected in AD patients, with a robust loss of cholinergic neurons, including those innervating the hippocampus and cortex.",
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     {
       "annotations": {
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           "Hippocampus": true
@@ -1473,13 +1715,16 @@
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       "evidence": "The popular amyloid cascade hypothesis posits that the gradual build-up of Abeta plaques leads to neuronal inflammation, dysfunction, and, eventually, cell death. The two brain regions most critically affected by this degeneration are the cortex and hippocampus, both of which are involved in cognition, learning, and memory.",
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@@ -1504,13 +1749,16 @@
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       "evidence": "M1 mAChRs have been demonstrated to potentiate NMDA-receptor signaling in the hippocampus and cortex,48,49 brain areas intimately associated with learning and memory. In addition, M1 KO mice displayed reduced hippocampal long-term potentiation, a mechanism heavily implicated in learning and memory. Behaviorally, M1 KO animals display deficits in several medial prefrontal cortex-dependent cognitive tasks, including non-matching-to- sample, win-shift radial arm maze, and social discrimination tasks.",
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@@ -1535,13 +1783,16 @@
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       "evidence": "The popular amyloid cascade hypothesis posits that the gradual build-up of Abeta plaques leads to neuronal inflammation, dysfunction, and, eventually, cell death. The two brain regions most critically affected by this degeneration are the cortex and hippocampus, both of which are involved in cognition, learning, and memory.",
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@@ -1566,13 +1817,16 @@
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       "evidence": "M1 mAChRs have been demonstrated to potentiate NMDA-receptor signaling in the hippocampus and cortex,48,49 brain areas intimately associated with learning and memory. In addition, M1 KO mice displayed reduced hippocampal long-term potentiation, a mechanism heavily implicated in learning and memory. Behaviorally, M1 KO animals display deficits in several medial prefrontal cortex-dependent cognitive tasks, including non-matching-to- sample, win-shift radial arm maze, and social discrimination tasks.",
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@@ -1597,13 +1851,16 @@
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       "evidence": "M1 mAChRs have been demonstrated to potentiate NMDA-receptor signaling in the hippocampus and cortex,48,49 brain areas intimately associated with learning and memory. In addition, M1 KO mice displayed reduced hippocampal long-term potentiation, a mechanism heavily implicated in learning and memory. Behaviorally, M1 KO animals display deficits in several medial prefrontal cortex-dependent cognitive tasks, including non-matching-to- sample, win-shift radial arm maze, and social discrimination tasks.",
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       "evidence": "In brain slice electrophysiology studies, BQCA enhanced excitatory postsynaptic currents in medial prefrontal cortical neurons,69 an area critical for higher cognitive, learning, and memory functions.70 In pre-clinical animal studies, BQCA reversed scopolamine-impaired contextual fear conditioning and rescued medial prefrontal cortex-dependent discrimination reversal learning deficits in a transgenic mouse model of AD.",
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@@ -1683,13 +1918,16 @@
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       "evidence": "The popular amyloid cascade hypothesis posits that the gradual build-up of Abeta plaques leads to neuronal inflammation, dysfunction, and, eventually, cell death. The two brain regions most critically affected by this degeneration are the cortex and hippocampus, both of which are involved in cognition, learning, and memory.",
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       "evidence": "M1 mAChRs have been demonstrated to potentiate NMDA-receptor signaling in the hippocampus and cortex,48,49 brain areas intimately associated with learning and memory. In addition, M1 KO mice displayed reduced hippocampal long-term potentiation, a mechanism heavily implicated in learning and memory. Behaviorally, M1 KO animals display deficits in several medial prefrontal cortex-dependent cognitive tasks, including non-matching-to- sample, win-shift radial arm maze, and social discrimination tasks.",
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       },
       "evidence": "The popular amyloid cascade hypothesis posits that the gradual build-up of Abeta plaques leads to neuronal inflammation, dysfunction, and, eventually, cell death. The two brain regions most critically affected by this degeneration are the cortex and hippocampus, both of which are involved in cognition, learning, and memory.",
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@@ -1776,13 +2020,16 @@
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       "evidence": "M1 mAChRs have been demonstrated to potentiate NMDA-receptor signaling in the hippocampus and cortex,48,49 brain areas intimately associated with learning and memory. In addition, M1 KO mice displayed reduced hippocampal long-term potentiation, a mechanism heavily implicated in learning and memory. Behaviorally, M1 KO animals display deficits in several medial prefrontal cortex-dependent cognitive tasks, including non-matching-to- sample, win-shift radial arm maze, and social discrimination tasks.",
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@@ -1807,13 +2054,16 @@
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       "evidence": "M1 mAChRs have been demonstrated to potentiate NMDA-receptor signaling in the hippocampus and cortex,48,49 brain areas intimately associated with learning and memory. In addition, M1 KO mice displayed reduced hippocampal long-term potentiation, a mechanism heavily implicated in learning and memory. Behaviorally, M1 KO animals display deficits in several medial prefrontal cortex-dependent cognitive tasks, including non-matching-to- sample, win-shift radial arm maze, and social discrimination tasks.",
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       "evidence": "In brain slice electrophysiology studies, BQCA enhanced excitatory postsynaptic currents in medial prefrontal cortical neurons,69 an area critical for higher cognitive, learning, and memory functions.70 In pre-clinical animal studies, BQCA reversed scopolamine-impaired contextual fear conditioning and rescued medial prefrontal cortex-dependent discrimination reversal learning deficits in a transgenic mouse model of AD.",
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       "evidence": "1 Several lines of evidence suggest that impaired cholinergic signaling plays a key role in mediating both the cognitive and the behavioral impairments observed in AD patients.12 The basal forebrain cholinergic system is disproportionately affected in AD patients, with a robust loss of cholinergic neurons, including those innervating the hippocampus and cortex.",
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       "evidence": "1 Several lines of evidence suggest that impaired cholinergic signaling plays a key role in mediating both the cognitive and the behavioral impairments observed in AD patients.12 The basal forebrain cholinergic system is disproportionately affected in AD patients, with a robust loss of cholinergic neurons, including those innervating the hippocampus and cortex.",
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@@ -1912,13 +2177,16 @@
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       "evidence": "Accumulating evidence suggests that the three clusters of SZ symptoms cannot be ascribed solely to alterations in monoaminergic signaling as dysregulation of glutamatergic, gamma-aminobutyric acid (GABA)-ergic, and cholinergic systems have also been reported",
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     {
       "annotations": {
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+        },
         "MeSHAnatomy": {
           "Cerebral Cortex": true,
           "Corpus Striatum": true,
@@ -1945,7 +2213,7 @@
       },
       "evidence": "Acetylcholine (ACh) is a neurotransmitter that modulates neuronal function in several areas of the CNS associated with AD and/or SZ pathology, including the striatum, cortex, hippocampus, and prefrontal cortex.5 ACh mediates its actions via two families of receptors, termed the muscarinic ACh receptors (mAChRs) and the nicotinic ACh receptors (nAChRs).",
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@@ -1954,6 +2222,11 @@
       "target": 37
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     {
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       "citation": {
         "authors": [
           "Choi DL",
@@ -1972,8 +2245,8 @@
         "volume": "10"
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       "evidence": "Two novel M4-selective compounds, VU10010 and LY2033298, represented a breakthrough when they were described in 2008.84,85 VU10010 is a potent M4-selective PAM that increases affinity/efficacy of ACh to promote M4 mAChR activation.",
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@@ -1982,10 +2255,13 @@
       "subject": {
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-      "target": 65
+      "target": 68
     },
     {
       "annotations": {
+        "Confidence": {
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+        },
         "MeSHAnatomy": {
           "Cerebral Cortex": true,
           "Corpus Striatum": true,
@@ -2012,7 +2288,7 @@
       },
       "evidence": "Acetylcholine (ACh) is a neurotransmitter that modulates neuronal function in several areas of the CNS associated with AD and/or SZ pathology, including the striatum, cortex, hippocampus, and prefrontal cortex.5 ACh mediates its actions via two families of receptors, termed the muscarinic ACh receptors (mAChRs) and the nicotinic ACh receptors (nAChRs).",
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@@ -2051,6 +2327,11 @@
       "target": 69
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     {
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       "citation": {
         "authors": [
           "Choi DL",
@@ -2070,13 +2351,16 @@
       },
       "evidence": "The mAChR family consists of five subtypes (M1 –M5) that can be found throughout the CNS and periphery. These receptors are guanosine nucleotide-binding protein (G-protein)-coupled receptors and can be subdivided based on their canonical signaling pathways.",
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       "relation": "isA",
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     {
       "annotations": {
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+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -2100,13 +2384,16 @@
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       "evidence": " In addition, administration of nonselective muscarinic antagonists can produce or exacerbate cognitive deficits in animals,15 as well as in AD patients and both young and old control subjects,16,17 suggesting that mAChRs can directly modulate cognition.",
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     {
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         "MeSHAnatomy": {
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@@ -2133,7 +2420,7 @@
       },
       "evidence": "Acetylcholine (ACh) is a neurotransmitter that modulates neuronal function in several areas of the CNS associated with AD and/or SZ pathology, including the striatum, cortex, hippocampus, and prefrontal cortex.5 ACh mediates its actions via two families of receptors, termed the muscarinic ACh receptors (mAChRs) and the nicotinic ACh receptors (nAChRs).",
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@@ -2143,6 +2430,9 @@
     },
     {
       "annotations": {
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+        },
         "MeSHAnatomy": {
           "Corpus Striatum": true,
           "Hippocampus": true,
@@ -2168,12 +2458,17 @@
       },
       "evidence": "The M1 mAChR subtype is the most predominantly expressed mAChR subtype in the CNS and is expressed in several brain regions implicated in the regulation of cognitive processes, including the striatum, prefrontal cortex, and hippocampus.",
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       "citation": {
         "authors": [
           "Choi DL",
@@ -2193,7 +2488,7 @@
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       "evidence": "Subsequent optimization produced two analogs of AC-42 (AC-260584 and 77-LH-28-1), which maintained M1 selectivity and possessed properties suitable for use in animal models. Both AC-260584 and 77-LH-28-1 displayed antipsychotic and cognition-enhancing efficacy in pre-clinical models",
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       "relation": "increases",
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@@ -2202,6 +2497,11 @@
       "target": 51
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     {
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       "citation": {
         "authors": [
           "Choi DL",
@@ -2221,7 +2521,7 @@
       },
       "evidence": "Interestingly, these M1-deficient mice display increased amphetamine-induced hyperlocomotion and dopamine neurotransmission,47 indicating that M1 modulation may have antipsychotic potential.",
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       "object": {
         "modifier": "Activity"
       },
@@ -2230,6 +2530,11 @@
       "target": 5
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Choi DL",
@@ -2249,13 +2554,16 @@
       },
       "evidence": "Interestingly, these M1-deficient mice display increased amphetamine-induced hyperlocomotion and dopamine neurotransmission,47 indicating that M1 modulation may have antipsychotic potential.",
       "key": "a3fbc493259063824f1e627bfc53edf44b24d6805b8aac626e1e135ab9ef3dac6ad546ad06510d71f3df1160321318b11e0f2f49fdbede2cdfc66dfa5af3800c",
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       "relation": "decreases",
       "source": 65,
       "target": 42
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Cerebral Cortex": true,
           "Hippocampus": true
@@ -2280,7 +2588,7 @@
       },
       "evidence": "M1 mAChRs have been demonstrated to potentiate NMDA-receptor signaling in the hippocampus and cortex,48,49 brain areas intimately associated with learning and memory. In addition, M1 KO mice displayed reduced hippocampal long-term potentiation, a mechanism heavily implicated in learning and memory. Behaviorally, M1 KO animals display deficits in several medial prefrontal cortex-dependent cognitive tasks, including non-matching-to- sample, win-shift radial arm maze, and social discrimination tasks.",
       "key": "0f0425a9e8ec1cf51a217a3ddf4dc5c62512db8cc99a8ea8f9c95eb031c401f8f12a81583a07650681ddb1ff74c01abe0abae5982d94b9050cd6f2a87f7f94ca",
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       "object": {
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       },
@@ -2290,6 +2598,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "CA1 Region, Hippocampal": true
         }
@@ -2313,7 +2624,7 @@
       },
       "evidence": "Another early allosteric agonist, TBPB (1-(1’-(2-methylbenzyl) -1,4’-bipiperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-1), also exhibited impressive selectivity for M1 mAChRs and potentiated NMDA receptor currents in CA1 hippocampal cells. ",
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       "object": {
         "modifier": "Activity"
       },
@@ -2326,6 +2637,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Cerebral Cortex": true,
           "Hippocampus": true
@@ -2350,12 +2664,17 @@
       },
       "evidence": "M1 mAChRs have been demonstrated to potentiate NMDA-receptor signaling in the hippocampus and cortex,48,49 brain areas intimately associated with learning and memory. In addition, M1 KO mice displayed reduced hippocampal long-term potentiation, a mechanism heavily implicated in learning and memory. Behaviorally, M1 KO animals display deficits in several medial prefrontal cortex-dependent cognitive tasks, including non-matching-to- sample, win-shift radial arm maze, and social discrimination tasks.",
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       "relation": "increases",
       "source": 65,
       "target": 45
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     {
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+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Choi DL",
@@ -2375,7 +2694,7 @@
       },
       "evidence": "The first subtype-selective M1 PAM to be characterized was benzyl quinolone carboxylic acid (BQCA);68 BQCA exhibited high selectivity with no activity at mAChR subtypes M2–M5 and induced up to a 129-fold leftward shift in ACh potency at the M1 mAChR",
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       "relation": "increases",
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       "subject": {
@@ -2384,6 +2703,11 @@
       "target": 4
     },
     {
+      "annotations": {
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+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Choi DL",
@@ -2403,7 +2727,7 @@
       },
       "evidence": "Recent drug discovery efforts in our group have yielded novel M1-selective PAMs VU0405652 (ML169) and VU0456940, both of which potentiate M1-mediated non-amyloidogenic amyloid precursor protein (APPsalpha) processing, suggesting disease-modifying potential in AD",
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       "object": {
         "modifier": "Degradation"
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@@ -2415,6 +2739,11 @@
       "target": 14
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     {
+      "annotations": {
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+          "High": true
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       "citation": {
         "authors": [
           "Choi DL",
@@ -2434,12 +2763,17 @@
       },
       "evidence": "Conversely, the nonselective mAChR agonist BuTAC ([5R-(exo)]-6-[4-butylthio-1,2,5-thiadiazol-3-yl]-1-azabicyclo-[3.2.1]-octane) shows an antipsychotic profile when tested in numerous preclinical animal models. Administration of BuTAC reduces apomorphine-induced climbing and apomorphine-induced disruptions of prepulse inhibition78,79 and reduces conditioned avoidance responding in wild-type, but not M4 KO mice.",
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       "relation": "association",
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     {
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       "citation": {
         "authors": [
           "Choi DL",
@@ -2459,12 +2793,17 @@
       },
       "evidence": "The M4 receptor is highly expressed in the striatum, hippocampus, and neocortex,45,46 suggesting that this mAChR subtype is ideally located to modulate dopaminergic signaling. In support of this hypothesis, M4 KO mice exhibit a hyperdopaminergic phenotype that is resistant to mAChR agonist-induced attenuation of dopamine levels.",
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     {
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       "citation": {
         "authors": [
           "Choi DL",
@@ -2484,12 +2823,17 @@
       },
       "evidence": "The M4 receptor is highly expressed in the striatum, hippocampus, and neocortex,45,46 suggesting that this mAChR subtype is ideally located to modulate dopaminergic signaling. In support of this hypothesis, M4 KO mice exhibit a hyperdopaminergic phenotype that is resistant to mAChR agonist-induced attenuation of dopamine levels.",
       "key": "a3d62d00ebf358fc53e1c5fb8c8fb0eb6155e3b2cc7e69221ecfd614ea6cb4aeb0756343d27905d125468b0cc05a7211de7cfdaccb1d0c80f7776f79e0ead83e",
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       "relation": "association",
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     {
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       "citation": {
         "authors": [
           "Choi DL",
@@ -2509,12 +2853,17 @@
       },
       "evidence": "The M4 receptor is highly expressed in the striatum, hippocampus, and neocortex,45,46 suggesting that this mAChR subtype is ideally located to modulate dopaminergic signaling. In support of this hypothesis, M4 KO mice exhibit a hyperdopaminergic phenotype that is resistant to mAChR agonist-induced attenuation of dopamine levels.",
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       "relation": "association",
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     {
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       "citation": {
         "authors": [
           "Choi DL",
@@ -2534,13 +2883,16 @@
       },
       "evidence": "The M4 receptor is highly expressed in the striatum, hippocampus, and neocortex,45,46 suggesting that this mAChR subtype is ideally located to modulate dopaminergic signaling. In support of this hypothesis, M4 KO mice exhibit a hyperdopaminergic phenotype that is resistant to mAChR agonist-induced attenuation of dopamine levels.",
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       "relation": "regulates",
       "source": 68,
       "target": 48
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "MeSHAnatomy": {
           "Hippocampus": true
         }
@@ -2564,7 +2916,7 @@
       },
       "evidence": "In brain slices, VU10010 selectively potentiated mAChR-mediated reductions in glutamatergic, but not GABAergic, signaling in hippocampal neurons, indicating a key role for M4 in regulating hippocampal function, and possibly in modulating cognition.",
       "key": "42b93ee6b034b20b5d7e65543c93913b0950c07dd5aa08a171802fe6cebe1df2c16bafa528c29cf126469b7afb5881b799c62f39bfebcb7ad2c4778d963365ba",
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       "relation": "decreases",
       "source": 68,
       "subject": {
@@ -2572,6 +2924,39 @@
       },
       "target": 49
     },
+    {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Hippocampus": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Choi DL",
+          "Conn PJ",
+          "Foster DJ",
+          "Rook JM"
+        ],
+        "date": "2014-01-01",
+        "first": "Foster DJ",
+        "last": "Rook JM",
+        "name": "Neuropsychiatric disease and treatment",
+        "pages": "183-91",
+        "reference": "24511233",
+        "title": "Activation of M1 and M4 muscarinic receptors as potential treatments for Alzheimer's disease and schizophrenia.",
+        "type": "PubMed",
+        "volume": "10"
+      },
+      "evidence": "In brain slices, VU10010 selectively potentiated mAChR-mediated reductions in glutamatergic, but not GABAergic, signaling in hippocampal neurons, indicating a key role for M4 in regulating hippocampal function, and possibly in modulating cognition.",
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       "relation": "hasComponent",
@@ -2585,6 +2970,11 @@
       "target": 72
     },
     {
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+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Choi DL",
@@ -2604,12 +2994,17 @@
       },
       "evidence": "M1, M3, and M5 all signal primarily via the Galphaq G-protein and induce Ca2+ mobilization and inositol trisphosphate (IP3) production, while M2 and M4 signal via the Galphai G-protein to inhibit cyclic adenosine monophosphate (cAMP) production.",
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     },
     {
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       "citation": {
         "authors": [
           "Choi DL",
@@ -2629,7 +3024,7 @@
       },
       "evidence": "M1, M3, and M5 all signal primarily via the Galphaq G-protein and induce Ca2+ mobilization and inositol trisphosphate (IP3) production, while M2 and M4 signal via the Galphai G-protein to inhibit cyclic adenosine monophosphate (cAMP) production.",
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@@ -2647,6 +3042,11 @@
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     {
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           "Choi DL",
@@ -2666,12 +3066,17 @@
       },
       "evidence": "M1, M3, and M5 all signal primarily via the Galphaq G-protein and induce Ca2+ mobilization and inositol trisphosphate (IP3) production, while M2 and M4 signal via the Galphai G-protein to inhibit cyclic adenosine monophosphate (cAMP) production.",
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     {
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       "citation": {
         "authors": [
           "Choi DL",
@@ -2691,7 +3096,7 @@
       },
       "evidence": "M1, M3, and M5 all signal primarily via the Galphaq G-protein and induce Ca2+ mobilization and inositol trisphosphate (IP3) production, while M2 and M4 signal via the Galphai G-protein to inhibit cyclic adenosine monophosphate (cAMP) production.",
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@@ -2709,6 +3114,11 @@
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     {
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@@ -2728,12 +3138,17 @@
       },
       "evidence": "M1, M3, and M5 all signal primarily via the Galphaq G-protein and induce Ca2+ mobilization and inositol trisphosphate (IP3) production, while M2 and M4 signal via the Galphai G-protein to inhibit cyclic adenosine monophosphate (cAMP) production.",
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     {
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         "authors": [
           "Choi DL",
@@ -2753,7 +3168,7 @@
       },
       "evidence": "M1, M3, and M5 all signal primarily via the Galphaq G-protein and induce Ca2+ mobilization and inositol trisphosphate (IP3) production, while M2 and M4 signal via the Galphai G-protein to inhibit cyclic adenosine monophosphate (cAMP) production.",
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@@ -2771,6 +3186,11 @@
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     {
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           "Choi DL",
@@ -2790,7 +3210,7 @@
       },
       "evidence": "M1, M3, and M5 all signal primarily via the Galphaq G-protein and induce Ca2+ mobilization and inositol trisphosphate (IP3) production, while M2 and M4 signal via the Galphai G-protein to inhibit cyclic adenosine monophosphate (cAMP) production.",
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@@ -2808,6 +3228,11 @@
       "target": 71
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     {
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           "Choi DL",
@@ -2827,12 +3252,17 @@
       },
       "evidence": "M1, M3, and M5 all signal primarily via the Galphaq G-protein and induce Ca2+ mobilization and inositol trisphosphate (IP3) production, while M2 and M4 signal via the Galphai G-protein to inhibit cyclic adenosine monophosphate (cAMP) production.",
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     {
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       "citation": {
         "authors": [
           "Choi DL",
@@ -2852,12 +3282,17 @@
       },
       "evidence": "AD is the most commonly diagnosed form of dementia and currently affects approximately 35 million individuals worldwide.7 AD is a progressive neurodegenerative disease that is characterized by a host of cognitive deficits, including impairments in learning and memory. In addition to the well-documented cognitive impairments, AD patients also display behavioral disturbances, including anxiety, depression, and psychosis",
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     {
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       "citation": {
         "authors": [
           "Choi DL",
@@ -2877,12 +3312,17 @@
       },
       "evidence": "Age is the primary risk factor for AD, and the disease usually manifests in individuals after the age of 60 years. Due to an aging population, the prevalence of AD is predicted to rise to 66 million people by the year 2030.",
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       "relation": "association",
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     {
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       "citation": {
         "authors": [
           "Choi DL",
@@ -2902,12 +3342,17 @@
       },
       "evidence": "The hallmarks of AD pathology are the accumulation of amyloid-beta (Abeta) peptide aggregates (neuritic plaques) and hyperphosphorylated tau protein (neurofibrillary tangles).",
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     {
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       "citation": {
         "authors": [
           "Choi DL",
@@ -2927,12 +3372,17 @@
       },
       "evidence": "The hallmarks of AD pathology are the accumulation of amyloid-beta (Abeta) peptide aggregates (neuritic plaques) and hyperphosphorylated tau protein (neurofibrillary tangles).",
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       "relation": "association",
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       "target": 13
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     {
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+          "High": true
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       "citation": {
         "authors": [
           "Choi DL",
@@ -2952,13 +3402,16 @@
       },
       "evidence": "The hallmarks of AD pathology are the accumulation of amyloid-beta (Abeta) peptide aggregates (neuritic plaques) and hyperphosphorylated tau protein (neurofibrillary tangles).",
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       "relation": "biomarkerFor",
       "source": 86,
       "target": 78
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Cerebral Cortex": true,
           "Hippocampus": true
@@ -2983,13 +3436,16 @@
       },
       "evidence": "The popular amyloid cascade hypothesis posits that the gradual build-up of Abeta plaques leads to neuronal inflammation, dysfunction, and, eventually, cell death. The two brain regions most critically affected by this degeneration are the cortex and hippocampus, both of which are involved in cognition, learning, and memory.",
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     {
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         "MeSHAnatomy": {
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           "Hippocampus": true
@@ -3014,12 +3470,17 @@
       },
       "evidence": "The popular amyloid cascade hypothesis posits that the gradual build-up of Abeta plaques leads to neuronal inflammation, dysfunction, and, eventually, cell death. The two brain regions most critically affected by this degeneration are the cortex and hippocampus, both of which are involved in cognition, learning, and memory.",
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       "relation": "increases",
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@@ -3039,13 +3500,16 @@
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       "evidence": "The hallmarks of AD pathology are the accumulation of amyloid-beta (Abeta) peptide aggregates (neuritic plaques) and hyperphosphorylated tau protein (neurofibrillary tangles).",
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       "relation": "biomarkerFor",
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     {
       "annotations": {
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         "MeSHAnatomy": {
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           "Hippocampus": true
@@ -3070,13 +3534,16 @@
       },
       "evidence": "The popular amyloid cascade hypothesis posits that the gradual build-up of Abeta plaques leads to neuronal inflammation, dysfunction, and, eventually, cell death. The two brain regions most critically affected by this degeneration are the cortex and hippocampus, both of which are involved in cognition, learning, and memory.",
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         "MeSHAnatomy": {
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           "Hippocampus": true
@@ -3101,13 +3568,16 @@
       },
       "evidence": "The popular amyloid cascade hypothesis posits that the gradual build-up of Abeta plaques leads to neuronal inflammation, dysfunction, and, eventually, cell death. The two brain regions most critically affected by this degeneration are the cortex and hippocampus, both of which are involved in cognition, learning, and memory.",
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     {
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         "MeSHAnatomy": {
           "Cerebral Cortex": true,
           "Hippocampus": true
@@ -3132,13 +3602,16 @@
       },
       "evidence": "M1 mAChRs have been demonstrated to potentiate NMDA-receptor signaling in the hippocampus and cortex,48,49 brain areas intimately associated with learning and memory. In addition, M1 KO mice displayed reduced hippocampal long-term potentiation, a mechanism heavily implicated in learning and memory. Behaviorally, M1 KO animals display deficits in several medial prefrontal cortex-dependent cognitive tasks, including non-matching-to- sample, win-shift radial arm maze, and social discrimination tasks.",
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           "Hippocampus": true
@@ -3163,13 +3636,16 @@
       },
       "evidence": "The popular amyloid cascade hypothesis posits that the gradual build-up of Abeta plaques leads to neuronal inflammation, dysfunction, and, eventually, cell death. The two brain regions most critically affected by this degeneration are the cortex and hippocampus, both of which are involved in cognition, learning, and memory.",
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         "MeSHAnatomy": {
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           "Hippocampus": true
@@ -3194,12 +3670,17 @@
       },
       "evidence": "M1 mAChRs have been demonstrated to potentiate NMDA-receptor signaling in the hippocampus and cortex,48,49 brain areas intimately associated with learning and memory. In addition, M1 KO mice displayed reduced hippocampal long-term potentiation, a mechanism heavily implicated in learning and memory. Behaviorally, M1 KO animals display deficits in several medial prefrontal cortex-dependent cognitive tasks, including non-matching-to- sample, win-shift radial arm maze, and social discrimination tasks.",
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         "authors": [
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@@ -3219,13 +3700,16 @@
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       "evidence": "The M4 receptor is highly expressed in the striatum, hippocampus, and neocortex,45,46 suggesting that this mAChR subtype is ideally located to modulate dopaminergic signaling. In support of this hypothesis, M4 KO mice exhibit a hyperdopaminergic phenotype that is resistant to mAChR agonist-induced attenuation of dopamine levels.",
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         "MeSHAnatomy": {
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@@ -3250,13 +3734,16 @@
       },
       "evidence": "The popular amyloid cascade hypothesis posits that the gradual build-up of Abeta plaques leads to neuronal inflammation, dysfunction, and, eventually, cell death. The two brain regions most critically affected by this degeneration are the cortex and hippocampus, both of which are involved in cognition, learning, and memory.",
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         "MeSHAnatomy": {
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           "Hippocampus": true
@@ -3281,13 +3768,16 @@
       },
       "evidence": "The popular amyloid cascade hypothesis posits that the gradual build-up of Abeta plaques leads to neuronal inflammation, dysfunction, and, eventually, cell death. The two brain regions most critically affected by this degeneration are the cortex and hippocampus, both of which are involved in cognition, learning, and memory.",
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@@ -3312,13 +3802,16 @@
       },
       "evidence": "M1 mAChRs have been demonstrated to potentiate NMDA-receptor signaling in the hippocampus and cortex,48,49 brain areas intimately associated with learning and memory. In addition, M1 KO mice displayed reduced hippocampal long-term potentiation, a mechanism heavily implicated in learning and memory. Behaviorally, M1 KO animals display deficits in several medial prefrontal cortex-dependent cognitive tasks, including non-matching-to- sample, win-shift radial arm maze, and social discrimination tasks.",
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         "MeSHAnatomy": {
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           "Hippocampus": true
@@ -3343,13 +3836,16 @@
       },
       "evidence": "The popular amyloid cascade hypothesis posits that the gradual build-up of Abeta plaques leads to neuronal inflammation, dysfunction, and, eventually, cell death. The two brain regions most critically affected by this degeneration are the cortex and hippocampus, both of which are involved in cognition, learning, and memory.",
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         "MeSHAnatomy": {
           "Cerebral Cortex": true,
           "Hippocampus": true
@@ -3374,13 +3870,16 @@
       },
       "evidence": "M1 mAChRs have been demonstrated to potentiate NMDA-receptor signaling in the hippocampus and cortex,48,49 brain areas intimately associated with learning and memory. In addition, M1 KO mice displayed reduced hippocampal long-term potentiation, a mechanism heavily implicated in learning and memory. Behaviorally, M1 KO animals display deficits in several medial prefrontal cortex-dependent cognitive tasks, including non-matching-to- sample, win-shift radial arm maze, and social discrimination tasks.",
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     {
       "annotations": {
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         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -3404,12 +3903,17 @@
       },
       "evidence": " In addition, administration of nonselective muscarinic antagonists can produce or exacerbate cognitive deficits in animals,15 as well as in AD patients and both young and old control subjects,16,17 suggesting that mAChRs can directly modulate cognition.",
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           "Choi DL",
@@ -3429,12 +3933,17 @@
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       "evidence": "Furthermore, administration of nonselective muscarinic antagonists can induce cognitive deficits and psychosis in humans,16,37 indicating that mAChR activation may provide pro-cognitive and antipsychotic efficacy.",
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     {
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       "citation": {
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           "Choi DL",
@@ -3454,13 +3963,16 @@
       },
       "evidence": "Furthermore, administration of nonselective muscarinic antagonists can induce cognitive deficits and psychosis in humans,16,37 indicating that mAChR activation may provide pro-cognitive and antipsychotic efficacy.",
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     {
       "annotations": {
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         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -3484,13 +3996,16 @@
       },
       "evidence": "The current primary treatments for AD symptoms are acetylcholinesterase inhibitors (AChEIs) such as donepezil, tacrine, galantamine, and rivastigmine, which potentiate cholinergic signaling.18,19 These treatments not only provide improvements in cognitive symptoms associated with AD,20,21 but also show efficacy in treating the psychiatric symptoms.",
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       "relation": "isA",
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     {
       "annotations": {
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+          "High": true
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         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -3514,13 +4029,16 @@
       },
       "evidence": "The current primary treatments for AD symptoms are acetylcholinesterase inhibitors (AChEIs) such as donepezil, tacrine, galantamine, and rivastigmine, which potentiate cholinergic signaling.18,19 These treatments not only provide improvements in cognitive symptoms associated with AD,20,21 but also show efficacy in treating the psychiatric symptoms.",
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     },
     {
       "annotations": {
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+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -3544,13 +4062,16 @@
       },
       "evidence": "The current primary treatments for AD symptoms are acetylcholinesterase inhibitors (AChEIs) such as donepezil, tacrine, galantamine, and rivastigmine, which potentiate cholinergic signaling.18,19 These treatments not only provide improvements in cognitive symptoms associated with AD,20,21 but also show efficacy in treating the psychiatric symptoms.",
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     {
       "annotations": {
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         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -3574,12 +4095,17 @@
       },
       "evidence": "The current primary treatments for AD symptoms are acetylcholinesterase inhibitors (AChEIs) such as donepezil, tacrine, galantamine, and rivastigmine, which potentiate cholinergic signaling.18,19 These treatments not only provide improvements in cognitive symptoms associated with AD,20,21 but also show efficacy in treating the psychiatric symptoms.",
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           "Choi DL",
@@ -3599,12 +4125,17 @@
       },
       "evidence": "Unfortunately, cardiovascular and gastrointestinal side effects are often observed with these treatments, effects thought to be mediated by peripherally located ACh receptors. Despite this, AChEIs remain modestly beneficial for treating AD and other forms of dementia.",
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     {
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@@ -3624,13 +4155,16 @@
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       "evidence": "Unfortunately, cardiovascular and gastrointestinal side effects are often observed with these treatments, effects thought to be mediated by peripherally located ACh receptors. Despite this, AChEIs remain modestly beneficial for treating AD and other forms of dementia.",
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     {
       "annotations": {
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         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -3654,13 +4188,16 @@
       },
       "evidence": "The current primary treatments for AD symptoms are acetylcholinesterase inhibitors (AChEIs) such as donepezil, tacrine, galantamine, and rivastigmine, which potentiate cholinergic signaling.18,19 These treatments not only provide improvements in cognitive symptoms associated with AD,20,21 but also show efficacy in treating the psychiatric symptoms.",
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     {
       "annotations": {
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         "MeSHDisease": {
           "Alzheimer Disease": true
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@@ -3684,13 +4221,16 @@
       },
       "evidence": "The current primary treatments for AD symptoms are acetylcholinesterase inhibitors (AChEIs) such as donepezil, tacrine, galantamine, and rivastigmine, which potentiate cholinergic signaling.18,19 These treatments not only provide improvements in cognitive symptoms associated with AD,20,21 but also show efficacy in treating the psychiatric symptoms.",
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         "MeSHDisease": {
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@@ -3714,12 +4254,17 @@
       },
       "evidence": "The current primary treatments for AD symptoms are acetylcholinesterase inhibitors (AChEIs) such as donepezil, tacrine, galantamine, and rivastigmine, which potentiate cholinergic signaling.18,19 These treatments not only provide improvements in cognitive symptoms associated with AD,20,21 but also show efficacy in treating the psychiatric symptoms.",
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@@ -3739,12 +4284,17 @@
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       "evidence": "Furthermore, administration of nonselective muscarinic antagonists can induce cognitive deficits and psychosis in humans,16,37 indicating that mAChR activation may provide pro-cognitive and antipsychotic efficacy.",
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@@ -3764,12 +4314,17 @@
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       "evidence": "Unfortunately, cardiovascular and gastrointestinal side effects are often observed with these treatments, effects thought to be mediated by peripherally located ACh receptors. Despite this, AChEIs remain modestly beneficial for treating AD and other forms of dementia.",
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@@ -3789,12 +4344,17 @@
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       "evidence": "The hallmark psychotic symptoms of SZ are the positive cluster and include auditory hallucinations, delusional beliefs, and disorganized thoughts and speech. SZ patients also exhibit negative symptoms, including anhedonia, dysfunctional social interactions, and poverty of thoughts and speech, as well as cognitive disturbances affecting several behavioral domains, including working memory, attention, and executive function",
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       "evidence": "The hallmark psychotic symptoms of SZ are the positive cluster and include auditory hallucinations, delusional beliefs, and disorganized thoughts and speech. SZ patients also exhibit negative symptoms, including anhedonia, dysfunctional social interactions, and poverty of thoughts and speech, as well as cognitive disturbances affecting several behavioral domains, including working memory, attention, and executive function",
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       "evidence": "The hallmark psychotic symptoms of SZ are the positive cluster and include auditory hallucinations, delusional beliefs, and disorganized thoughts and speech. SZ patients also exhibit negative symptoms, including anhedonia, dysfunctional social interactions, and poverty of thoughts and speech, as well as cognitive disturbances affecting several behavioral domains, including working memory, attention, and executive function",
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@@ -4129,12 +4743,17 @@
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       "evidence": "Of these, the M1/M4 -preferring agonist xanomeline was the only one to progress to a phase III clinical trial, where it was assessed for efficacy in ameliorating cognitive deficits observed in AD patients. While xanomeline showed a trend toward improving cognitive function in these patients, this effect did not reach statistical significance. However, this agonist did produce surprisingly robust and dose-dependent reductions in hallucinations, delusions, vocal outbursts, and other behavioral disturbances in these patients",
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       "evidence": " In addition, xanomeline produced statistically significant improvements in verbal learning and short-term memory, indicating efficacy in treating cognitive symptoms.40 Unfortunately, gastrointestinal side effects were observed, and dose limitations have removed it from consideration for long-term clinical use.",
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       "evidence": " In addition, xanomeline produced statistically significant improvements in verbal learning and short-term memory, indicating efficacy in treating cognitive symptoms.40 Unfortunately, gastrointestinal side effects were observed, and dose limitations have removed it from consideration for long-term clinical use.",
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@@ -4254,7 +4893,7 @@
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       "evidence": "Both VU0152100 and VU0152099 effectively reversed amphetamine-induced hyperlocomotion, demonstrating antipsychotic-like activity in preclinical models.",
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@@ -4282,12 +4926,17 @@
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       "evidence": "N-methyl-D-aspartate (NMDA) receptors play a critical role in regulating synaptic plasticity, and disrupted NMDA-receptor neurotransmission is thought to underlie the cognitive deficits observed in numerous psychiatric diseases.",
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@@ -4307,13 +4956,16 @@
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       "evidence": "N-methyl-D-aspartate (NMDA) receptors play a critical role in regulating synaptic plasticity, and disrupted NMDA-receptor neurotransmission is thought to underlie the cognitive deficits observed in numerous psychiatric diseases.",
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         "MeSHAnatomy": {
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           "Hippocampus": true
@@ -4338,13 +4990,16 @@
       },
       "evidence": "M1 mAChRs have been demonstrated to potentiate NMDA-receptor signaling in the hippocampus and cortex,48,49 brain areas intimately associated with learning and memory. In addition, M1 KO mice displayed reduced hippocampal long-term potentiation, a mechanism heavily implicated in learning and memory. Behaviorally, M1 KO animals display deficits in several medial prefrontal cortex-dependent cognitive tasks, including non-matching-to- sample, win-shift radial arm maze, and social discrimination tasks.",
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         "MeSHAnatomy": {
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           "Hippocampus": true
@@ -4369,13 +5024,16 @@
       },
       "evidence": "M1 mAChRs have been demonstrated to potentiate NMDA-receptor signaling in the hippocampus and cortex,48,49 brain areas intimately associated with learning and memory. In addition, M1 KO mice displayed reduced hippocampal long-term potentiation, a mechanism heavily implicated in learning and memory. Behaviorally, M1 KO animals display deficits in several medial prefrontal cortex-dependent cognitive tasks, including non-matching-to- sample, win-shift radial arm maze, and social discrimination tasks.",
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     {
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         "MeSHDisease": {
           "Alzheimer Disease": true
         },
@@ -4402,7 +5060,7 @@
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       "evidence": "Finally, studies in mice exhibiting AD-like Abeta plaque pathologies found that deletion of M1 increased amyloidogenic processes, suggesting that M1 may play a role in regulating AD disease progression.51",
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@@ -4411,6 +5069,11 @@
       "target": 2
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     {
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@@ -4430,7 +5093,7 @@
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       "evidence": "Subsequent optimization produced two analogs of AC-42 (AC-260584 and 77-LH-28-1), which maintained M1 selectivity and possessed properties suitable for use in animal models. Both AC-260584 and 77-LH-28-1 displayed antipsychotic and cognition-enhancing efficacy in pre-clinical models",
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@@ -4439,6 +5102,11 @@
       "target": 65
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     {
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@@ -4458,7 +5126,7 @@
       },
       "evidence": "Subsequent optimization produced two analogs of AC-42 (AC-260584 and 77-LH-28-1), which maintained M1 selectivity and possessed properties suitable for use in animal models. Both AC-260584 and 77-LH-28-1 displayed antipsychotic and cognition-enhancing efficacy in pre-clinical models",
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@@ -4468,6 +5136,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
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         "MeSHAnatomy": {
           "CA1 Region, Hippocampal": true
         }
@@ -4491,7 +5162,7 @@
       },
       "evidence": "Another early allosteric agonist, TBPB (1-(1’-(2-methylbenzyl) -1,4’-bipiperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-1), also exhibited impressive selectivity for M1 mAChRs and potentiated NMDA receptor currents in CA1 hippocampal cells. ",
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@@ -4500,6 +5171,11 @@
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     {
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@@ -4519,7 +5195,7 @@
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       "evidence": "Moreover, additional pre-clinical studies with TBPB demonstrated efficacy in reducing antipsychotic-like behaviors and in reversing scopolamine-impaired acquisition of contextual fear.59 Studies in cell lines also demonstrated that TBPB promoted a non-amyloidogenic pathway and decreased Abeta production, indicating that M1 modulation may have efficacy in the treatment of both symptomatic and pathologic features of AD",
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@@ -4528,6 +5204,11 @@
       "target": 10
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     {
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@@ -4547,12 +5228,17 @@
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       "evidence": "Moreover, additional pre-clinical studies with TBPB demonstrated efficacy in reducing antipsychotic-like behaviors and in reversing scopolamine-impaired acquisition of contextual fear.59 Studies in cell lines also demonstrated that TBPB promoted a non-amyloidogenic pathway and decreased Abeta production, indicating that M1 modulation may have efficacy in the treatment of both symptomatic and pathologic features of AD",
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@@ -4572,7 +5258,7 @@
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       "evidence": "Moreover, additional pre-clinical studies with TBPB demonstrated efficacy in reducing antipsychotic-like behaviors and in reversing scopolamine-impaired acquisition of contextual fear.59 Studies in cell lines also demonstrated that TBPB promoted a non-amyloidogenic pathway and decreased Abeta production, indicating that M1 modulation may have efficacy in the treatment of both symptomatic and pathologic features of AD",
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       "evidence": "More recently, the M1-selective allosteric agonist VU0357017 was discovered, which displayed improved potency via binding to a novel allosteric site on the M1 mAChR. VU0357017 significantly blocked scopolamine-impaired contextual fear conditioning and enhanced spatial and contextual fear learning",
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@@ -4625,7 +5321,7 @@
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       "evidence": "More recently, the M1-selective allosteric agonist VU0357017 was discovered, which displayed improved potency via binding to a novel allosteric site on the M1 mAChR. VU0357017 significantly blocked scopolamine-impaired contextual fear conditioning and enhanced spatial and contextual fear learning",
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@@ -4653,7 +5354,7 @@
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       "evidence": "More recently, the M1-selective allosteric agonist VU0357017 was discovered, which displayed improved potency via binding to a novel allosteric site on the M1 mAChR. VU0357017 significantly blocked scopolamine-impaired contextual fear conditioning and enhanced spatial and contextual fear learning",
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     {
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@@ -4690,7 +5396,7 @@
       },
       "evidence": "More recently, the M1-selective allosteric agonist VU0357017 was discovered, which displayed improved potency via binding to a novel allosteric site on the M1 mAChR. VU0357017 significantly blocked scopolamine-impaired contextual fear conditioning and enhanced spatial and contextual fear learning",
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     {
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@@ -4730,12 +5441,17 @@
       },
       "evidence": "A recent clinical study utilizing the M1-selective allosteric agonist GSK1034702 demonstrated pro-cognitive efficacy in a nicotine abstinence model of episodic memory impairment in smokers, 67 providing exciting evidence that M1-selective activation can provide pro-cognitive benefits in humans",
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@@ -4755,7 +5471,7 @@
       },
       "evidence": "The first subtype-selective M1 PAM to be characterized was benzyl quinolone carboxylic acid (BQCA);68 BQCA exhibited high selectivity with no activity at mAChR subtypes M2–M5 and induced up to a 129-fold leftward shift in ACh potency at the M1 mAChR",
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@@ -4765,6 +5481,9 @@
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     {
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         "MeSHAnatomy": {
           "Prefrontal Cortex": true
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@@ -4788,13 +5507,16 @@
       },
       "evidence": "In brain slice electrophysiology studies, BQCA enhanced excitatory postsynaptic currents in medial prefrontal cortical neurons,69 an area critical for higher cognitive, learning, and memory functions.70 In pre-clinical animal studies, BQCA reversed scopolamine-impaired contextual fear conditioning and rescued medial prefrontal cortex-dependent discrimination reversal learning deficits in a transgenic mouse model of AD.",
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@@ -4818,7 +5540,7 @@
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       "evidence": "In brain slice electrophysiology studies, BQCA enhanced excitatory postsynaptic currents in medial prefrontal cortical neurons,69 an area critical for higher cognitive, learning, and memory functions.70 In pre-clinical animal studies, BQCA reversed scopolamine-impaired contextual fear conditioning and rescued medial prefrontal cortex-dependent discrimination reversal learning deficits in a transgenic mouse model of AD.",
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@@ -4851,13 +5576,16 @@
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@@ -4881,13 +5609,16 @@
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@@ -4911,13 +5642,16 @@
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@@ -4941,13 +5675,16 @@
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       "evidence": "In brain slice electrophysiology studies, BQCA enhanced excitatory postsynaptic currents in medial prefrontal cortical neurons,69 an area critical for higher cognitive, learning, and memory functions.70 In pre-clinical animal studies, BQCA reversed scopolamine-impaired contextual fear conditioning and rescued medial prefrontal cortex-dependent discrimination reversal learning deficits in a transgenic mouse model of AD.",
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@@ -4971,13 +5708,16 @@
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       "evidence": "In brain slice electrophysiology studies, BQCA enhanced excitatory postsynaptic currents in medial prefrontal cortical neurons,69 an area critical for higher cognitive, learning, and memory functions.70 In pre-clinical animal studies, BQCA reversed scopolamine-impaired contextual fear conditioning and rescued medial prefrontal cortex-dependent discrimination reversal learning deficits in a transgenic mouse model of AD.",
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       "evidence": "In brain slice electrophysiology studies, BQCA enhanced excitatory postsynaptic currents in medial prefrontal cortical neurons,69 an area critical for higher cognitive, learning, and memory functions.70 In pre-clinical animal studies, BQCA reversed scopolamine-impaired contextual fear conditioning and rescued medial prefrontal cortex-dependent discrimination reversal learning deficits in a transgenic mouse model of AD.",
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       "evidence": "Recent drug discovery efforts in our group have yielded novel M1-selective PAMs VU0405652 (ML169) and VU0456940, both of which potentiate M1-mediated non-amyloidogenic amyloid precursor protein (APPsalpha) processing, suggesting disease-modifying potential in AD",
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       "evidence": "Recent drug discovery efforts in our group have yielded novel M1-selective PAMs VU0405652 (ML169) and VU0456940, both of which potentiate M1-mediated non-amyloidogenic amyloid precursor protein (APPsalpha) processing, suggesting disease-modifying potential in AD",
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       "evidence": "Conversely, the nonselective mAChR agonist BuTAC ([5R-(exo)]-6-[4-butylthio-1,2,5-thiadiazol-3-yl]-1-azabicyclo-[3.2.1]-octane) shows an antipsychotic profile when tested in numerous preclinical animal models. Administration of BuTAC reduces apomorphine-induced climbing and apomorphine-induced disruptions of prepulse inhibition78,79 and reduces conditioned avoidance responding in wild-type, but not M4 KO mice.",
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@@ -5110,12 +5870,17 @@
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       "evidence": "Conversely, the nonselective mAChR agonist BuTAC ([5R-(exo)]-6-[4-butylthio-1,2,5-thiadiazol-3-yl]-1-azabicyclo-[3.2.1]-octane) shows an antipsychotic profile when tested in numerous preclinical animal models. Administration of BuTAC reduces apomorphine-induced climbing and apomorphine-induced disruptions of prepulse inhibition78,79 and reduces conditioned avoidance responding in wild-type, but not M4 KO mice.",
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@@ -5135,7 +5900,7 @@
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       "evidence": "Conversely, the nonselective mAChR agonist BuTAC ([5R-(exo)]-6-[4-butylthio-1,2,5-thiadiazol-3-yl]-1-azabicyclo-[3.2.1]-octane) shows an antipsychotic profile when tested in numerous preclinical animal models. Administration of BuTAC reduces apomorphine-induced climbing and apomorphine-induced disruptions of prepulse inhibition78,79 and reduces conditioned avoidance responding in wild-type, but not M4 KO mice.",
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@@ -5163,7 +5933,7 @@
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       "evidence": "LY2033298, a structurally distinct M4-selective PAM, was similarly efficacious in several preclinical models of psychosis, including conditioned avoidance responding and apomorphine-impaired prepulse inhibition",
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@@ -5216,12 +5996,17 @@
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       "evidence": "The M4 receptor is highly expressed in the striatum, hippocampus, and neocortex,45,46 suggesting that this mAChR subtype is ideally located to modulate dopaminergic signaling. In support of this hypothesis, M4 KO mice exhibit a hyperdopaminergic phenotype that is resistant to mAChR agonist-induced attenuation of dopamine levels.",
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@@ -5241,12 +6026,17 @@
       },
       "evidence": "The M4 receptor is highly expressed in the striatum, hippocampus, and neocortex,45,46 suggesting that this mAChR subtype is ideally located to modulate dopaminergic signaling. In support of this hypothesis, M4 KO mice exhibit a hyperdopaminergic phenotype that is resistant to mAChR agonist-induced attenuation of dopamine levels.",
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@@ -5266,7 +6056,7 @@
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       "evidence": "Two novel M4-selective compounds, VU10010 and LY2033298, represented a breakthrough when they were described in 2008.84,85 VU10010 is a potent M4-selective PAM that increases affinity/efficacy of ACh to promote M4 mAChR activation.",
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@@ -5276,6 +6066,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "MeSHAnatomy": {
           "Hippocampus": true
         }
@@ -5299,7 +6092,7 @@
       },
       "evidence": "In brain slices, VU10010 selectively potentiated mAChR-mediated reductions in glutamatergic, but not GABAergic, signaling in hippocampal neurons, indicating a key role for M4 in regulating hippocampal function, and possibly in modulating cognition.",
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@@ -5308,6 +6101,44 @@
       "target": 68
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     {
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+        }
+      },
+      "citation": {
+        "authors": [
+          "Choi DL",
+          "Conn PJ",
+          "Foster DJ",
+          "Rook JM"
+        ],
+        "date": "2014-01-01",
+        "first": "Foster DJ",
+        "last": "Rook JM",
+        "name": "Neuropsychiatric disease and treatment",
+        "pages": "183-91",
+        "reference": "24511233",
+        "title": "Activation of M1 and M4 muscarinic receptors as potential treatments for Alzheimer's disease and schizophrenia.",
+        "type": "PubMed",
+        "volume": "10"
+      },
+      "evidence": "Both VU0152100 and VU0152099 effectively reversed amphetamine-induced hyperlocomotion, demonstrating antipsychotic-like activity in preclinical models.",
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+      "target": 5
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       "citation": {
         "authors": [
           "Choi DL",
@@ -5327,7 +6158,7 @@
       },
       "evidence": "Both VU0152100 and VU0152099 effectively reversed amphetamine-induced hyperlocomotion, demonstrating antipsychotic-like activity in preclinical models.",
       "key": "40523ee969ec650085e664500ab8c9b290b103ba3fdb9be3c1b07a8512187e35565effa1d72f98d7468f3bc68c888ac7268e3af282f95fd560bbc57b50072478",
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       "object": {
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@@ -5336,6 +6167,11 @@
       "target": 5
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     {
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       "citation": {
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@@ -5355,7 +6191,7 @@
       },
       "evidence": "LY2033298, a structurally distinct M4-selective PAM, was similarly efficacious in several preclinical models of psychosis, including conditioned avoidance responding and apomorphine-impaired prepulse inhibition",
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diff --git a/hbp_knowledge/receptors/dani2007.bel.json b/hbp_knowledge/receptors/dani2007.bel.json
index 5c623bc53..05f39dab3 100644
--- a/hbp_knowledge/receptors/dani2007.bel.json
+++ b/hbp_knowledge/receptors/dani2007.bel.json
@@ -44,6 +44,9 @@
   "links": [
     {
       "annotations": {
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         "MeSHAnatomy": {
           "Presynaptic Terminals": true
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@@ -65,13 +68,16 @@
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       "evidence": "Presynaptic and preterminal nicotinic receptors enhance neurotransmitter release, and postsynaptic and nonsynaptic nAChRs mediate excitation as well as activity-dependent modulation of circuits and intracellular enzymatic processes. ",
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       "target": 38
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     {
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@@ -93,7 +99,7 @@
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@@ -103,6 +109,9 @@
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     {
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@@ -125,12 +134,20 @@
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     {
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@@ -148,7 +165,7 @@
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@@ -158,6 +175,9 @@
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@@ -180,12 +200,20 @@
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@@ -203,12 +231,17 @@
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@@ -249,7 +287,7 @@
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@@ -261,6 +299,9 @@
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@@ -395,12 +461,17 @@
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@@ -441,12 +517,17 @@
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@@ -510,7 +601,7 @@
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@@ -608,7 +719,7 @@
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@@ -618,12 +729,12 @@
         "Cell": {
           "cholinergic neuron": true
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         "MeSHAnatomy": {
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@@ -797,7 +933,7 @@
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       "target": 25
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@@ -833,7 +974,7 @@
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     },
     {
       "annotations": {
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         "MeSHAnatomy": {
           "Presynaptic Terminals": true
         }
@@ -864,7 +1008,7 @@
       },
       "evidence": "In addition, nAChR activity produces a depolarization that activates voltage-gated calcium channels in the presynaptic terminal (87). ",
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     {
       "annotations": {
+        "Confidence": {
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+        },
         "MeSHAnatomy": {
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           "Neocortex": true
@@ -896,7 +1043,7 @@
       },
       "evidence": "Activation of nAChRs on distal apical dendrites depolarizes the cell and promotes action potential firing",
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@@ -922,7 +1074,7 @@
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@@ -961,7 +1118,7 @@
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           "Hippocampus": true,
           "Presynaptic Terminals": true
@@ -1006,7 +1166,7 @@
       },
       "evidence": "Presynaptic and preterminal nAChRs increase the release of neurotransmitters in the hippocampus, particularly the main neurotransmitters, GABA and glutamate (41, 78, 81, 97).",
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     {
       "annotations": {
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           "Presynaptic Terminals": true
@@ -1048,7 +1211,7 @@
       },
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     {
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@@ -1092,7 +1258,7 @@
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@@ -1118,7 +1289,7 @@
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@@ -1150,7 +1324,7 @@
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@@ -1163,9 +1337,8 @@
         "Cell": {
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-        "MeSHAnatomy": {
-          "Dendrites": true,
-          "Neocortex": true
+        "Confidence": {
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@@ -1185,7 +1358,7 @@
       },
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@@ -1194,6 +1367,9 @@
       "annotations": {
         "Cell": {
           "dopaminergic neuron": true
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@@ -1213,7 +1389,7 @@
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         "Cell": {
           "midbrain dopaminergic neuron": true
         },
-        "MeSHAnatomy": {
-          "Dendrites": true,
-          "Neocortex": true
+        "Confidence": {
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         }
       },
       "citation": {
@@ -1245,12 +1420,17 @@
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@@ -1268,7 +1448,7 @@
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@@ -1277,6 +1457,11 @@
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@@ -1294,12 +1479,17 @@
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@@ -1317,7 +1507,7 @@
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@@ -1366,7 +1566,7 @@
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@@ -1499,8 +1719,8 @@
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@@ -1555,6 +1780,9 @@
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           "glutamatergic neuron": true
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       "evidence": "Decline, disruption, or alterations of nicotinic cholinergic mechanisms have been implicated in various dysfunctions, such as schizophrenia, epilepsy, autism, Alzheimer’s disease (AD), and addiction (17–23).",
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@@ -1712,12 +1970,17 @@
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       "evidence": "Genetic evidence has linked nicotinic receptors to epilepsy and schizophrenia, and studies with mutant mice have implicated nAChRs in pain mechanisms, anxiety, and depression.",
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@@ -1804,7 +2082,7 @@
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@@ -1830,12 +2113,17 @@
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@@ -1853,12 +2141,17 @@
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@@ -1876,7 +2169,7 @@
       },
       "evidence": "Nicotinic mechanisms contribute to cognitive function, and the decline of nicotinic mechanisms or loss of nAChRs has been observed in AD, dementia with Lewy bodies, Down syndrome, autism, and Parkinson’s disease (20, 140).",
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@@ -1902,7 +2200,7 @@
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       "evidence": "Nicotinic mechanisms contribute to cognitive function, and the decline of nicotinic mechanisms or loss of nAChRs has been observed in AD, dementia with Lewy bodies, Down syndrome, autism, and Parkinson’s disease (20, 140).",
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@@ -1912,12 +2210,12 @@
         "Cell": {
           "cholinergic neuron": true
         },
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Cerebral Cortex": true,
           "Hippocampus": true
-        },
-        "MeSHDisease": {
-          "Alzheimer Disease": true
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       "citation": {
@@ -1937,7 +2235,7 @@
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       "evidence": "As AD worsens, cholinergic neurons are progressively lost and the number of nAChRs declines, particularly in the hippocampus and cortex (140, 158).",
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@@ -1947,8 +2245,8 @@
         "Cell": {
           "cholinergic neuron": true
         },
-        "MeSHDisease": {
-          "Alzheimer Disease": true
+        "Confidence": {
+          "High": true
         }
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       "citation": {
@@ -1968,7 +2266,7 @@
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       "evidence": "The most well-appreciated neuronal loss, however, is in the cholinergic system (155, 156), particularly the basal forebrain cholinergic system comprised of the medial septal nucleus, the horizontal and vertical diagonal bands of Broca, and the nucleus basalis of Meynert (157).",
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       "relation": "positiveCorrelation",
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       "target": 36
@@ -1978,12 +2276,12 @@
         "Cell": {
           "cholinergic neuron": true
         },
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Cerebral Cortex": true,
           "Hippocampus": true
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-        "MeSHDisease": {
-          "Alzheimer Disease": true
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       "citation": {
@@ -2003,15 +2301,15 @@
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       "evidence": "As AD worsens, cholinergic neurons are progressively lost and the number of nAChRs declines, particularly in the hippocampus and cortex (140, 158).",
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       "relation": "positiveCorrelation",
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       "target": 36
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     {
       "annotations": {
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-          "Alzheimer Disease": true
+        "Confidence": {
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@@ -2031,12 +2329,17 @@
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       "evidence": "Although Aβ peptides negatively alter the cholinergic system at multiple sites, including ACh synthesis, ACh release, and muscarinic receptors (157), the discovery that Aβ1−42 binds to α7 nAChRs with high affinity suggested the potential for a causal role of nAChRs in AD (159, 160).",
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@@ -2054,13 +2357,16 @@
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       "evidence": "Decline, disruption, or alterations of nicotinic cholinergic mechanisms have been implicated in various dysfunctions, such as schizophrenia, epilepsy, autism, Alzheimer’s disease (AD), and addiction (17–23).",
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     {
       "annotations": {
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+          "High": true
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         "MeSHAnatomy": {
           "Presynaptic Terminals": true
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@@ -2082,7 +2388,7 @@
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       "evidence": "In addition, nAChR activity produces a depolarization that activates voltage-gated calcium channels in the presynaptic terminal (87). ",
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@@ -2108,7 +2419,7 @@
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@@ -2144,7 +2460,7 @@
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@@ -2198,12 +2519,17 @@
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       "evidence": "In some cases, the highly calcium-permeable α7-containing (α7∗) nAChRs mediate the increased release of neurotransmitter, but in other cases different nAChR subtypes are involved.",
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       "relation": "increases",
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@@ -2221,7 +2547,7 @@
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       "evidence": "Preterminal nAChRs located before the presynaptic terminal bouton indirectly affect neurotransmitter release by activating voltage-gated channels and, potentially, initiating action potentials (78, 91, 93).",
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@@ -2233,6 +2559,9 @@
       "annotations": {
         "Cell": {
           "dopaminergic neuron": true
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+        "Confidence": {
+          "High": true
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@@ -2252,7 +2581,7 @@
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       "evidence": "Simultaneously, nicotine activates presynaptic α7∗ nAChRs, boosting glutamatergic synaptic transmission onto DA neurons (23, 88, 123, 134).",
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@@ -2265,6 +2594,9 @@
         "Cell": {
           "dopaminergic neuron": true
         },
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Presynaptic Terminals": true
         }
@@ -2286,7 +2618,7 @@
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       "evidence": "Postsynaptic β2∗ nAChRs initially depolarize DA neurons, causing them to fire action potentials while presynaptic α7∗ nAChRs boost glutamate release. ",
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@@ -2309,8 +2641,8 @@
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     {
       "annotations": {
-        "MeSHDisease": {
-          "Alzheimer Disease": true
+        "Confidence": {
+          "Medium": true
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@@ -2330,7 +2662,7 @@
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       "evidence": "This prospect was supported by the finding that α7 nAChRs were found in plaques (159), and α7 and α4 subunits positively correlated with neurons that accumulated Aβ and hyperphosphorylated tau in AD brain tissue (161).",
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@@ -2340,11 +2672,11 @@
         "Cell": {
           "neuron": true
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+        "Confidence": {
+          "Medium": true
+        },
         "MeSHAnatomy": {
           "Brain": true
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-        "MeSHDisease": {
-          "Alzheimer Disease": true
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@@ -2364,7 +2696,7 @@
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       "evidence": "This prospect was supported by the finding that α7 nAChRs were found in plaques (159), and α7 and α4 subunits positively correlated with neurons that accumulated Aβ and hyperphosphorylated tau in AD brain tissue (161).",
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@@ -2374,11 +2706,11 @@
         "Cell": {
           "neuron": true
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+        "Confidence": {
+          "Medium": true
+        },
         "MeSHAnatomy": {
           "Brain": true
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-        "MeSHDisease": {
-          "Alzheimer Disease": true
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@@ -2398,12 +2730,17 @@
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       "evidence": "This prospect was supported by the finding that α7 nAChRs were found in plaques (159), and α7 and α4 subunits positively correlated with neurons that accumulated Aβ and hyperphosphorylated tau in AD brain tissue (161).",
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       "relation": "positiveCorrelation",
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     {
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+          "High": true
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+      },
       "citation": {
         "authors": [
           "Bertrand D",
@@ -2421,7 +2758,7 @@
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       "evidence": "This calcium influx can trigger calcium-induced calcium release from intracellular stores (86).",
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@@ -2453,6 +2790,11 @@
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+          "High": true
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+      },
       "citation": {
         "authors": [
           "Bertrand D",
@@ -2470,7 +2812,7 @@
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       "evidence": "Similarly, replacement of the α7 leucine at the synaptic, extracellular end (position 254 or 255) of the pore by threonine dramatically reduced the calcium permeability of the α7 receptors.",
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@@ -2489,6 +2831,11 @@
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       "citation": {
         "authors": [
           "Bertrand D",
@@ -2506,7 +2853,7 @@
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@@ -2525,6 +2872,11 @@
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       "citation": {
         "authors": [
           "Bertrand D",
@@ -2542,7 +2894,7 @@
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       "evidence": "Unlike many neurotransmitter signals that are shaped by pumps that return the transmitter to the intracellular space, the spread of ACh from the release site is determined by diffusion and by acetylcholinesterase (AChE) hydrolysis of ACh.",
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       "object": {
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@@ -2558,6 +2910,11 @@
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     {
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         "authors": [
           "Bertrand D",
@@ -2575,7 +2932,7 @@
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       "evidence": "Another important aspect of this diffusive ACh signal is that its eventual hydrolysis creates choline, which also activates and desensitizes nAChRs in a subtype-selective manner (54, 55).",
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@@ -2665,12 +3035,17 @@
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@@ -2732,7 +3112,7 @@
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@@ -3629,7 +4138,7 @@
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@@ -3665,15 +4179,15 @@
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-          "Presynaptic Terminals": true
+        "Confidence": {
+          "Medium": true
         }
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         "type": "PubMed",
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       "annotations": {
-        "MeSHAnatomy": {
-          "CA3 Region, Hippocampal": true
-        },
-        "Species": {
-          "10116": true
+        "Confidence": {
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@@ -3785,7 +4238,7 @@
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       "annotations": {
         "Cell": {
           "dopaminergic neuron": true
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       },
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         "Cell": {
           "neuron": true
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+        "Confidence": {
+          "High": true
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         "MeSHAnatomy": {
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@@ -3850,7 +4309,7 @@
       },
       "evidence": "Nicotine decreases tonic DA release in the striatum that is evoked by single action potentials (127), and nicotine also alters the frequency dependence of DA release that is electrically evoked by stimulus trains (130, 131).",
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     {
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         "MeSHAnatomy": {
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@@ -3891,7 +4353,7 @@
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       "evidence": "Simultaneously, nicotine activates presynaptic α7∗ nAChRs, boosting glutamatergic synaptic transmission onto DA neurons (23, 88, 123, 134).",
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+          "Presynaptic Terminals": true
+        }
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+          "Bertrand D",
+          "Dani JA"
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+        "last": "Bertrand D",
+        "name": "Annual review of pharmacology and toxicology",
+        "pages": "699-729",
+        "reference": "17009926",
+        "title": "Nicotinic acetylcholine receptors and nicotinic cholinergic mechanisms of the central nervous system.",
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+      "evidence": "This effect of preterminal nAChRs is inhibited by tetrodotoxin, which blocks sodium channels and, thus, prevents the regenerative voltage-dependent activation of calcium channels in the presynaptic bouton.",
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       "annotations": {
         "Cell": {
           "midbrain dopaminergic neuron": true
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+        "last": "Bertrand D",
+        "name": "Annual review of pharmacology and toxicology",
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+        "reference": "17009926",
+        "title": "Nicotinic acetylcholine receptors and nicotinic cholinergic mechanisms of the central nervous system.",
+        "type": "PubMed",
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+      "evidence": "Acting through these excitatory and inhibitory inputs and nAChRs located on the DA neurons, nicotinic receptors influence the firing modes and firing frequency of DA neurons (119, 121).",
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         "MeSHAnatomy": {
-          "Dendrites": true,
-          "Neocortex": true
+          "CA3 Region, Hippocampal": true
+        },
+        "Species": {
+          "10116": true
+        }
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+        "last": "Bertrand D",
+        "name": "Annual review of pharmacology and toxicology",
+        "pages": "699-729",
+        "reference": "17009926",
+        "title": "Nicotinic acetylcholine receptors and nicotinic cholinergic mechanisms of the central nervous system.",
+        "type": "PubMed",
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+          "midbrain dopaminergic neuron": true
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+          "High": true
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@@ -3977,7 +4545,7 @@
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       "evidence": "Acting through these excitatory and inhibitory inputs and nAChRs located on the DA neurons, nicotinic receptors influence the firing modes and firing frequency of DA neurons (119, 121).",
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@@ -3987,6 +4555,9 @@
         "Cell": {
           "neuron": true
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+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Corpus Striatum": true
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@@ -4008,7 +4579,7 @@
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       "evidence": "Nicotine decreases tonic DA release in the striatum that is evoked by single action potentials (127), and nicotine also alters the frequency dependence of DA release that is electrically evoked by stimulus trains (130, 131).",
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@@ -4031,6 +4602,9 @@
         "Cell": {
           "dopaminergic neuron": true
         },
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Post-Synaptic Density": true
         }
@@ -4052,7 +4626,7 @@
       },
       "evidence": "Postsynaptic β2∗ nAChRs initially depolarize DA neurons, causing them to fire action potentials while presynaptic α7∗ nAChRs boost glutamate release. ",
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@@ -4060,11 +4634,42 @@
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+        "first": "Dani JA",
+        "last": "Bertrand D",
+        "name": "Annual review of pharmacology and toxicology",
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+        "reference": "17009926",
+        "title": "Nicotinic acetylcholine receptors and nicotinic cholinergic mechanisms of the central nervous system.",
+        "type": "PubMed",
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+      "evidence": " Moreover, although nicotine increases wakefulness in wild-type mice, it does not affect β2−/− mice. Overall, stimulation of nAChRs promotes arousal and REM sleep.",
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     {
       "annotations": {
         "Cell": {
           "dopaminergic neuron": true
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+        "Confidence": {
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+        },
         "MeSHAnatomy": {
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@@ -4086,7 +4691,7 @@
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       "evidence": "Postsynaptic β2∗ nAChRs initially depolarize DA neurons, causing them to fire action potentials while presynaptic α7∗ nAChRs boost glutamate release. ",
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@@ -4095,6 +4700,9 @@
       "annotations": {
         "Cell": {
           "glutamatergic neuron": true
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@@ -4114,12 +4722,17 @@
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       "evidence": " The combination of enhanced glutamatergic release and strong postsynaptic response produces LTP of the glutamatergic afferents.",
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@@ -4137,7 +4750,7 @@
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@@ -4146,6 +4759,11 @@
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@@ -4163,12 +4781,17 @@
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@@ -4186,7 +4809,7 @@
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@@ -4195,6 +4818,11 @@
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@@ -4212,12 +4840,17 @@
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@@ -4235,7 +4868,7 @@
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       "evidence": "Nicotinic mechanisms contribute to cognitive function, and the decline of nicotinic mechanisms or loss of nAChRs has been observed in AD, dementia with Lewy bodies, Down syndrome, autism, and Parkinson’s disease (20, 140).",
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@@ -4244,6 +4877,11 @@
       "target": 60
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Bertrand D",
@@ -4261,12 +4899,17 @@
       },
       "evidence": "Nicotinic mechanisms contribute to cognitive function, and the decline of nicotinic mechanisms or loss of nAChRs has been observed in AD, dementia with Lewy bodies, Down syndrome, autism, and Parkinson’s disease (20, 140).",
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       "relation": "negativeCorrelation",
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       "target": 60
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Bertrand D",
@@ -4284,12 +4927,17 @@
       },
       "evidence": "Genetic evidence has linked nicotinic receptors to epilepsy and schizophrenia, and studies with mutant mice have implicated nAChRs in pain mechanisms, anxiety, and depression.",
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       "relation": "association",
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       "target": 60
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     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Bertrand D",
@@ -4307,12 +4955,17 @@
       },
       "evidence": "Genetic evidence has linked nicotinic receptors to epilepsy and schizophrenia, and studies with mutant mice have implicated nAChRs in pain mechanisms, anxiety, and depression.",
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       "relation": "association",
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       "target": 60
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     {
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+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
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           "Bertrand D",
@@ -4330,13 +4983,16 @@
       },
       "evidence": "Genetic evidence has linked nicotinic receptors to epilepsy and schizophrenia, and studies with mutant mice have implicated nAChRs in pain mechanisms, anxiety, and depression.",
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       "relation": "association",
       "source": 82,
       "target": 60
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Amygdala": true,
           "Hippocampus": true
@@ -4362,7 +5018,7 @@
       },
       "evidence": "For example, local infusion of the α7 antagonist, methyllycaconitine (MLA), or the β2∗ antagonist, dihydro-β-erythroidine (DHβE), into the basolateral amygdala, the ventral hippocampus, or the dorsal hippocampus impairs the working memory of rats seeking food reward within a 16-arm radial maze (146–148).",
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@@ -4372,6 +5028,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Amygdala": true,
           "Hippocampus": true
@@ -4397,13 +5056,16 @@
       },
       "evidence": "For example, local infusion of the α7 antagonist, methyllycaconitine (MLA), or the β2∗ antagonist, dihydro-β-erythroidine (DHβE), into the basolateral amygdala, the ventral hippocampus, or the dorsal hippocampus impairs the working memory of rats seeking food reward within a 16-arm radial maze (146–148).",
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+      "line": 401,
       "relation": "decreases",
       "source": 27,
       "target": 48
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Amygdala": true,
           "Hippocampus": true
@@ -4429,7 +5091,7 @@
       },
       "evidence": "For example, local infusion of the α7 antagonist, methyllycaconitine (MLA), or the β2∗ antagonist, dihydro-β-erythroidine (DHβE), into the basolateral amygdala, the ventral hippocampus, or the dorsal hippocampus impairs the working memory of rats seeking food reward within a 16-arm radial maze (146–148).",
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@@ -4439,6 +5101,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Amygdala": true,
           "Hippocampus": true
@@ -4464,12 +5129,17 @@
       },
       "evidence": "For example, local infusion of the α7 antagonist, methyllycaconitine (MLA), or the β2∗ antagonist, dihydro-β-erythroidine (DHβE), into the basolateral amygdala, the ventral hippocampus, or the dorsal hippocampus impairs the working memory of rats seeking food reward within a 16-arm radial maze (146–148).",
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+      "line": 403,
       "relation": "decreases",
       "source": 7,
       "target": 48
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     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Bertrand D",
@@ -4487,12 +5157,17 @@
       },
       "evidence": "During attention tasks, the nicotinic antagonist, mecamylamine, impaired accuracy or reaction time (151, 152) and nicotinic agonists improved accuracy (153). ",
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+      "line": 417,
       "relation": "isA",
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       "target": 11
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     {
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+          "High": true
+        }
+      },
       "citation": {
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           "Bertrand D",
@@ -4510,7 +5185,7 @@
       },
       "evidence": "During attention tasks, the nicotinic antagonist, mecamylamine, impaired accuracy or reaction time (151, 152) and nicotinic agonists improved accuracy (153). ",
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@@ -4520,8 +5195,8 @@
         "Cell": {
           "cholinergic neuron": true
         },
-        "MeSHDisease": {
-          "Alzheimer Disease": true
+        "Confidence": {
+          "High": true
         }
       },
       "citation": {
@@ -4541,7 +5216,7 @@
       },
       "evidence": "The most well-appreciated neuronal loss, however, is in the cholinergic system (155, 156), particularly the basal forebrain cholinergic system comprised of the medial septal nucleus, the horizontal and vertical diagonal bands of Broca, and the nucleus basalis of Meynert (157).",
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       "relation": "positiveCorrelation",
       "source": 36,
       "target": 72
@@ -4551,12 +5226,12 @@
         "Cell": {
           "cholinergic neuron": true
         },
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Cerebral Cortex": true,
           "Hippocampus": true
-        },
-        "MeSHDisease": {
-          "Alzheimer Disease": true
         }
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       "citation": {
@@ -4576,15 +5251,15 @@
       },
       "evidence": "As AD worsens, cholinergic neurons are progressively lost and the number of nAChRs declines, particularly in the hippocampus and cortex (140, 158).",
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       "relation": "positiveCorrelation",
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       "target": 72
     },
     {
       "annotations": {
-        "MeSHDisease": {
-          "Alzheimer Disease": true
+        "Confidence": {
+          "High": true
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       "citation": {
@@ -4604,15 +5279,15 @@
       },
       "evidence": "The most commonly prescribed treatments for AD are acetylcholinesterase inhibitors, which decrease the hydrolysis rate of ACh and, thereby, enhance cholinergic signaling. One such drug, galantamine (Reminyl\u0002), also potentiates nAChRs (66).",
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       "relation": "decreases",
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       "target": 72
     },
     {
       "annotations": {
-        "MeSHDisease": {
-          "Alzheimer Disease": true
+        "Confidence": {
+          "High": true
         }
       },
       "citation": {
@@ -4632,7 +5307,7 @@
       },
       "evidence": "The most commonly prescribed treatments for AD are acetylcholinesterase inhibitors, which decrease the hydrolysis rate of ACh and, thereby, enhance cholinergic signaling. One such drug, galantamine (Reminyl\u0002), also potentiates nAChRs (66).",
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@@ -4642,8 +5317,8 @@
     },
     {
       "annotations": {
-        "MeSHDisease": {
-          "Alzheimer Disease": true
+        "Confidence": {
+          "High": true
         }
       },
       "citation": {
@@ -4663,15 +5338,15 @@
       },
       "evidence": "The most commonly prescribed treatments for AD are acetylcholinesterase inhibitors, which decrease the hydrolysis rate of ACh and, thereby, enhance cholinergic signaling. One such drug, galantamine (Reminyl\u0002), also potentiates nAChRs (66).",
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       "relation": "decreases",
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       "target": 85
     },
     {
       "annotations": {
-        "MeSHDisease": {
-          "Alzheimer Disease": true
+        "Confidence": {
+          "High": true
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       },
       "citation": {
@@ -4691,7 +5366,7 @@
       },
       "evidence": "The most commonly prescribed treatments for AD are acetylcholinesterase inhibitors, which decrease the hydrolysis rate of ACh and, thereby, enhance cholinergic signaling. One such drug, galantamine (Reminyl\u0002), also potentiates nAChRs (66).",
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@@ -4701,8 +5376,8 @@
     },
     {
       "annotations": {
-        "MeSHDisease": {
-          "Alzheimer Disease": true
+        "Confidence": {
+          "High": true
         }
       },
       "citation": {
@@ -4722,15 +5397,15 @@
       },
       "evidence": "The most commonly prescribed treatments for AD are acetylcholinesterase inhibitors, which decrease the hydrolysis rate of ACh and, thereby, enhance cholinergic signaling. One such drug, galantamine (Reminyl\u0002), also potentiates nAChRs (66).",
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       "relation": "isA",
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       "target": 3
     },
     {
       "annotations": {
-        "MeSHDisease": {
-          "Alzheimer Disease": true
+        "Confidence": {
+          "High": true
         }
       },
       "citation": {
@@ -4750,7 +5425,7 @@
       },
       "evidence": "The most commonly prescribed treatments for AD are acetylcholinesterase inhibitors, which decrease the hydrolysis rate of ACh and, thereby, enhance cholinergic signaling. One such drug, galantamine (Reminyl\u0002), also potentiates nAChRs (66).",
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@@ -4760,8 +5435,8 @@
     },
     {
       "annotations": {
-        "MeSHDisease": {
-          "Alzheimer Disease": true
+        "Confidence": {
+          "High": true
         }
       },
       "citation": {
@@ -4781,15 +5456,15 @@
       },
       "evidence": "Although Aβ peptides negatively alter the cholinergic system at multiple sites, including ACh synthesis, ACh release, and muscarinic receptors (157), the discovery that Aβ1−42 binds to α7 nAChRs with high affinity suggested the potential for a causal role of nAChRs in AD (159, 160).",
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       "relation": "decreases",
       "source": 5,
       "target": 14
     },
     {
       "annotations": {
-        "MeSHDisease": {
-          "Alzheimer Disease": true
+        "Confidence": {
+          "High": true
         }
       },
       "citation": {
@@ -4809,7 +5484,7 @@
       },
       "evidence": "Although Aβ peptides negatively alter the cholinergic system at multiple sites, including ACh synthesis, ACh release, and muscarinic receptors (157), the discovery that Aβ1−42 binds to α7 nAChRs with high affinity suggested the potential for a causal role of nAChRs in AD (159, 160).",
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           "fromLoc": {
@@ -4829,8 +5504,8 @@
     },
     {
       "annotations": {
-        "MeSHDisease": {
-          "Alzheimer Disease": true
+        "Confidence": {
+          "High": true
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       "citation": {
@@ -4850,7 +5525,7 @@
       },
       "evidence": "Although Aβ peptides negatively alter the cholinergic system at multiple sites, including ACh synthesis, ACh release, and muscarinic receptors (157), the discovery that Aβ1−42 binds to α7 nAChRs with high affinity suggested the potential for a causal role of nAChRs in AD (159, 160).",
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@@ -4863,11 +5538,11 @@
         "Cell": {
           "neuron": true
         },
+        "Confidence": {
+          "Medium": true
+        },
         "MeSHAnatomy": {
           "Brain": true
-        },
-        "MeSHDisease": {
-          "Alzheimer Disease": true
         }
       },
       "citation": {
@@ -4887,7 +5562,7 @@
       },
       "evidence": "This prospect was supported by the finding that α7 nAChRs were found in plaques (159), and α7 and α4 subunits positively correlated with neurons that accumulated Aβ and hyperphosphorylated tau in AD brain tissue (161).",
       "key": "731f46f17c1e03086847123f12ae1cf5ad99ba9ca6f3111583ac22c0fde09e73cda4fa90b1a29a1a95e77e48bb33dfc1a37516912347d39820da5def54e3e7bd",
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       "relation": "positiveCorrelation",
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@@ -4897,11 +5572,11 @@
         "Cell": {
           "neuron": true
         },
+        "Confidence": {
+          "Medium": true
+        },
         "MeSHAnatomy": {
           "Brain": true
-        },
-        "MeSHDisease": {
-          "Alzheimer Disease": true
         }
       },
       "citation": {
@@ -4921,7 +5596,7 @@
       },
       "evidence": "This prospect was supported by the finding that α7 nAChRs were found in plaques (159), and α7 and α4 subunits positively correlated with neurons that accumulated Aβ and hyperphosphorylated tau in AD brain tissue (161).",
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       "relation": "positiveCorrelation",
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@@ -4940,8 +5615,8 @@
     },
     {
       "annotations": {
-        "MeSHDisease": {
-          "Alzheimer Disease": true
+        "Confidence": {
+          "High": true
         }
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       "citation": {
@@ -4961,15 +5636,15 @@
       },
       "evidence": "Although Aβ peptides negatively alter the cholinergic system at multiple sites, including ACh synthesis, ACh release, and muscarinic receptors (157), the discovery that Aβ1−42 binds to α7 nAChRs with high affinity suggested the potential for a causal role of nAChRs in AD (159, 160).",
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       "relation": "association",
       "source": 51,
       "target": 72
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     {
       "annotations": {
-        "MeSHDisease": {
-          "Alzheimer Disease": true
+        "Confidence": {
+          "Medium": true
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       "citation": {
@@ -4989,7 +5664,7 @@
       },
       "evidence": "This prospect was supported by the finding that α7 nAChRs were found in plaques (159), and α7 and α4 subunits positively correlated with neurons that accumulated Aβ and hyperphosphorylated tau in AD brain tissue (161).",
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@@ -4999,11 +5674,11 @@
         "Cell": {
           "neuron": true
         },
+        "Confidence": {
+          "Medium": true
+        },
         "MeSHAnatomy": {
           "Brain": true
-        },
-        "MeSHDisease": {
-          "Alzheimer Disease": true
         }
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       "citation": {
@@ -5023,7 +5698,7 @@
       },
       "evidence": "This prospect was supported by the finding that α7 nAChRs were found in plaques (159), and α7 and α4 subunits positively correlated with neurons that accumulated Aβ and hyperphosphorylated tau in AD brain tissue (161).",
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       "relation": "positiveCorrelation",
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@@ -5033,11 +5708,11 @@
         "Cell": {
           "neuron": true
         },
+        "Confidence": {
+          "Medium": true
+        },
         "MeSHAnatomy": {
           "Brain": true
-        },
-        "MeSHDisease": {
-          "Alzheimer Disease": true
         }
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       "citation": {
@@ -5057,7 +5732,7 @@
       },
       "evidence": "This prospect was supported by the finding that α7 nAChRs were found in plaques (159), and α7 and α4 subunits positively correlated with neurons that accumulated Aβ and hyperphosphorylated tau in AD brain tissue (161).",
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       "relation": "positiveCorrelation",
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@@ -5073,11 +5748,11 @@
         "Cell": {
           "neuron": true
         },
+        "Confidence": {
+          "Medium": true
+        },
         "MeSHAnatomy": {
           "Brain": true
-        },
-        "MeSHDisease": {
-          "Alzheimer Disease": true
         }
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       "citation": {
@@ -5097,7 +5772,7 @@
       },
       "evidence": "This prospect was supported by the finding that α7 nAChRs were found in plaques (159), and α7 and α4 subunits positively correlated with neurons that accumulated Aβ and hyperphosphorylated tau in AD brain tissue (161).",
       "key": "03017e4ec7417f29e559a73c232b9d9ea2a383f45227d4c8712ac6281059678f98b544110e8a8152ab4e89cba4107b99de6b6f02c3720831da1837435e0471f7",
-      "line": 361,
+      "line": 471,
       "relation": "positiveCorrelation",
       "source": 63,
       "target": 5
@@ -5107,11 +5782,11 @@
         "Cell": {
           "neuron": true
         },
+        "Confidence": {
+          "Medium": true
+        },
         "MeSHAnatomy": {
           "Brain": true
-        },
-        "MeSHDisease": {
-          "Alzheimer Disease": true
         }
       },
       "citation": {
@@ -5131,7 +5806,7 @@
       },
       "evidence": "This prospect was supported by the finding that α7 nAChRs were found in plaques (159), and α7 and α4 subunits positively correlated with neurons that accumulated Aβ and hyperphosphorylated tau in AD brain tissue (161).",
       "key": "e0b3f9f6b450d94c5590ffe095209d25f08601dbfea2ccb262e27e54c1be40127537d7e9b20f2cd9558b370a7b9417901eb88b4e5285c85ba268ae91a12b3e89",
-      "line": 362,
+      "line": 472,
       "relation": "positiveCorrelation",
       "source": 63,
       "target": 71
@@ -5144,8 +5819,8 @@
     },
     {
       "annotations": {
-        "MeSHDisease": {
-          "Epilepsy": true
+        "Confidence": {
+          "High": true
         }
       },
       "citation": {
@@ -5165,15 +5840,15 @@
       },
       "evidence": "A mutation in the gene encoding the α4 nAChR subunit (CHRNA4) causes a genetically transmissible form of epilepsy, which was the first discovery of a human disease associated with a neuronal nAChR (165, 166). The mutation has been identified as a single base substitution converting a serine into threonine (S248F) in the TM2 domain of the α4 subunit (165).",
       "key": "d0669e9143b60d4535695949eaea741641072e7322bf1696f3b7e944275b3f91ca304c25779ffa18d2f3c4a8e3dc1bfafb72f48ebfb1e674705c34219fd8a40e",
-      "line": 370,
+      "line": 480,
       "relation": "increases",
       "source": 64,
       "target": 83
     },
     {
       "annotations": {
-        "MeSHDisease": {
-          "Epilepsy": true
+        "Confidence": {
+          "High": true
         }
       },
       "citation": {
@@ -5193,7 +5868,7 @@
       },
       "evidence": "Subsequent to the original discovery, several other families suffering from typical ADNFLE or nocturnal frontal lobe epilepsy (NFLE) have been found to have a mutation either in α4 or β2 (encoded by CHRNB2) (165, 166, 168–170).",
       "key": "b5671cb2a349b872f30401b3c1ec65e46e60e882beb9f9fff18cfb65c82b12ebf7c38de02c1e648a440e2cdf71f5262501da20b04a36a3dac17a213ad030908c",
-      "line": 373,
+      "line": 485,
       "relation": "positiveCorrelation",
       "source": 56,
       "target": 74
@@ -5206,8 +5881,8 @@
     },
     {
       "annotations": {
-        "MeSHDisease": {
-          "Epilepsy": true
+        "Confidence": {
+          "High": true
         }
       },
       "citation": {
@@ -5227,15 +5902,15 @@
       },
       "evidence": "Subsequent to the original discovery, several other families suffering from typical ADNFLE or nocturnal frontal lobe epilepsy (NFLE) have been found to have a mutation either in α4 or β2 (encoded by CHRNB2) (165, 166, 168–170).",
       "key": "a53c11cefe2e2deab58437e6995e73e89650b8598690d257be027e69de3c7ca6b1ad22a397cf2b8a51240eab38b96a687e9f81f7872695f5c06cc14562384a1c",
-      "line": 373,
+      "line": 485,
       "relation": "positiveCorrelation",
       "source": 74,
       "target": 56
     },
     {
       "annotations": {
-        "MeSHDisease": {
-          "Epilepsy": true
+        "Confidence": {
+          "High": true
         }
       },
       "citation": {
@@ -5255,15 +5930,15 @@
       },
       "evidence": "Subsequent to the original discovery, several other families suffering from typical ADNFLE or nocturnal frontal lobe epilepsy (NFLE) have been found to have a mutation either in α4 or β2 (encoded by CHRNB2) (165, 166, 168–170).",
       "key": "ab9c1bbd96721202c1990e636d1625d600073dab91d7ea1504fb74d04b6ef8a25e1d976b16419e8ca4b17c470701be4a6570c019c8f0fe119e51e14bed4ca745",
-      "line": 374,
+      "line": 486,
       "relation": "positiveCorrelation",
       "source": 74,
       "target": 58
     },
     {
       "annotations": {
-        "MeSHDisease": {
-          "Epilepsy": true
+        "Confidence": {
+          "High": true
         }
       },
       "citation": {
@@ -5283,7 +5958,7 @@
       },
       "evidence": "Subsequent to the original discovery, several other families suffering from typical ADNFLE or nocturnal frontal lobe epilepsy (NFLE) have been found to have a mutation either in α4 or β2 (encoded by CHRNB2) (165, 166, 168–170).",
       "key": "e3d7a1a42835ef6c3cce56aff65e087fab33e1ffd4ca194d7941a59ee102aba4edfd516f772fe6efed12df553a0592dbab7409849044b0cfb6c552f850bbde02",
-      "line": 374,
+      "line": 486,
       "relation": "positiveCorrelation",
       "source": 58,
       "target": 74
diff --git a/hbp_knowledge/receptors/francis2016.bel.json b/hbp_knowledge/receptors/francis2016.bel.json
index bfc8dbb63..eb3090c26 100644
--- a/hbp_knowledge/receptors/francis2016.bel.json
+++ b/hbp_knowledge/receptors/francis2016.bel.json
@@ -8,6 +8,7 @@
     "annotation_url": {
       "Cell": "https://arty.scai.fraunhofer.de/artifactory/bel/annotation/cell/cell-20170511.belanno",
       "CellStructure": "https://arty.scai.fraunhofer.de/artifactory/bel/annotation/cell-structure/cell-structure-20170511.belanno",
+      "Confidence": "https://arty.scai.fraunhofer.de/artifactory/bel/annotation/confidence/confidence-1.0.0.belanno",
       "Disease": "https://arty.scai.fraunhofer.de/artifactory/bel/annotation/disease/disease-20170511.belanno",
       "MeSHAnatomy": "https://arty.scai.fraunhofer.de/artifactory/bel/annotation/mesh-anatomy/mesh-anatomy-20170511.belanno"
     },
@@ -35,6 +36,9 @@
   "links": [
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Disease": {
           "Alzheimer's disease": true
         }
@@ -55,13 +59,16 @@
       },
       "evidence": "From the perspective of brain histopathology, Alzheimer's disease has three characteristic features—the appearance of beta-amyloid plaques, the presence of neurofibrillary tangles, and the loss of neuronal cells",
       "key": "d2f85b0f09e45ae4602c5160ecfe95db19f1187d704659905b1d23340278d7ef8e7892668ec85ef916a40d1442b1f52124c791784851e6f4335ec42b44e48d3b",
-      "line": 54,
+      "line": 55,
       "relation": "association",
-      "source": 32,
-      "target": 38
+      "source": 34,
+      "target": 40
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Disease": {
           "Alzheimer's disease": true
         }
@@ -82,13 +89,16 @@
       },
       "evidence": "From the perspective of brain histopathology, Alzheimer's disease has three characteristic features—the appearance of beta-amyloid plaques, the presence of neurofibrillary tangles, and the loss of neuronal cells",
       "key": "90ec1ff7ff1c47555bbaf1cd7cb58c0231280cd60b789dbb94cb9191ff21bffdb43afe5f6985df6688c69ae2d4cba2b4b0af57462687c28bddc675f2442ae8e6",
-      "line": 56,
+      "line": 57,
       "relation": "association",
-      "source": 32,
-      "target": 39
+      "source": 34,
+      "target": 41
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Disease": {
           "Alzheimer's disease": true
         }
@@ -109,13 +119,16 @@
       },
       "evidence": "From the perspective of brain histopathology, Alzheimer's disease has three characteristic features—the appearance of beta-amyloid plaques, the presence of neurofibrillary tangles, and the loss of neuronal cells",
       "key": "0126b9c92054d5a4b83d3e5d5c34fe7547e07e3478eab6a4ab2860ec07808292dd06b280044ec8d3e6ddb2b18ed12b931dc1e15a228aa822bb3af831674840de",
-      "line": 58,
+      "line": 59,
       "relation": "association",
-      "source": 32,
-      "target": 20
+      "source": 34,
+      "target": 22
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Disease": {
           "Alzheimer's disease": true
         }
@@ -136,13 +149,16 @@
       },
       "evidence": "Although the loss of neurons leads to deficits in neurotransmission, even neurons that are not dead may exhibit impaired neurotransmission in Alzheimer's disease",
       "key": "733240d2c86dc3eb2da21d83343e999b6d7746f2918ec819bfde32985321056bfbc16a96bf1745ebfb412bd04a04948ebdfc66228dffc99129e1f9402ee68dfe",
-      "line": 70,
+      "line": 72,
       "relation": "decreases",
-      "source": 32,
-      "target": 21
+      "source": 34,
+      "target": 23
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Disease": {
           "Alzheimer's disease": true
         }
@@ -163,13 +179,16 @@
       },
       "evidence": "Among the systems affected in patients with Alzheimer's disease are the cholinergic and glutamatergic neurotransmission systems. These two systems play key roles in cognition and, as a result, contemporary pharmacologic agents used in the treatment of Alzheimer's disease are designed to restore their functioning",
       "key": "d394c95a98c95571255683628804068686a42795d9f3c6ed6de306d758d5622fb08ce660fb55b5d35608e93c4160d8f24b98827d199431d2b10ef1ea8c24b493",
-      "line": 85,
+      "line": 88,
       "relation": "decreases",
-      "source": 32,
-      "target": 14
+      "source": 34,
+      "target": 16
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Disease": {
           "Alzheimer's disease": true
         }
@@ -190,13 +209,16 @@
       },
       "evidence": "Among the systems affected in patients with Alzheimer's disease are the cholinergic and glutamatergic neurotransmission systems. These two systems play key roles in cognition and, as a result, contemporary pharmacologic agents used in the treatment of Alzheimer's disease are designed to restore their functioning",
       "key": "c191c9e1b57da32c2ef940f68c2dd34c18b6d408f854a248d7421f072caa613dcf50f53b61b0e74cff1f9e56cd6861d4ebf0cb6099b1eae7ffeefd4c9472ee0f",
-      "line": 87,
+      "line": 90,
       "relation": "decreases",
-      "source": 32,
-      "target": 18
+      "source": 34,
+      "target": 20
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "Disease": {
           "Alzheimer's disease": true
         }
@@ -217,7 +239,7 @@
       },
       "evidence": "For example, the activity of choline acetyltransferase, the enzyme that catalyzes the synthesis of ACh from choline and acetyl coenzyme A, is reduced to 35% to 50% of normal levels in Alzheimer's disease",
       "key": "dafe7fad315ca10e1d37e76205a7bd99773d50e8011c821af001a6979f4f482b41bdabf0057fa5637c370eaa288f98dd9dfdca9dfa6e6a340428d5499f8d7189",
-      "line": 105,
+      "line": 109,
       "object": {
         "effect": {
           "name": "cat",
@@ -226,11 +248,14 @@
         "modifier": "Activity"
       },
       "relation": "decreases",
-      "source": 32,
-      "target": 27
+      "source": 34,
+      "target": 29
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Disease": {
           "Alzheimer's disease": true
         }
@@ -251,13 +276,16 @@
       },
       "evidence": "Furthermore, synaptic reuptake of choline, which is essential for the synthesis of ACh molecules that are to be released into the synaptic cleft in subsequent rounds of neurotransmission, is reduced to -60% of normal levels in Alzheimer's disease, and direct measurement reveals that levels of ACh synthesis are reduced by one half in affected patients.",
       "key": "bb6f68b5b7d65989217c1b28d4a3da1d4e36dd57a119f3630d192ada3210c5549163369e457ebce28ad077cfb70a0aa866541fad7a43e5b2a1c7f59fdc098c62",
-      "line": 121,
+      "line": 126,
       "relation": "decreases",
-      "source": 32,
-      "target": 17
+      "source": 34,
+      "target": 19
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Disease": {
           "Alzheimer's disease": true
         }
@@ -278,12 +306,17 @@
       },
       "evidence": "Furthermore, synaptic reuptake of choline, which is essential for the synthesis of ACh molecules that are to be released into the synaptic cleft in subsequent rounds of neurotransmission, is reduced to -60% of normal levels in Alzheimer's disease, and direct measurement reveals that levels of ACh synthesis are reduced by one half in affected patients.",
       "key": "1bc560209993a04f0b66c9b25d49846c270c8b267714a86743711f90db0ede011973d5238a4b34091c110906297aa6dac5a57055280e3b9529ecd7f170dde21e",
-      "line": 123,
+      "line": 128,
       "relation": "decreases",
-      "source": 32,
-      "target": 15
+      "source": 34,
+      "target": 17
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Francis PT"
@@ -300,16 +333,19 @@
       },
       "evidence": "Despite the various cholinergic abnormalities seen in Alzheimer's disease, ACh receptor systems remain relatively unaltered in affected patients.8",
       "key": "deb0e82cf418aeac17acda683b1cf6338a91bf2eb99616a2d1aa216c8336ec729988409992f0e44d708861b64d5ca5aac87820e56ea8b18812cd95a5c1711950",
-      "line": 144,
+      "line": 151,
       "relation": "causesNoChange",
-      "source": 32,
-      "target": 30
+      "source": 34,
+      "target": 32
     },
     {
       "annotations": {
         "Cell": {
           "glial cell": true
         },
+        "Confidence": {
+          "High": true
+        },
         "Disease": {
           "Alzheimer's disease": true
         },
@@ -334,16 +370,19 @@
       },
       "evidence": "In patients with Alzheimer's disease, available evidence points to a disruption in the glutamatergic neurotransmission cycle at the point of glial cell reuptake of free glutamate from the synapse. Neuropathologic studies have documented reduced levels of glutamate reuptake in the frontal and temporal cortices of patients with Alzheimer's disease,10 possibly due to oxidative modification of the glutamate transporter 1 molecule. Furthermore, diminished uptake by vesicular glutamate transporter has been reported in patients with Alzheimer's disease",
       "key": "c0beeef82d7c175be6fdac9bc0a494eccc7a2f4a3b5860978d291f9748950e50f9c35af63e715b4e91f8ea8a2a4a7032f0d67276f5bf4aef4bf4fcff81003909",
-      "line": 222,
+      "line": 233,
       "relation": "decreases",
-      "source": 32,
-      "target": 19
+      "source": 34,
+      "target": 21
     },
     {
       "annotations": {
         "Cell": {
           "glial cell": true
         },
+        "Confidence": {
+          "High": true
+        },
         "Disease": {
           "Alzheimer's disease": true
         },
@@ -368,22 +407,18 @@
       },
       "evidence": "In patients with Alzheimer's disease, available evidence points to a disruption in the glutamatergic neurotransmission cycle at the point of glial cell reuptake of free glutamate from the synapse. Neuropathologic studies have documented reduced levels of glutamate reuptake in the frontal and temporal cortices of patients with Alzheimer's disease,10 possibly due to oxidative modification of the glutamate transporter 1 molecule. Furthermore, diminished uptake by vesicular glutamate transporter has been reported in patients with Alzheimer's disease",
       "key": "3547af790a3820be8d8a91b1c23c95caaf62053628720bb3ae88527787c93829321c1cc9aff83f3cf002f6517c824081f588a732e6ba6373ebff11bc689d7e96",
-      "line": 223,
+      "line": 234,
       "relation": "decreases",
-      "source": 32,
-      "target": 16
+      "source": 34,
+      "target": 18
     },
     {
       "annotations": {
-        "Cell": {
-          "glial cell": true
+        "Confidence": {
+          "High": true
         },
         "Disease": {
           "Alzheimer's disease": true
-        },
-        "MeSHAnatomy": {
-          "Frontal Lobe": true,
-          "Temporal Lobe": true
         }
       },
       "citation": {
@@ -402,22 +437,18 @@
       },
       "evidence": "Second, because of this background signal, as well as the fact that neurons are left with smaller amounts of neurotransmitter to release into the synapse during neuronal firing, the 'peak signal'—the difference between synaptic glutamate concentration during neuronal activity and synaptic glutamate concentration under resting conditions—is attenuated, leading to suboptimal neurotransmission as exemplified by a lack of long-term potentiation (LTP)",
       "key": "ab3c6eaa8d5171030f376fd4d45275f9f5eec7b19005d51417d10a781777d38fffe4dfe0e5c14aa7c2d885720c1224a9dc739f06de388fdca1d6736481c8275f",
-      "line": 257,
+      "line": 272,
       "relation": "decreases",
-      "source": 32,
-      "target": 16
+      "source": 34,
+      "target": 18
     },
     {
       "annotations": {
-        "Cell": {
-          "glial cell": true
+        "Confidence": {
+          "High": true
         },
         "Disease": {
           "Alzheimer's disease": true
-        },
-        "MeSHAnatomy": {
-          "Frontal Lobe": true,
-          "Temporal Lobe": true
         }
       },
       "citation": {
@@ -436,19 +467,15 @@
       },
       "evidence": "Second, because of this background signal, as well as the fact that neurons are left with smaller amounts of neurotransmitter to release into the synapse during neuronal firing, the 'peak signal'—the difference between synaptic glutamate concentration during neuronal activity and synaptic glutamate concentration under resting conditions—is attenuated, leading to suboptimal neurotransmission as exemplified by a lack of long-term potentiation (LTP)",
       "key": "d706426ad8c91b3f155d3501ed0741597dcc7657bde90be056370a2055a47f158e460d09a6999cfcb32b74244922a0140a223585bbeb02189569fef3c79e84ce",
-      "line": 258,
+      "line": 273,
       "relation": "decreases",
-      "source": 32,
-      "target": 22
+      "source": 34,
+      "target": 24
     },
     {
       "annotations": {
-        "Cell": {
-          "glial cell": true
-        },
-        "MeSHAnatomy": {
-          "Frontal Lobe": true,
-          "Temporal Lobe": true
+        "Confidence": {
+          "High": true
         }
       },
       "citation": {
@@ -467,13 +494,16 @@
       },
       "evidence": "It is believed that LTP, which can persist at a given synapse for periods ranging from hours to months, models the processes of learning and memory, and a number of studies have demonstrated a loss of LTP in animal models of Alzheimer's disease.",
       "key": "e64c7a1a5a8fd16f054bdfe1ff720ed9b03404f54411c3334617fd4f9d97e8829d8d767ef811eaa728d7a7bbfc05e0e09476024a0d8bc73f1ab08f1bd698008f",
-      "line": 272,
+      "line": 288,
       "relation": "decreases",
-      "source": 32,
-      "target": 22
+      "source": 34,
+      "target": 24
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Disease": {
           "Alzheimer's disease": true
         }
@@ -494,13 +524,16 @@
       },
       "evidence": "In Alzheimer's disease, however, it is believed that Mg2+ is displaced from the NMDA receptor calcium channel even under resting conditions, due to the elevated levels of glutamate that are present in the synapse at all times.13 It has been hypothesized that this constant activation of NMDA receptors leads to neuronal overactivity while also contributing to an unfavorable signal-to-noise ratio during glutamatergic neurotransmission and, hence, to the absence of LTP.",
       "key": "403759457499261bb27a2b2bf702b5993e0565a59f3e7b576b46b4cca4cf8868bee70b47b1be490a0a89186b91cfe9fbb2971dbc3e3b928b8097ec24ad40c726",
-      "line": 332,
+      "line": 351,
       "relation": "decreases",
-      "source": 32,
-      "target": 24
+      "source": 34,
+      "target": 26
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Disease": {
           "Alzheimer's disease": true
         }
@@ -521,13 +554,16 @@
       },
       "evidence": "From the perspective of brain histopathology, Alzheimer's disease has three characteristic features—the appearance of beta-amyloid plaques, the presence of neurofibrillary tangles, and the loss of neuronal cells",
       "key": "e4958ae5b4ffc8145e7f3b5f882bbb28431152f8584ed51df08a5770d35a6a1449cde4aae26d4a4d0a441ed6cc19c558fdc58ae3d149b7c72c2dc2f7ed5b1019",
-      "line": 54,
+      "line": 55,
       "relation": "association",
-      "source": 38,
-      "target": 32
+      "source": 40,
+      "target": 34
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Disease": {
           "Alzheimer's disease": true
         }
@@ -548,13 +584,16 @@
       },
       "evidence": "From the perspective of brain histopathology, Alzheimer's disease has three characteristic features—the appearance of beta-amyloid plaques, the presence of neurofibrillary tangles, and the loss of neuronal cells",
       "key": "14e056b4d642c120a5c0a5f0c56f9838be4e9607bf25b673b3d9c233cbf90722ab2014b33664e2af17d3a73afc33f1068ef6b7644cb75228c69c71959072a0f1",
-      "line": 56,
+      "line": 57,
       "relation": "association",
-      "source": 39,
-      "target": 32
+      "source": 41,
+      "target": 34
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Disease": {
           "Alzheimer's disease": true
         }
@@ -575,25 +614,21 @@
       },
       "evidence": "From the perspective of brain histopathology, Alzheimer's disease has three characteristic features—the appearance of beta-amyloid plaques, the presence of neurofibrillary tangles, and the loss of neuronal cells",
       "key": "3d1b16870120601e0f09a1cac4c4adc06ad5efcf6c04dbe41cfe5e458f03664027883007438096cab60ff788d3a890cba50bd1fe9635bc3bc0bda534bcdd2fe2",
-      "line": 58,
+      "line": 59,
       "relation": "association",
-      "source": 20,
-      "target": 32
+      "source": 22,
+      "target": 34
     },
     {
       "annotations": {
-        "Cell": {
-          "glial cell": true
-        },
         "CellStructure": {
           "Post-Synaptic Density": true
         },
+        "Confidence": {
+          "High": true
+        },
         "Disease": {
           "Alzheimer's disease": true
-        },
-        "MeSHAnatomy": {
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@@ -990,14 +1091,17 @@
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@@ -1282,19 +1446,15 @@
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-        "MeSHAnatomy": {
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-          "Temporal Lobe": true
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@@ -1313,10 +1473,10 @@
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           "Mitochondria": true
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@@ -1346,9 +1509,9 @@
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@@ -1366,6 +1529,9 @@
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           "Mitochondria": true
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@@ -1386,25 +1552,21 @@
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-          "Temporal Lobe": true
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@@ -1423,13 +1585,13 @@
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@@ -1439,6 +1601,9 @@
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@@ -1459,22 +1624,18 @@
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@@ -1493,15 +1654,18 @@
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@@ -1520,15 +1684,18 @@
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@@ -1547,25 +1714,21 @@
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@@ -1618,19 +1777,15 @@
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@@ -1649,19 +1804,15 @@
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@@ -1680,16 +1831,19 @@
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       "annotations": {
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@@ -1710,28 +1864,31 @@
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@@ -1752,16 +1909,19 @@
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       "evidence": "Pyramidal neurons, which account for ~70% of all neurons in the neocortex, use glutamate as their primary neurotransmitter. Nonetheless, in addition to possessing glutamatergic receptors on their surface, these neurons often also possess cholinergic receptors, which are capable of receiving cholinergic inputs into the neocortex from the basal forebrain. The presence of these cholinergic receptors has been putatively linked to an important finding regarding the interaction between the cholinergic and glutamatergic neurotransmission systems. In particular, rodent studies have revealed that cholinesterase inhibitors (ChEIs) promote the release of glutamate from pyramidal neurons,16 with the proposed explanation being that ChEI administration leads to increased cortical ACh concentrations and, consequently, increased binding of ACh by cholinergic receptors on pyramidal neurons, thereby stimulating neuronal firing (ie, glutamate release).",
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@@ -1785,15 +1945,18 @@
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       "evidence": "Pyramidal neurons, which account for ~70% of all neurons in the neocortex, use glutamate as their primary neurotransmitter. Nonetheless, in addition to possessing glutamatergic receptors on their surface, these neurons often also possess cholinergic receptors, which are capable of receiving cholinergic inputs into the neocortex from the basal forebrain. The presence of these cholinergic receptors has been putatively linked to an important finding regarding the interaction between the cholinergic and glutamatergic neurotransmission systems. In particular, rodent studies have revealed that cholinesterase inhibitors (ChEIs) promote the release of glutamate from pyramidal neurons,16 with the proposed explanation being that ChEI administration leads to increased cortical ACh concentrations and, consequently, increased binding of ACh by cholinergic receptors on pyramidal neurons, thereby stimulating neuronal firing (ie, glutamate release).",
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@@ -1812,16 +1975,19 @@
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       "evidence": "With regard to the glutamatergic system, studies suggest that ChEIs may stimulate the release of glutamate from pyramidal neurons during normal neuronal activity, while NMDA receptor antagonists are believed to block the abnormal neuronal activity that results from the presence of excess glutamate in the synapse under resting conditions. Thus, ChEIs and NMDA receptor antagonists appear to have complementary effects, as the former enhance the signals received by postsynaptic neurons during normal neurotransmission, and the latter diminish the background 'noise' that is constantly being detected by those same receptors.",
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         "MeSHAnatomy": {
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@@ -1845,12 +2011,17 @@
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       "evidence": "Pyramidal neurons, which account for ~70% of all neurons in the neocortex, use glutamate as their primary neurotransmitter. Nonetheless, in addition to possessing glutamatergic receptors on their surface, these neurons often also possess cholinergic receptors, which are capable of receiving cholinergic inputs into the neocortex from the basal forebrain. The presence of these cholinergic receptors has been putatively linked to an important finding regarding the interaction between the cholinergic and glutamatergic neurotransmission systems. In particular, rodent studies have revealed that cholinesterase inhibitors (ChEIs) promote the release of glutamate from pyramidal neurons,16 with the proposed explanation being that ChEI administration leads to increased cortical ACh concentrations and, consequently, increased binding of ACh by cholinergic receptors on pyramidal neurons, thereby stimulating neuronal firing (ie, glutamate release).",
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@@ -1867,22 +2038,25 @@
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           "pyramidal neuron": true
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@@ -1906,18 +2080,23 @@
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       "evidence": "Pyramidal neurons, which account for ~70% of all neurons in the neocortex, use glutamate as their primary neurotransmitter. Nonetheless, in addition to possessing glutamatergic receptors on their surface, these neurons often also possess cholinergic receptors, which are capable of receiving cholinergic inputs into the neocortex from the basal forebrain. The presence of these cholinergic receptors has been putatively linked to an important finding regarding the interaction between the cholinergic and glutamatergic neurotransmission systems. In particular, rodent studies have revealed that cholinesterase inhibitors (ChEIs) promote the release of glutamate from pyramidal neurons,16 with the proposed explanation being that ChEI administration leads to increased cortical ACh concentrations and, consequently, increased binding of ACh by cholinergic receptors on pyramidal neurons, thereby stimulating neuronal firing (ie, glutamate release).",
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     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Francis PT"
@@ -1934,25 +2113,28 @@
       },
       "evidence": "In individuals with normal cognitive functioning, Mg2+ blocks the passage of Ca2+ through the neuronal NMDA receptor calcium channel under resting conditions, but it is readily displaced when membrane depolarization occurs and synaptic glutamate concentrations are at peak levels (ie, when neuronal firing occurs).",
       "key": "7b86228713165518318980ef761864315213e2943b1c080f27603c36a8ddb55231ab5f085c4c33916840b13f4674b6f57a71137e6060e0a77bbb21dc67309fd0",
-      "line": 317,
+      "line": 335,
       "relation": "decreases",
-      "source": 4,
-      "target": 23
+      "source": 5,
+      "target": 25
     },
     {
       "key": "e95174bfb259c588a0e43fe8aa39786749f33ac9e574f4336912b868290199b7b9fbd478ea288eb616ed688da8eacca6c9159523602fe2f4f7a00a552fdd003d",
       "relation": "hasComponent",
-      "source": 23,
-      "target": 1
+      "source": 25,
+      "target": 2
     },
     {
       "key": "c6c93c4ba92fdfd1d5fd864b15baf8afca372bf45fa37aeafbcea86329f23e6262d707729d65a17e1cb6652dfa8fb3774cde136654e2f3d6a98f010675c79777",
       "relation": "hasComponent",
-      "source": 23,
-      "target": 29
+      "source": 25,
+      "target": 31
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Disease": {
           "Alzheimer's disease": true
         }
@@ -1973,28 +2155,31 @@
       },
       "evidence": "In Alzheimer's disease, however, it is believed that Mg2+ is displaced from the NMDA receptor calcium channel even under resting conditions, due to the elevated levels of glutamate that are present in the synapse at all times.13 It has been hypothesized that this constant activation of NMDA receptors leads to neuronal overactivity while also contributing to an unfavorable signal-to-noise ratio during glutamatergic neurotransmission and, hence, to the absence of LTP.",
       "key": "469486ec193be119b5aa3b669e22551869af86f27a64e1837467b9b91412dd5db96b409d7fa4bb2c11fc892ef9b5ce0382fb5041b9e18a0be7bd01f7259a83ef",
-      "line": 333,
+      "line": 352,
       "relation": "decreases",
-      "source": 29,
+      "source": 31,
       "subject": {
         "modifier": "Activity"
       },
-      "target": 22
+      "target": 24
     },
     {
       "key": "6c89fd6aeb892b3499a9b6cbee0da5e489a4b99da9cfd684df9ba23ef12406af688d6d1d3785cc3428feac7f7248d3959fc63a958b4ec19921e1ab0d72a15dd8",
       "relation": "hasComponent",
-      "source": 24,
-      "target": 4
+      "source": 26,
+      "target": 5
     },
     {
       "key": "bfdcc9c4f2ec63c56cef2535b5e9075e6e41837b99d84378082483c381ed67091d4c87729c24a22a3ad54b8b3a2aec9d8ffe303712abb6675743a657d026adcc",
       "relation": "hasComponent",
-      "source": 24,
-      "target": 29
+      "source": 26,
+      "target": 31
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Disease": {
           "Alzheimer's disease": true
         }
@@ -2015,13 +2200,16 @@
       },
       "evidence": "According to the proposed hypothesis, memantine has the ability to block the passage of Ca2+ through the calcium channel even when, as in Alzheimer's disease, resting synaptic glutamate levels are abnormally high, but it is still readily displaced at peak synaptic glutamate concentrations.13 In other words, the clinical efficacy of memantine appears to stem from its ability to prevent neuronal overactivity without also hindering normal neurotransmission.",
       "key": "584e435421589ca0a29b5e262319e29d8b55e7385de4a950143e3796ef1bb5be4a339029c555d6686c2a495df1dfd13e26dcb68e761cbeafa498516807a5fd10",
-      "line": 350,
+      "line": 370,
       "relation": "decreases",
-      "source": 7,
-      "target": 23
+      "source": 9,
+      "target": 25
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Disease": {
           "Alzheimer's disease": true
         }
@@ -2042,12 +2230,17 @@
       },
       "evidence": "According to the proposed hypothesis, memantine has the ability to block the passage of Ca2+ through the calcium channel even when, as in Alzheimer's disease, resting synaptic glutamate levels are abnormally high, but it is still readily displaced at peak synaptic glutamate concentrations.13 In other words, the clinical efficacy of memantine appears to stem from its ability to prevent neuronal overactivity without also hindering normal neurotransmission.",
       "key": "e669b90f592712553da5ffa5785b38f89fae7684772b71b89ff8ec67b411dd893058771d30e9275579f22904dbe4fa79dd0b32f615bf531ae2522ae447b88c6b",
-      "line": 352,
+      "line": 372,
       "relation": "causesNoChange",
-      "source": 7,
-      "target": 21
+      "source": 9,
+      "target": 23
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Francis PT"
@@ -2064,15 +2257,18 @@
       },
       "evidence": "ChEIs are believed to target cholinergic abnormalities in Alzheimer's disease, although there is evidence indicating that their therapeutic effect may be via the glutamatergic system. NMDA receptor antagonists, in contrast, are believed to target the glutamatergic system directly",
       "key": "e64cfb73c8ada562d0ea31f87cfa3ae8075d22dc23345d0a726d6839c5ea3310ffc523c3526e3648f5f51ced6f4a14cd75c91a4755a57d72838a8a13663215ba",
-      "line": 379,
+      "line": 401,
       "relation": "association",
       "source": 0,
-      "target": 18
+      "target": 20
     },
     {
       "annotations": {
         "Cell": {
           "pyramidal neuron": true
+        },
+        "Confidence": {
+          "High": true
         }
       },
       "citation": {
@@ -2091,13 +2287,13 @@
       },
       "evidence": "With regard to the glutamatergic system, studies suggest that ChEIs may stimulate the release of glutamate from pyramidal neurons during normal neuronal activity, while NMDA receptor antagonists are believed to block the abnormal neuronal activity that results from the presence of excess glutamate in the synapse under resting conditions. Thus, ChEIs and NMDA receptor antagonists appear to have complementary effects, as the former enhance the signals received by postsynaptic neurons during normal neurotransmission, and the latter diminish the background 'noise' that is constantly being detected by those same receptors.",
       "key": "1329e4a62207f811a69dc330a33ae9defe21f9bb232d22906fcf7ceacc96a7baf5f6fad5b3a87c66431ca18efb0e6add4aab8d19cf2a4f84e3762000d7ac9fa2",
-      "line": 399,
+      "line": 422,
       "object": {
         "modifier": "Activity"
       },
       "relation": "decreases",
       "source": 0,
-      "target": 10
+      "target": 12
     }
   ],
   "multigraph": true,
@@ -2109,6 +2305,13 @@
       "name": "NMDA receptor antagonist",
       "namespace": "CHEBI"
     },
+    {
+      "bel": "a(CHEBI:\"acetyl-CoA\")",
+      "function": "Abundance",
+      "id": "a5fa305d2e2001d715f893ae6c2d622f7e9190eff20a4c42d6ac7af0177896d9464cdd5304827d22ac2fce8b653837ad54d0a95422b99f8fbf8e348571b0e739",
+      "name": "acetyl-CoA",
+      "namespace": "CHEBI"
+    },
     {
       "bel": "a(CHEBI:\"calcium(2+)\")",
       "function": "Abundance",
@@ -2144,6 +2347,13 @@
       "name": "acetylcholine",
       "namespace": "CHEBI"
     },
+    {
+      "bel": "a(CHEBI:choline)",
+      "function": "Abundance",
+      "id": "88fb57fa667be5fcf348ed86cb041de48401b10103512c286ebe600483744af962b0f34c7d2f8cfb57af6f72aaab29d8787cb64de2aa5d58ecd6fe01876d0cee",
+      "name": "choline",
+      "namespace": "CHEBI"
+    },
     {
       "bel": "a(CHEBI:glutamine)",
       "function": "Abundance",
@@ -2437,6 +2647,36 @@
       "id": "57fd983c3b4355ab5d48d9f22714190313dd4d486c12fa9e15fb06686ae551ec367274c7ba60e22deb098f72c31d2fa25f721f99996aca1fe6c446d919fb69b5",
       "name": "D058225",
       "namespace": "MESH"
+    },
+    {
+      "bel": "rxn(reactants(a(CHEBI:\"acetyl-CoA\"), a(CHEBI:choline)), products(a(CHEBI:acetylcholine)))",
+      "function": "Reaction",
+      "id": "67e4f589cdce9497a0a43da03a8a402f89eb6cbd8d585bdd7e3d9026082992e885b82103d791702e1926577a12111ec9021e85e2923ffe51f46285bfce1b08a6",
+      "products": [
+        {
+          "bel": "a(CHEBI:acetylcholine)",
+          "function": "Abundance",
+          "id": "bae5841bb74f1e9eb73cd433cda657927031217c24e17f21bb2975128d1d9be4dc899448ede71d9aa18224145a1681b90b33287454eabf938f405bc1b8894b62",
+          "name": "acetylcholine",
+          "namespace": "CHEBI"
+        }
+      ],
+      "reactants": [
+        {
+          "bel": "a(CHEBI:\"acetyl-CoA\")",
+          "function": "Abundance",
+          "id": "a5fa305d2e2001d715f893ae6c2d622f7e9190eff20a4c42d6ac7af0177896d9464cdd5304827d22ac2fce8b653837ad54d0a95422b99f8fbf8e348571b0e739",
+          "name": "acetyl-CoA",
+          "namespace": "CHEBI"
+        },
+        {
+          "bel": "a(CHEBI:choline)",
+          "function": "Abundance",
+          "id": "88fb57fa667be5fcf348ed86cb041de48401b10103512c286ebe600483744af962b0f34c7d2f8cfb57af6f72aaab29d8787cb64de2aa5d58ecd6fe01876d0cee",
+          "name": "choline",
+          "namespace": "CHEBI"
+        }
+      ]
     }
   ]
 }
\ No newline at end of file
diff --git a/hbp_knowledge/receptors/lombardo2015.bel.json b/hbp_knowledge/receptors/lombardo2015.bel.json
index fb6542ad6..8067f6902 100644
--- a/hbp_knowledge/receptors/lombardo2015.bel.json
+++ b/hbp_knowledge/receptors/lombardo2015.bel.json
@@ -55,6 +55,11 @@
   },
   "links": [
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -72,12 +77,17 @@
       },
       "evidence": "Dementia is a debilitating condition frequent in ageing populations, and Alzheimer's Disease (AD) accounts for 70% of all dementia cases. AD is characterized by neuropathological hallmarks consisting of an accumulation of Amyloid beta peptide (Ab) in extracellular plaques, intracellular deposits of tau protein, neuronal loss and, more recently, a prominent synaptic loss was identified (Braak and Braak,1991; Masliah et al., 2001; Selkoe,1991; Spires-Jones and Hyman, 2014)",
       "key": "4c8a101299120b251c3845d083fb2954db5c97a7e1a0064772776cdd982a4112187ec21c6a95569d6d07392a3d32091f9a339316f03332a36abc272ff2554d6d",
-      "line": 82,
+      "line": 83,
       "relation": "association",
       "source": 56,
       "target": 123
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -95,12 +105,17 @@
       },
       "evidence": "Dementia is a debilitating condition frequent in ageing populations, and Alzheimer's Disease (AD) accounts for 70% of all dementia cases. AD is characterized by neuropathological hallmarks consisting of an accumulation of Amyloid beta peptide (Ab) in extracellular plaques, intracellular deposits of tau protein, neuronal loss and, more recently, a prominent synaptic loss was identified (Braak and Braak,1991; Masliah et al., 2001; Selkoe,1991; Spires-Jones and Hyman, 2014)",
       "key": "d1b1c861a9396d55dd0188806da30904a8d10fa2e51dade309549c700c8d04cd3f0c13d77f8b39587c4567b64e70478a8449fde563312d974896855c2509ea5b",
-      "line": 82,
+      "line": 83,
       "relation": "association",
       "source": 123,
       "target": 56
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -118,12 +133,17 @@
       },
       "evidence": "Dementia is a debilitating condition frequent in ageing populations, and Alzheimer's Disease (AD) accounts for 70% of all dementia cases. AD is characterized by neuropathological hallmarks consisting of an accumulation of Amyloid beta peptide (Ab) in extracellular plaques, intracellular deposits of tau protein, neuronal loss and, more recently, a prominent synaptic loss was identified (Braak and Braak,1991; Masliah et al., 2001; Selkoe,1991; Spires-Jones and Hyman, 2014)",
       "key": "85e5f42bbbf8cece80175f9db9ff0176b6460fdf382549fb8a3bfb702b4f27ce06b230c3e95e9aac40dd62509239d0438c6df21bd9155f4aaec24206eb90f41a",
-      "line": 83,
+      "line": 84,
       "relation": "association",
       "source": 123,
       "target": 117
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -141,12 +161,17 @@
       },
       "evidence": "Dementia is a debilitating condition frequent in ageing populations, and Alzheimer's Disease (AD) accounts for 70% of all dementia cases. AD is characterized by neuropathological hallmarks consisting of an accumulation of Amyloid beta peptide (Ab) in extracellular plaques, intracellular deposits of tau protein, neuronal loss and, more recently, a prominent synaptic loss was identified (Braak and Braak,1991; Masliah et al., 2001; Selkoe,1991; Spires-Jones and Hyman, 2014)",
       "key": "55acd487426ab0bacb51a0ec10d53bef2372d8f6993b841410eccb2924fee75c69e4f12fb739428577a201d859bfcff85a0b640d4fdd2e3289bfe297603c5fd3",
-      "line": 83,
+      "line": 84,
       "relation": "association",
       "source": 117,
       "target": 123
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -164,12 +189,17 @@
       },
       "evidence": "Dementia is a debilitating condition frequent in ageing populations, and Alzheimer's Disease (AD) accounts for 70% of all dementia cases. AD is characterized by neuropathological hallmarks consisting of an accumulation of Amyloid beta peptide (Ab) in extracellular plaques, intracellular deposits of tau protein, neuronal loss and, more recently, a prominent synaptic loss was identified (Braak and Braak,1991; Masliah et al., 2001; Selkoe,1991; Spires-Jones and Hyman, 2014)",
       "key": "22996f1eb252ad9e93deaadca6088a578fdb8680cbb98546339e0c48ec1ce388349fd0412daa965ca402a0acfe30cb223ba78478fa55f49207f033c5de0da331",
-      "line": 84,
+      "line": 85,
       "relation": "positiveCorrelation",
       "source": 117,
       "target": 120
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -187,12 +217,17 @@
       },
       "evidence": "Dementia is a debilitating condition frequent in ageing populations, and Alzheimer's Disease (AD) accounts for 70% of all dementia cases. AD is characterized by neuropathological hallmarks consisting of an accumulation of Amyloid beta peptide (Ab) in extracellular plaques, intracellular deposits of tau protein, neuronal loss and, more recently, a prominent synaptic loss was identified (Braak and Braak,1991; Masliah et al., 2001; Selkoe,1991; Spires-Jones and Hyman, 2014)",
       "key": "25f5dec77f38590fd24335b73cf6d7799115b59af1bf735a6b21dd1cbf602056e1e69046206d00812f1b5a8dcfc7e2326110861cbc4f1e5879ac35f4c94bb893",
-      "line": 85,
+      "line": 86,
       "relation": "positiveCorrelation",
       "source": 117,
       "target": 107
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -210,12 +245,17 @@
       },
       "evidence": "Dementia is a debilitating condition frequent in ageing populations, and Alzheimer's Disease (AD) accounts for 70% of all dementia cases. AD is characterized by neuropathological hallmarks consisting of an accumulation of Amyloid beta peptide (Ab) in extracellular plaques, intracellular deposits of tau protein, neuronal loss and, more recently, a prominent synaptic loss was identified (Braak and Braak,1991; Masliah et al., 2001; Selkoe,1991; Spires-Jones and Hyman, 2014)",
       "key": "246845fdd37c00fc31b824cc9db2d6376551f510a0e6d261e5b125b85db48417a5cc1a656811e0c631213ccd761c2e6091b255a014862b8d1d902cf102d40e15",
-      "line": 86,
+      "line": 87,
       "relation": "positiveCorrelation",
       "source": 117,
       "target": 48
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -233,13 +273,16 @@
       },
       "evidence": "Dementia is a debilitating condition frequent in ageing populations, and Alzheimer's Disease (AD) accounts for 70% of all dementia cases. AD is characterized by neuropathological hallmarks consisting of an accumulation of Amyloid beta peptide (Ab) in extracellular plaques, intracellular deposits of tau protein, neuronal loss and, more recently, a prominent synaptic loss was identified (Braak and Braak,1991; Masliah et al., 2001; Selkoe,1991; Spires-Jones and Hyman, 2014)",
       "key": "2a629c2db5abce8b885b1f5b6e2d669d252845836eaf8bb19c88a3f7a2f74b9f3ed088836d00d79f801c53d14fac43fecc64963e920b7713367a0ea3e3e6e394",
-      "line": 87,
+      "line": 88,
       "relation": "negativeCorrelation",
       "source": 117,
       "target": 12
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "MeSHAnatomy": {
           "Brain": true
         }
@@ -261,13 +304,16 @@
       },
       "evidence": "In addition, anatomical studies in AD patients showed a massive loss of brain white matter and a specific reduction of cholinergic neurons of the basal forebrain (Auld et al., 2002; Bowen et al., 1976; Coyle et al., 1983; Kim et al., 2013; Whitehouse et al., 1981, 1982)",
       "key": "101090643948ea48efc3c35ec5473aafe7f1c0dec115336e50fcc872ad00628b3e4a20edaa0fb2d27efc015ef989fd9f7a32fb7afbdef59adc64e35b95fb5805",
-      "line": 94,
+      "line": 97,
       "relation": "negativeCorrelation",
       "source": 117,
       "target": 31
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "MeSHAnatomy": {
           "Basal Forebrain": true
         }
@@ -289,13 +335,16 @@
       },
       "evidence": "In addition, anatomical studies in AD patients showed a massive loss of brain white matter and a specific reduction of cholinergic neurons of the basal forebrain (Auld et al., 2002; Bowen et al., 1976; Coyle et al., 1983; Kim et al., 2013; Whitehouse et al., 1981, 1982)",
       "key": "9a6152b2f2cff70b6c28f5ece7516e6e1e0aeca8029c08416ac057689a00887953759c47f219507f89a158046167b65a6c21d91e77a046d5fc6b067b6a6f95a8",
-      "line": 96,
+      "line": 101,
       "relation": "negativeCorrelation",
       "source": 117,
       "target": 24
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Cerebral Cortex": true
         }
@@ -317,13 +366,16 @@
       },
       "evidence": "Binding studies performed with the use of [3H]-nicotine and [3H]-ACh showed a significant reduction in nicotine and ACh binding sites in cerebral cortex of patients suffering from AD, demonstrating a decrease of both nAChR and mAChR populations (Gotti et al., 2006a; Paterson and Nordberg, 2000; Perry et al., 1981, 1985, 1987, 1988; Shimohama et al., 1986; Whitehouse et al., 1981, 1982, 1986)",
       "key": "345e397d2be6587205ae218c1759aabff5f58a555ad5c08e673457ba0fe1ea8d8bb413ade0f5e69626ab1f3cc80e17b613ba237588bfe432489fcf20c717a2df",
-      "line": 134,
+      "line": 151,
       "relation": "decreases",
       "source": 117,
       "target": 77
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Cerebral Cortex": true
         }
@@ -345,13 +397,16 @@
       },
       "evidence": "Binding studies performed with the use of [3H]-nicotine and [3H]-ACh showed a significant reduction in nicotine and ACh binding sites in cerebral cortex of patients suffering from AD, demonstrating a decrease of both nAChR and mAChR populations (Gotti et al., 2006a; Paterson and Nordberg, 2000; Perry et al., 1981, 1985, 1987, 1988; Shimohama et al., 1986; Whitehouse et al., 1981, 1982, 1986)",
       "key": "5af06b028439e86b2cb4f178721b886b3857e0e83b4b4e24f42011f4c386f4e5b78b80d6ebe9f60b1d3fe50d90787901bee8ff5b965f5a624b25e96119f7b914",
-      "line": 135,
+      "line": 152,
       "relation": "decreases",
       "source": 117,
       "target": 76
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Cerebral Cortex": true
         }
@@ -373,13 +428,16 @@
       },
       "evidence": "Binding studies performed with the use of [3H]-nicotine and [3H]-ACh showed a significant reduction in nicotine and ACh binding sites in cerebral cortex of patients suffering from AD, demonstrating a decrease of both nAChR and mAChR populations (Gotti et al., 2006a; Paterson and Nordberg, 2000; Perry et al., 1981, 1985, 1987, 1988; Shimohama et al., 1986; Whitehouse et al., 1981, 1982, 1986)",
       "key": "9a45e0948fd8512b1ef0304697713a0154bf3be65a2140ab1f48dbe6e93eea0ac33e7814b173f6fb5d8d2b44660d05c17c322ced67df53d39627f4f4bf455cc5",
-      "line": 136,
+      "line": 153,
       "relation": "decreases",
       "source": 117,
       "target": 79
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Cerebral Cortex": true
         }
@@ -401,13 +459,16 @@
       },
       "evidence": "Binding studies performed with the use of [3H]-nicotine and [3H]-ACh showed a significant reduction in nicotine and ACh binding sites in cerebral cortex of patients suffering from AD, demonstrating a decrease of both nAChR and mAChR populations (Gotti et al., 2006a; Paterson and Nordberg, 2000; Perry et al., 1981, 1985, 1987, 1988; Shimohama et al., 1986; Whitehouse et al., 1981, 1982, 1986)",
       "key": "82ceb98c663a3677c72be7ffef280fca2c63ce9827d01beb7dd98216cd19637159c03a30cf77d4ec343559a8bfd866cb413c21d38b6f0b42e8748d6f63a9a6e5",
-      "line": 137,
+      "line": 154,
       "relation": "decreases",
       "source": 117,
       "target": 78
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Cerebral Cortex": true
         }
@@ -429,13 +490,16 @@
       },
       "evidence": "Binding studies performed with the use of [3H]-nicotine and [3H]-ACh showed a significant reduction in nicotine and ACh binding sites in cerebral cortex of patients suffering from AD, demonstrating a decrease of both nAChR and mAChR populations (Gotti et al., 2006a; Paterson and Nordberg, 2000; Perry et al., 1981, 1985, 1987, 1988; Shimohama et al., 1986; Whitehouse et al., 1981, 1982, 1986)",
       "key": "3b5adaf4ba17518ba0df0c985119429f4210f6e903795be07fce8f969bdddb355b00b54414ef3af3f5a58e3d3d2180433f08087bea8bf44f60f089d863083407",
-      "line": 138,
+      "line": 155,
       "relation": "decreases",
       "source": 117,
       "target": 89
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Cerebral Cortex": true
         }
@@ -457,13 +521,16 @@
       },
       "evidence": "Binding studies performed with the use of [3H]-nicotine and [3H]-ACh showed a significant reduction in nicotine and ACh binding sites in cerebral cortex of patients suffering from AD, demonstrating a decrease of both nAChR and mAChR populations (Gotti et al., 2006a; Paterson and Nordberg, 2000; Perry et al., 1981, 1985, 1987, 1988; Shimohama et al., 1986; Whitehouse et al., 1981, 1982, 1986)",
       "key": "8769f68e6e97d46051d559ea7e4136a4997a5bba75c42183880ad07332bce27f250e8ba998f3a3e7eb6ad098d6df30b57be9a6fc124038f4711bb66113802283",
-      "line": 139,
+      "line": 156,
       "relation": "decreases",
       "source": 117,
       "target": 88
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Brain": true
         }
@@ -485,7 +552,7 @@
       },
       "evidence": "In addition to nAChRs and mAChRs, the enzyme choline acetyltransferase (ChAT), involved in ACh production, is also affected in AD. The activity of this ChAT enzyme, and consequently the synthesis of ACh, is decreased in AD brains",
       "key": "76b76b8e01215f098913104e245c933c4fae025a3a6aee75f4bf64d161e1b46c281156f39bcb1eec633ad82118b9976fe76026edd918121d43767769aaaaa470",
-      "line": 148,
+      "line": 167,
       "object": {
         "modifier": "Activity"
       },
@@ -495,6 +562,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Brain": true
         }
@@ -516,13 +586,16 @@
       },
       "evidence": "In addition to nAChRs and mAChRs, the enzyme choline acetyltransferase (ChAT), involved in ACh production, is also affected in AD. The activity of this ChAT enzyme, and consequently the synthesis of ACh, is decreased in AD brains",
       "key": "9f5284cbcf4c4bc0b5da63859d7624927d0987c9d5cca0f13c7b9d4825ad8bb5aacf2bde8fef18f0dd5874b9532c728c65cc101bbb2aba6817544e3b1a93db37",
-      "line": 149,
+      "line": 168,
       "relation": "decreases",
       "source": 117,
       "target": 6
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -544,13 +617,16 @@
       },
       "evidence": "With the progression of the disease the amount of Abeta increases, it starts to accumulate, and becomes toxic for the neurons (Hernandez et al., 2010)",
       "key": "f99ef920403716bde6b0601b1a7bd181bd277811f9f30f452a2b5f465b0285874dc1a57609bfe445609756d0d3ee678701c631e4591e61f1f63a97fab82631cf",
-      "line": 531,
+      "line": 673,
       "relation": "positiveCorrelation",
       "source": 117,
       "target": 3
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -572,12 +648,17 @@
       },
       "evidence": "With the progression of the disease the amount of Abeta increases, it starts to accumulate, and becomes toxic for the neurons (Hernandez et al., 2010)",
       "key": "e782dcad229a94e6d0bddfe0a7598a5c9bac6f4f11024ad3e3c86737ad1741118b67ba20e21b2ba1668bdcddd021c83225ee7d2065e315662594463fe37acbc9",
-      "line": 532,
+      "line": 674,
       "relation": "positiveCorrelation",
       "source": 117,
       "target": 21
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -595,12 +676,17 @@
       },
       "evidence": "Wang et al. showed that the association between FLNA and the alpha7 subunit is elevated in AD samples compared to age matched controls",
       "key": "275f16ffc8a9a2ebde11babb37576af31f8c51a5cb6aea7d5ae038a3de00f25b04c7c43eecc4f9be5d1c0579106d1cd086b9c1a6944bd1d3658e839a49f2fbea",
-      "line": 705,
+      "line": 902,
       "relation": "positiveCorrelation",
       "source": 117,
       "target": 83
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -618,13 +704,16 @@
       },
       "evidence": "Dementia is a debilitating condition frequent in ageing populations, and Alzheimer's Disease (AD) accounts for 70% of all dementia cases. AD is characterized by neuropathological hallmarks consisting of an accumulation of Amyloid beta peptide (Ab) in extracellular plaques, intracellular deposits of tau protein, neuronal loss and, more recently, a prominent synaptic loss was identified (Braak and Braak,1991; Masliah et al., 2001; Selkoe,1991; Spires-Jones and Hyman, 2014)",
       "key": "09e7a139109ee79e7fcca6298600897e4043bc967bdc23c66d71755f005e73263f018b096f87e334d2ea3acc4200bc391b3bcd102f7cee68a4917fd30cf873c4",
-      "line": 84,
+      "line": 85,
       "relation": "positiveCorrelation",
       "source": 120,
       "target": 117
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -646,12 +735,17 @@
       },
       "evidence": "They showed that alpha7 subunits co-localize with Abeta1-42 in senile plaques of brain slices obtained from patients that suffered from sporadic AD",
       "key": "79ace0a09551975b01b035156255554239726679bacbc326f4e4ebf2522d8a80f0be0442874c3c3fa4d56f8c3103249fb2dc124e0bcf7af399db834ef91388a8",
-      "line": 277,
+      "line": 341,
       "relation": "association",
       "source": 120,
       "target": 66
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -669,12 +763,17 @@
       },
       "evidence": "Dementia is a debilitating condition frequent in ageing populations, and Alzheimer's Disease (AD) accounts for 70% of all dementia cases. AD is characterized by neuropathological hallmarks consisting of an accumulation of Amyloid beta peptide (Ab) in extracellular plaques, intracellular deposits of tau protein, neuronal loss and, more recently, a prominent synaptic loss was identified (Braak and Braak,1991; Masliah et al., 2001; Selkoe,1991; Spires-Jones and Hyman, 2014)",
       "key": "e17daa3943838c2fb68d95fc174f95e34a55c50acf7ce0129f7eef16f4a03b84d7fd799f2a907904e1f6c720f74785f7fb9ffd371be90ffad897edd1702e1ee6",
-      "line": 85,
+      "line": 86,
       "relation": "positiveCorrelation",
       "source": 107,
       "target": 117
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -692,12 +791,17 @@
       },
       "evidence": "Dementia is a debilitating condition frequent in ageing populations, and Alzheimer's Disease (AD) accounts for 70% of all dementia cases. AD is characterized by neuropathological hallmarks consisting of an accumulation of Amyloid beta peptide (Ab) in extracellular plaques, intracellular deposits of tau protein, neuronal loss and, more recently, a prominent synaptic loss was identified (Braak and Braak,1991; Masliah et al., 2001; Selkoe,1991; Spires-Jones and Hyman, 2014)",
       "key": "ffb546cb58f1c61b1ae267d4023532a6385f99ba2847e27511d63f28678f1d801c4198d74a797b4e6a5c8bd67301a7aa28f7045225d065c2303dd33b428ffad1",
-      "line": 86,
+      "line": 87,
       "relation": "positiveCorrelation",
       "source": 48,
       "target": 117
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -715,13 +819,16 @@
       },
       "evidence": "Dementia is a debilitating condition frequent in ageing populations, and Alzheimer's Disease (AD) accounts for 70% of all dementia cases. AD is characterized by neuropathological hallmarks consisting of an accumulation of Amyloid beta peptide (Ab) in extracellular plaques, intracellular deposits of tau protein, neuronal loss and, more recently, a prominent synaptic loss was identified (Braak and Braak,1991; Masliah et al., 2001; Selkoe,1991; Spires-Jones and Hyman, 2014)",
       "key": "9a666ed22b8577f0179cba3b2ca9e6a53c7f5f6e62fe06f0881f795b21dac1f72ab17f33ce18fe70b62e224137fb43be99a0a829ad7389545b5e29ba2c5c7ea3",
-      "line": 87,
+      "line": 88,
       "relation": "negativeCorrelation",
       "source": 12,
       "target": 117
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "MeSHAnatomy": {
           "Brain": true
         }
@@ -743,13 +850,16 @@
       },
       "evidence": "In addition, anatomical studies in AD patients showed a massive loss of brain white matter and a specific reduction of cholinergic neurons of the basal forebrain (Auld et al., 2002; Bowen et al., 1976; Coyle et al., 1983; Kim et al., 2013; Whitehouse et al., 1981, 1982)",
       "key": "863c1d678c14915b44cde371f94ad5ce08784c397d9f8df3189f437ed2d989d43aeb848de095ce8406af79a6311355529528ca1ca39a694a348a869576c813a1",
-      "line": 94,
+      "line": 97,
       "relation": "negativeCorrelation",
       "source": 31,
       "target": 117
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "MeSHAnatomy": {
           "Basal Forebrain": true
         }
@@ -771,12 +881,17 @@
       },
       "evidence": "In addition, anatomical studies in AD patients showed a massive loss of brain white matter and a specific reduction of cholinergic neurons of the basal forebrain (Auld et al., 2002; Bowen et al., 1976; Coyle et al., 1983; Kim et al., 2013; Whitehouse et al., 1981, 1982)",
       "key": "85e6c0564fe3db5c9db7fef1d1c8409a6d72598d25321580c5c4c8cc5946dfdc5d281614c72a80f1f416f933f3857c38f9538edd04b9003fe56e7ed94e709f80",
-      "line": 96,
+      "line": 101,
       "relation": "negativeCorrelation",
       "source": 24,
       "target": 117
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -794,13 +909,16 @@
       },
       "evidence": "Several studies demonstrated the pivotal role of these cholinergic nuclei in cognitive functions",
       "key": "748ce208045eda2332be622c43861ac7fa4823ae335764fd5913ce35f2cbf7910667ed0c1af966eb53ecc845e70f505653661855b2f21596a4818ae5b3adc13d",
-      "line": 100,
+      "line": 107,
       "relation": "association",
       "source": 24,
       "target": 57
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -822,12 +940,17 @@
       },
       "evidence": "The role of the cholinergic system in cognition and the modification observed in neurodegenerative diseases, and in particular in the case of AD, led to the formulation of the “cholinergic hypothesis” of geriatric disorders (Bartus et al., 1982; Contestabile, 2011), according to which the reduction in cholinergic innervation is responsible for the cognitive decline observed in AD patients",
       "key": "c2a883a0a3faf8b20d3c818cea2b53d57f3dadccfcb4e3b9ddc2442774266a121742cf55ce6c36455e6e93d22505fdfae2a9f7b873a287b716ca3c4d02937e2d",
-      "line": 166,
+      "line": 189,
       "relation": "increases",
       "source": 24,
       "target": 57
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -845,12 +968,17 @@
       },
       "evidence": "The cholinergic system is also involved in attention processes (Muir et al., 1993; Sarter and Bruno, 1997; Wenk, 1997)",
       "key": "395015a6b9606f6ac4ff8136bfd0bbce3dd7a319d28ba455d66086fc9a1810d0bc2e67f2e3792b81fe24df2e9a4c99c6e8ecea73a73d03ed2b6216a11b9a89f0",
-      "line": 109,
+      "line": 120,
       "relation": "association",
       "source": 24,
       "target": 122
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -868,12 +996,17 @@
       },
       "evidence": "Several studies demonstrated the pivotal role of these cholinergic nuclei in cognitive functions",
       "key": "91ca60dd09384d9d9e7782054003f4184f67a68cbce1841596d6be4d5cd0a17a334d89e9bfba7aa31f70479a7b4d59d03d33fae7e2c093fa74a3ddc0a85f869f",
-      "line": 100,
+      "line": 107,
       "relation": "association",
       "source": 57,
       "target": 24
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -891,7 +1024,7 @@
       },
       "evidence": "Woolf (1998) proposed a model in which acetylcholine (ACh) release leads to the modulation of cortical circuitry that finally encodes for storage of long-term memory",
       "key": "c03497a9c84b57b6c620085b7f6d6f41e8af9b9ef93a508828f94c8c10a745ceeccf4993268efe795077695d9f88c4f8c0d4e47d71a1c515c6441ebd28dd4347",
-      "line": 105,
+      "line": 114,
       "relation": "regulates",
       "source": 6,
       "subject": {
@@ -910,6 +1043,11 @@
       "target": 45
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -927,7 +1065,7 @@
       },
       "evidence": "Aged beta2 null mutant mice have a thinner cortex compared to agematched wild-type controls (Zoli et al., 1999). This work should be pursued further as it indicates a “neurotrophic” action of beta2 receptor activation by endogenous ACh (Zanardi et al., 2007)",
       "key": "98cec85a7c830c0be38c2ad2a7d36becce0b78e98da396b25e6686d8d62586369a479890f768c1cf09bf38958f0a99c9f366fd7dc0ce3cc1494308109db86515",
-      "line": 262,
+      "line": 320,
       "object": {
         "modifier": "Activity"
       },
@@ -939,6 +1077,9 @@
       "annotations": {
         "Cell": {
           "oocyte": true
+        },
+        "Confidence": {
+          "High": true
         }
       },
       "citation": {
@@ -958,7 +1099,7 @@
       },
       "evidence": "A different set of experiments demonstrated that Abeta enhances ACh activation of the alpha4beta2 nAChRs expressed in oocytes, this first activation of the receptor was followed by its inhibition (Pym et al., 2005)",
       "key": "76179fa094ccb9e5200feba48201d824f8307987fa60c1ee707dd3e7b7582284e26f3a0acebe08df8fbca0e9e2888216bbe0cac10717b4f4dfec68422d99c26a",
-      "line": 374,
+      "line": 466,
       "object": {
         "modifier": "Activity"
       },
@@ -970,6 +1111,11 @@
       "target": 17
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -987,13 +1133,16 @@
       },
       "evidence": "The cholinergic system is also involved in attention processes (Muir et al., 1993; Sarter and Bruno, 1997; Wenk, 1997)",
       "key": "f5c923004bdf56c0748274c1f70e0bc7d8aa0f04bf545dd698df17cdf2087b46301fa6a595b2a7c80ccac366849c577aa8fa9b9edca952fe7cddbc33b4468caf",
-      "line": 109,
+      "line": 120,
       "relation": "association",
       "source": 122,
       "target": 24
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Prefrontal Cortex": true
         }
@@ -1015,7 +1164,7 @@
       },
       "evidence": "In a mouse model, the lack of ACh receptors in the prefrontal cortex (PFC) was demonstrated to be responsible for attention deficit, restored by the expression of the receptor in this area (Guillem et al., 2011)",
       "key": "48993f3832f8930e155c9a518426f7b0633888057172a5d18a6334d6d50929454b403c06abf533b3538b0d73d19a999ed406e79f34416dbf5ddfb3cc05ca9baf",
-      "line": 115,
+      "line": 128,
       "relation": "increases",
       "source": 27,
       "target": 122
@@ -1033,6 +1182,11 @@
       "target": 89
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -1050,12 +1204,17 @@
       },
       "evidence": "The neurotransmitter ACh binds to two families of receptors, nicotinic acetylcholine receptors (nAChRs) and muscarinic acetylcholine receptors (mAChRs). Both families of receptors regulate the cognitive processes mentioned above (Ghoneim and Mewaldt, 1977; Petersen, 1977; Sarter and Paolone, 2011), and are both affected in AD",
       "key": "9f57c755a7bac20a9fc80e701a9cbab7dd876e3673ee7297a65139aa81efc9d70cf165984ed8a28477d80be32e65724b97d01d46024ccdb6f70fb50e662e01bd",
-      "line": 124,
+      "line": 139,
       "relation": "regulates",
       "source": 89,
       "target": 57
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -1073,7 +1232,7 @@
       },
       "evidence": "Nicotinic receptors are transmembrane pentameric proteins that belong to the “cys-loop” superfamily of ligand-gated ion channels together with GABAA, GABAC, glycine and 5- hydroxytryptamine (5-HT3) ionotropic receptors (Changeux and Edelstein, 1998; Le Novère and Changeux, 1995)",
       "key": "2af6c48bcea12fff4469615cf943dc3e91ccae024e780876c8682596aa43ccb352735c649254386635410602de63bba608efaf14835d0731e6cec2952b8fdd0b",
-      "line": 173,
+      "line": 198,
       "relation": "isA",
       "source": 89,
       "target": 26
@@ -1145,6 +1304,11 @@
       "target": 105
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -1162,12 +1326,17 @@
       },
       "evidence": "The five subunits that compose the receptor are assembled around a central hydrophilic pore that mediates the flow of the cations K+, Na+ and Ca++. In the human nervous system, there are eight alpha subunits (alpha2-alpha7, alpha9, alpha10) and three beta subunits (beta2-beta4) that assemble in different combinations to generate a variety of nAChR subtypes with distinct electrophysiological properties and brain localization (Albuquerque et al., 2009; Gotti et al., 2006b, 2007, 2009)",
       "key": "1bec10c6b6ff7d205df17766c28de0054387f58d5bfb2e3c0620988f104cfcb736d2e7819f4c1c214187af51fea556a94f7c53b91220b865e3b9873b53d55417",
-      "line": 185,
+      "line": 212,
       "relation": "regulates",
       "source": 89,
       "target": 51
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -1185,12 +1354,17 @@
       },
       "evidence": "The five subunits that compose the receptor are assembled around a central hydrophilic pore that mediates the flow of the cations K+, Na+ and Ca++. In the human nervous system, there are eight alpha subunits (alpha2-alpha7, alpha9, alpha10) and three beta subunits (beta2-beta4) that assemble in different combinations to generate a variety of nAChR subtypes with distinct electrophysiological properties and brain localization (Albuquerque et al., 2009; Gotti et al., 2006b, 2007, 2009)",
       "key": "96dc7d0cbc1b60b400281ddfdf7852e01ad8d990904b85a594d85e27e60e2b6be5ef9bfff935c9073d8e25e0cedcb0c898da4d7cf76ea3fa70f9fe8ba3214bed",
-      "line": 186,
+      "line": 213,
       "relation": "regulates",
       "source": 89,
       "target": 54
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -1208,7 +1382,7 @@
       },
       "evidence": "The five subunits that compose the receptor are assembled around a central hydrophilic pore that mediates the flow of the cations K+, Na+ and Ca++. In the human nervous system, there are eight alpha subunits (alpha2-alpha7, alpha9, alpha10) and three beta subunits (beta2-beta4) that assemble in different combinations to generate a variety of nAChR subtypes with distinct electrophysiological properties and brain localization (Albuquerque et al., 2009; Gotti et al., 2006b, 2007, 2009)",
       "key": "2eb38ad70fa7dd88ae7b8c0d25fdefbd75c2ec656aa734ed5a0530456b431ca5d6e171ed52d25c4d1b2bb8e54de159f2fd0c8edb2e42902b0f9393de457c167d",
-      "line": 187,
+      "line": 214,
       "relation": "regulates",
       "source": 89,
       "target": 40
@@ -1218,6 +1392,9 @@
         "Cell": {
           "GABAergic neuron": true
         },
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Hippocampus": true
         }
@@ -1239,7 +1416,7 @@
       },
       "evidence": "They demonstrated that Abeta1-42 drives a reversible inhibition of nAChR-mediated currents in hippocampal GABAergic neurons recorded from rat slices. In these experimental conditions the most effective Abeta1-42 concentration was 500 nM, but inhibition was found also at the lower concentration of 100 nM",
       "key": "9286e3453979f88d7e05bc314aa8ca7254d3ccaf15a70f082128ca5ecbeefc1ad472ece95901f802590f68d1a20d34f1d0bffb7c1ec80618604f749d9b30489a",
-      "line": 345,
+      "line": 429,
       "relation": "increases",
       "source": 89,
       "subject": {
@@ -1249,6 +1426,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -1270,13 +1450,16 @@
       },
       "evidence": "These experiments confirmed that the level of expression of APP and the consequent synthesis of Ab were comparable between mouse lines, demonstrating that the difference in cognitive deficit and neuropathology were mediated exclusively by the nicotinic recept",
       "key": "a05b2b3f396f9c9b4bf87c768142c1d69c28c4a8bc85171408e331359e6021172bd65d281a4022bae46109ed4b157e70e371fa4d279b27f0392e9aabc3627430",
-      "line": 491,
+      "line": 620,
       "relation": "regulates",
       "source": 89,
       "target": 118
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -1298,7 +1481,7 @@
       },
       "evidence": "This kinase is sensitive to Ca++, whose levels are increased following nAChR activation (Oddo et al., 2005)",
       "key": "3a6a4d3ac231ad9f9674a06523949ce90db00f87d064f2f6b06611d0f9888a108745cfec6bef6e40775209b597d204cc92ad75e6bf06554f41d52d2600ec59bf",
-      "line": 614,
+      "line": 785,
       "relation": "increases",
       "source": 89,
       "subject": {
@@ -1319,6 +1502,11 @@
       "target": 88
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -1336,7 +1524,7 @@
       },
       "evidence": "The neurotransmitter ACh binds to two families of receptors, nicotinic acetylcholine receptors (nAChRs) and muscarinic acetylcholine receptors (mAChRs). Both families of receptors regulate the cognitive processes mentioned above (Ghoneim and Mewaldt, 1977; Petersen, 1977; Sarter and Paolone, 2011), and are both affected in AD",
       "key": "4f3e830cb89120f3180e82fe23f35ad5692f3c1047c574aef4c49ecfb20407b1425888d5c4055c8a34c42622748b591a06fad682f2b96849b779ff0defb4b241",
-      "line": 126,
+      "line": 141,
       "relation": "regulates",
       "source": 88,
       "target": 57
@@ -1354,6 +1542,11 @@
       "target": 89
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -1371,13 +1564,16 @@
       },
       "evidence": "Akt phosphorylation mediates the downstream activation of an antiapoptotic pathway, which is also activated by nicotine treatment (Kihara et al., 2001)",
       "key": "8ecf04aa4c0c7e31c976f1b66a225338b9b3fd982674cbdf217f286300ebeae3e9b8ca3697fa6cc4c0dcece1f3174c43adad0b27fe398dad86c4fde42550c07c",
-      "line": 424,
+      "line": 534,
       "relation": "decreases",
       "source": 9,
       "target": 39
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -1399,13 +1595,16 @@
       },
       "evidence": "The analysis of the Abeta fraction reduced by nicotine showed that mainly insoluble Ab1-40/42 was affected while there was no change in soluble Abeta (Nordberg et al., 2002)",
       "key": "e718173c69218f4c024474dfd8efc8a900d24f91033c96316c03d7f462295e4c8418bf6b2e97d58bdf86f2394437eae2f30ca5a4f629408edde781510b13f357",
-      "line": 559,
+      "line": 711,
       "relation": "decreases",
       "source": 9,
       "target": 2
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -1427,13 +1626,16 @@
       },
       "evidence": "The short-term treatment of 10 days showed a significant reduction in cortical insoluble Abeta1-40/42",
       "key": "889605dcb4cbed2bc21f361b4a0d4931b8524428fe138fbbd7675764e974e6e32aca835728de9c8e360c60bd374f06cb1a3ff58ec0b8fdb33666889d4471ec63",
-      "line": 564,
+      "line": 718,
       "relation": "decreases",
       "source": 9,
       "target": 2
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -1455,13 +1657,16 @@
       },
       "evidence": "The analysis of the Abeta fraction reduced by nicotine showed that mainly insoluble Ab1-40/42 was affected while there was no change in soluble Abeta (Nordberg et al., 2002)",
       "key": "9b7fd346e8d0c6a32a1311db0ffd33243923cccd7b367d9c45862109bdf5f9019e69bb850f2c0e05010d9e38914d1b7ab244f2ffdadf376c44c854778b40cabc",
-      "line": 560,
+      "line": 712,
       "relation": "decreases",
       "source": 9,
       "target": 1
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -1483,13 +1688,16 @@
       },
       "evidence": "The short-term treatment of 10 days showed a significant reduction in cortical insoluble Abeta1-40/42",
       "key": "f6f5339aaa6ab3756c3d25137932f9704266f87f1663ae4a14dbc10b4350e1e321877bbff55f215a1092350e09c279b1f72daa6dc278bcbef7632a4dd41cb22f",
-      "line": 565,
+      "line": 719,
       "relation": "decreases",
       "source": 9,
       "target": 1
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Blood Vessels": true
         },
@@ -1514,13 +1722,16 @@
       },
       "evidence": "Long-term nicotine administration elicited a reduction in Abeta deposits in blood vessel",
       "key": "2b675c6ad8152f29b712153448fa870e61333a449e8d6f5330bee0bae6098fa91ed435a194a8702a0e7a5a0cc2c9e966538ba32cde60b71a0c76ae11241cefb7",
-      "line": 569,
+      "line": 725,
       "relation": "decreases",
       "source": 9,
       "target": 3
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -1542,13 +1753,16 @@
       },
       "evidence": "APPSwe mice at 14.5 months have fewer alphaBungarotoxin binding sites, while in transgenic mice treated with nicotine the number of alphaBungarotoxin binding sites was recovered and comparable to non transgenic age-matched control mice, suggesting that there was an increase in the population of alpha7 nAChRs (Hellstrom-Lindahl et al., 2004)",
       "key": "70fa506534938df6309c008eda796c2de46bdd6d5cf990872fc615d929d74733f69251e050e3b771860d83ff4ddfef54c31a67fd24ca7f2bace8e501f60b4743",
-      "line": 577,
+      "line": 734,
       "relation": "increases",
       "source": 9,
       "target": 32
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -1570,7 +1784,7 @@
       },
       "evidence": "The explanation proposed by the authors is that alpha7 nAChR activation through nicotine binding could promote survival pathways and recover the synaptic damage caused by Abeta (Inestrosa et al., 2013)",
       "key": "0ac1cd66916f5a94db15774f9448c2706d0b2a30b770c23be451edbd28167a110085c1478582af509fc1c5582184b16b5351df9d13cd0fea3a0c235b291b634a",
-      "line": 596,
+      "line": 761,
       "object": {
         "modifier": "Activity"
       },
@@ -1580,6 +1794,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -1601,13 +1818,16 @@
       },
       "evidence": "Nicotine treatment improved the memory deficit, highlighted with the Morris water maze task. Surprisingly, this study showed a dose dependent increase of alpha7 nAChR, a result that is in contrast with the literature (Oddo et al., 2005)",
       "key": "a94f76d68a70a2ee05c73dd9009496affa72d123fa9ab8fa9677db6c4c4ed8ca96122d8e6be1be8e199ab700827756568b0a0625574998fe1db8825541544724",
-      "line": 627,
+      "line": 802,
       "relation": "increases",
       "source": 9,
       "target": 32
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -1629,13 +1849,16 @@
       },
       "evidence": "Mice aged 6 months were treated for one month with nicotine injections, which led to an improvement in working and episodic memory compared to non-treated transgenic mice",
       "key": "95714c11ebf8983a41e3052eeafa1463751c839e7e8f7e31d50a23455a163a8b2de713df077e34a1a25320ec03c0eac447afbac95eefa0d0f1460362db4a2f6d",
-      "line": 583,
+      "line": 742,
       "relation": "increases",
       "source": 9,
       "target": 119
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -1657,13 +1880,16 @@
       },
       "evidence": "Like the young mice, they also displayed an improvement in spatial memory, demonstrating that nicotine enhances memory in both young and old mice",
       "key": "b64f1f336ac33acd4e816f86cd6c9de5605909571bf52eb0ec31e9fb2b781f0c9fdc7db6031f5191fb4620a33eb454c4a8b9610a378a0f5a4529f79c66231fad",
-      "line": 587,
+      "line": 748,
       "relation": "increases",
       "source": 9,
       "target": 121
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -1685,13 +1911,16 @@
       },
       "evidence": "The amount of Abeta was quantified, and following nicotine injections a reduction in Abeta, particularly in the oligomeric form, was found",
       "key": "12902f79b0590253ce5490acddceb65852966a3928d8fafa8827dc4e9fef0648b89e48523fd4dff0eb7a2fa5cd2da6bb6e7657cf899da87f735d85e7f02c929c",
-      "line": 591,
+      "line": 754,
       "relation": "decreases",
       "source": 9,
       "target": 22
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "CA1 Region, Hippocampal": true,
           "Pyramidal Cells": true
@@ -1717,13 +1946,16 @@
       },
       "evidence": "The long-term nicotine treatment caused faster tau aggregation in CA1 pyramidal neurons",
       "key": "03fb49ba672e5fe4d37a83934695a569d23bc189d9d3797c98c80845b1dd130167da90cef7685945e25270ec1b320e70c7b33f777312e0bd12c2a01e41fcab3d",
-      "line": 603,
+      "line": 770,
       "relation": "increases",
       "source": 9,
       "target": 16
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -1745,13 +1977,16 @@
       },
       "evidence": "The possible mechanism by which nicotine enhances the aggregation of tau is through the activation of p38-MAP kinase",
       "key": "a487e813a59e7cfa4d33ec839bad2188500ba461e3598a63ee0ff01da6e624e4960b6888f36d77e4daf6375a39508570709fc792ac308d363f5d9a5d91e21fa7",
-      "line": 608,
+      "line": 777,
       "relation": "increases",
       "source": 9,
       "target": 16
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -1773,13 +2008,16 @@
       },
       "evidence": "The possible mechanism by which nicotine enhances the aggregation of tau is through the activation of p38-MAP kinase",
       "key": "10c4e42d004c8e3b4c3348ed3f20a93b03589d006b675cea95dcfb13ba55e9416c042c4594329e652107863d6dccf6fb16b56ef33305489faf69a837ba1356f2",
-      "line": 609,
+      "line": 778,
       "relation": "increases",
       "source": 9,
       "target": 49
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -1801,13 +2039,16 @@
       },
       "evidence": "Even though nicotine showed a positive effect reducing plaque load (Hellstrom-Lindahl et al., 2004; Inestrosa et al., 2013; Nordberg et al., 2002), its use in AD treatment should be limited due to its toxic effect on tau pathology",
       "key": "3ffb5329a2b3ea3c3d69dd41eb7fafe99b1a58b219330c42d13e34172b1f317f7034b3c3d98c5f4d2421c482069aff166bdb43ffe18e2678097f38f5ae20a3a1",
-      "line": 620,
+      "line": 793,
       "relation": "decreases",
       "source": 9,
       "target": 120
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -1829,13 +2070,16 @@
       },
       "evidence": "Nicotine treatment improved the memory deficit, highlighted with the Morris water maze task. Surprisingly, this study showed a dose dependent increase of alpha7 nAChR, a result that is in contrast with the literature (Oddo et al., 2005)",
       "key": "438ff33f2cbfc20c0d64c0e943593d7c7aedad42c32af62bd42902a268d6126b44b1d3a95b16cab7aabeeb3e31f4b6322399d7ef628717806a5dac1205cd83e8",
-      "line": 626,
+      "line": 801,
       "relation": "increases",
       "source": 9,
       "target": 58
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -1857,7 +2101,7 @@
       },
       "evidence": "Wild-type mice treated with nicotine or with SSR180711, another partial agonist of alpha7 (Biton et al., 2006), showed increased LTP, while the transgenic AD model APPSwe/PS1DE9 showed no effect on LTP following SSR180711 treatment",
       "key": "0765c713bb9ecd8557549abba02ca1a62512baebe2dbb737ffa5f7621a83e18889fc1a1f1ab795bdcc45743c3a65e379f7ccf546e070a1a93cd601d7031f0636",
-      "line": 648,
+      "line": 831,
       "relation": "increases",
       "source": 9,
       "target": 46
@@ -1876,6 +2120,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Brain": true
         }
@@ -1897,7 +2144,7 @@
       },
       "evidence": "In addition to nAChRs and mAChRs, the enzyme choline acetyltransferase (ChAT), involved in ACh production, is also affected in AD. The activity of this ChAT enzyme, and consequently the synthesis of ACh, is decreased in AD brains",
       "key": "f240d567b312bf1df93cd3974ec35b45b834bd7df3e4464fd9290e8418c5286c51d359a7238687374bf2c39f836173381893024609291073edf58f3c0ae18b6f",
-      "line": 147,
+      "line": 166,
       "relation": "increases",
       "source": 94,
       "subject": {
@@ -1906,6 +2153,11 @@
       "target": 6
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -1923,7 +2175,7 @@
       },
       "evidence": "In addition, several authors observed a reduction in the activity of acetylcholinesterase (AChE), the enzyme that metabolises ACh after its release in the synaptic cleft (Auld et al., 2002; Bowen et al., 1976; Coyle et al., 1983; Davies and Maloney, 1976; Perry et al., 1978)",
       "key": "2fb7c7a758fc8f2b65bb76528f13e7bbd5d56abb3f498da5498eb527d425862965b9bf9940a5ecc96415acd70f3f737df454895017d9e47a7016d1279d0d0420",
-      "line": 157,
+      "line": 178,
       "relation": "increases",
       "source": 91,
       "subject": {
@@ -1956,6 +2208,11 @@
       "target": 30
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -1973,12 +2230,17 @@
       },
       "evidence": "The subtype alpha4beta2 is characterized by lower calcium ion permeability and a slow desensitization rate compared to the homopentameric alpha7 nAChR (Quick and Lester, 2002)",
       "key": "d16c9a786f647d69af3935cf205f7cfd20e51c910d316d89d37a29191c1a8ff5d5359172143fbe6d03fb616754973461bc284f5202a660522252051361a3b5ad",
-      "line": 234,
+      "line": 282,
       "relation": "negativeCorrelation",
       "source": 40,
       "target": 17
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -1996,7 +2258,7 @@
       },
       "evidence": "The subtype alpha4beta2 is characterized by lower calcium ion permeability and a slow desensitization rate compared to the homopentameric alpha7 nAChR (Quick and Lester, 2002)",
       "key": "e6c27107fc3cef3875625362bfba4ade1a11583635f8dcd0a82ad0f6a852807719a0a1f7ad3a28da6cf69edebfc01c394a7f3fbed43f14ac98576057ab389576",
-      "line": 235,
+      "line": 283,
       "relation": "positiveCorrelation",
       "source": 40,
       "target": 32
@@ -2014,6 +2276,11 @@
       "target": 101
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -2031,7 +2298,7 @@
       },
       "evidence": "Later it was shown that Abeta is able to activate also beta2*-nAChRs (beta2 subunit-containing nAChRs)",
       "key": "e87db43f054b40c191e711472a92ebdace67961f9fb9f0a8e57d8e29203e4b0da4dcd59d7b61593bb6f5e5a95ad5ecb05bb9a37584bb2d3b0d19053a64f76062",
-      "line": 225,
+      "line": 269,
       "object": {
         "modifier": "Activity"
       },
@@ -2040,6 +2307,11 @@
       "target": 23
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -2057,7 +2329,7 @@
       },
       "evidence": "This class of receptors seems to be particularly sensitive to Abeta-induced toxicity (Khiroug et al., 2002; Liu et al.,2009, 2012)",
       "key": "a205d3214d99e324850f30dcee36dd3bb554cc0064fcce2854507333c82cade50c03d840b0fb2e872a02e2e35f87ae5b31e6d11a797122ee7c6d15bf05063d51",
-      "line": 245,
+      "line": 297,
       "relation": "negativeCorrelation",
       "source": 3,
       "subject": {
@@ -2066,6 +2338,11 @@
       "target": 18
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -2083,7 +2360,7 @@
       },
       "evidence": "Modulation of nAChRs by Abeta was also found in ex vivo studies: Pettit and colleagues (2001) used rat hippocampal slices to show that Abeta1-42 incubation is able to reduce postsynaptic currents and open probability of both alpha7 and non-alpha7 nAChRs subtypes, demonstrating an interaction between Abeta and other nAChR subunits",
       "key": "dd31041a4577cf14f602fe3775c0f7b0da9aaa5f1264a88460883e2004443069b137503df654819b04761a621f58e601329b56075af8c02abc00c6413760ab3d",
-      "line": 318,
+      "line": 394,
       "object": {
         "modifier": "Activity"
       },
@@ -2092,6 +2369,11 @@
       "target": 89
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -2109,7 +2391,7 @@
       },
       "evidence": "It was then postulated that Abeta-nAChR interaction has a physiological role in neuronal homeostasis that is disrupted when Abeta concentrations increase in a pathological context, leading to receptor inhibition and possible cellular toxicity (Dineley et al., 2001; Parri et al., 2011)",
       "key": "ea9d5d5bc16d7cffc08818a8dd1918b700e4fbf8921a8ebac0875232bd17fc5075c0d5b7e973f091a51bdfa882833d943d5d23173382249937ecf1b3be3f3c1c",
-      "line": 464,
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       "object": {
         "modifier": "Activity"
       },
@@ -2121,6 +2403,9 @@
       "annotations": {
         "Cell": {
           "oocyte": true
+        },
+        "Confidence": {
+          "High": true
         }
       },
       "citation": {
@@ -2140,7 +2425,7 @@
       },
       "evidence": "A different set of experiments demonstrated that Abeta enhances ACh activation of the alpha4beta2 nAChRs expressed in oocytes, this first activation of the receptor was followed by its inhibition (Pym et al., 2005)",
       "key": "bc48c08c720c28df01d647af999d833c4729d16389ccda397dd0ed4c1ceb2995544ed54e27109bf410c06fb70e1c1172e33ce9e3df801ebb9f103b258a1eb021",
-      "line": 373,
+      "line": 465,
       "object": {
         "modifier": "Activity"
       },
@@ -2149,6 +2434,11 @@
       "target": 6
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -2166,7 +2456,7 @@
       },
       "evidence": "However, alpha7 nAChR activation was observed in X. laevis oocytes when a range of Abeta concentration spanning from 1 to 100 pM was applied (Dineley et al., 2002)",
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       "object": {
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@@ -2175,6 +2465,11 @@
       "target": 32
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -2192,7 +2487,7 @@
       },
       "evidence": "In this system enhancement of Akt phosphorylation and activation of ERK pathway was observed following alpha7 agonist treatment, suggesting that Abeta inhibits the neuroprotective effect of alpha7 nAChR activation (Zhi et al., 2014)",
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       "object": {
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       },
@@ -2202,6 +2497,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Hippocampus": true
         }
@@ -2223,12 +2521,17 @@
       },
       "evidence": "An in vivo Abeta infusion in mice was able to enhance hippocampal dependent memory, highlighted with memory tasks such as the Morris water maze and contextual fear conditioning, which are both hippocampus dependent behavioural tasks (Puzzo et al.,2008)",
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+      "line": 559,
       "relation": "increases",
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       "target": 58
     },
     {
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+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -2246,13 +2549,16 @@
       },
       "evidence": "It was then postulated that Abeta-nAChR interaction has a physiological role in neuronal homeostasis that is disrupted when Abeta concentrations increase in a pathological context, leading to receptor inhibition and possible cellular toxicity (Dineley et al., 2001; Parri et al., 2011)",
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+      "line": 588,
       "relation": "decreases",
       "source": 3,
       "target": 47
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -2274,13 +2580,16 @@
       },
       "evidence": "With the progression of the disease the amount of Abeta increases, it starts to accumulate, and becomes toxic for the neurons (Hernandez et al., 2010)",
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+      "line": 673,
       "relation": "positiveCorrelation",
       "source": 3,
       "target": 117
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -2302,7 +2611,7 @@
       },
       "evidence": "The explanation proposed by the authors is that alpha7 nAChR activation through nicotine binding could promote survival pathways and recover the synaptic damage caused by Abeta (Inestrosa et al., 2013)",
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       "relation": "decreases",
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       "target": 12
@@ -2320,6 +2629,14 @@
       "target": 103
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -2337,12 +2654,17 @@
       },
       "evidence": "The alpha7 homomeric receptor demonstrates a wide-spread localization in the brain and is characterized by a high calcium ion permeability and a fast desensitization rate (Dani and Bertrand, 2007; Quick and Lester, 2002)",
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+      "line": 229,
       "relation": "increases",
       "source": 32,
       "target": 40
     },
     {
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+        "Confidence": {
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+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -2360,13 +2682,16 @@
       },
       "evidence": "The subtype alpha4beta2 is characterized by lower calcium ion permeability and a slow desensitization rate compared to the homopentameric alpha7 nAChR (Quick and Lester, 2002)",
       "key": "113c7c60951316600af3af6049650353f1f2ab87572d2179a7072890ce31cec4a955216342ec893d8c3bd63ca69fe6ff1dde324341bc8e07acbd8b24a96b84c5",
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+      "line": 283,
       "relation": "positiveCorrelation",
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       "target": 40
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "MeSHAnatomy": {
           "Presynaptic Terminals": true
         }
@@ -2388,7 +2713,7 @@
       },
       "evidence": "alpha7 nAChR on presynaptic terminals mediate release of others neurotransmitters (Wonnacott et al., 2006), while a postsynaptic or somatic localization elicits important changes in intracellular Ca++ concentration, that can activate second messenger pathways mediating cellular processes such as neuronal survival and gene expression (Berg and Conroy, 2002; Messi et al., 1997; Morley and Happe, 2000)",
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       "object": {
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@@ -2408,6 +2733,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "MeSHAnatomy": {
           "Cell Body": true
         }
@@ -2429,13 +2757,16 @@
       },
       "evidence": "alpha7 nAChR on presynaptic terminals mediate release of others neurotransmitters (Wonnacott et al., 2006), while a postsynaptic or somatic localization elicits important changes in intracellular Ca++ concentration, that can activate second messenger pathways mediating cellular processes such as neuronal survival and gene expression (Berg and Conroy, 2002; Messi et al., 1997; Morley and Happe, 2000)",
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       "relation": "regulates",
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       "target": 53
     },
     {
       "annotations": {
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+          "Medium": true
+        },
         "MeSHAnatomy": {
           "Cell Body": true
         }
@@ -2457,13 +2788,16 @@
       },
       "evidence": "alpha7 nAChR on presynaptic terminals mediate release of others neurotransmitters (Wonnacott et al., 2006), while a postsynaptic or somatic localization elicits important changes in intracellular Ca++ concentration, that can activate second messenger pathways mediating cellular processes such as neuronal survival and gene expression (Berg and Conroy, 2002; Messi et al., 1997; Morley and Happe, 2000)",
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       "relation": "regulates",
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       "target": 47
     },
     {
       "annotations": {
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         "MeSHAnatomy": {
           "Cell Body": true
         }
@@ -2485,12 +2819,17 @@
       },
       "evidence": "alpha7 nAChR on presynaptic terminals mediate release of others neurotransmitters (Wonnacott et al., 2006), while a postsynaptic or somatic localization elicits important changes in intracellular Ca++ concentration, that can activate second messenger pathways mediating cellular processes such as neuronal survival and gene expression (Berg and Conroy, 2002; Messi et al., 1997; Morley and Happe, 2000)",
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       "relation": "regulates",
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       "target": 43
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     {
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+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -2508,7 +2847,7 @@
       },
       "evidence": "Moreover, it was demonstrated that the activation of alpha7 nAChRs is important during development for the maturation of glutamatergic synapses (Lozada et al., 2012)",
       "key": "c0c95354b3ce3206a6624c4a5b00d66ee724d44b3083ec1864ead733bcd66fd6a64a24e90b55500a1373e8ffc01be420d8a90623c04f82c47fedbab5506c98e6",
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       "relation": "increases",
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       "subject": {
@@ -2517,6 +2856,11 @@
       "target": 11
     },
     {
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+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -2534,7 +2878,7 @@
       },
       "evidence": "In a different study, rat hippocampus and cortex were investigated and the activation of both alpha7 and non-alpha7 receptors was obtained with an enhancement of Ca++ influx into the neuron following the application of picomolar (pM) concentrations of Abeta1-42",
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@@ -2554,6 +2898,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -2575,7 +2922,7 @@
       },
       "evidence": "The incubation with S 24795 was able to normalize Ca++ influx mediated by both alpha7 nAChR and NMDAR (Wang et al., 2009, 2010)",
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@@ -2597,6 +2944,11 @@
       "target": 4
     },
     {
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+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -2613,14 +2965,20 @@
         "volume": "96"
       },
       "evidence": "This enhancement of synaptic plasticity and the activation of intracellular pathways are mediated by the activation of alpha7 nAChRs (Dineley et al., 2001; Parri et al., 2011; Plant et al., 2003; Puzzo et al., 2008)",
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       "relation": "increases",
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+      "subject": {
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       "target": 50
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -2642,12 +3000,17 @@
       },
       "evidence": "It was proposed that the positive action of PREGS is mediated by alpha7 nAChR",
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       "citation": {
         "authors": [
           "Lombardo S",
@@ -2664,13 +3027,21 @@
         "volume": "96"
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       "evidence": "This enhancement of synaptic plasticity and the activation of intracellular pathways are mediated by the activation of alpha7 nAChRs (Dineley et al., 2001; Parri et al., 2011; Plant et al., 2003; Puzzo et al., 2008)",
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       "target": 44
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     {
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+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -2688,12 +3059,17 @@
       },
       "evidence": "In this system enhancement of Akt phosphorylation and activation of ERK pathway was observed following alpha7 agonist treatment, suggesting that Abeta inhibits the neuroprotective effect of alpha7 nAChR activation (Zhi et al., 2014)",
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     {
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+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -2711,12 +3087,17 @@
       },
       "evidence": "In this system enhancement of Akt phosphorylation and activation of ERK pathway was observed following alpha7 agonist treatment, suggesting that Abeta inhibits the neuroprotective effect of alpha7 nAChR activation (Zhi et al., 2014)",
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     {
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+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -2734,13 +3115,16 @@
       },
       "evidence": "In this system enhancement of Akt phosphorylation and activation of ERK pathway was observed following alpha7 agonist treatment, suggesting that Abeta inhibits the neuroprotective effect of alpha7 nAChR activation (Zhi et al., 2014)",
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       "relation": "decreases",
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       "target": 59
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -2762,7 +3146,7 @@
       },
       "evidence": "Methyllycaconitine (MLA), an alpha7 nAChR antagonist, showed neuroprotective effect on mouse and rat primary cell culture (Martin et al., 2004)",
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@@ -2772,6 +3156,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -2793,7 +3180,7 @@
       },
       "evidence": "The explanation proposed by the authors is that alpha7 nAChR activation through nicotine binding could promote survival pathways and recover the synaptic damage caused by Abeta (Inestrosa et al., 2013)",
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       "subject": {
@@ -2803,6 +3190,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -2824,7 +3214,7 @@
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       "evidence": "The explanation proposed by the authors is that alpha7 nAChR activation through nicotine binding could promote survival pathways and recover the synaptic damage caused by Abeta (Inestrosa et al., 2013)",
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       "subject": {
@@ -2834,6 +3224,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -2855,7 +3248,7 @@
       },
       "evidence": "It was proposed that the positive action of PREGS is mediated by alpha7 nAChR",
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@@ -2865,6 +3258,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -2886,13 +3282,16 @@
       },
       "evidence": "It was proposed that the positive action of PREGS is mediated by alpha7 nAChR",
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       "target": 57
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     {
       "annotations": {
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+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -2914,13 +3313,16 @@
       },
       "evidence": "It was proposed that the positive action of PREGS is mediated by alpha7 nAChR",
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+      "line": 850,
       "relation": "increases",
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       "target": 55
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -2942,7 +3344,7 @@
       },
       "evidence": "In a study conducted by Zhi et al. (2014), this molecule was used to treat a mouse model obtained with injections of the peptide Aß25-35. Administration for 11 days of SV improved memory performance in the Morris water maze task and promoted survival of CA1 pyramidal cells. This effect was proposed to be promoted by alpha7 nAChRs, since it is blocked by MLA administration (Zhi et al., 2014)",
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       "object": {
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@@ -2952,6 +3354,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -2973,13 +3378,16 @@
       },
       "evidence": "In a study conducted by Zhi et al. (2014), this molecule was used to treat a mouse model obtained with injections of the peptide Aß25-35. Administration for 11 days of SV improved memory performance in the Morris water maze task and promoted survival of CA1 pyramidal cells. This effect was proposed to be promoted by alpha7 nAChRs, since it is blocked by MLA administration (Zhi et al., 2014)",
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+      "line": 880,
       "relation": "increases",
       "source": 32,
       "target": 58
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "CA1 Region, Hippocampal": true,
           "Pyramidal Cells": true
@@ -3005,12 +3413,17 @@
       },
       "evidence": "In a study conducted by Zhi et al. (2014), this molecule was used to treat a mouse model obtained with injections of the peptide Aß25-35. Administration for 11 days of SV improved memory performance in the Morris water maze task and promoted survival of CA1 pyramidal cells. This effect was proposed to be promoted by alpha7 nAChRs, since it is blocked by MLA administration (Zhi et al., 2014)",
       "key": "30c097363f63dc335173608a59d8ed563acccb33bedab017de6e5363d53dfc421978204866f5a7313d6a152ba440d149f3c49230874d289ce55037ddb9ad9f21",
-      "line": 691,
+      "line": 884,
       "relation": "decreases",
       "source": 32,
       "target": 39
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -3028,7 +3441,7 @@
       },
       "evidence": "It was then postulated that Abeta-nAChR interaction has a physiological role in neuronal homeostasis that is disrupted when Abeta concentrations increase in a pathological context, leading to receptor inhibition and possible cellular toxicity (Dineley et al., 2001; Parri et al., 2011)",
       "key": "1b46c6c49b8f4d280965566f2ac58b825b145933cb448ac034f92583a8a7e37eb066fec7a666176b841359d922e9adebdbf3a08db04476e86107f75c6c762f4f",
-      "line": 463,
+      "line": 586,
       "relation": "association",
       "source": 47,
       "target": 70
@@ -3046,6 +3459,11 @@
       "target": 103
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -3063,12 +3481,17 @@
       },
       "evidence": "This subunit commonly forms heteropentameric receptors in combination with the alpha4 subunit",
       "key": "d758b912613d5f2b6494c3437ab4062aaecd9ed6a1e54b55a1aa2a504670ae52ced552592f588d745f4ff54b1bd3f261807d1807ddccd00e43dfd637e2f6904b",
-      "line": 230,
+      "line": 276,
       "relation": "increases",
       "source": 81,
       "target": 17
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -3086,12 +3509,17 @@
       },
       "evidence": "The subtype alpha4beta2 is characterized by lower calcium ion permeability and a slow desensitization rate compared to the homopentameric alpha7 nAChR (Quick and Lester, 2002)",
       "key": "411e763283d2b99e04fc7aa5a3fc6192f583f71d873b029148577c78a545b2f496b806d53e568b7e839589dc1bdf8ebe774867f02b4e8829b051efb75fd2971c",
-      "line": 234,
+      "line": 282,
       "relation": "negativeCorrelation",
       "source": 17,
       "target": 40
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -3109,7 +3537,7 @@
       },
       "evidence": "Arora et al. (2013) investigated, in a cellular system, the effect of prolonged Abeta exposure on nAChR function. The rodent neuroblastoma cell line NG108-15 was transfected with alpha4beta2 nAChRs and treated for three days with 100 nM Abeta. The following acute stimulation with Abeta and nicotine led to receptor activation that caused a perturbation of intracellular calcium homeostasis followed by mitochondrial dysfunction and increased oxidative stress (Arora et al., 2013)",
       "key": "600774b8356e599c51eadd276ee8cac906bc6d9c6de556616c99c4fd50ce97babc5102ab73cb7665998ca4d2cf7e117d7a8df162074cbc37082a21e1af13a22e",
-      "line": 408,
+      "line": 512,
       "relation": "decreases",
       "source": 17,
       "subject": {
@@ -3118,6 +3546,11 @@
       "target": 41
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -3135,7 +3568,7 @@
       },
       "evidence": "Arora et al. (2013) investigated, in a cellular system, the effect of prolonged Abeta exposure on nAChR function. The rodent neuroblastoma cell line NG108-15 was transfected with alpha4beta2 nAChRs and treated for three days with 100 nM Abeta. The following acute stimulation with Abeta and nicotine led to receptor activation that caused a perturbation of intracellular calcium homeostasis followed by mitochondrial dysfunction and increased oxidative stress (Arora et al., 2013)",
       "key": "147b700a6db5f488b93baeba102e9fd80ac839d0332593fc428086530bf436ba49c5b2433174d19cc1ca1793a3ee346a888be20df256a563cae01c1746db0b3a",
-      "line": 409,
+      "line": 513,
       "relation": "increases",
       "source": 17,
       "subject": {
@@ -3144,6 +3577,11 @@
       "target": 116
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -3161,7 +3599,7 @@
       },
       "evidence": "Arora et al. (2013) investigated, in a cellular system, the effect of prolonged Abeta exposure on nAChR function. The rodent neuroblastoma cell line NG108-15 was transfected with alpha4beta2 nAChRs and treated for three days with 100 nM Abeta. The following acute stimulation with Abeta and nicotine led to receptor activation that caused a perturbation of intracellular calcium homeostasis followed by mitochondrial dysfunction and increased oxidative stress (Arora et al., 2013)",
       "key": "f55e373f41b7520ee498ef68833712337fcd32d4daa4e8cd1825776a83c28854d5e0b1353194a941b87a67a9162df0f3924d1a62c0f058952191c040c19fb26c",
-      "line": 410,
+      "line": 514,
       "relation": "increases",
       "source": 17,
       "subject": {
@@ -3182,6 +3620,11 @@
       "target": 103
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -3199,12 +3642,17 @@
       },
       "evidence": "In addition to the alpha4beta2 subtype, it was demonstrated that the alpha7 subunit is able to coassemble with the beta2 subunit to form a heteropentameric receptor",
       "key": "b38869b31f3336e78e04a4637727ec96cf3ef3ab59de4425c386c652a2e930ce5bfec98019afdafea6d487e1c8f3fbdf37be502e330616048a92b06acaa3f7f5",
-      "line": 240,
+      "line": 290,
       "relation": "increases",
       "source": 82,
       "target": 18
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -3222,7 +3670,7 @@
       },
       "evidence": "Under these experimental conditions, alpha7 and beta2 are able to co-assemble into a functional receptor that localizes at the cell surface",
       "key": "7f93dfe2036c84de60a2587b6217b61a430647fdffe97754d43a04359b982afa4061f818c722396c6cf763a1ac502c7e3011d2af25e66c6041cb1951bcabc296",
-      "line": 249,
+      "line": 303,
       "object": {
         "effect": {
           "fromLoc": {
@@ -3241,6 +3689,11 @@
       "target": 18
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -3258,7 +3711,7 @@
       },
       "evidence": "This class of receptors seems to be particularly sensitive to Abeta-induced toxicity (Khiroug et al., 2002; Liu et al.,2009, 2012)",
       "key": "f8fdb625fb9ac7a7d4d4ce18c1df1253506d2c03fe05cc54066adb1f142157f0e409074a4c2b3188efc08c1acb0149bc8719ed559a275f8c15bdaf3f7dba8e70",
-      "line": 245,
+      "line": 297,
       "object": {
         "modifier": "Activity"
       },
@@ -3268,6 +3721,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Brain": true
         }
@@ -3289,12 +3745,17 @@
       },
       "evidence": "The importance of beta2 in maintaining brain homeostasis during normal ageing was highlighted in the KO mouse for this subunit",
       "key": "8468d588aeffc60317290a52e9335efb4df73abebbd8c8a439cae7ccaf0843e6bc3672b2cf6e666ca79a29eb53d97a682c9cdef6e1388d11e984e7e83f25f6a8",
-      "line": 254,
+      "line": 310,
       "relation": "regulates",
       "source": 112,
       "target": 62
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -3312,12 +3773,17 @@
       },
       "evidence": "Aged beta2 null mutant mice have a thinner cortex compared to agematched wild-type controls (Zoli et al., 1999). This work should be pursued further as it indicates a “neurotrophic” action of beta2 receptor activation by endogenous ACh (Zanardi et al., 2007)",
       "key": "62e5c840e452878ef30f3c375e108ff5601cf6e6299e46391f24309daf86b45ec7580985fa23dc02c59ce4d5f759cc18600d6606f7a9674bc62b8a0d02cbec7d",
-      "line": 261,
+      "line": 319,
       "relation": "increases",
       "source": 112,
       "target": 25
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -3335,12 +3801,17 @@
       },
       "evidence": "Null mutant beta2 mice were also tested to determine the role of this subunit in cognition. Guillem et al. (2011) showed that these mice exhibit an attention deficit which was restored by re-expression of this subunit with a lentiviral vector in the PFC",
       "key": "9c6a40383bd60075ab34e3ad37eb022d857517378a0a4d076f0d03aedce29c8a0478025860e0f7f80e5c42569d01e7a2bd4a1f3abd9e0fddc3f75f0f01407c7a",
-      "line": 268,
+      "line": 328,
       "relation": "increases",
       "source": 112,
       "target": 122
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -3358,7 +3829,7 @@
       },
       "evidence": "Null mutant beta2 mice were also tested to determine the role of this subunit in cognition. Guillem et al. (2011) showed that these mice exhibit an attention deficit which was restored by re-expression of this subunit with a lentiviral vector in the PFC",
       "key": "1b1bce426bcdfeda5b8f08735a22a630021f1fd2a1be7db7a71466693e3347739b4156a26fddcef6b03a035eb8fc60e8193003e0ecb8965f71b4e4de003f699e",
-      "line": 269,
+      "line": 329,
       "relation": "increases",
       "source": 112,
       "target": 57
@@ -3377,6 +3848,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -3398,13 +3872,16 @@
       },
       "evidence": "The mechanism proposed is that the Aß-alpha7 nAChR interaction could activate neuroprotective downstream pathways (Parri et al., 2011), and that at the same time the interaction engages Abeta preventing its aggregation",
       "key": "f6a7d8df90e7bde44f8aa8701af0169cf52baf7b38f04494b8bd145085cf2f2e2e3613095adbf6deab2d8fc9efa5d7efaf6c09dea778c9d1ff5eae0708b26743",
-      "line": 525,
+      "line": 665,
       "relation": "decreases",
       "source": 69,
       "target": 59
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -3426,7 +3903,7 @@
       },
       "evidence": "The mechanism proposed is that the Aß-alpha7 nAChR interaction could activate neuroprotective downstream pathways (Parri et al., 2011), and that at the same time the interaction engages Abeta preventing its aggregation",
       "key": "2f2432a3ba93318988a11d4bad44af4fce332e74fd165bf29fd5d06d736878281a6fa77480cbc05d4804c3aa54f8040c252f6112e25eafce2569fdfa18b1bc04",
-      "line": 526,
+      "line": 666,
       "relation": "decreases",
       "source": 69,
       "target": 21
@@ -3445,6 +3922,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -3466,12 +3946,17 @@
       },
       "evidence": "They showed that alpha7 subunits co-localize with Abeta1-42 in senile plaques of brain slices obtained from patients that suffered from sporadic AD",
       "key": "478177f9baf8541923a6eb54ab2c4287dfe4fd9a8edc36260a94b293284dfe61f240a720727425377a657a155d62cc91b07a675fd411e04eea0e336ecf302c1b",
-      "line": 277,
+      "line": 341,
       "relation": "association",
       "source": 66,
       "target": 120
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -3489,7 +3974,7 @@
       },
       "evidence": "Modulation of nAChRs by Abeta was also found in ex vivo studies: Pettit and colleagues (2001) used rat hippocampal slices to show that Abeta1-42 incubation is able to reduce postsynaptic currents and open probability of both alpha7 and non-alpha7 nAChRs subtypes, demonstrating an interaction between Abeta and other nAChR subunits",
       "key": "9876fe437196a5b3476c62e4a68e2821c5ab7954b9d86152b4c4958bd10446ba6aa744943fa8bc006463959aa34471e59299906e625220af20335ba87c954dcd",
-      "line": 319,
+      "line": 395,
       "relation": "decreases",
       "source": 2,
       "target": 61
@@ -3499,6 +3984,9 @@
         "Cell": {
           "GABAergic neuron": true
         },
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Hippocampus": true
         }
@@ -3520,7 +4008,7 @@
       },
       "evidence": "They demonstrated that Abeta1-42 drives a reversible inhibition of nAChR-mediated currents in hippocampal GABAergic neurons recorded from rat slices. In these experimental conditions the most effective Abeta1-42 concentration was 500 nM, but inhibition was found also at the lower concentration of 100 nM",
       "key": "4716a3cd0ba268dc5eb0f6c2950c0b64fa6d862a0043841229b0550432439ae76ecd56ce65e217096d41e81ae98e22376c989f9d5f8b7bcc0b55cd2f2ed991ad",
-      "line": 346,
+      "line": 430,
       "relation": "decreases",
       "source": 2,
       "target": 61
@@ -3530,6 +4018,9 @@
         "Cell": {
           "GABAergic neuron": true
         },
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Hippocampus": true
         }
@@ -3551,7 +4042,7 @@
       },
       "evidence": "They demonstrated that Abeta1-42 drives a reversible inhibition of nAChR-mediated currents in hippocampal GABAergic neurons recorded from rat slices. In these experimental conditions the most effective Abeta1-42 concentration was 500 nM, but inhibition was found also at the lower concentration of 100 nM",
       "key": "c620618b9b44b1343d6e51dbf298b2317bf375fb58867b1b88a3e0f799610db49276dfc196865c06c71eab58d86de8b8515836061add5dd6594e099a2064028a",
-      "line": 344,
+      "line": 428,
       "object": {
         "modifier": "Activity"
       },
@@ -3560,6 +4051,11 @@
       "target": 89
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -3577,7 +4073,7 @@
       },
       "evidence": "With the use of selective antagonists it was possible to determine that inhibition operates on both alpha7 and non-alpha7 receptors (Pettit et al., 2001)",
       "key": "f3c55c7ce304575af651e751382d716b808b032ae9f8fd0f3c83b0798f1868f17aad14ac39529c44ff85cb7b87c7eb21ec980baed84f04394f2a62969314aa16",
-      "line": 356,
+      "line": 442,
       "object": {
         "modifier": "Activity"
       },
@@ -3586,6 +4082,11 @@
       "target": 89
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -3603,7 +4104,7 @@
       },
       "evidence": "With the use of selective antagonists it was possible to determine that inhibition operates on both alpha7 and non-alpha7 receptors (Pettit et al., 2001)",
       "key": "b4e492bda7518c7134ca2e5d797d05cbc17a560c161cba8dbfd020aea662b01ca4b75553af240259df4d2951e2d5123e49b256fd6522974db34721de0db0b6f6",
-      "line": 355,
+      "line": 441,
       "object": {
         "modifier": "Activity"
       },
@@ -3613,6 +4114,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Hippocampus": true,
           "Neurons": true
@@ -3635,7 +4139,7 @@
       },
       "evidence": "The incubation of cultured rat hippocampal neurons with Abeta1-42 resulted in inhibition of alpha7 nAChRs, more precisely of both somato-dendritic and presynaptic populations of receptors",
       "key": "d6d447e537f312828352c52047842d8fe04c8585819a63415fc433335a508ac5446b2a88d80501e693d140f584a51dcb891e602f0fe70da38a497ccea5cfbc4f",
-      "line": 386,
+      "line": 482,
       "object": {
         "modifier": "Activity"
       },
@@ -3644,6 +4148,11 @@
       "target": 32
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -3661,7 +4170,7 @@
       },
       "evidence": "Further studies showed an inhibitory effect of Abeta1-42 on human alpha4beta2 nAChRs transfected in the cell line (SHEP1) (Wu et al., 2004)",
       "key": "f2c82bed72fd258072c2cf4814617cc58475bd76ffd924b0909a52edbde4604c79ae60c0abbde69c46da5cab60a1b9f542b7ec6801e9e871c04e9a1cd276b3b7",
-      "line": 393,
+      "line": 490,
       "object": {
         "modifier": "Activity"
       },
@@ -3670,6 +4179,11 @@
       "target": 17
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -3687,12 +4201,17 @@
       },
       "evidence": "Subsequent to incubation with pM concentrations of Abeta1-42 monomers and oligomers, an increase of hippocampal LTP was observed",
       "key": "4cd18c7e7eaca4b15433377e119bce99f14875185d021831b41fd74a17fcfae1240589e42a2643dc66543e87a113329f0012cadcef71535a33e417f45c2449c1",
-      "line": 429,
+      "line": 541,
       "relation": "increases",
       "source": 2,
       "target": 46
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -3710,7 +4229,7 @@
       },
       "evidence": "Experiments performed with fragments of Abeta helped identify the sequence responsible for the interaction with alpha7, which corresponds to the amino acid residues 12-28 of the Abeta sequence (Wang et al., 2000b)",
       "key": "5cdd0737439cac0f2b78d84de56d92727fbc32b400275f4f6a711ea41e1f163334803ad130b942dab1175f1a6f0579bcb9fbb010cca4c7bbcdea4873c0f5cc8f",
-      "line": 289,
+      "line": 357,
       "relation": "increases",
       "source": 93,
       "target": 80
@@ -3734,6 +4253,11 @@
       "target": 101
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -3751,7 +4275,7 @@
       },
       "evidence": "Subsequently, competition studies performed by incubating alpha7 nAChRs with Abeta and alpha-Bungarotoxin showed that the application of alpha-Bungarotoxin is able to decrease the amount of Abeta bound to alpha7 nAChRs, suggesting that both molecules compete for the same ligand binding domain (Wang et al., 2000b)",
       "key": "84c03f669dc6b3be2dee18a2ceb4460b961b6d484a99e2798c0649305791804abf9e9e2a4aa1aa78994123b2c51c5674aec0962d28f08d8b8474d997949e65ba",
-      "line": 295,
+      "line": 365,
       "relation": "decreases",
       "source": 33,
       "target": 69
@@ -3772,6 +4296,9 @@
       "annotations": {
         "Cell": {
           "oocyte": true
+        },
+        "Confidence": {
+          "Medium": true
         }
       },
       "citation": {
@@ -3791,7 +4318,7 @@
       },
       "evidence": "Experiments performed on X. laevis oocytes transiently transfected with alpha7 or alpha4beta2 cDNA showed a concentration dependent effect of Abeta on receptor inhibition. In this case the peptide used was Abeta1-40 and the concentrations adopted were between 0.1 and 10 mM, with increased Abeta concentration resulting in a bigger inhibition of the receptor (Tozaki et al., 2002)",
       "key": "444aa35a605d90376634352354400298b51f91749202c71aff40166b1da18bf7cc9061db91570f5cfadcd28e6dc339223f918e42ba4a186e10adcc809023aa94",
-      "line": 365,
+      "line": 453,
       "object": {
         "modifier": "Activity"
       },
@@ -3803,6 +4330,9 @@
       "annotations": {
         "Cell": {
           "oocyte": true
+        },
+        "Confidence": {
+          "Medium": true
         }
       },
       "citation": {
@@ -3822,7 +4352,7 @@
       },
       "evidence": "Experiments performed on X. laevis oocytes transiently transfected with alpha7 or alpha4beta2 cDNA showed a concentration dependent effect of Abeta on receptor inhibition. In this case the peptide used was Abeta1-40 and the concentrations adopted were between 0.1 and 10 mM, with increased Abeta concentration resulting in a bigger inhibition of the receptor (Tozaki et al., 2002)",
       "key": "b0bd5277ec29796aea2aa6e6fca6f80edcd07af89d6537c1e06902fe7dd6cea69529a405a9874725e842de59b5ae7e3bdf1a67559fa4938f4cf5c4eff786f8ba",
-      "line": 366,
+      "line": 454,
       "object": {
         "modifier": "Activity"
       },
@@ -3856,6 +4386,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -3877,13 +4410,16 @@
       },
       "evidence": "This AD model displays spatial memory deficit at 13-16 months of age, while APP-alpha7KO mice did not exhibit any memory deficit, suggesting that the absence of the alpha7 subunit of the nicotinic receptor protects against the behavioural deficit caused by expression of the mutated forms of APP in this AD model",
       "key": "d5ec66f55a7464f877c09ee6afade009bc4990c8fe0e28ba70ce5d559a3df9a68fc63d52a610ca7e91398bb7bb078e45b134347dd72509dbfcf860c027de198c",
-      "line": 478,
+      "line": 603,
       "relation": "decreases",
       "source": 111,
       "target": 121
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -3905,13 +4441,16 @@
       },
       "evidence": "In the APP-alpha7KO line the lack of alpha7 was sufficient to preserve synaptic terminals and dendrites, rescuing levels of synaptophysin and MAP2 to reach that of aged-matched WT controls",
       "key": "3e5bd9fc71eaf5f6446db9a838a570598b5406d739a64c1095f7757448d9cf891dff1fac1921cdfff9d47623800da70c5450689e95f4e372c1a288e93ad36b16",
-      "line": 483,
+      "line": 610,
       "relation": "decreases",
       "source": 111,
       "target": 114
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -3933,13 +4472,16 @@
       },
       "evidence": "In the APP-alpha7KO line the lack of alpha7 was sufficient to preserve synaptic terminals and dendrites, rescuing levels of synaptophysin and MAP2 to reach that of aged-matched WT controls",
       "key": "bdb939b65ba45923294bda3310d89ce3d98bcb224785092f93f38f7e6b7342ed93b8c3d0b637ba7e365c40e4e1b7b29d87c26a70986781e0b871c04ec4031650",
-      "line": 484,
+      "line": 611,
       "relation": "decreases",
       "source": 111,
       "target": 113
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Hippocampus": true
         },
@@ -3964,13 +4506,16 @@
       },
       "evidence": "Signs of neuropathology were found in APP-alpha7KO illustrated by loss of MAP2 immunoreactivity in the hippocampus",
       "key": "f67d8f60c004a9c429ef02e5e5304a8f7cacc2bdc8ae6889c3a1f7a0676c357745591287133c69910432e6fc8c7edb9a46190d8be33597c295a10676d8ea6b5e",
-      "line": 519,
+      "line": 657,
       "relation": "increases",
       "source": 111,
       "target": 113
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -3992,13 +4537,16 @@
       },
       "evidence": "The authors postulated that the absence of alpha7 could prevent Abeta intracellular accumulation ameliorating the cognitive neuropathology and its phenotypic association (Dziewczapolski et al., 2009)",
       "key": "93349634a246f4b739fa085097e178f5b6f54aa8c9e38b007f92a855e72049973ce35b1be8e751a90215b9550967bc26208cb6b1cf508672e96cc644768e61f5",
-      "line": 496,
+      "line": 627,
       "relation": "increases",
       "source": 111,
       "target": 3
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Hippocampus": true
         },
@@ -4023,13 +4571,16 @@
       },
       "evidence": "In the hippocampus, it was shown that APP-alpha7KO mice had high levels of Abeta, although significantly less than APP mice, an effect which is not due to modification of the APP expression level,equivalent in the two lines",
       "key": "1a40878f01872a3a05911984f7c06a20d5eba05709f806d6ea4dcbfa478c6e2c7b00e364c7269f2b4a18682cf8c5c6ff69c450b8c6a982fab22c66136c93e782",
-      "line": 509,
+      "line": 643,
       "relation": "decreases",
       "source": 111,
       "target": 3
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -4051,13 +4602,16 @@
       },
       "evidence": "The authors postulated that the absence of alpha7 could prevent Abeta intracellular accumulation ameliorating the cognitive neuropathology and its phenotypic association (Dziewczapolski et al., 2009)",
       "key": "32cfa9434d1664c2aa2c11597911b7dda6d4218eff9f56f99f226d9811c015654c5e3527bb2f001e5d0b820eb359c33c73536f68e3321e7a5371b891b833f3b8",
-      "line": 497,
+      "line": 628,
       "relation": "increases",
       "source": 111,
       "target": 57
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -4079,13 +4633,16 @@
       },
       "evidence": "The contextual fear conditioning and the novel object recognition tasks both showed that the cognitive deficits worsen when alpha7 is absent",
       "key": "c8e6c9f7f729cd485343d566ea8b6bc7b7ab249de11f22c0fefbd09a8f94a06bce6434905d6850d1291aa1a822a399a6618460ada2657543dcd5869610dd3b01",
-      "line": 503,
+      "line": 635,
       "relation": "decreases",
       "source": 111,
       "target": 118
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -4107,7 +4664,7 @@
       },
       "evidence": "As a consequence of the lower Abeta concentration, the plaque load was clearly reduced in APP-alpha7KO mice",
       "key": "f20bb27de202ffc3f6fe323128b6cdf2bd8125d0ad8e483be6a3c28e01e1333b23d35b253d92a50f93041542981f3ec73241a225ab34c443d62a9ee1668cd3ee",
-      "line": 514,
+      "line": 650,
       "relation": "increases",
       "source": 111,
       "target": 120
@@ -4149,6 +4706,11 @@
       "target": 89
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -4166,12 +4728,17 @@
       },
       "evidence": "However, it is clear that nAChR-Aß interaction initiates intracellular signalling implicating a set of transduction cascades",
       "key": "b215d243a8689888f4d67d64b27d280d9c1e65caf19be22658c2995ddb21d206f38e74c37a338563cbbf58e6c5f3e63469d87c136a0d29b52b9cd8214a0112bb",
-      "line": 419,
+      "line": 527,
       "relation": "increases",
       "source": 70,
       "target": 44
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -4189,12 +4756,17 @@
       },
       "evidence": "On the other hand, an opposite effect was shown with Abeta-nAChR interaction being responsible for inhibition of survival pathways",
       "key": "7fa25984bfb50c0eff54ee95d1d6cb11df37b083ea19e4a8f8042b7aee47bac6379e4129cd12bf7645d30c9bbf16d498659370f4623a47441853ee04918b2a9c",
-      "line": 447,
+      "line": 566,
       "relation": "decreases",
       "source": 70,
       "target": 60
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -4212,7 +4784,7 @@
       },
       "evidence": "It was then postulated that Abeta-nAChR interaction has a physiological role in neuronal homeostasis that is disrupted when Abeta concentrations increase in a pathological context, leading to receptor inhibition and possible cellular toxicity (Dineley et al., 2001; Parri et al., 2011)",
       "key": "a74c3ea4e441839fce7c465b12fc50b87998afc0421ed9bb2039fcbfdb0fca2423c83c8ff8d660cffea2ae8125bb4d846ba418533d2a5fccb52f15a5d7c0a48a",
-      "line": 463,
+      "line": 586,
       "relation": "association",
       "source": 70,
       "target": 47
@@ -4242,6 +4814,11 @@
       "target": 23
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -4259,7 +4836,7 @@
       },
       "evidence": "In both hippocampal interneurons and oocytes they observed a block of beta2*-nAChRs, that could be prevented by the application of a positive allosteric modulator (PAM) specific for beta2 subunit containing receptors, desformylflustrabromine (dFBr) (Pandya and Yakel, 2011)",
       "key": "2ee97ddb0cd27a924caa1b3cd03f3c5f5e83478fa0368411140e8c1adae8d4d01a6e747e95cafe49cd5433249cf5d408ce16624cca0b1ce41bcb0bbb086727a2",
-      "line": 331,
+      "line": 411,
       "object": {
         "modifier": "Activity"
       },
@@ -4268,6 +4845,14 @@
       "target": 23
     },
     {
+      "annotations": {
+        "CellLine": {
+          "SH-SY5Y": true
+        },
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -4285,7 +4870,7 @@
       },
       "evidence": "The oligomeric form of Abeta1-40 was able to activate alpha7 nAChR expressed in SH-SY5Y cell line (Lilja et al., 2011)",
       "key": "56e8773c1c3ae749ca9f79c70abb3e17b3ee16f70db6eca361ea9ae4fadcdb2ff1550fe57cfe70979ce1c3d9dc57538dca42c560fd4bc250b3d9d9c80779e1ed",
-      "line": 397,
+      "line": 497,
       "object": {
         "modifier": "Activity"
       },
@@ -4306,6 +4891,11 @@
       "target": 9
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -4323,7 +4913,7 @@
       },
       "evidence": "Arora et al. (2013) investigated, in a cellular system, the effect of prolonged Abeta exposure on nAChR function. The rodent neuroblastoma cell line NG108-15 was transfected with alpha4beta2 nAChRs and treated for three days with 100 nM Abeta. The following acute stimulation with Abeta and nicotine led to receptor activation that caused a perturbation of intracellular calcium homeostasis followed by mitochondrial dysfunction and increased oxidative stress (Arora et al., 2013)",
       "key": "43b81798eb23fc6976db141b2c7e38b89f3a540bb4ba1fecce08de425a618e12554f60524b3ca42bf3eff5a488ca19bbd31da62d14e6c6e123bf85f796e7faed",
-      "line": 407,
+      "line": 511,
       "object": {
         "modifier": "Activity"
       },
@@ -4332,6 +4922,11 @@
       "target": 17
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -4349,7 +4944,7 @@
       },
       "evidence": "Akt phosphorylation mediates the downstream activation of an antiapoptotic pathway, which is also activated by nicotine treatment (Kihara et al., 2001)",
       "key": "749ad9210cae98df365c6cdf64a610e0a6837bfbae2d02ea181defddac6ddfffe33545850b79e8ee590e311a3d8f7fb6ec9a5dc2c1c34825a2a198711db42d3a",
-      "line": 423,
+      "line": 533,
       "relation": "decreases",
       "source": 87,
       "target": 39
@@ -4362,6 +4957,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -4383,7 +4981,7 @@
       },
       "evidence": "In a mouse model of AD, cotinine treatment decreased the plaque load and was able to activate the Akt pathway, that was shown to be neuroprotective (Echeverria et al., 2011)",
       "key": "83ddf08350125475afeb96368828c66ebb7bc0b06ea60b31322d2a0a2b6d90f3f12c6ec0ef9ffd47309a3e99ed8a39a72936a260a44e684c8f5818a7a84a059a",
-      "line": 633,
+      "line": 810,
       "relation": "decreases",
       "source": 86,
       "subject": {
@@ -4392,6 +4990,11 @@
       "target": 59
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -4409,13 +5012,16 @@
       },
       "evidence": "Subsequent to incubation with pM concentrations of Abeta1-42 monomers and oligomers, an increase of hippocampal LTP was observed",
       "key": "e8098a8c1917b084d1dba0502d6de044c55e5546c44005d27071f9ffc520a161629883c52a8d2d9b77bbc4a39b5ee11124ea393ee6dcc3411bd8a689c834597c",
-      "line": 428,
+      "line": 540,
       "relation": "increases",
       "source": 20,
       "target": 46
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -4437,7 +5043,7 @@
       },
       "evidence": "This AD model displays spatial memory deficit at 13-16 months of age, while APP-alpha7KO mice did not exhibit any memory deficit, suggesting that the absence of the alpha7 subunit of the nicotinic receptor protects against the behavioural deficit caused by expression of the mutated forms of APP in this AD model",
       "key": "4e9e7bf6d771c7e455f82de360964cc52d7056e9631044578a7817d78fe667893f5612b05f52c7e132b402e8a35131052fee167f8ea30cbf158b013e21e0a787",
-      "line": 477,
+      "line": 602,
       "relation": "decreases",
       "source": 110,
       "target": 121
@@ -4456,6 +5062,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -4477,13 +5086,16 @@
       },
       "evidence": "With the progression of the disease the amount of Abeta increases, it starts to accumulate, and becomes toxic for the neurons (Hernandez et al., 2010)",
       "key": "0c7fad872cfbe113386c3bd149cb09d6a682ada496ca6583aad387763c4df3a65c08dcba90f05bb1066e98fc9cd2d01bd4c1d59fa9474506b2b69c60d44da1ca",
-      "line": 532,
+      "line": 674,
       "relation": "positiveCorrelation",
       "source": 21,
       "target": 117
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -4505,13 +5117,16 @@
       },
       "evidence": "Cotinine is a nicotine metabolite known for its positive effects on memory and attention and lower toxicity compared to nicotine (Hatsukami et al., 1997)",
       "key": "ca33fb698765cf4450f1615faa9f9edbbda6b73d41bdd023e81673b12b9eb1d52bd77f08e011eee0f0cc530d90084574b8fa2d254b8911c93788b361b952f809",
-      "line": 536,
+      "line": 680,
       "relation": "increases",
       "source": 0,
       "target": 122
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -4533,13 +5148,16 @@
       },
       "evidence": "Cotinine is a nicotine metabolite known for its positive effects on memory and attention and lower toxicity compared to nicotine (Hatsukami et al., 1997)",
       "key": "c0f16e59d63a964828269c9c77ddf75aa7ed5aac53c0666b69715a2d4381ce11020d293701f3fa1ee9df99f398fc366338b46ee5d7d9d6575e8aa99f78517235",
-      "line": 537,
+      "line": 681,
       "relation": "increases",
       "source": 0,
       "target": 58
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -4561,13 +5179,16 @@
       },
       "evidence": "In a mouse model of AD, cotinine treatment decreased the plaque load and was able to activate the Akt pathway, that was shown to be neuroprotective (Echeverria et al., 2011)",
       "key": "bbd90cad61733e178ce6f322be861ba5df61c36efb7a4b34573e1ebf7e44d9fa604100f8b2ceabf1c9da6b38ea20ea99e645c8e56bfb202b33906e994546b08e",
-      "line": 631,
+      "line": 808,
       "relation": "decreases",
       "source": 0,
       "target": 120
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -4589,7 +5210,7 @@
       },
       "evidence": "In a mouse model of AD, cotinine treatment decreased the plaque load and was able to activate the Akt pathway, that was shown to be neuroprotective (Echeverria et al., 2011)",
       "key": "24d74d7a977f94d83c266ac949ef5473ccb244d749de4c4126f892b68a2c5490eb75816daed8c9aea558edd1d40f3f3f47250a1052ed78bc4604527b3958e6c3",
-      "line": 632,
+      "line": 809,
       "object": {
         "modifier": "Activity"
       },
@@ -4599,6 +5220,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -4620,7 +5244,7 @@
       },
       "evidence": "Cotinine is an alpha7 nAChR PAM (positive allosteric modulator)",
       "key": "1f40322d4be20d78d3932ad8e56f169bc480d23cd2a056537e9926d9c177da4cf3435d0071044ce48a3f83c89f72de0638760a2c307242fc97f0bca2afd41c3a",
-      "line": 636,
+      "line": 815,
       "object": {
         "modifier": "Activity"
       },
@@ -4630,6 +5254,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -4651,7 +5278,7 @@
       },
       "evidence": "Methyllycaconitine (MLA), an alpha7 nAChR antagonist, showed neuroprotective effect on mouse and rat primary cell culture (Martin et al., 2004)",
       "key": "a410f0a3378c0af4de1f12cd806489f17415ef587eebe012e20153ea2345b6cd87e9e00262235b84b9fbcd793d4f2d831b65de1814f0d580313593b66fdd3c00",
-      "line": 541,
+      "line": 687,
       "object": {
         "modifier": "Activity"
       },
@@ -4661,6 +5288,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -4682,13 +5312,16 @@
       },
       "evidence": "Methyllycaconitine (MLA), an alpha7 nAChR antagonist, showed neuroprotective effect on mouse and rat primary cell culture (Martin et al., 2004)",
       "key": "232c23b7c72a934e1b00701fb40b3559d0f95407a33c3d501330b3613beba40a539f9d8505bbc4af043aa53a7fb5872e60e3b12af8203f68c5c12eab65fee094",
-      "line": 542,
+      "line": 688,
       "relation": "decreases",
       "source": 7,
       "target": 59
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -4710,13 +5343,16 @@
       },
       "evidence": "Another molecule investigated was 2-[2-(4- bromophenyl)-2-oxoethyl]-1-methyl pyridinium (S 24795), a partial alpha7 nAChR agonist. When this molecule was applied to synaptosomal preparations from rat frontal cortex and post mortem human AD samples it was able to dissociate Abeta in a concentration dependent manner",
       "key": "05555d85102da28aaee468291fb48e1f21ca63175cd9fa56101ff0c721af521dc5be59869d1d79c17809ac884ace336c13af965d6f5d16b633221292fb6ec756",
-      "line": 548,
+      "line": 696,
       "relation": "decreases",
       "source": 15,
       "target": 3
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -4738,7 +5374,7 @@
       },
       "evidence": "The incubation with S 24795 was able to normalize Ca++ influx mediated by both alpha7 nAChR and NMDAR (Wang et al., 2009, 2010)",
       "key": "e95915e338417ca60663ce34df37328a71d99b56c88a58944af5c4c04920f8c2064529fec91e2c7b8e91cf87e564c83495dc8bddbec15b315ebbab3f02de394b",
-      "line": 554,
+      "line": 704,
       "object": {
         "effect": {
           "fromLoc": {
@@ -4758,6 +5394,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -4779,7 +5418,7 @@
       },
       "evidence": "The incubation with S 24795 was able to normalize Ca++ influx mediated by both alpha7 nAChR and NMDAR (Wang et al., 2009, 2010)",
       "key": "c1b46b00dd828dd21b1255597dc86f2c4448c4e5b65bb64ff0ae335e80b58001cbd897f2b53f44418aca55e7ef77b726b97bb690e153e32690c267ba6be6b993",
-      "line": 553,
+      "line": 703,
       "object": {
         "effect": {
           "fromLoc": {
@@ -4799,6 +5438,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -4820,13 +5462,16 @@
       },
       "evidence": "The possible mechanism by which nicotine enhances the aggregation of tau is through the activation of p38-MAP kinase",
       "key": "ed93ffc2f94f63c1acf166fc5f5de0c7eb72c517ea96cc9a2567f405a40d6f48ffab028a07aac67b93f5c6ee2e746708a323dc4f57866af98bdc2f74e76b1ec5",
-      "line": 610,
+      "line": 779,
       "relation": "increases",
       "source": 49,
       "target": 16
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -4848,13 +5493,16 @@
       },
       "evidence": "Whilst the spatial memory deficit was restored by 4OH-GTS-21 treatment, this molecule had no effect on neuronal density (Ren et al., 2007)",
       "key": "459781cc6240c443d26ca2cdd3d77abc6411f4044df2c89dbaf97840521dd188d5e2f702f22d718004c1aa9c1dc2a2aa9a21dd1d6eb75b6d5aa0344b1c7ae25c",
-      "line": 641,
+      "line": 822,
       "relation": "increases",
       "source": 13,
       "target": 121
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -4876,13 +5524,16 @@
       },
       "evidence": "Whilst the spatial memory deficit was restored by 4OH-GTS-21 treatment, this molecule had no effect on neuronal density (Ren et al., 2007)",
       "key": "52cda23f781a6ed6d47816d3c723fe9335812b93a07b015a876b64fc8a4442473bccda0f42115fa6d09a37ead5afe1ccd039b052732739371dba2e4cb6571a83",
-      "line": 642,
+      "line": 823,
       "relation": "causesNoChange",
       "source": 13,
       "target": 47
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -4904,13 +5555,16 @@
       },
       "evidence": "Wild-type mice treated with nicotine or with SSR180711, another partial agonist of alpha7 (Biton et al., 2006), showed increased LTP, while the transgenic AD model APPSwe/PS1DE9 showed no effect on LTP following SSR180711 treatment",
       "key": "4b1e000bda7f8ab2a39ba26a6c8d50f247e4cc676b5b639cb3d37de8596e01a2cb1f243fd32be73c5f7932880e571854130a39c7fd2734c8605c6142d9a6248e",
-      "line": 649,
+      "line": 832,
       "relation": "increases",
       "source": 36,
       "target": 46
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -4932,13 +5586,16 @@
       },
       "evidence": "Pregnenolone sulfate (PREGS) is an endogenous steroid known to ameliorate cognitive performance in animals. PREGS is a modulator of synaptic plasticity, acting on the activation of glutamatergic transmission (Smith et al., 2014)",
       "key": "867407fd99e2cc3812063b91456c2a07479ed3506a1837655e9a8a65ccc4d9ae50b12ada8b4f52d2e46f34c2d6fa5a3cc4ee567a41032797032b54bc17d8399b",
-      "line": 655,
+      "line": 840,
       "relation": "increases",
       "source": 5,
       "target": 57
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -4960,13 +5617,16 @@
       },
       "evidence": "Pregnenolone sulfate (PREGS) is an endogenous steroid known to ameliorate cognitive performance in animals. PREGS is a modulator of synaptic plasticity, acting on the activation of glutamatergic transmission (Smith et al., 2014)",
       "key": "20f4cf935cd34968e0b280a908fff86cda843f7f6050321ef9a0ffa14532e19e3a3362232d6f5408316ff85acb78c1cd97a4fa5d06f5644b2c0534f7e7651f7b",
-      "line": 656,
+      "line": 841,
       "relation": "increases",
       "source": 5,
       "target": 50
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -4988,13 +5648,16 @@
       },
       "evidence": "Pregnenolone sulfate (PREGS) is an endogenous steroid known to ameliorate cognitive performance in animals. PREGS is a modulator of synaptic plasticity, acting on the activation of glutamatergic transmission (Smith et al., 2014)",
       "key": "790386c896e7324be7c611a18b33a7c08ffa55f7ffb0df7ebaa8ba0db88a4bcef299249c07b4da897a9464362649cfc162421835428ffd0e80d22e95d5f77ab6",
-      "line": 657,
+      "line": 842,
       "relation": "increases",
       "source": 5,
       "target": 55
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -5016,13 +5679,16 @@
       },
       "evidence": "The treatment improved spatial memory and reduced apoptosis in CA1 pyramidal cells",
       "key": "fab9e7ea158b6c1b01d508693f84a48ce8d6d0b9e74015e419b2e19a26c4500e6f1f90530922ff5e80c858a07ba107288f9fb918e41e1115e4276fb1e53c6238",
-      "line": 667,
+      "line": 856,
       "relation": "increases",
       "source": 5,
       "target": 121
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "CA1 Region, Hippocampal": true,
           "Pyramidal Cells": true
@@ -5048,13 +5714,16 @@
       },
       "evidence": "The treatment improved spatial memory and reduced apoptosis in CA1 pyramidal cells",
       "key": "9bc84e66286b715a30a4a3ccd0bc4b1a2bd20456a0078991f8a488cae7d4042ef0b1ba91ea84b6fb8143864323001032bf943d262c23d693b39358248d403f4a",
-      "line": 669,
+      "line": 858,
       "relation": "decreases",
       "source": 5,
       "target": 39
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -5076,13 +5745,16 @@
       },
       "evidence": "Simvastatin (SV) is a statin commonly used in the clinic to control cholesterol levels and it was shown to improve cognitive function in AD patients (Simons et al., 2002; Sparks et al., 2006)",
       "key": "caa9c6f6fe50d6b9c8d069fdd5d9a162c0f59f3afe1be9295ea25f0d42c1ac0b3f3901db57b2975e284deffac49eab069a7841c00069132526cdc021669222fa",
-      "line": 675,
+      "line": 866,
       "relation": "regulates",
       "source": 10,
       "target": 42
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -5104,13 +5776,16 @@
       },
       "evidence": "Simvastatin (SV) is a statin commonly used in the clinic to control cholesterol levels and it was shown to improve cognitive function in AD patients (Simons et al., 2002; Sparks et al., 2006)",
       "key": "8ee486e5ce775756e1f5f530d5b20d05757a261cf2389a0f4614f3563251d6c34150248617e466e03e52ae19652b89af7d432001c982d02078bc1088456f000e",
-      "line": 676,
+      "line": 867,
       "relation": "increases",
       "source": 10,
       "target": 57
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "CA1 Region, Hippocampal": true,
           "Pyramidal Cells": true
@@ -5136,7 +5811,7 @@
       },
       "evidence": "In a study conducted by Zhi et al. (2014), this molecule was used to treat a mouse model obtained with injections of the peptide Aß25-35. Administration for 11 days of SV improved memory performance in the Morris water maze task and promoted survival of CA1 pyramidal cells. This effect was proposed to be promoted by alpha7 nAChRs, since it is blocked by MLA administration (Zhi et al., 2014)",
       "key": "6b44b2f41a9ad2d8e63c02c337e3383a15a24ce5b6c702818635f98c2cab299cef341e42b021667995d32eeab0cb69332b7abc33f97dac438f63c384c9ae930a",
-      "line": 690,
+      "line": 883,
       "relation": "decreases",
       "source": 10,
       "target": 39
@@ -5155,6 +5830,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -5176,13 +5854,16 @@
       },
       "evidence": "In a study conducted by Zhi et al. (2014), this molecule was used to treat a mouse model obtained with injections of the peptide Aß25-35. Administration for 11 days of SV improved memory performance in the Morris water maze task and promoted survival of CA1 pyramidal cells. This effect was proposed to be promoted by alpha7 nAChRs, since it is blocked by MLA administration (Zhi et al., 2014)",
       "key": "4f9712b52124e4578080963b7eb7bb7cd85671e62f863c3dea856083878357ff5d54ed1c1bb735d604b7218bccda6629ef240ea236c535fcdc790907385eea47",
-      "line": 686,
+      "line": 879,
       "relation": "increases",
       "source": 85,
       "target": 58
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -5204,7 +5885,7 @@
       },
       "evidence": "In a study conducted by Zhi et al. (2014), this molecule was used to treat a mouse model obtained with injections of the peptide Aß25-35. Administration for 11 days of SV improved memory performance in the Morris water maze task and promoted survival of CA1 pyramidal cells. This effect was proposed to be promoted by alpha7 nAChRs, since it is blocked by MLA administration (Zhi et al., 2014)",
       "key": "921416edf0051517976df6667c07bbbb74780b65f35be69127d9a9c2e3212fe8cb4a26a1c7b3b69bdfaeb7d6c14015b9594a47644ce0751dd28ee0138c9f8385",
-      "line": 688,
+      "line": 881,
       "object": {
         "modifier": "Activity"
       },
@@ -5231,6 +5912,11 @@
       "target": 106
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -5248,7 +5934,7 @@
       },
       "evidence": "The intracellular signalling initiated by the binding of Abeta to nAChR at the cell surface requires the recruitment of Filamin A (FLNA), a scaffold protein that is known to crosslink actin, and in addition could also have a function in certain intracellular pathways (Stossel et al., 2001)",
       "key": "4ac7dfa2764df488f397834c7f629fd0bd936d30af2219a2b257e5560c679b1e617580b884c8e32ff76c61aa649eecdefd301273c54118dbdffe02dbdb26a498",
-      "line": 701,
+      "line": 896,
       "relation": "increases",
       "source": 71,
       "target": 44
@@ -5266,6 +5952,11 @@
       "target": 106
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -5283,12 +5974,17 @@
       },
       "evidence": "Wang et al. showed that the association between FLNA and the alpha7 subunit is elevated in AD samples compared to age matched controls",
       "key": "6f64954abf05c287ac19835dfb9a95fd0c533e204e32c5c6f69a0ee0565b624aa2bfad758c9f5aeb679f70a989fd6773412125d5b9bded8e6cbf840ed02aa1bf",
-      "line": 705,
+      "line": 902,
       "relation": "positiveCorrelation",
       "source": 83,
       "target": 117
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -5306,12 +6002,17 @@
       },
       "evidence": "A novel molecule called PTI-125 was used to interfere with the interaction of FLNA and alpha7. The treatment with PTI-125 prevents FLNA binding to alpha7 and as consequence reduces the affinity of Abeta for nAChRs, attenuating the toxic effect of Abeta (Wang et al., 2012)",
       "key": "1e09b05a6ded10091a8645e1817e39dad1a5815659938e1b6386360732d662edf7c69fdc301a32b936af89115678a0cc43d7e57fe9d8a17ca9408e0dc4a23131",
-      "line": 711,
+      "line": 910,
       "relation": "decreases",
       "source": 14,
       "target": 83
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -5329,12 +6030,17 @@
       },
       "evidence": "A novel molecule called PTI-125 was used to interfere with the interaction of FLNA and alpha7. The treatment with PTI-125 prevents FLNA binding to alpha7 and as consequence reduces the affinity of Abeta for nAChRs, attenuating the toxic effect of Abeta (Wang et al., 2012)",
       "key": "c5ff97baec34a15941b230d31a1bdbb2ef831380e83c9d8b795472a7533984e330179cb84ff3c43964b913e6b5cebd9435864483b81cf6c58edf90cb9619f3ce",
-      "line": 712,
+      "line": 911,
       "relation": "decreases",
       "source": 14,
       "target": 70
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Lombardo S",
@@ -5352,7 +6058,7 @@
       },
       "evidence": "A novel molecule called PTI-125 was used to interfere with the interaction of FLNA and alpha7. The treatment with PTI-125 prevents FLNA binding to alpha7 and as consequence reduces the affinity of Abeta for nAChRs, attenuating the toxic effect of Abeta (Wang et al., 2012)",
       "key": "3f7ca52509ce04490c744fb4a70dd6a9bb4f37f5d1735879fd049a9dc921436c3ea5c1409bad3cbf9d172d26b6bbc3bc68968b5b49888af38500345085bc18d0",
-      "line": 713,
+      "line": 912,
       "object": {
         "modifier": "Activity"
       },
diff --git a/hbp_knowledge/receptors/lombardo2015b.bel.json b/hbp_knowledge/receptors/lombardo2015b.bel.json
index 82f2d5071..69fa5c4df 100644
--- a/hbp_knowledge/receptors/lombardo2015b.bel.json
+++ b/hbp_knowledge/receptors/lombardo2015b.bel.json
@@ -54,6 +54,9 @@
   "links": [
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Dentate Gyrus": true
         },
@@ -80,13 +83,16 @@
       },
       "evidence": " However, the analysis of the recognition percentage for the same set of data showed that GFP-WT spent significantly more time exploring the novel object compared with APP-WT (p = 0.0032; Fig. 2E), suggesting the presence of a memory deficit in the APP-WT group.",
       "key": "696e76011c7300d50f155f270cab3da8d518db609fce23615060e1f7c0609f6716760d65a746b9df1a68d3c6673fbe776ae73b9410ab0974a15bd1c096a7ecd1",
-      "line": 87,
+      "line": 88,
       "relation": "increases",
       "source": 13,
       "target": 18
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Dentate Gyrus": true
         },
@@ -113,13 +119,16 @@
       },
       "evidence": "Hence, the transduction of hAPP-SLA in DG induces recognition memory deficits as supported by NPR and NOR tasks",
       "key": "c2ce9a0d81ab30ffdc337f0a2d76bd1c8dadd11937ee71983c6400017154a01ac84c62053adae84cf8d0bdcbb752e362f96acebdb40d25b1f3205880d5b1f5db",
-      "line": 103,
+      "line": 110,
       "relation": "increases",
       "source": 13,
       "target": 18
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Dentate Gyrus": true
         },
@@ -146,13 +155,16 @@
       },
       "evidence": "Similarly, in the NOR task (15 months p.i.), both the GFP-beta2 and the APP-beta2 displayed higher exploration of the novel object (p < 0.0001 and p = 0.0001, respectively; Fig. 4C and D), with no differences between the 2 groups in the recognition index (p = 0.7; Fig. 4E), meaning that beta2 mice injected with hAPP-SLA did not exhibit the recognition memory deficit observed in APP-WT",
       "key": "ff1a129c5eee5644576b32230652c53e04a118b1bcbb61e96d7895cc731ec6f27c118001e595e521c7258f1e34260500df1cf81a641b71bcd88f6504b0483483",
-      "line": 131,
+      "line": 146,
       "relation": "increases",
       "source": 13,
       "target": 18
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Dentate Gyrus": true
         },
@@ -179,13 +191,16 @@
       },
       "evidence": "The locomotor behavior during the NOR habituation phase was measured by the total distance traveled: APP-WT showed higher locomotor activity compared with GFP-WT (p = 0.0027; Fig. 2F)",
       "key": "5fa7d71d909a6668043de5e44428055eb439d6a8ea8572e1e51082379f9b57f0fb86468c446239c69646aeb39b3e1cc921ea322ccef518ae211f3f7e85101c4a",
-      "line": 93,
+      "line": 96,
       "relation": "increases",
       "source": 13,
       "target": 6
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Dentate Gyrus": true
         },
@@ -212,13 +227,16 @@
       },
       "evidence": "We finally measured anxiety levels using the LDB paradigm. No differences were observed between both groups for the index of time spent in the lit compartment (p = 0.7) as well as for the number of transitions (p = 0.2; Fig. 2GeH)",
       "key": "59ac265c475d697aa163250916ca42f384d771a86b1c984568bb523195ad80ba1355952a581215b377106d7acd5bd849538c29f91d8205913f02b78e8bcdd4fd",
-      "line": 99,
+      "line": 104,
       "relation": "causesNoChange",
       "source": 13,
       "target": 20
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Dentate Gyrus": true
         },
@@ -245,13 +263,16 @@
       },
       "evidence": "We did not detect any glia or microglia activation in WT-APP (Fig. 3C and F) compared with WT-GFP (Fig. 3B and E), meaning that the neuroinflammation does not play a role in the memory deficit we observed",
       "key": "5a11a04f8c099ed26b9671af8e7e9261d9541010a200f6977e57e76b7202cb6b3e3b8242fc9f5fe949f7c63456f7bb72017bcd132f175bdb980973a8fe7e390c",
-      "line": 109,
+      "line": 118,
       "relation": "causesNoChange",
       "source": 13,
       "target": 4
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Dentate Gyrus": true
         },
@@ -278,7 +299,7 @@
       },
       "evidence": "We did not detect any glia or microglia activation in WT-APP (Fig. 3C and F) compared with WT-GFP (Fig. 3B and E), meaning that the neuroinflammation does not play a role in the memory deficit we observed",
       "key": "8292c2cb3d3a2ff2381b073aba86d2d7c3111bd7a55fa636e55a4d184047dd6e03768d9b727896a2443a9b6c7166a3d1ffd3b2a8c9c74549e8b596b4eaed7115",
-      "line": 110,
+      "line": 119,
       "object": {
         "modifier": "Activity"
       },
@@ -288,6 +309,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Dentate Gyrus": true
         },
@@ -314,13 +338,16 @@
       },
       "evidence": "In addition, viral transduction did not induce any neuroinflammation, as shown in WT noninjected mice (Fig. 3A and D)",
       "key": "251af39a20ffa6f9b12dd8a84739a3d729bc57d1f2cf185961e9c27ce63e9f2a83668846bb53c98dff8d37a0f6f2260df168459c6c5081b3cebe26bf76abad71",
-      "line": 114,
+      "line": 125,
       "relation": "causesNoChange",
       "source": 13,
       "target": 3
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Species": {
           "10090": true
         }
@@ -344,13 +371,16 @@
       },
       "evidence": "The presence of oligomeric Abeta in APP-WT was confirmed with the antibody VHH 31-1, specific for oligomeric forms of Abeta (Lafaye et al., 2009)",
       "key": "fe0aef6615826d3429465bd3a480bf144d002e8cf579c64b607d34c69cb57e70457efa92e6abcf255fb4bc9697ab2e5ac0a43b1b1407e2c651d69e6a00a0c164",
-      "line": 187,
+      "line": 220,
       "relation": "increases",
       "source": 13,
       "target": 1
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Dentate Gyrus": true
         },
@@ -377,13 +407,16 @@
       },
       "evidence": "Abeta was mainly found in the polymorphic layer of the DG (Fig. 6, arrows)",
       "key": "6865e8eb20b392fdff5b98446614065d9392d4908ee65ed09364063d67fdcf148fe2d848f2e21c3c1ad214254b701408713cb51b96672a2dc7521dce44ac4b1c",
-      "line": 193,
+      "line": 228,
       "relation": "increases",
       "source": 13,
       "target": 1
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Dentate Gyrus": true
         },
@@ -410,7 +443,7 @@
       },
       "evidence": "Abeta intracellular accumulation in DG polymorphic layer was also confirmed with the rat monoclonal 7H3D6 antibody, also specific for oligomeric Abeta (Kumar et al., 2013) (Fig. 7, arrow)",
       "key": "f8ddbf9a5e10ff12ffdc9f524ace704a5658bb2309fdba217ff98b4e4d34714f3fa2b46a79bab2aa89d06f177c145c38c9bdfdd37da12dd812b21b1fce66f497",
-      "line": 199,
+      "line": 236,
       "relation": "increases",
       "source": 13,
       "target": 1
@@ -423,6 +456,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Dentate Gyrus": true
         },
@@ -449,7 +485,7 @@
       },
       "evidence": "We did not detect any glia or microglia activation in WT-APP (Fig. 3C and F) compared with WT-GFP (Fig. 3B and E), meaning that the neuroinflammation does not play a role in the memory deficit we observed",
       "key": "5297432d248722ae343dc2edea6e0cae2a6a82c29a827f3afbb162d85d5b5f2e40d26b8ec4e2636974a3977c88ec6b3901d29ed6c36cd97a95a97621c6b49faf",
-      "line": 108,
+      "line": 117,
       "relation": "causesNoChange",
       "source": 3,
       "target": 18
@@ -468,6 +504,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Dentate Gyrus": true
         },
@@ -494,13 +533,16 @@
       },
       "evidence": "In the NPR task (7 months p.i.), the GFP-beta2 spent significantly more time exploring the novel compartment (p = 0.003; Fig. 4A), as well as APP-beta2 (p = 0.017; Fig. 4B).",
       "key": "187df6342b3887a6b75c32b6f781b73beeb28c230c32da972163a26a0d8d496b2b0a2a5e933ee2e8abcee9f3b3d973eae8f6e52f5d3a4b9c88a0d427b0418080",
-      "line": 120,
+      "line": 133,
       "relation": "decreases",
       "source": 10,
       "target": 18
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Dentate Gyrus": true
         },
@@ -527,13 +569,16 @@
       },
       "evidence": "Similarly, in the NOR task (15 months p.i.), both the GFP-beta2 and the APP-beta2 displayed higher exploration of the novel object (p < 0.0001 and p = 0.0001, respectively; Fig. 4C and D), with no differences between the 2 groups in the recognition index (p = 0.7; Fig. 4E), meaning that beta2 mice injected with hAPP-SLA did not exhibit the recognition memory deficit observed in APP-WT",
       "key": "8cc414ad1cfa92bc7d6d9093a518fb3eabd465ac19604f0135bc04511da5e37bebef6c6e6592129ccc1c6b1d235ba293a9ac186be41edf701234e4de70d5efc6",
-      "line": 130,
+      "line": 145,
       "relation": "decreases",
       "source": 10,
       "target": 18
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Hippocampus": true
         },
@@ -560,13 +605,16 @@
       },
       "evidence": "We then investigated the presence of Abeta aggregates in the hippocampus of APP-beta2 and APP-alpha7. In APP-beta2, a positive staining for Abeta oligomers using the VHH 31-1 antibody was found (Fig. 8, arrows)",
       "key": "78c6f3f223991b807bec4ec603599ccbff8dae449765e2945290cf3c8c117b5ad92bc4a7f90d49e457c46e5fe9d6f8ef5a83cfdbacf6c658c304e0a430ae1cc4",
-      "line": 208,
+      "line": 247,
       "relation": "decreases",
       "source": 10,
       "target": 1
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Dentate Gyrus": true
         },
@@ -593,13 +641,16 @@
       },
       "evidence": "In the NPR task (7 months p.i.), the GFP-beta2 spent significantly more time exploring the novel compartment (p = 0.003; Fig. 4A), as well as APP-beta2 (p = 0.017; Fig. 4B).",
       "key": "57becf0e9171afc64da5de8c193919c6000bc53ae6d4a67f7af9d5c3b9caaf99ea61cbae2bfd77afc50364cbaff6cfb89ab4cb8e93e2146582996a475139e297",
-      "line": 121,
+      "line": 134,
       "relation": "decreases",
       "source": 15,
       "target": 18
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Dentate Gyrus": true
         },
@@ -626,7 +677,7 @@
       },
       "evidence": "We observed intracellular Abeta staining in the polymorphic layer of the DG that was absent in GFP-beta2 (Fig. 8)",
       "key": "c1319e936e32eaf2c1bc0e9271f64710ac1b7722569c5e132149b394ef994662b375ed5be8aff5338520ca84b32b653c7858321c07104b491a1c9dc7ea1d0360",
-      "line": 214,
+      "line": 256,
       "relation": "increases",
       "source": 15,
       "target": 0
@@ -645,6 +696,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Dentate Gyrus": true
         },
@@ -671,7 +725,7 @@
       },
       "evidence": "The hAPP-SLA transduction in DG did not induce a memory deficit in beta2 KO, meaning that the Abeta/beta2-nAChR interaction is required to drive the memory deficit in this model",
       "key": "48542658768f2b8a3ca0b64255492ffdbef52ae31e47865046369d14fb36508b520343ec7d0746ccf5e0392d4a76354745dc3b4197f4d59488907bd5c1872377",
-      "line": 137,
+      "line": 154,
       "relation": "increases",
       "source": 8,
       "target": 18
@@ -690,6 +744,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Dentate Gyrus": true
         },
@@ -716,7 +773,7 @@
       },
       "evidence": "The hAPP-SLA transduction in DG did not induce a memory deficit in beta2 KO, meaning that the Abeta/beta2-nAChR interaction is required to drive the memory deficit in this model",
       "key": "726e615ce1b24e693cb85de05ea9ff03828c39de5e38a332fdeaf9de24cfeb56d23eeb131debf265ade35df09331e8822e8852ea1fdf7f71631577a289883812",
-      "line": 138,
+      "line": 155,
       "relation": "increases",
       "source": 7,
       "target": 18
@@ -735,6 +792,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Dentate Gyrus": true
         },
@@ -761,13 +821,16 @@
       },
       "evidence": "At 7 months p.i., both GFP-alpha7 (p = 0.9; Fig. 5A) and APP-alpha7 groups (p = 0.3; Fig. 5B) displayed a memory deficit in the NPR task.",
       "key": "1c92b25412d175309f81d5af0e12bc9147e1703404e20d8ef51e820458829309888dc7155a285a13ece9ad7345d2f37194a3d0f9a120291a6bdf5c7d17144556",
-      "line": 143,
+      "line": 162,
       "relation": "decreases",
       "source": 9,
       "target": 18
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Dentate Gyrus": true
         },
@@ -794,13 +857,16 @@
       },
       "evidence": "The analysis of the total exploration time during the NOR task showed that GFP-alpha7 spent similar time exploring the familiar and the novel objects (p = 0.76; Fig. 5D), whereas APP-alpha7 spent significantly more time exploring the novel object compared with the familiar one (p = 0.01; Fig. 5E)",
       "key": "fef4f35397d812afb93f9129940800fa2f55b403bc54583d4882f22c9cb297ed701c719ae0d8ac2fc6c37aa84b98cdc30e475f8c918f8a911b6d61b259a9dbf7",
-      "line": 164,
+      "line": 189,
       "relation": "decreases",
       "source": 9,
       "target": 18
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Dentate Gyrus": true
         },
@@ -827,13 +893,16 @@
       },
       "evidence": "In the NOR task (15 months p.i.) as well, both GFP-alpha7 and APP-alpha7 displayed a cognitive impairment (Fig. 5DeE)",
       "key": "9dbc893ac6131787df69505abb8bfec39e84cdb7fc443a167848c366e53356843c7b4e9f76d665a38eef2524970a82df237063a70d3b80d410fa412b237d8fa9",
-      "line": 155,
+      "line": 178,
       "relation": "decreases",
       "source": 9,
       "target": 17
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Dentate Gyrus": true
         },
@@ -860,13 +929,16 @@
       },
       "evidence": "Immunofluorescence performed with VHH 31-1 on brain slices of APP-alpha7 mice also showed intracellular Abeta oligomers in the polymorphic layer (Fig. 8, arrows), whereas GFP-alpha7 mice did not show any Abeta oligomers",
       "key": "a26bdc2a06762ffdcbcecb9739d49bb211713edb5be8bb7fc6ad64c6a9cfc9f659d160bca12c5e11a944ab78984dfff75c31e9ad02f17dc933ffa3fbce4d41e4",
-      "line": 219,
+      "line": 263,
       "relation": "decreases",
       "source": 9,
       "target": 1
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Dentate Gyrus": true
         },
@@ -893,13 +965,16 @@
       },
       "evidence": "Noninjected mice spent the same amount of time exploring novel and familiar compartments during the test session (p = 0.6; Fig. 5C), confirming the presence of a constitutive recognition memory deficit in age-matched alpha7 KO mice",
       "key": "4fedeb30bba41af7446db102cc3873d0c76f513db8fd3e3ff845eafcb9b57d5c1dd810b1be6eb350a706154c7df1ae77ffc8500db670438d9daa8642a5b2e680",
-      "line": 150,
+      "line": 171,
       "relation": "decreases",
       "source": 14,
       "target": 18
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Dentate Gyrus": true
         },
@@ -926,13 +1001,16 @@
       },
       "evidence": "Because the alpha7 KO had a memory deficit independent of hAPP-SLA expression, we could not draw any conclusion on the role of alpha7 in the memory deficit observed",
       "key": "a1270d2e7110257aaf6b969f43596fdf4f8fc2de98b636b73a0a3949c7d5fe25f011034e46126efd73b444472ac88bc5e77908219290dc84a16cbfd5703ac482",
-      "line": 169,
+      "line": 196,
       "relation": "decreases",
       "source": 14,
       "target": 18
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Dentate Gyrus": true
         },
@@ -959,13 +1037,16 @@
       },
       "evidence": "In the NOR task (15 months p.i.) as well, both GFP-alpha7 and APP-alpha7 displayed a cognitive impairment (Fig. 5DeE)",
       "key": "cf52362db1f027b0f2b6442e9c40234f0aa58ee5d751b451302b7ce7d69c1b2f0d1dd4233ba887cd05732884e78a7b116cd9b38746c44ab47794de318efca869",
-      "line": 156,
+      "line": 179,
       "relation": "decreases",
       "source": 14,
       "target": 17
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Dentate Gyrus": true
         },
@@ -992,13 +1073,16 @@
       },
       "evidence": "However, we identify a possible role of the alpha7 subunit in the normal aging process that should be further investigated",
       "key": "993e451b69a506601decb3064fb64794cf16b97fe061e0a09450e30e56096347c5b6e835c5a39f6cb328c731b5f1e37f35b7c69691f6d13a5242bf07bb232fb9",
-      "line": 173,
+      "line": 202,
       "relation": "association",
       "source": 14,
       "target": 5
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Dentate Gyrus": true
         },
@@ -1025,13 +1109,16 @@
       },
       "evidence": "Immunofluorescence performed with VHH 31-1 on brain slices of APP-alpha7 mice also showed intracellular Abeta oligomers in the polymorphic layer (Fig. 8, arrows), whereas GFP-alpha7 mice did not show any Abeta oligomers",
       "key": "987e77ed21784417ed89f4d9ff98c97ca2218aa2780c16b103f0ca8d27d104fceefa6f548292b63cefc01331c49f335f0e9e889cb70e135b26cbfab431f8296d",
-      "line": 220,
+      "line": 264,
       "relation": "increases",
       "source": 14,
       "target": 1
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         },
@@ -1058,13 +1145,16 @@
       },
       "evidence": "Several studies showed that in AD animal models, the appearance of the cognitive deficits precedes plaque deposition (Casas et al., 2004; Gouras et al., 2000; Kumar et al., 2013; Wirths et al., 2004)",
       "key": "4eda0dd905fd453a9b07c6c24f59d1741bf621aa609f77a24af17f8ad795250f2b38fc10807b52cce1cbcc9dbc825c8837a590b08f4a399b26968918b3dcdda6",
-      "line": 182,
+      "line": 213,
       "relation": "increases",
       "source": 17,
       "target": 19
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Dentate Gyrus": true
         },
@@ -1091,13 +1181,16 @@
       },
       "evidence": "However, we identify a possible role of the alpha7 subunit in the normal aging process that should be further investigated",
       "key": "7fee6d5d0b528894457cb1e092731a5d04c40d5edfb5a239ebbf555955205065840dff31a1dc315b96df400d4d044ca6816d452248100723319818cce97c4930",
-      "line": 173,
+      "line": 202,
       "relation": "association",
       "source": 5,
       "target": 14
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         },
@@ -1124,7 +1217,7 @@
       },
       "evidence": "Several studies showed that in AD animal models, the appearance of the cognitive deficits precedes plaque deposition (Casas et al., 2004; Gouras et al., 2000; Kumar et al., 2013; Wirths et al., 2004)",
       "key": "a7996e3726089d0ae541b2ea46c98e0ad29cf6b399f95fa82ec58b02805426875a472a25df5180b34c0a97e675e9343ff3db9caabbcdf3ed7f27f482de8a0604",
-      "line": 181,
+      "line": 212,
       "relation": "increases",
       "source": 16,
       "target": 17
diff --git a/hbp_knowledge/receptors/lorenz2014.bel.json b/hbp_knowledge/receptors/lorenz2014.bel.json
index 62022a3b3..caa8ae429 100644
--- a/hbp_knowledge/receptors/lorenz2014.bel.json
+++ b/hbp_knowledge/receptors/lorenz2014.bel.json
@@ -49,6 +49,11 @@
   },
   "links": [
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Buck A",
@@ -72,12 +77,17 @@
       },
       "evidence": "Performance was impaired, compared with a normal population, in the subtests Figure Recall and Figure Saving. These both subtests examined non-verbal functions, namely non-verbal memory and visuoconstructive ability.",
       "key": "dc893583023e405a74df6d48b01003ad1460ca9004646eddec4703fc18da2632068cc7824b7ad1878ffa09f735332c5e2c0275a541700a5ddf1cced2d6be6b9a",
-      "line": 60,
+      "line": 61,
       "relation": "decreases",
       "source": 7,
       "target": 8
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Buck A",
@@ -101,12 +111,17 @@
       },
       "evidence": "We found high correlation coefficients for four brain regions (right superior parietal lobule, left thalamus, right pos- terior subcortical region, and left posterior subcor- tical region) and two CERAD subtests (Word List Intrusions and Boston Naming Test), some of them were statistically significant.",
       "key": "172d654c2a5e22facc84b22449ccb29240e33a20beacd4edf371c016d9b1570ae8f74915f2795099efcbfcffe72f3c8734d72e829f1e75d9a072a4c28d82ec14",
-      "line": 78,
+      "line": 86,
       "relation": "association",
       "source": 7,
       "target": 8
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Buck A",
@@ -130,12 +145,17 @@
       },
       "evidence": "Furthermore, we studied in these 17 IPD patients (at Hoehn and Yahr stage 1 and 2) whether there were differences of the a4b2 nAchR densities in the brain hemisphere contralateral to the clinically more affected body side (=contralat- eral hemisphere) compared to the brain hemi- sphere ipsilateral to the clinically more affected body side (=ipsilateral hemisphere).",
       "key": "2cedadca94d04d91fba4fe83c63f09576bc9953198a075aaa2aba3746a459334883c08348b1dbeb2d68d0099bf60549ba87b713732a981a22b991a1e83dd974d",
-      "line": 73,
+      "line": 79,
       "relation": "association",
       "source": 7,
       "target": 6
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Buck A",
@@ -159,12 +179,17 @@
       },
       "evidence": "We found high correlation coefficients for four brain regions (right superior parietal lobule, left thalamus, right pos- terior subcortical region, and left posterior subcor- tical region) and two CERAD subtests (Word List Intrusions and Boston Naming Test), some of them were statistically significant.",
       "key": "16e2cc93576cf7540b1fd2d5ceb4f32df94214fa033817c49263b5fa7909914e1faaaab5f948ff673dec4da40138579809fc7564955cd8c87efbec72ed01d34b",
-      "line": 78,
+      "line": 86,
       "relation": "association",
       "source": 8,
       "target": 7
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Buck A",
@@ -188,12 +213,17 @@
       },
       "evidence": "We found high correlation coefficients for four brain regions (right superior parietal lobule, left thalamus, right pos- terior subcortical region, and left posterior subcor- tical region) and two CERAD subtests (Word List Intrusions and Boston Naming Test), some of them were statistically significant.",
       "key": "26047e629ba22740b0b77dfcd27e20bc005f6997349e42f520d66946f16967b783cab2a97a6711b073e35d27d69ad3c1b8e1966f6d994091a3c02204cd944230",
-      "line": 79,
+      "line": 87,
       "relation": "association",
       "source": 8,
       "target": 6
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Buck A",
@@ -217,12 +247,17 @@
       },
       "evidence": "The most intense accumulation of 5-I-A-85380 was detected in both thalami, pons and midbrain, and both nuclei lentiformes",
       "key": "94b74813d147ed22d032207003ecf5979e5c1c0acef08cf76ccf0918fe9df24d441598ad442b6a23f22138cd612f83ca2f2d33aca6dbd07888e086d1adbe5416",
-      "line": 64,
+      "line": 66,
       "relation": "association",
       "source": 6,
       "target": 5
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Buck A",
@@ -246,12 +281,17 @@
       },
       "evidence": "We found high correlation coefficients for four brain regions (right superior parietal lobule, left thalamus, right pos- terior subcortical region, and left posterior subcor- tical region) and two CERAD subtests (Word List Intrusions and Boston Naming Test), some of them were statistically significant.",
       "key": "bbf90111764e0251398ba1b3987ae324873a14141b62d3ea1c2612c034288b56dd836794c2f58c4e531d52fcfbd89aabd403443cf2b3dce6dfcda11e56184f81",
-      "line": 77,
+      "line": 85,
       "relation": "association",
       "source": 6,
       "target": 5
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Buck A",
@@ -275,12 +315,17 @@
       },
       "evidence": "The most intense accumulation of 5-I-A-85380 was detected in both thalami, pons and midbrain, and both nuclei lentiformes",
       "key": "c6964edbf4617d9bc21975f8594fdff60c7e068fa1653c3f7e65c094e6c967ef7058256ed9bc2abd5584becdfd9cd12257c339750fb34440137ba7bc7637f665",
-      "line": 65,
+      "line": 67,
       "relation": "association",
       "source": 6,
       "target": 4
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Buck A",
@@ -304,12 +349,17 @@
       },
       "evidence": "The most intense accumulation of 5-I-A-85380 was detected in both thalami, pons and midbrain, and both nuclei lentiformes",
       "key": "bf8ca35b69e5a8d594e1ddab2a5d04241137c5d8f8d7d0d320eb07105e45368a73102e1c2f61127de11f0d8e947250b048a5894b9dd8e070c0ac2b3efe7cc1d2",
-      "line": 66,
+      "line": 68,
       "relation": "association",
       "source": 6,
       "target": 3
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Buck A",
@@ -333,12 +383,17 @@
       },
       "evidence": "The most intense accumulation of 5-I-A-85380 was detected in both thalami, pons and midbrain, and both nuclei lentiformes",
       "key": "2bddeaccfb697a1bb45b421e68d3365f88b769b6349c084a78c6c9c7abafd79acdbc315da720aa0bd59826f99ac24a0b5690427f3401e7b153a190c92e328df9",
-      "line": 67,
+      "line": 69,
       "relation": "association",
       "source": 6,
       "target": 0
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Buck A",
@@ -362,12 +417,17 @@
       },
       "evidence": "The right cerebellar white matter revealed a sig- nificantly higher 5-I-A-85380 uptake than the left cerebellar white matter.",
       "key": "badfa29bbae554b2557553327d57e4ede17a8ac3604354054825adcd75a4ca374d3573f3eeb3627a3ecbfb94b3f49633bf5301ae33c1551fb59afc23f6cbf71f",
-      "line": 70,
+      "line": 74,
       "relation": "positiveCorrelation",
       "source": 6,
       "target": 2
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Buck A",
@@ -391,12 +451,17 @@
       },
       "evidence": "Furthermore, we studied in these 17 IPD patients (at Hoehn and Yahr stage 1 and 2) whether there were differences of the a4b2 nAchR densities in the brain hemisphere contralateral to the clinically more affected body side (=contralat- eral hemisphere) compared to the brain hemi- sphere ipsilateral to the clinically more affected body side (=ipsilateral hemisphere).",
       "key": "dcd9556aec9ced470399ed2efbf624fcf9091c78e7ab838bfdd16c49b230173dbcc027669c90ae6dbaee787d430b8a918923e5ac6330b41518737e51c132d379",
-      "line": 73,
+      "line": 79,
       "relation": "association",
       "source": 6,
       "target": 7
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Buck A",
@@ -420,12 +485,17 @@
       },
       "evidence": "We found high correlation coefficients for four brain regions (right superior parietal lobule, left thalamus, right pos- terior subcortical region, and left posterior subcor- tical region) and two CERAD subtests (Word List Intrusions and Boston Naming Test), some of them were statistically significant.",
       "key": "5fb1a2e8368ab9dd6875b07e71863ca0779919edcff4ddab8c19ad332e89ce6cbffa98167ec8ad4535c57aa3d99f59497277d03d6ed04079fb84b2382bf91534",
-      "line": 76,
+      "line": 84,
       "relation": "association",
       "source": 6,
       "target": 1
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Buck A",
@@ -449,12 +519,17 @@
       },
       "evidence": "We found high correlation coefficients for four brain regions (right superior parietal lobule, left thalamus, right pos- terior subcortical region, and left posterior subcor- tical region) and two CERAD subtests (Word List Intrusions and Boston Naming Test), some of them were statistically significant.",
       "key": "79ce761ff79b72481567a3d6e460889e4ce05c76fc45a0da1fce4dc4803ed34dfee6f91095b45f28336670fe87b1cdc4a0d8bda49561d36567bff7d4d9e6ad9a",
-      "line": 79,
+      "line": 87,
       "relation": "association",
       "source": 6,
       "target": 8
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Buck A",
@@ -478,12 +553,17 @@
       },
       "evidence": "The most intense accumulation of 5-I-A-85380 was detected in both thalami, pons and midbrain, and both nuclei lentiformes",
       "key": "1fafd7a43a6919d188b31e061cb399c3988383030fab53307f4ffa35604569a2b115867d15beccfac9c716d003b1f989ecac12f31a91eee394faf08623e55f31",
-      "line": 64,
+      "line": 66,
       "relation": "association",
       "source": 5,
       "target": 6
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Buck A",
@@ -507,12 +587,17 @@
       },
       "evidence": "We found high correlation coefficients for four brain regions (right superior parietal lobule, left thalamus, right pos- terior subcortical region, and left posterior subcor- tical region) and two CERAD subtests (Word List Intrusions and Boston Naming Test), some of them were statistically significant.",
       "key": "300e8bc9712831a617e7835e6507c0b68137227eab750877d6302f67f4b6f89b5aea23d9d8e6a234a6dd61d98f9487aa5fd4dbf3edbcba54878522f7846472b1",
-      "line": 77,
+      "line": 85,
       "relation": "association",
       "source": 5,
       "target": 6
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Buck A",
@@ -536,12 +621,17 @@
       },
       "evidence": "The most intense accumulation of 5-I-A-85380 was detected in both thalami, pons and midbrain, and both nuclei lentiformes",
       "key": "d4233d08112e4df8085b091e2e3a5ea8e451ca32355e79984dd03ceeb1489ef3df0174917a6ce018d88fcbc2ab634bc16f2dd6474833e3d8823a81a84caf0e5f",
-      "line": 65,
+      "line": 67,
       "relation": "association",
       "source": 4,
       "target": 6
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Buck A",
@@ -565,12 +655,17 @@
       },
       "evidence": "The most intense accumulation of 5-I-A-85380 was detected in both thalami, pons and midbrain, and both nuclei lentiformes",
       "key": "561c12e40e02347020421df26b32feecac99ca5eb19452c52f940844b38df917f607da3c884e40afa18ff7defa4328d826f19ca4c984208e4338bd798d023d4f",
-      "line": 66,
+      "line": 68,
       "relation": "association",
       "source": 3,
       "target": 6
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Buck A",
@@ -594,12 +689,17 @@
       },
       "evidence": "The most intense accumulation of 5-I-A-85380 was detected in both thalami, pons and midbrain, and both nuclei lentiformes",
       "key": "e4c5822e5d4b15e275e4954230d7491daf2f09f72acbd573cf0b955466393fddf2de8a4a7c73b78306b3bc22c507f1270466e0fb3f2ac77d3712f957d7fab52c",
-      "line": 67,
+      "line": 69,
       "relation": "association",
       "source": 0,
       "target": 6
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Buck A",
@@ -623,12 +723,17 @@
       },
       "evidence": "The right cerebellar white matter revealed a sig- nificantly higher 5-I-A-85380 uptake than the left cerebellar white matter.",
       "key": "9d2217a42e1b46ff7fe435d2a6b90edf75e534607eb0b077c064a81b836ca34450040b89f7eaef512d3c94e0e7a09f7ef15273be9425dc0ce141df60f8baa9bb",
-      "line": 70,
+      "line": 74,
       "relation": "positiveCorrelation",
       "source": 2,
       "target": 6
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Buck A",
@@ -652,7 +757,7 @@
       },
       "evidence": "We found high correlation coefficients for four brain regions (right superior parietal lobule, left thalamus, right pos- terior subcortical region, and left posterior subcor- tical region) and two CERAD subtests (Word List Intrusions and Boston Naming Test), some of them were statistically significant.",
       "key": "81a47ae68fe1a2cb18196483420fb7e6ee9e24d01c764482ecc052a724e1f63426e4a19eccf4d389b6c903cac74b470c0be856e5d3af316a6d1e3826851f8201",
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diff --git a/hbp_knowledge/receptors/mandrekar2011.bel.json b/hbp_knowledge/receptors/mandrekar2011.bel.json
index 571ea953a..37bc1e54e 100644
--- a/hbp_knowledge/receptors/mandrekar2011.bel.json
+++ b/hbp_knowledge/receptors/mandrekar2011.bel.json
@@ -98,7 +98,7 @@
       },
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@@ -129,7 +129,7 @@
       },
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@@ -157,7 +157,7 @@
       },
       "evidence": "  In this study, it was shown that samples from human AD brains as well as two aged mouse models of AD showed increased mRNA levels of the M2 markers, Arg1 and Ym1, when compared to age matched controls [101].",
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@@ -185,7 +185,7 @@
       },
       "evidence": "  In this study, it was shown that samples from human AD brains as well as two aged mouse models of AD showed increased mRNA levels of the M2 markers, Arg1 and Ym1, when compared to age matched controls [101].",
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@@ -213,7 +213,7 @@
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@@ -241,7 +241,7 @@
       },
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@@ -269,7 +269,7 @@
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       "relation": "decreases",
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@@ -297,7 +297,7 @@
       },
       "evidence": "It has been postulated that soluble or small oligomeric forms of Ab have deleterious effects in the brain, inducing impaired synaptic function and promoting neuronal degeneration [5]. ",
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@@ -325,7 +325,7 @@
       },
       "evidence": "It has been postulated that soluble or small oligomeric forms of Ab have deleterious effects in the brain, inducing impaired synaptic function and promoting neuronal degeneration [5]. ",
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       "relation": "decreases",
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@@ -353,7 +353,7 @@
       },
       "evidence": "It has been postulated that soluble or small oligomeric forms of Ab have deleterious effects in the brain, inducing impaired synaptic function and promoting neuronal degeneration [5]. ",
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@@ -381,7 +381,7 @@
       },
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@@ -409,7 +409,7 @@
       },
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@@ -440,7 +440,7 @@
       },
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@@ -484,7 +484,7 @@
       },
       "evidence": "The plaque-associated microglia secrete a variety of cytotoxic species including the inflammatory cytokines, INF-g, TNF-a, IL-1b and IL-6 and chemokines, most prominently CCL2 [10-12]. ",
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@@ -528,7 +528,7 @@
       },
       "evidence": "The plaque-associated microglia secrete a variety of cytotoxic species including the inflammatory cytokines, INF-g, TNF-a, IL-1b and IL-6 and chemokines, most prominently CCL2 [10-12]. ",
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@@ -572,7 +572,7 @@
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       "evidence": "The plaque-associated microglia secrete a variety of cytotoxic species including the inflammatory cytokines, INF-g, TNF-a, IL-1b and IL-6 and chemokines, most prominently CCL2 [10-12]. ",
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@@ -616,7 +616,7 @@
       },
       "evidence": "The plaque-associated microglia secrete a variety of cytotoxic species including the inflammatory cytokines, INF-g, TNF-a, IL-1b and IL-6 and chemokines, most prominently CCL2 [10-12]. ",
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@@ -657,7 +657,7 @@
       },
       "evidence": "The development of dense-core amyloid plaques is associated with a robust immune response mediated by microglial cells.",
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@@ -685,7 +685,7 @@
       },
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@@ -713,7 +713,7 @@
       },
       "evidence": "The deposition of fibrillar Ab in the AD brain results in the recruitment of microglia to the plaques owing to their expression of CCL2, which acts to attract microglia [82].",
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@@ -744,7 +744,7 @@
       },
       "evidence": "In the past decade, drugs targeting the NRs, peroxisome proliferator-activated receptor g (PPARg) and liver X receptor (LXR) have shown to ameliorate pathogenesis in animal models of AD.",
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@@ -778,7 +778,7 @@
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       "object": {
         "modifier": "Degradation"
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@@ -815,7 +815,7 @@
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@@ -849,7 +849,7 @@
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       "evidence": "Activation of these receptors has been shown to suppress microglial-mediated inflammatory responses both in vitro and in vivo.",
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@@ -883,7 +883,7 @@
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       "evidence": "PPAR-g is involved in lipid storage, insulin sensitivity and energy metabolism and has been shown to promote adipocyte differentiation [21]. ",
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@@ -914,7 +914,7 @@
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@@ -945,7 +945,7 @@
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       "evidence": "PPAR-g is involved in lipid storage, insulin sensitivity and energy metabolism and has been shown to promote adipocyte differentiation [21]. ",
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@@ -976,7 +976,7 @@
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@@ -1007,7 +1007,7 @@
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       "evidence": " Numerous studies have shown that both PPAR-g and LXRs induce the expression of ApoE and ABCA1 and it is through the expression of these proteins that they exert their effects on amyloid pathology.",
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@@ -1038,7 +1038,7 @@
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       "evidence": " Numerous studies have shown that both PPAR-g and LXRs induce the expression of ApoE and ABCA1 and it is through the expression of these proteins that they exert their effects on amyloid pathology.",
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@@ -3693,7 +3693,7 @@
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       "evidence": "The synthetic TZD PPAR-g agonists are widely prescribed for the treatment of type 2 diabetes mellitus, and have also been shown to be efficacious in a number of CNS disease models [21]. Currently, two TZD agonists, Actos (pioglitazone) and Avandia (rosiglitazone), are FDA approved for the treatment of diabetes.",
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       "evidence": "Pedersen and Flynn examined the effects of rosiglitazone and found that activation of PPAR-g ameliorated behavioral deficits in the Tg2576 AD mouse model. However, these animals displayed no changes in plaque pathology, but had reduced brain Ab42 levels. ",
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       },
       "evidence": "Pedersen and Flynn examined the effects of rosiglitazone and found that activation of PPAR-g ameliorated behavioral deficits in the Tg2576 AD mouse model. However, these animals displayed no changes in plaque pathology, but had reduced brain Ab42 levels. ",
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@@ -3777,7 +3777,7 @@
       },
       "evidence": " These animals were treated with a low dose of rosiglitazone (3 mg/kg/ day) for 12 weeks and evaluated for plaque deposition and behavior. These animals displayed an approximate 50% decrease in amyloid deposition, a decrease in Ab oligomers, preservation of pre and postsynaptic proteins and the attenuation of cognitive deficits in the Morris water maze. ",
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       },
       "evidence": "Pedersen and Flynn examined the effects of rosiglitazone and found that activation of PPAR-g ameliorated behavioral deficits in the Tg2576 AD mouse model. However, these animals displayed no changes in plaque pathology, but had reduced brain Ab42 levels. ",
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       },
       "evidence": " These animals were treated with a low dose of rosiglitazone (3 mg/kg/ day) for 12 weeks and evaluated for plaque deposition and behavior. These animals displayed an approximate 50% decrease in amyloid deposition, a decrease in Ab oligomers, preservation of pre and postsynaptic proteins and the attenuation of cognitive deficits in the Morris water maze. ",
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       "evidence": " These animals were treated with a low dose of rosiglitazone (3 mg/kg/ day) for 12 weeks and evaluated for plaque deposition and behavior. These animals displayed an approximate 50% decrease in amyloid deposition, a decrease in Ab oligomers, preservation of pre and postsynaptic proteins and the attenuation of cognitive deficits in the Morris water maze. ",
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       },
       "evidence": " The authors argue that the effects of rosiglitazone were due to the activation of the wnt signaling cascade which they show by an increase in b-catenin expression and a decrease in GSK-3b levels [63].",
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       },
       "evidence": " The authors argue that the effects of rosiglitazone were due to the activation of the wnt signaling cascade which they show by an increase in b-catenin expression and a decrease in GSK-3b levels [63].",
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       },
       "evidence": "While the authors did not detect an increase in ApoE levels in the treated animals, they did observe a modest increase in ABCA1 levels and argue that the enhanced Ab clearance could be attributed to an increase in lipidation of ApoE by ABCA1 [64]. ",
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       },
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       },
       "evidence": " A Phase II clinical trial in which patients were treated with rosiglitazone for 6 months showed improvements in attention and memory retention, but only in patients who did not have an APOE4 allele.",
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       },
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       },
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       },
       "evidence": "The PPAR-d agonist GW501516 induced expression of ABCA1 and apolipoprotein A1, a peripheral lipid transporter, in macrophages [71]. ",
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       },
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       },
       "evidence": "In a study reported by Kalinin et al., treatment of 5xFAD mice with the PPAR-d agonist, GW742, resulted in decreased plaque burden and an increase in the expression of two Ab proteases, neprilysin and IDE [72].",
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       },
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       },
       "evidence": " ATRA not only activates RXR but also activates the retinoic acid receptor. ",
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       "evidence": " Treatment of 5-month-old APP/PS1 mice for 8 weeks with ATRA (20 mg/kg/day) resulted in significant decreases in Ab deposition and tau phosphorylation in these mice. Additionally, it attenuated memory deficits seen in the Morris water maze [77]. ",
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       },
       "evidence": " Treatment of 5-month-old APP/PS1 mice for 8 weeks with ATRA (20 mg/kg/day) resulted in significant decreases in Ab deposition and tau phosphorylation in these mice. Additionally, it attenuated memory deficits seen in the Morris water maze [77]. ",
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       "evidence": " Treatment of 5-month-old APP/PS1 mice for 8 weeks with ATRA (20 mg/kg/day) resulted in significant decreases in Ab deposition and tau phosphorylation in these mice. Additionally, it attenuated memory deficits seen in the Morris water maze [77]. ",
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       "evidence": "Bexarotene is a highly specific RXR agonist and is currently FDA approved with a favorable side effect profile. Studies in our laboratory have shown that treatment of APP/ PS1 animals with bexarotene for only 3 days results in a dramatic induction of ApoE and ABCA1 and the rapid reversal of AD-associated pathological hallmarks including reduction in amyloid deposition and deficits in behavior as well as neural networks.",
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       "evidence": "Bexarotene is a highly specific RXR agonist and is currently FDA approved with a favorable side effect profile. Studies in our laboratory have shown that treatment of APP/ PS1 animals with bexarotene for only 3 days results in a dramatic induction of ApoE and ABCA1 and the rapid reversal of AD-associated pathological hallmarks including reduction in amyloid deposition and deficits in behavior as well as neural networks.",
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       },
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       },
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       "evidence": " More recently, a naturally occurring RXR agonist, honokiol, has been identified. This agonist is capable of activating RXR/LXR heterodimers and has been shown to induce the expression of ABCA1 and ApoE and should be tested in AD models [75,78].",
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       },
       "evidence": " More recently, a naturally occurring RXR agonist, honokiol, has been identified. This agonist is capable of activating RXR/LXR heterodimers and has been shown to induce the expression of ABCA1 and ApoE and should be tested in AD models [75,78].",
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       "evidence": " More recently, a naturally occurring RXR agonist, honokiol, has been identified. This agonist is capable of activating RXR/LXR heterodimers and has been shown to induce the expression of ABCA1 and ApoE and should be tested in AD models [75,78].",
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@@ -4585,7 +4585,7 @@
       },
       "evidence": " More recently, a naturally occurring RXR agonist, honokiol, has been identified. This agonist is capable of activating RXR/LXR heterodimers and has been shown to induce the expression of ABCA1 and ApoE and should be tested in AD models [75,78].",
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       "evidence": "  In this study, it was shown that samples from human AD brains as well as two aged mouse models of AD showed increased mRNA levels of the M2 markers, Arg1 and Ym1, when compared to age matched controls [101].",
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       "evidence": "  In this study, it was shown that samples from human AD brains as well as two aged mouse models of AD showed increased mRNA levels of the M2 markers, Arg1 and Ym1, when compared to age matched controls [101].",
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       "evidence": "The Ab peptide is generated by the sequential cleavage of the amyloid precursor protein (APP) by the b and g secretases, resulting in the generation of peptides 40 or 42 amino acids in length [2].",
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       "evidence": "The Ab peptide is generated by the sequential cleavage of the amyloid precursor protein (APP) by the b and g secretases, resulting in the generation of peptides 40 or 42 amino acids in length [2].",
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       "evidence": "The Ab peptide is generated by the sequential cleavage of the amyloid precursor protein (APP) by the b and g secretases, resulting in the generation of peptides 40 or 42 amino acids in length [2].",
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@@ -4837,7 +4837,7 @@
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@@ -4865,7 +4865,7 @@
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@@ -4893,7 +4893,7 @@
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@@ -4924,7 +4924,7 @@
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       "evidence": "The ApoE4 allele is most important genetic risk factor for AD, while the ApoE2 allele is thought to be protective.",
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@@ -4952,7 +4952,7 @@
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@@ -4980,7 +4980,7 @@
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@@ -5008,7 +5008,7 @@
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diff --git a/hbp_knowledge/receptors/matta2017.bel.json b/hbp_knowledge/receptors/matta2017.bel.json
index 80f7cea05..ae1a8fa69 100644
--- a/hbp_knowledge/receptors/matta2017.bel.json
+++ b/hbp_knowledge/receptors/matta2017.bel.json
@@ -53,6 +53,11 @@
   },
   "links": [
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@@ -75,12 +80,17 @@
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@@ -103,12 +113,17 @@
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@@ -131,12 +146,17 @@
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@@ -158,14 +178,17 @@
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-      "line": 109,
-      "relation": "increases",
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@@ -192,13 +215,16 @@
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       "target": 21
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     {
       "annotations": {
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         "MeSHAnatomy": {
           "Substantia Nigra": true
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@@ -225,18 +251,23 @@
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       "evidence": "In substantia nigra, postsynaptic nicotinic receptors induce inward currents to excite dopaminergic neurons that project to corpus striatum (Matsubayashi et al., 2003)",
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@@ -259,13 +290,16 @@
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         "MeSHAnatomy": {
           "Basal Ganglia": true,
           "Prefrontal Cortex": true
@@ -293,12 +327,17 @@
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@@ -321,84 +360,83 @@
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@@ -421,12 +459,17 @@
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@@ -449,12 +492,17 @@
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@@ -477,13 +525,49 @@
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+      "citation": {
+        "authors": [
+          "Bredt DS",
+          "Davini WB",
+          "Gu S",
+          "Harrington AW",
+          "Lord B",
+          "Matta JA",
+          "Siuda ER"
+        ],
+        "date": "2017-04-25",
+        "first": "Matta JA",
+        "last": "Bredt DS",
+        "name": "Cell reports",
+        "pages": "688-696",
+        "reference": "28445721",
+        "title": "NACHO Mediates Nicotinic Acetylcholine Receptor Function throughout the Brain.",
+        "type": "PubMed",
+        "volume": "19"
+      },
+      "evidence": "Indeed, presynaptic effects of nAChRs in regulating dopamine release in basal ganglia and prefrontal cortex likely participate in nicotine’s addictive and cognitive effects, respectively (Jasinska et al., 2014)",
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         "Species": {
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@@ -510,12 +594,17 @@
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       "citation": {
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@@ -538,12 +627,17 @@
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       "evidence": "nAChRs also underlie the behavioral and addictive properties of nicotine",
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     {
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+        }
+      },
       "citation": {
         "authors": [
           "Bredt DS",
@@ -566,7 +660,7 @@
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       "evidence": "Numerous studies have shown that chronic nicotine exposure enhances surface expression of nAChRs, especially for the alpha4beta2 subtype (Schwartz and Kellar, 1983)",
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@@ -581,38 +675,15 @@
         "modifier": "Translocation"
       },
       "relation": "increases",
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-        "first": "Matta JA",
-        "last": "Bredt DS",
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-        "reference": "28445721",
-        "title": "NACHO Mediates Nicotinic Acetylcholine Receptor Function throughout the Brain.",
-        "type": "PubMed",
-        "volume": "19"
+      "annotations": {
+        "Confidence": {
+          "High": true
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@@ -862,12 +973,17 @@
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@@ -952,15 +1078,20 @@
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       "evidence": "In C. elegans, RIC-3 protein is essential for nAChR function (Nguyen et al., 1995), and mammalian RIC-3 has modest and mixed effects on nAChRs (Halevi et al., 2003; Millar, 2008)",
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       "evidence": "For alpha7 and alpha3beta2, RIC-3 did not enable detectable [3H]epibatidine binding, yet RIC-3 profoundly augmented the effects of NACHO on [3H]epibatidine binding to either receptor subtype (Figures 3A and S1A)",
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       "evidence": "As previously reported using fluorescently labeled alpha-bungarotoxin (Gu et al., 2016), NACHO enabled formation of assembled surface alpha7 receptors, and RIC-3 further enhanced this (Figures 3E and 3F)",
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@@ -1080,15 +1226,20 @@
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       "evidence": "Using a genomic cDNA screening strategy, we recently identified NACHO (Gu et al., 2016), a small multi-pass transmembrane protein enriched in neuronal endoplasmic reticulum (ER) that can mediate functional reconstitution of alpha7 receptors in non-neuronal cell lines",
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@@ -1111,7 +1262,7 @@
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@@ -1137,6 +1288,11 @@
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@@ -1172,6 +1328,11 @@
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@@ -1194,12 +1355,12 @@
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       "evidence": "As published previously (Gu et al., 2016), ACh evoked currents from alpha7 require NACHO, and currents from alpha4beta2 were augmented ~3-fold by NACHO, which did not alter the desensitization kinetics of alpha4beta2 receptors (Figures 1A and 1B)",
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@@ -1210,6 +1371,11 @@
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@@ -1232,7 +1398,7 @@
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       "evidence": "As previously published (Gu et al., 2016), robust surface alpha7 and alpha4beta2 expression required co-transfection with NACHO (Figures 1C and D), and we find that alpha3beta2 is also NACHO-dependent (Figures 1C and D)",
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@@ -1259,6 +1425,9 @@
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@@ -1285,9 +1454,9 @@
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       "evidence": "Our previous studies demonstrated that NACHO promotes assembly of alpha7 receptors as evidenced by alpha-bungarotoxin labeling, (Gu et al., 2016) which in brain only binds with high affinity to properly folded pentameric alpha7 receptors (Couturier et al., 1990; Schoepfer et al., 1990)",
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@@ -1298,6 +1467,11 @@
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       "evidence": "In membranes from alpha7-transfected cells, [3H]epibatidine binding absolutely required NACHO (Figure 2A), which fits with an essential role for NACHO in alpha7 assembly",
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@@ -1355,7 +1534,7 @@
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@@ -1403,15 +1587,20 @@
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@@ -1434,15 +1623,20 @@
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@@ -1465,15 +1659,20 @@
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+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Bredt DS",
@@ -1496,15 +1695,20 @@
       },
       "evidence": "NACHO does not affect function of ion channels gated by numerous other ligands including glutamate, GABA, serotonin, and capsaicin, suggesting that NACHO represents the only essential client-specific chaperone yet identified for any mammalian neurotransmitter receptor (Gu et al., 2016)",
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       "object": {
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       "relation": "causesNoChange",
-      "source": 52,
+      "source": 54,
       "target": 7
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Bredt DS",
@@ -1527,12 +1731,12 @@
       },
       "evidence": "As published previously (Gu et al., 2016), ACh evoked currents from alpha7 require NACHO, and currents from alpha4beta2 were augmented ~3-fold by NACHO, which did not alter the desensitization kinetics of alpha4beta2 receptors (Figures 1A and 1B)",
       "key": "357c5038fd9844c1182b07dd7b8e14507bf16b96e63192a4a2a93911337477e1d99e79aec65ef6203b2d2efc200c3b755f7e634c3336854bd4dcebe4368cd524",
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       "subject": {
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           "name": "chap",
@@ -1543,6 +1747,11 @@
       "target": 4
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Bredt DS",
@@ -1565,7 +1774,7 @@
       },
       "evidence": "As previously published (Gu et al., 2016), robust surface alpha7 and alpha4beta2 expression required co-transfection with NACHO (Figures 1C and D), and we find that alpha3beta2 is also NACHO-dependent (Figures 1C and D)",
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@@ -1580,7 +1789,7 @@
         "modifier": "Translocation"
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       "relation": "increases",
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       "subject": {
         "effect": {
           "name": "chap",
@@ -1591,6 +1800,11 @@
       "target": 4
     },
     {
+      "annotations": {
+        "Confidence": {
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+        }
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       "citation": {
         "authors": [
           "Bredt DS",
@@ -1613,9 +1827,9 @@
       },
       "evidence": "Cells transfected with alpha4beta2 or alpha3beta4 alone showed [3H]epibatidine binding, and this was markedly increased (5- to 10-fold) in presence of NACHO (Figures 2B and 2D)",
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@@ -1626,6 +1840,11 @@
       "target": 4
     },
     {
+      "annotations": {
+        "Confidence": {
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+        }
+      },
       "citation": {
         "authors": [
           "Bredt DS",
@@ -1648,12 +1867,12 @@
       },
       "evidence": "We now also find that alpha3beta2 receptor function in HEK cells requires NACHO, and these channels showed desensitization kinetics generally similar to alpha4beta2 (Figures 1A and 1B)",
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@@ -1664,6 +1883,11 @@
       "target": 12
     },
     {
+      "annotations": {
+        "Confidence": {
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+        }
+      },
       "citation": {
         "authors": [
           "Bredt DS",
@@ -1686,7 +1910,7 @@
       },
       "evidence": "As previously published (Gu et al., 2016), robust surface alpha7 and alpha4beta2 expression required co-transfection with NACHO (Figures 1C and D), and we find that alpha3beta2 is also NACHO-dependent (Figures 1C and D)",
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@@ -1701,7 +1925,7 @@
         "modifier": "Translocation"
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       "relation": "increases",
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       "subject": {
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           "name": "chap",
@@ -1712,6 +1936,11 @@
       "target": 12
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Bredt DS",
@@ -1734,9 +1963,9 @@
       },
       "evidence": "Similarly, quantifiable [3H]epibatidine binding to alpha3beta2 required cotransfection with NACHO (Figure 2C)",
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       "subject": {
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           "name": "chap",
@@ -1747,6 +1976,11 @@
       "target": 12
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "Bredt DS",
@@ -1769,12 +2003,12 @@
       },
       "evidence": "For alpha3beta4 alone, ACh evoked large slowly-desensitizing responses, and NACHO amplified their magnitudes ~5-fold (Figures 1A and 1B)",
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       "subject": {
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           "name": "chap",
@@ -1785,6 +2019,11 @@
       "target": 13
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Bredt DS",
@@ -1807,7 +2046,7 @@
       },
       "evidence": " For alpha3beta4 alone, we found abundant surface labeling and this was enhanced by NACHO (Figures 1C and 1D)",
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@@ -1822,7 +2061,7 @@
         "modifier": "Translocation"
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@@ -1833,6 +2072,11 @@
       "target": 13
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
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       "citation": {
         "authors": [
           "Bredt DS",
@@ -1855,9 +2099,9 @@
       },
       "evidence": "Cells transfected with alpha4beta2 or alpha3beta4 alone showed [3H]epibatidine binding, and this was markedly increased (5- to 10-fold) in presence of NACHO (Figures 2B and 2D)",
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@@ -1868,6 +2112,11 @@
       "target": 13
     },
     {
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+        "Confidence": {
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       "citation": {
         "authors": [
           "Bredt DS",
@@ -1890,9 +2139,9 @@
       },
       "evidence": "In membranes from alpha7-transfected cells, [3H]epibatidine binding absolutely required NACHO (Figure 2A), which fits with an essential role for NACHO in alpha7 assembly",
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@@ -1903,6 +2152,11 @@
       "target": 29
     },
     {
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+        }
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       "citation": {
         "authors": [
           "Bredt DS",
@@ -1925,9 +2179,9 @@
       },
       "evidence": "Similarly, quantifiable [3H]epibatidine binding to alpha3beta2 required cotransfection with NACHO (Figure 2C)",
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@@ -1938,6 +2192,11 @@
       "target": 30
     },
     {
+      "annotations": {
+        "Confidence": {
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+        }
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       "citation": {
         "authors": [
           "Bredt DS",
@@ -1960,9 +2219,9 @@
       },
       "evidence": "Cells transfected with alpha4beta2 or alpha3beta4 alone showed [3H]epibatidine binding, and this was markedly increased (5- to 10-fold) in presence of NACHO (Figures 2B and 2D)",
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@@ -1973,6 +2232,11 @@
       "target": 26
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Bredt DS",
@@ -1995,9 +2259,9 @@
       },
       "evidence": "Cells transfected with alpha4beta2 or alpha3beta4 alone showed [3H]epibatidine binding, and this was markedly increased (5- to 10-fold) in presence of NACHO (Figures 2B and 2D)",
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@@ -2008,6 +2272,11 @@
       "target": 31
     },
     {
+      "annotations": {
+        "Confidence": {
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+        }
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       "citation": {
         "authors": [
           "Bredt DS",
@@ -2030,12 +2299,17 @@
       },
       "evidence": "However, we did find that NACHO enhances [3H]epibatidine binding to cells transfected with alpha6beta2beta3 (Figure 4C) indicating that NACHO can enhance intracellular receptor assembly",
       "key": "05a01c0f0f30128ec2ebaab0a3d64c35b0dfded623f2cfb42e47a7d9e21ef3e56322390184ee994c28b5758432bea12ade5c8f3fabbfd07c479efe739bfeeae6",
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       "target": 28
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     {
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       "citation": {
         "authors": [
           "Bredt DS",
@@ -2058,12 +2332,17 @@
       },
       "evidence": "Whereas this subunit combination is not competent to form a functional channel (Champtiaux et al., 2002; Dash et al., 2014; Kuryatov et al., 2000), NACHO still mediated partial receptor assembly as reflected by [3H]epibatidine binding (Figure 4D)",
       "key": "c3612c36db5cf54e73876d184c21e5b657a0d97970c54645d1e50dd4a6e2169e3617d59c1cabc0f26fbae778134279831c90ab75ccead29a20511999891c27b7",
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       "relation": "increases",
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       "target": 28
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     {
+      "annotations": {
+        "Confidence": {
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+        }
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       "citation": {
         "authors": [
           "Bredt DS",
@@ -2086,13 +2365,16 @@
       },
       "evidence": "Whereas this subunit combination is not competent to form a functional channel (Champtiaux et al., 2002; Dash et al., 2014; Kuryatov et al., 2000), NACHO still mediated partial receptor assembly as reflected by [3H]epibatidine binding (Figure 4D)",
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       "target": 10
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     {
       "annotations": {
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         "Species": {
           "10090": true
         }
@@ -2119,9 +2401,9 @@
       },
       "evidence": "Importantly, NACHO knockout mice show complete loss of alpha7 ligand binding and channel function indicating that NACHO is required for formation of alpha7 receptors (Gu et al., 2016)",
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@@ -2133,6 +2415,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Species": {
           "10090": true
         }
@@ -2159,13 +2444,16 @@
       },
       "evidence": "These experiments showed that NACHO is most concentrated in the heavy (P3) and light (P4) microsomal fractions (Figures 3C and 3D), which contain resident endoplasmic reticulum (ER) proteins including calnexin",
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       "relation": "association",
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+      "target": 56
     },
     {
       "annotations": {
+        "Confidence": {
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+        },
         "Species": {
           "10090": true
         }
@@ -2192,13 +2480,16 @@
       },
       "evidence": "We previously showed that [125I]alpha-bungarotoxin binding is absent in NACHO knockout mice brain (Gu et al., 2016), which express normal levels of RIC-3 mRNA (Figure S1B)",
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       "target": 35
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Cerebral Cortex": true,
           "Corpus Striatum": true,
@@ -2230,13 +2521,16 @@
       },
       "evidence": "[125I]epibatidine binding was decreased in all brain regions evaluated—it was reduced by 66% in cortex, 39% in striatum, and 51% in medial vestibular nucleus (MVN) (Figures 5A and 5D)",
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       "target": 27
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     {
       "annotations": {
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         "Species": {
           "10090": true
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@@ -2263,13 +2557,16 @@
       },
       "evidence": "This partial reduction fits with our data showing that NACHO enhances [3H]epibatidine binding to alpha4beta2 and other heteromeric nAChRs but that some [3H]epibatidine binding occurs to certain heteromeric nAChRs in the absence of NACHO (Figure 2B)",
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+      "source": 57,
       "target": 26
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Corpus Striatum": true
         },
@@ -2299,13 +2596,16 @@
       },
       "evidence": "Labeling of alpha6-containing nAChRs in striatum by [125I]conotoxin MII is virtually abolished in NACHO knockout mice (Figures 5B and 5D), indicating a vital role for NACHO in assembly of these presynaptic receptors",
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       "target": 5
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "MeSHAnatomy": {
           "Brain": true
         },
@@ -2334,14 +2634,23 @@
         "volume": "19"
       },
       "evidence": "Consistent with our previous autoradiographic results (Gu et al., 2016), we found no detectable [3H]alpha-bungarotoxin binding to brain membranes from NACHO knockouts",
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+      "line": 411,
+      "object": {
+        "location": {
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+          "namespace": "GO"
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       "relation": "increases",
-      "source": 55,
-      "target": 33
+      "source": 57,
+      "target": 34
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Cerebral Cortex": true,
           "Corpus Striatum": true,
@@ -2373,13 +2682,16 @@
       },
       "evidence": "In membranes from cerebral cortex, hippocampus, and striatum, we found that levels of [3H]epibatidine binding sites are decreased by 50%–75%",
       "key": "3b21a87093ed4837822d4080520379dc85715624b8d415c70208e632c84a9181627047e62765789fed880409067754c7879893ece80c13b2d17be76500cbea00",
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+      "target": 39
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Species": {
           "10090": true
         }
@@ -2406,13 +2718,16 @@
       },
       "evidence": "A very recent study also reported memory defects in mice lacking NACHO/TMEM35 done by scientists unaware of NACHO’s role in controlling nAChRs (Kennedy et al., 2016)",
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       "relation": "regulates",
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-      "target": 36
+      "source": 57,
+      "target": 39
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Superior Cervical Ganglion": true
         },
@@ -2442,13 +2757,16 @@
       },
       "evidence": "NACHO knockouts did not show changes in levels of [3H]epibatidine binding to membranes from superior cervical ganglia (wild-type [WT] 329.0 ± 17.2, knockout [KO] 322.8 ± 4.0 fmol/mg protein), which primarily express receptors containing alpha3beta4-containing receptors (David et al., 2010)",
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@@ -2475,13 +2793,16 @@
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       "evidence": "General characterization showed that the knockout mice as compared to their wild-type littermates show no changes in body weight, have slight increases in body temperature (Figures S3A and S3B), and exhibit significantly enhanced locomotor activity (Figures S2A and S2B)",
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@@ -2508,13 +2829,16 @@
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@@ -2541,13 +2865,16 @@
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@@ -2574,13 +2901,16 @@
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@@ -2607,13 +2937,16 @@
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@@ -2640,13 +2973,16 @@
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@@ -2711,30 +3040,45 @@
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@@ -2806,16 +3276,61 @@
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@@ -2846,7 +3366,7 @@
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-      "key": "aad28732a46c68335c68da9e9540c69960e97637e86a43ee56ff350e79e35996615ddd61d68f64b926a48cf719786b3bda44676903526abf1ad55dda2020372d",
-      "relation": "hasComponent",
-      "source": 33,
+      "source": 34,
       "target": 14
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Species": {
           "10090": true
         }
@@ -2915,14 +3432,21 @@
       },
       "evidence": "General characterization showed that the knockout mice as compared to their wild-type littermates show no changes in body weight, have slight increases in body temperature (Figures S3A and S3B), and exhibit significantly enhanced locomotor activity (Figures S2A and S2B)",
       "key": "5143bef3c70dc538f4325c20ce44df85a892d50d77e002014c44e67ac30837e08e4f170bc115c85a865291e9a9ee6286aa15281f160fd7b3ac25c22fba44e75a",
-      "line": 350,
+      "line": 442,
       "relation": "association",
       "source": 20,
-      "target": 55
+      "target": 57
     }
   ],
   "multigraph": true,
   "nodes": [
+    {
+      "bel": "a(CHEBI:acetylcholine)",
+      "function": "Abundance",
+      "id": "bae5841bb74f1e9eb73cd433cda657927031217c24e17f21bb2975128d1d9be4dc899448ede71d9aa18224145a1681b90b33287454eabf938f405bc1b8894b62",
+      "name": "acetylcholine",
+      "namespace": "CHEBI"
+    },
     {
       "bel": "a(CHEBI:epibatidine)",
       "function": "Abundance",
@@ -2937,13 +3461,6 @@
       "name": "nicotine",
       "namespace": "CHEBI"
     },
-    {
-      "bel": "a(GO:membrane)",
-      "function": "Abundance",
-      "id": "09305a501cf3bf7a45ecb4a391b757c0608c849562404df8ccaf5fa0f6d76dd5598dc0d1c9c8e6e81321e583573b3b88f512123c22e62dc747cfc499a822e3cc",
-      "name": "membrane",
-      "namespace": "GO"
-    },
     {
       "bel": "a(GO:synapse)",
       "function": "Abundance",
@@ -3253,16 +3770,16 @@
       ]
     },
     {
-      "bel": "complex(a(GO:membrane), a(MESH:Bungarotoxins))",
+      "bel": "complex(a(MESH:\"alpha7 Nicotinic Acetylcholine Receptor\"), a(MESH:Bungarotoxins))",
       "function": "Complex",
-      "id": "031f37019663ef5084e016d92ec6acd3e15d88b90071102fa23a357dfb20b2cf9a922d8d334c69f65aa7c399d6df58816341470c050f2bfc7af29026291489e6",
+      "id": "196cd5ab9b083c7faaed04a55fcdd079541ab15f8b2258242029ac3fb0602ecb70a9d7d37056b07c3f87867d917f49fe671af8221ec65b372f18fce053100002",
       "members": [
         {
-          "bel": "a(GO:membrane)",
+          "bel": "a(MESH:\"alpha7 Nicotinic Acetylcholine Receptor\")",
           "function": "Abundance",
-          "id": "09305a501cf3bf7a45ecb4a391b757c0608c849562404df8ccaf5fa0f6d76dd5598dc0d1c9c8e6e81321e583573b3b88f512123c22e62dc747cfc499a822e3cc",
-          "name": "membrane",
-          "namespace": "GO"
+          "id": "24bfa0a4dedd705b999b510936aa1c989978fdeec807bf3046bd5178bd8e69ebbf2b1d2d2cd30ce5df8058656f59f497172cea193c9743a405bfb38be1aac50b",
+          "name": "alpha7 Nicotinic Acetylcholine Receptor",
+          "namespace": "MESH"
         },
         {
           "bel": "a(MESH:Bungarotoxins)",
@@ -3274,17 +3791,10 @@
       ]
     },
     {
-      "bel": "complex(a(MESH:\"alpha7 Nicotinic Acetylcholine Receptor\"), a(MESH:Bungarotoxins))",
+      "bel": "complex(a(MESH:Bungarotoxins))",
       "function": "Complex",
-      "id": "196cd5ab9b083c7faaed04a55fcdd079541ab15f8b2258242029ac3fb0602ecb70a9d7d37056b07c3f87867d917f49fe671af8221ec65b372f18fce053100002",
+      "id": "13a5b3171b4bdbcc832510f9ee7c4e2b48ad36a617fded77e597cc5f53ed04d6ca8f1fc95c2df58d6a8267316697361fd49631a2268e411d6e6964401192f2e0",
       "members": [
-        {
-          "bel": "a(MESH:\"alpha7 Nicotinic Acetylcholine Receptor\")",
-          "function": "Abundance",
-          "id": "24bfa0a4dedd705b999b510936aa1c989978fdeec807bf3046bd5178bd8e69ebbf2b1d2d2cd30ce5df8058656f59f497172cea193c9743a405bfb38be1aac50b",
-          "name": "alpha7 Nicotinic Acetylcholine Receptor",
-          "namespace": "MESH"
-        },
         {
           "bel": "a(MESH:Bungarotoxins)",
           "function": "Abundance",
@@ -3315,6 +3825,69 @@
         }
       ]
     },
+    {
+      "bel": "composite(a(CHEBI:nicotine), p(HGNC:TMEM35A))",
+      "function": "Composite",
+      "id": "836ff512bbf7e48c87a25c50cd3a94dd70b8e1146853ee0c570a4d28fdd043d19ae8d0c62865961decefc42b8fc23c5878eb25b56a9e7838362a0e4483c4cf46",
+      "members": [
+        {
+          "bel": "a(CHEBI:nicotine)",
+          "function": "Abundance",
+          "id": "81813864e07e0e955a0ccf7e9ec2430ce5cdbeae237c18991897f8314b29bdb2d0985dedfa71377ab67541fbcea0567e323d0cf47a5517efc83a67ac442abdb8",
+          "name": "nicotine",
+          "namespace": "CHEBI"
+        },
+        {
+          "bel": "p(HGNC:TMEM35A)",
+          "function": "Protein",
+          "id": "62d7b8949d28b1a914b324e4f2658416567c05bcd325776e0b92512d40cd111761661c7e1b3f009b0cdaa5270f56f7178e86cb93a5cb402ad517223d1f77edbe",
+          "name": "TMEM35A",
+          "namespace": "HGNC"
+        }
+      ]
+    },
+    {
+      "bel": "composite(a(MESH:Bungarotoxins), p(HGNC:TMEM35A))",
+      "function": "Composite",
+      "id": "b50d334a581322e74ccd363bb4558b7d1f6258853b590ea45cd3277405a38ba24b83f10c4c3553700a1ef4eda2ce75ff9f9c06f5eee305a92760da8a12b09200",
+      "members": [
+        {
+          "bel": "a(MESH:Bungarotoxins)",
+          "function": "Abundance",
+          "id": "e82ea3e9e348ccc642bfadc616f1a99ecd72a491d90148c9f3dab9d287736cbe6dc1c75aa356f12fe0d4f03ed52017ac9fd4193be328c15a06a0c26397db3fd2",
+          "name": "Bungarotoxins",
+          "namespace": "MESH"
+        },
+        {
+          "bel": "p(HGNC:TMEM35A)",
+          "function": "Protein",
+          "id": "62d7b8949d28b1a914b324e4f2658416567c05bcd325776e0b92512d40cd111761661c7e1b3f009b0cdaa5270f56f7178e86cb93a5cb402ad517223d1f77edbe",
+          "name": "TMEM35A",
+          "namespace": "HGNC"
+        }
+      ]
+    },
+    {
+      "bel": "composite(p(HGNC:RIC3), p(HGNC:TMEM35A))",
+      "function": "Composite",
+      "id": "eecdf13cc1aa68f9cb46c25bad92c9b4c567f1bf323b4ce7edba9c86a826d6416b3c42b4a2a4f3b203922d4e80ee530006985add9492b5dc19d7e21a8357460b",
+      "members": [
+        {
+          "bel": "p(HGNC:RIC3)",
+          "function": "Protein",
+          "id": "9ac95c76af66ed4e313c12c5b1edb4a0901635db9e4af0e51c9a82e895d636702cb4c11121b56d1a2149c1e632d835be9a8050cb4fa5563df261dbbb59733f12",
+          "name": "RIC3",
+          "namespace": "HGNC"
+        },
+        {
+          "bel": "p(HGNC:TMEM35A)",
+          "function": "Protein",
+          "id": "62d7b8949d28b1a914b324e4f2658416567c05bcd325776e0b92512d40cd111761661c7e1b3f009b0cdaa5270f56f7178e86cb93a5cb402ad517223d1f77edbe",
+          "name": "TMEM35A",
+          "namespace": "HGNC"
+        }
+      ]
+    },
     {
       "bel": "p(FPLX:CHRN)",
       "function": "Protein",
@@ -3336,13 +3909,6 @@
       "name": "HBP00174",
       "namespace": "HBP"
     },
-    {
-      "bel": "p(HGNC:CHRNA1)",
-      "function": "Protein",
-      "id": "2c954be76ae672869d04b052482aff81e8668f2b0c084e05a07b56bc45478c32c71764e3875f446be6d7e0117f400a88ca72e5d5fc0029229d0c16c4ae3e8e6f",
-      "name": "CHRNA1",
-      "namespace": "HGNC"
-    },
     {
       "bel": "p(HGNC:CHRNA10)",
       "function": "Protein",
diff --git a/hbp_knowledge/receptors/miwa2011.bel.json b/hbp_knowledge/receptors/miwa2011.bel.json
index 152efd5d8..82dbe86d5 100644
--- a/hbp_knowledge/receptors/miwa2011.bel.json
+++ b/hbp_knowledge/receptors/miwa2011.bel.json
@@ -54,6 +54,9 @@
   "links": [
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Brain": true
         }
@@ -76,13 +79,16 @@
       },
       "evidence": "In 2011, we know that cholinergic actions in the brain govern various processes: cognition (attention and executive function) (Couey et al., 2007; Levin and Rezvani, 2007; Heath and Picciotto, 2009; Howe et al., 2010), learning and memory (Gould, 2006; Couey et al., 2007; Levin and Rezvani, 2007), mood (anxiety, depression) (Picciotto et al., 2008), reward (addiction, craving) (Tang and Dani, 2009), and sensory processing (Heath and Picciotto, 2009)",
       "key": "077a7d797c2d31099e376d78ef7b8a87c0fc38372e57e774e2907a89ca120f83748e6b69e2ce4ccbc52ef049a50c122ea0b68c92e74eea0db913220f76e6e564",
-      "line": 82,
+      "line": 83,
       "relation": "association",
       "source": 35,
       "target": 36
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Brain": true
         }
@@ -105,13 +111,16 @@
       },
       "evidence": "In 2011, we know that cholinergic actions in the brain govern various processes: cognition (attention and executive function) (Couey et al., 2007; Levin and Rezvani, 2007; Heath and Picciotto, 2009; Howe et al., 2010), learning and memory (Gould, 2006; Couey et al., 2007; Levin and Rezvani, 2007), mood (anxiety, depression) (Picciotto et al., 2008), reward (addiction, craving) (Tang and Dani, 2009), and sensory processing (Heath and Picciotto, 2009)",
       "key": "6066535209a3520cedadef8168346d53067acf272090e62248b5a95af76b011d0d821c47d6562463b561beefb79caac30587c31ebfa79e491b6571353ba3fe1e",
-      "line": 83,
+      "line": 84,
       "relation": "association",
       "source": 35,
       "target": 37
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Brain": true
         }
@@ -134,13 +143,16 @@
       },
       "evidence": "In 2011, we know that cholinergic actions in the brain govern various processes: cognition (attention and executive function) (Couey et al., 2007; Levin and Rezvani, 2007; Heath and Picciotto, 2009; Howe et al., 2010), learning and memory (Gould, 2006; Couey et al., 2007; Levin and Rezvani, 2007), mood (anxiety, depression) (Picciotto et al., 2008), reward (addiction, craving) (Tang and Dani, 2009), and sensory processing (Heath and Picciotto, 2009)",
       "key": "ad19bbfec6e006984ff31a5022cdbc4d96ab469af9205d51152c2900e4ca538131601a0e055c19f461606450fcbdf03c395fa011b11cadec1a74aa8e356c2a6d",
-      "line": 84,
+      "line": 85,
       "relation": "association",
       "source": 35,
       "target": 38
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Brain": true
         }
@@ -163,13 +175,16 @@
       },
       "evidence": "In 2011, we know that cholinergic actions in the brain govern various processes: cognition (attention and executive function) (Couey et al., 2007; Levin and Rezvani, 2007; Heath and Picciotto, 2009; Howe et al., 2010), learning and memory (Gould, 2006; Couey et al., 2007; Levin and Rezvani, 2007), mood (anxiety, depression) (Picciotto et al., 2008), reward (addiction, craving) (Tang and Dani, 2009), and sensory processing (Heath and Picciotto, 2009)",
       "key": "80d3ac19457c21817895f143026b46407ce30957e2ddc756a40d85fc5dc0ee258c60f31d1ba9d9cd7f6a377e54bcea7b86f4657306efb8e31df5d36dbd0cea88",
-      "line": 85,
+      "line": 86,
       "relation": "association",
       "source": 35,
       "target": 98
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Brain": true
         }
@@ -192,13 +207,16 @@
       },
       "evidence": "In 2011, we know that cholinergic actions in the brain govern various processes: cognition (attention and executive function) (Couey et al., 2007; Levin and Rezvani, 2007; Heath and Picciotto, 2009; Howe et al., 2010), learning and memory (Gould, 2006; Couey et al., 2007; Levin and Rezvani, 2007), mood (anxiety, depression) (Picciotto et al., 2008), reward (addiction, craving) (Tang and Dani, 2009), and sensory processing (Heath and Picciotto, 2009)",
       "key": "00f4044562d36072a03594871ef3b9a151d767a53556941ad53cea07eda2258ad321e3a1aa4606f0519f4e7f41867315a54cb63c16018ebf87b99a0aa1d617a4",
-      "line": 86,
+      "line": 87,
       "relation": "association",
       "source": 35,
       "target": 101
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Brain": true
         }
@@ -221,12 +239,17 @@
       },
       "evidence": "In 2011, we know that cholinergic actions in the brain govern various processes: cognition (attention and executive function) (Couey et al., 2007; Levin and Rezvani, 2007; Heath and Picciotto, 2009; Howe et al., 2010), learning and memory (Gould, 2006; Couey et al., 2007; Levin and Rezvani, 2007), mood (anxiety, depression) (Picciotto et al., 2008), reward (addiction, craving) (Tang and Dani, 2009), and sensory processing (Heath and Picciotto, 2009)",
       "key": "247a1aa77c230224f63874e4e663516b10c55aedd674c79eed04ff45e926e96feee1e7f251d04dc9f1fce381a9ab9ceeecb068634ec0e9c48457be296d7a33ca",
-      "line": 87,
+      "line": 88,
       "relation": "association",
       "source": 35,
       "target": 33
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -245,13 +268,16 @@
       },
       "evidence": "While genetic linkages of lynx family members to neurological disorders have not been found, evidence for cholinergic dysregulation has been linked to a lynx family member expressed in nonneuronal tissues and involved in human disease (Chimienti et al., 2003), and as such, alterations in lynx dosage may be useful in ameliorating cognitive decline associated with neuropsychiatric disorders.",
       "key": "f6e23656d43312d616b4b197564c6593fbdaae4ac549de4b79942f57932c7f281e29abd52d705d54e6c634d08086d231fa85bc1de63e55c74ed2aefc1f5a841b",
-      "line": 288,
+      "line": 340,
       "relation": "association",
       "source": 35,
       "target": 76
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Brain": true
         }
@@ -274,12 +300,17 @@
       },
       "evidence": "In 2011, we know that cholinergic actions in the brain govern various processes: cognition (attention and executive function) (Couey et al., 2007; Levin and Rezvani, 2007; Heath and Picciotto, 2009; Howe et al., 2010), learning and memory (Gould, 2006; Couey et al., 2007; Levin and Rezvani, 2007), mood (anxiety, depression) (Picciotto et al., 2008), reward (addiction, craving) (Tang and Dani, 2009), and sensory processing (Heath and Picciotto, 2009)",
       "key": "bcd2c0bd9eca33aa747327d6e99419c7adfb51294d1ed930388ff0582c8611a9efed9345fd2ab98f01b00a63d067fab63267b19cbca6007911b58e16f0aa548a",
-      "line": 82,
+      "line": 83,
       "relation": "association",
       "source": 36,
       "target": 35
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -298,12 +329,17 @@
       },
       "evidence": "In rodents and humans, the hippocampus is importantly implicated in cognitive sensitization, and alpha4beta2* nAChRs play key roles (Levin et al., 2006; Davis and Gould, 2009)",
       "key": "3737be0670f16839b88d75bc85c6360488838edccb67f230fbd370760c81f0cd6f102cb39878d904a8f7adefe684407615287d27a654e0d014109037e74eddb8",
-      "line": 496,
+      "line": 610,
       "relation": "positiveCorrelation",
       "source": 36,
       "target": 11
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -322,12 +358,17 @@
       },
       "evidence": "Single-nucleotide polymorphisms found in the human alpha5, alpha3, beta4 gene cluster are associated with nicotine dependence and its age-dependent onset; number of cigarettes smoked per day and ‘‘pleasurable buzz’’ elicited by smoking; alcoholism, sensitivity to the depressant effects of alcohol, and age of alcohol initiation; cocaine dependence; opioid dependence; lung cancer; and cognitive flexibility (Erlich et al., 2010; Hansen et al., 2010; Improgo et al., 2010; Saccone et al., 2010; Zhang et al., 2010)",
       "key": "f4102e8eb90aa0433df205f7ce15f86d7cf767fdba4c7e28a08a7c36138b1f4aa6f253d30d565384433ec8ba90a62d5ad5d8d5c8d23e990b8fdcfb98b418baa4",
-      "line": 569,
+      "line": 703,
       "relation": "positiveCorrelation",
       "source": 36,
       "target": 67
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -346,12 +387,17 @@
       },
       "evidence": "Single-nucleotide polymorphisms found in the human alpha5, alpha3, beta4 gene cluster are associated with nicotine dependence and its age-dependent onset; number of cigarettes smoked per day and ‘‘pleasurable buzz’’ elicited by smoking; alcoholism, sensitivity to the depressant effects of alcohol, and age of alcohol initiation; cocaine dependence; opioid dependence; lung cancer; and cognitive flexibility (Erlich et al., 2010; Hansen et al., 2010; Improgo et al., 2010; Saccone et al., 2010; Zhang et al., 2010)",
       "key": "ddb4ce04651c023d9a831c25f7c3693ee24cfcb09f0865141433abba7c31013b5d26fb41a50cdead2b44390aaec61e0263a88a284a21a2997a2f21712e86656c",
-      "line": 575,
+      "line": 709,
       "relation": "positiveCorrelation",
       "source": 36,
       "target": 63
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -370,13 +416,16 @@
       },
       "evidence": "Single-nucleotide polymorphisms found in the human alpha5, alpha3, beta4 gene cluster are associated with nicotine dependence and its age-dependent onset; number of cigarettes smoked per day and ‘‘pleasurable buzz’’ elicited by smoking; alcoholism, sensitivity to the depressant effects of alcohol, and age of alcohol initiation; cocaine dependence; opioid dependence; lung cancer; and cognitive flexibility (Erlich et al., 2010; Hansen et al., 2010; Improgo et al., 2010; Saccone et al., 2010; Zhang et al., 2010)",
       "key": "46774a8ed75d47bd1df860b349b0982ab97a56358ccdbbd338616314e04f5c66cee07650246c1e87bd374804b2d8dbf09767fe0f7f385dfd844ca078232431eb",
-      "line": 581,
+      "line": 715,
       "relation": "positiveCorrelation",
       "source": 36,
       "target": 73
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Brain": true
         }
@@ -399,13 +448,16 @@
       },
       "evidence": "In 2011, we know that cholinergic actions in the brain govern various processes: cognition (attention and executive function) (Couey et al., 2007; Levin and Rezvani, 2007; Heath and Picciotto, 2009; Howe et al., 2010), learning and memory (Gould, 2006; Couey et al., 2007; Levin and Rezvani, 2007), mood (anxiety, depression) (Picciotto et al., 2008), reward (addiction, craving) (Tang and Dani, 2009), and sensory processing (Heath and Picciotto, 2009)",
       "key": "a07993855c74460c2ffc425ccf99e38994c5bfba0a11f6dccc4731bc0adfdfd5e0d4c91ed8d5174512b44697721f6ab452086995a39ecf62e5e51d2a9316bc5e",
-      "line": 83,
+      "line": 84,
       "relation": "association",
       "source": 37,
       "target": 35
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Brain": true
         }
@@ -428,13 +480,16 @@
       },
       "evidence": "In 2011, we know that cholinergic actions in the brain govern various processes: cognition (attention and executive function) (Couey et al., 2007; Levin and Rezvani, 2007; Heath and Picciotto, 2009; Howe et al., 2010), learning and memory (Gould, 2006; Couey et al., 2007; Levin and Rezvani, 2007), mood (anxiety, depression) (Picciotto et al., 2008), reward (addiction, craving) (Tang and Dani, 2009), and sensory processing (Heath and Picciotto, 2009)",
       "key": "e4c0cac4bd59fc2b5887ec5d966f498ede798389cfeccb78f601e82fceac1a21715936aeba53757c7c0b4e43459b622016b54e921c1e01a5e94dfa64c80163b2",
-      "line": 84,
+      "line": 85,
       "relation": "association",
       "source": 38,
       "target": 35
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Brain": true
         }
@@ -457,13 +512,16 @@
       },
       "evidence": "In 2011, we know that cholinergic actions in the brain govern various processes: cognition (attention and executive function) (Couey et al., 2007; Levin and Rezvani, 2007; Heath and Picciotto, 2009; Howe et al., 2010), learning and memory (Gould, 2006; Couey et al., 2007; Levin and Rezvani, 2007), mood (anxiety, depression) (Picciotto et al., 2008), reward (addiction, craving) (Tang and Dani, 2009), and sensory processing (Heath and Picciotto, 2009)",
       "key": "808cdcf7ea6950faf49ff003928eedab576ceed4bde2273bf331354975ac17595d44d8edf8543c28aaeb5026a9bb67b886743eb83a550860d4ce5a26459b7894",
-      "line": 85,
+      "line": 86,
       "relation": "association",
       "source": 98,
       "target": 35
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Brain": true
         }
@@ -486,13 +544,16 @@
       },
       "evidence": "In 2011, we know that cholinergic actions in the brain govern various processes: cognition (attention and executive function) (Couey et al., 2007; Levin and Rezvani, 2007; Heath and Picciotto, 2009; Howe et al., 2010), learning and memory (Gould, 2006; Couey et al., 2007; Levin and Rezvani, 2007), mood (anxiety, depression) (Picciotto et al., 2008), reward (addiction, craving) (Tang and Dani, 2009), and sensory processing (Heath and Picciotto, 2009)",
       "key": "0463d8800aaddde4e38d93b159be9a49957ab08d36cafe003bec4c9e3337f870740d279040d9c1737ea00b87e77e18c9fe90a7e53a558ca437cd916aadb6db8d",
-      "line": 86,
+      "line": 87,
       "relation": "association",
       "source": 101,
       "target": 35
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Brain": true
         }
@@ -515,12 +576,17 @@
       },
       "evidence": "In 2011, we know that cholinergic actions in the brain govern various processes: cognition (attention and executive function) (Couey et al., 2007; Levin and Rezvani, 2007; Heath and Picciotto, 2009; Howe et al., 2010), learning and memory (Gould, 2006; Couey et al., 2007; Levin and Rezvani, 2007), mood (anxiety, depression) (Picciotto et al., 2008), reward (addiction, craving) (Tang and Dani, 2009), and sensory processing (Heath and Picciotto, 2009)",
       "key": "99d73e51f49fc3c99a2c7292dbfb84cce477acb8bdf51b0dbb857e0d9c357582e5c455211aeb3d4899261d5b22d038cb31064ead71f88529f9550393e178a3de",
-      "line": 87,
+      "line": 88,
       "relation": "association",
       "source": 33,
       "target": 35
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -539,7 +605,7 @@
       },
       "evidence": "We now realize that acetylcholine liberated from cholinergic nerve terminals often activates both nAChRs and muscarinic receptors",
       "key": "022927761d289c7920b52c0290dfcc307aefa14ee2184e09e6994d937130f8535ce4562c3481bfbe4241bd0dccd68d5027e8a713cfaed801ab8cd23abdc2df01",
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+      "line": 95,
       "object": {
         "modifier": "Activity"
       },
@@ -548,6 +614,11 @@
       "target": 58
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -566,7 +637,7 @@
       },
       "evidence": "We now realize that acetylcholine liberated from cholinergic nerve terminals often activates both nAChRs and muscarinic receptors",
       "key": "d0a5884cf80437bb87e6c902d311217c0f1992846808dd13a0817b95bb7046820f1d4a9bdaa5c891b19c3b614d9bbe53c5e577c2ecba1ff1dd02332ebade307c",
-      "line": 93,
+      "line": 96,
       "object": {
         "modifier": "Activity"
       },
@@ -575,6 +646,11 @@
       "target": 59
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -593,7 +669,7 @@
       },
       "evidence": "A possible candidate is choline, which, in addition to its other development roles, activates alpha7 nAChRs at levels several fold higher than acetylcholine",
       "key": "6f667034ed3ec50f018048df3248ee1af0c3a518f984491e435d9064847f8422cc9d15eaa879746b06deed0c4188cfcb22571585dea8ffb916fe7eba4378b5ef",
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+      "line": 561,
       "object": {
         "modifier": "Activity"
       },
@@ -603,6 +679,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Presynaptic Terminals": true
         }
@@ -625,7 +704,7 @@
       },
       "evidence": "Most brain HS nAChRs reside on presynaptic terminals, where they stimulate neurotransmitter release (Gotti et al., 2006; Albuquerque et al., 2009)",
       "key": "f589bc2e5d3848f6505a0a068a7b0cef588d0ad878f9ec4efb4ddd63ecf06163cc8fb6a49b14c07d7b9dae734c2db178a26f8a60e44695f44b7f19e1f339b848",
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       "object": {
         "effect": {
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@@ -644,6 +723,11 @@
       "target": 7
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -662,7 +746,7 @@
       },
       "evidence": "As GPI-anchored proteins can bind to transmembrane receptors intracellularly, the interactions of lynx with nAChRs could potentially alter receptor trafficking, stoichiometry, and surface number (Lester et al., 2009)",
       "key": "fa4fba5a1a338e671defcf62bb24b4bca08ff73720c475b66cf061fd2de923f2b5a4a6229216d7649dfe3b6ee855d8d4de3e140620cfe9d0dab15a5ad73edee4",
-      "line": 174,
+      "line": 199,
       "relation": "association",
       "source": 59,
       "subject": {
@@ -671,6 +755,11 @@
       "target": 46
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -689,7 +778,7 @@
       },
       "evidence": "As GPI-anchored proteins can bind to transmembrane receptors intracellularly, the interactions of lynx with nAChRs could potentially alter receptor trafficking, stoichiometry, and surface number (Lester et al., 2009)",
       "key": "2d3cf77654365af1a7becf906982f23e77cd1c5d9498415ae7b85a33827255ecf3250660022af13f040f45abb78481f5573d6d323339e5e6448a0370dbe7f4b3",
-      "line": 175,
+      "line": 200,
       "relation": "association",
       "source": 59,
       "subject": {
@@ -708,6 +797,11 @@
       "target": 46
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -726,12 +820,17 @@
       },
       "evidence": "Abolishing receptor function through null mutations or pharmacological blockers of nAChRs abolished some of the gain-offunction phenotypes in lynx mouse models, indicating that nAChRs are necessary for the expression of lynx perturbations (Miwa et al., 2006)",
       "key": "3fa7aeba45d7112bae954ef6caac8ebeaa3652868d7123568a7ea7d791ef47ee594e03b7830bf11a02ae1236622a8194f967b138cf17d46f11cc3ae612c7e656",
-      "line": 253,
+      "line": 297,
       "relation": "regulates",
       "source": 59,
       "target": 76
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -750,7 +849,7 @@
       },
       "evidence": "Because excess activation of nAChRs damages neuronal health and brain function, organisms have a clear need to restrict the degree of nAChR activation",
       "key": "5932dc63134511d33a39d35e3136fd67c970a38ddb173de4b500a82f7c09f9414943a0a2bbc9128b3706f25987acc683de0e78a8d8a7328162759de5228ac3bc",
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+      "line": 311,
       "object": {
         "modifier": "Activity"
       },
@@ -762,6 +861,11 @@
       "target": 22
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -780,7 +884,7 @@
       },
       "evidence": "Because excess activation of nAChRs damages neuronal health and brain function, organisms have a clear need to restrict the degree of nAChR activation",
       "key": "73fbc39ff59003a52bf45f72a279b4f56dc2c4a59f0112f75a882c847ff12551c00f708320eb883c0a222a9d658b09a59003245a890b9b55ca1e0c3babf071f4",
-      "line": 264,
+      "line": 312,
       "relation": "negativeCorrelation",
       "source": 59,
       "subject": {
@@ -789,6 +893,11 @@
       "target": 24
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -807,12 +916,17 @@
       },
       "evidence": "Nicotinic receptor control over GABAergic neuronal development and mature activity may represent a point of convergence for diseases such as schizophrenia (see next section), some amblyopias (Bavelier et al., 2010), and some epilepsies (Klaassen et al., 2006), which distort the excitatory-inhibitory balance in general and implicate GABAergic signaling defects in particular",
       "key": "e3205a23b964a4b989f9754866a00a591291813d437dbe321ac9cff9a8bbacd6d81076b255aa5476083bea42374231f84932510fb332e5a083a31ec953267226",
-      "line": 318,
+      "line": 380,
       "relation": "regulates",
       "source": 59,
       "target": 25
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -831,7 +945,7 @@
       },
       "evidence": "Developmental changes in nAChR functions may play a role in nicotine addiction, as a central question in tobacco control is young adult smokers’ marked sensitivity to developing nicotine dependence (DSM-V Nicotine Workgroup, 2010; DiFranza et al., 2000; Difranza, 2010)",
       "key": "35a2ace91770212e8424bce2422b1ea8b617eac62e0f8e7d8cd4b5a637f365a734116b5276ca14adb5e6ec1657d10ff89492f395312f15c7f4715d292e70da95",
-      "line": 327,
+      "line": 391,
       "relation": "association",
       "source": 59,
       "subject": {
@@ -840,6 +954,11 @@
       "target": 93
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -858,7 +977,7 @@
       },
       "evidence": "Recent studies provide evidence both that nicotinic signaling partially underlies these schizophrenia-related inhibitory defects and that nicotinic drugs have possible therapeutic roles",
       "key": "b53636df1ada7b783a54805a19dcda0ece952f360b2604ee5cb86b49998f61c98bb7df72e2fcd15717302f33720e661a116897984dec4e8ba9c8a9a0f00f56c4",
-      "line": 337,
+      "line": 405,
       "relation": "association",
       "source": 59,
       "subject": {
@@ -867,6 +986,11 @@
       "target": 104
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -885,7 +1009,7 @@
       },
       "evidence": "Nicotinic activation of inhibitory interneurons increases their activity and activates nitric oxide synthetase",
       "key": "17e2175f79af5d66278492f535e95ae7f8c88ce0119325fadce89f5494830402f8a2f3c69a5f83e835857f158a50ea4d40477b3c1c10e5fcba35d84e38d32c08",
-      "line": 351,
+      "line": 423,
       "object": {
         "modifier": "Activity"
       },
@@ -894,6 +1018,11 @@
       "target": 15
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -912,7 +1041,7 @@
       },
       "evidence": "Nicotinic activation of inhibitory interneurons increases their activity and activates nitric oxide synthetase",
       "key": "26260cc88898f2750c4ad7703201fa8df8390c072cd4294a6c1735cda69dd53083884ad1d6417f2f38d0413b2553e1a410a7645a7e671e01df7a9374fe9ba957",
-      "line": 353,
+      "line": 425,
       "object": {
         "modifier": "Activity"
       },
@@ -922,6 +1051,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Brain": true
         }
@@ -944,12 +1076,17 @@
       },
       "evidence": "A major subtype in the brain is alpha4beta2; the (alpha42beta23) stoichiometry exhibits at least 10-fold-higher sensitivity than (alpha43beta22), so that only the former has the high sensitivity (HS) that allows activation at nicotine concentrations in the 0.1–1 mM range, produced by moderate tobacco use and by the various nicotine replacement therapies",
       "key": "c7bcc0119797e65cb0e430e4621e0489e8b1fa2dc59c64fa18885b837f4f34178c71a90dd95927fa75840279f570f9fa423a4380dd3f64ca0fc8146782f307f1",
-      "line": 101,
+      "line": 106,
       "relation": "increases",
       "source": 8,
       "target": 51
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -968,7 +1105,7 @@
       },
       "evidence": "alpha7 nAChRs also respond to nicotine concentrations roughly an order of magnitude higher than alpha42beta23, and alpha7 nAChRs have high Ca2+ permeability resembling that of NMDA receptors",
       "key": "31be1eb272d759152855fc5055e524070558d79a1c3b1748cb22034b79cb72352e254cac59593a7fa2359c610f868217d1913413f15b2b0e7cef6bac6f17e321",
-      "line": 107,
+      "line": 114,
       "object": {
         "modifier": "Activity"
       },
@@ -978,6 +1115,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Schizophrenia": true
         }
@@ -1000,7 +1140,7 @@
       },
       "evidence": "While it is not yet possible to know precisely how well a7 nAChRs are activated by smoked nicotine, one can reasonably hypothesize that the patients’ higher dose of nicotine activates alpha7 nAChRs (Adler et al., 1993; Papke and Thinschmidt, 1998; Royal College of Physicians, 2007)",
       "key": "8f96ffc9eac9c3ccd73908b25d3c2a2db56cdf13c563d52fd72a0da057cc03bc702c3f67a7a8238b1b60f7415f7b1e588e1792cd195db3ba1a8c717d9dfd7f71",
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+      "line": 503,
       "object": {
         "modifier": "Activity"
       },
@@ -1010,6 +1150,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Lung": true
         }
@@ -1032,7 +1175,7 @@
       },
       "evidence": "Evidence thus far indicates that the lynx family is regulated in response to relatively strong perturbations: downregulation in NKCC1 knockout mice (Pfeffer et al., 2009), in adenylyl cyclase mutant mice (Wieczorek et al., 2010), and by alpha7 nAChR blockade (Hruska et al., 2009), whereas it is upregulated at the close of the critical period in the visual cortex, and by nicotine in the lung (Sekhon et al., 2005)",
       "key": "c98a3ee5f9532d5a4cbeb743d2e8399773a75fe375ef8dfaa71def98ca54aaeef620589389daca22327665f0183063ee6f99657ad58f4c1e7980870d77165a11",
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+      "line": 329,
       "object": {
         "modifier": "Activity"
       },
@@ -1042,6 +1185,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Dopaminergic Neurons": true
         }
@@ -1064,7 +1210,7 @@
       },
       "evidence": "Nicotine both activates and desensitizes nAChRs in midbrain dopaminergic neurons (Brodie, 1991; Pidoplichko et al., 1997), and the pleasurable effects associated with nicotine intake occur in large part via the mesolimbic dopaminergic reward system (Corrigall et al., 1992; Koob and Volkow,2010)",
       "key": "a740b71dfbf28619bb31799fa07b479704b95a08d39eab879dd66d1eac9d081fcd081e9ac686cf4b6585c233c60369e855e98123d09a766736f8f4bd97152061",
-      "line": 483,
+      "line": 593,
       "object": {
         "modifier": "Activity"
       },
@@ -1073,6 +1219,11 @@
       "target": 59
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -1091,13 +1242,16 @@
       },
       "evidence": "This puzzle does not yet have a complete answer, but it is clear that chronic nicotine increases the number of nAChRs themselves (Marks et al., 1983; Schwartz and Kellar, 1983)",
       "key": "3d0560730482903bdae2f5e8e51d1770146c65c157a3e224214ac3dc24e2108f15a38bd800af99ba1cfb10133df324e5d53addacc24603d68ea6671be35f59f9",
-      "line": 518,
+      "line": 638,
       "relation": "increases",
       "source": 8,
       "target": 59
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "MeSHAnatomy": {
           "Cerebral Cortex": true,
           "Hypothalamus": true,
@@ -1122,13 +1276,16 @@
       },
       "evidence": "At the level of whole brain, chronic nicotine causes selective upregulation of nAChRs among major brain regions. Upregulation occurs in cortex, midbrain, and hypothalamus, but not in thalamus or cerebellum (Pauly et al., 1991; Marks et al., 1992; Nguyen et al., 2003; Nashmi et al., 2007; Doura et al., 2008)",
       "key": "2f49d91aa28728e47f1c280ee69b925977df71b6b9b23dcca52612dd7817cca77e6cfa86910fe40ca16a48806f0b4401cd9348e125567309936a11f6b719debb",
-      "line": 526,
+      "line": 648,
       "relation": "increases",
       "source": 8,
       "target": 59
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "MeSHAnatomy": {
           "Cerebellum": true,
           "Thalamus": true
@@ -1152,12 +1309,17 @@
       },
       "evidence": "At the level of whole brain, chronic nicotine causes selective upregulation of nAChRs among major brain regions. Upregulation occurs in cortex, midbrain, and hypothalamus, but not in thalamus or cerebellum (Pauly et al., 1991; Marks et al., 1992; Nguyen et al., 2003; Nashmi et al., 2007; Doura et al., 2008)",
       "key": "068d7875e2fef8f82651f14c12f807ace2274a19ec3bfe4a2fc8c055e48fe9efc2090730174308e3e0da206759d95537d004519681602756aa45b8b03d37296c",
-      "line": 528,
+      "line": 652,
       "relation": "causesNoChange",
       "source": 8,
       "target": 59
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -1176,13 +1338,16 @@
       },
       "evidence": "However, it is not known whether the nicotine-enhanced cognitive performance exceeds the level that would occur if the person had never begun to smoke, or after remaining abstinent for one year (the usual criterion for successful smoking cessation) (Levin et al., 2006)",
       "key": "dc43e976b2bdbc5a1822ed7bdc1156712b1dab65d73ba4f47e6bcff98e93069a2579b5b2138808dc1ebeb9ac2d256d83e19de5045b7e07ab8a483ba0bb57d8e5",
-      "line": 491,
+      "line": 603,
       "relation": "increases",
       "source": 8,
       "target": 36
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Dentate Gyrus": true,
           "Hippocampus": true
@@ -1206,13 +1371,16 @@
       },
       "evidence": "Chronic or acute nicotine enhances LTP in several regions of hippocampus, especially dentate gyrus (Nashmi et al., 2007; TangandDani, 2009;Pentonet al., 2011)",
       "key": "ae16173bb90752e25c106077ab71a18e8ee5ad4a60395e3307fb600d55ed72e43f69d2ce2d45c798d8b25181a125ef8949ad122ae2e12dbec01420d8fcf9c6a8",
-      "line": 502,
+      "line": 618,
       "relation": "increases",
       "source": 8,
       "target": 28
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Amygdala": true
         }
@@ -1235,13 +1403,16 @@
       },
       "evidence": "For instance, dopamine increases in the extended amygdala during stress, fear, and nicotine withdrawal (Inglis and Moghaddam, 1999; Pape, 2005; Grace et al., 2007; Gallagher et al., 2008; Koob, 2009; Marcinkiewcz et al., 2009)",
       "key": "d7b0f5a996771cbc5399419be160f7e61ae507431d7823616e99037b90f4ef84a208a7a16d01dc6630b10d54c299599a7484a9405a8d33ed6a07440f78cdf1cb",
-      "line": 512,
+      "line": 630,
       "relation": "decreases",
       "source": 8,
       "target": 6
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Dopaminergic Neurons": true,
           "Presynaptic Terminals": true
@@ -1265,7 +1436,7 @@
       },
       "evidence": "Chronic nicotine upregulates alpha4* nAChRs in dopaminergic presynaptic terminals, apparently leading to increased resting dopamine release from those terminals",
       "key": "7613e9acb9bda9f4aad17f8a51c86879bec8ce0bbfe87f56e4fec66051d87f51fa0ad65b34821cbae25aaa461afc9fda693dbaf4fb9f35122b7391ab665e4c65",
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+      "line": 787,
       "object": {
         "effect": {
           "fromLoc": {
@@ -1285,6 +1456,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Dentate Gyrus": true,
           "Entorhinal Cortex": true
@@ -1308,7 +1482,7 @@
       },
       "evidence": "In the medial perforant path, which mainly arises from layer II stellate cells, chronic nicotine upregulates alpha4beta2* nAChRs",
       "key": "f97bb6a4a04d60cd6a5e22921abcbf8f1e654c17577530a4db8e9268d8b2de297538be06a5974a1c43b2eeae5b64e60a9e5f10eb3ef312b5c02f880ef3133def",
-      "line": 546,
+      "line": 676,
       "object": {
         "modifier": "Activity"
       },
@@ -1318,6 +1492,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "GABAergic Neurons": true,
           "Mesencephalon": true
@@ -1341,7 +1518,7 @@
       },
       "evidence": "In midbrain, chronic nicotine treatment elicits a general increase in alpha4beta2* nAChRs in GABAergic neurons, but only in axon terminals of DA neurons",
       "key": "b06bb783e8fdccfd7a1828af2f981dfb23aafc5c606ea13fc426d345e684d610d2eb60ad23a7a0191ab749e9f47a85115bcb9467b255cbd66bd0f22d048ea780",
-      "line": 553,
+      "line": 685,
       "object": {
         "modifier": "Activity"
       },
@@ -1350,6 +1527,11 @@
       "target": 11
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -1368,7 +1550,7 @@
       },
       "evidence": "Because alpha4beta2 nAChRs are the most susceptible to nicotine-induced upregulation, the data again seem consistent with the idea that selective upregulation of alpha4beta2 nAChRs underlies nicotine dependence",
       "key": "a4b3bb821d3a50f03de7892400fb8d0dcd5b1923230b0b2f664ec2f57fef8b5a3f9e4de1fc2b67c800b6cc02363d89e90ed319c2d60efba8d76981f18dd21dd5",
-      "line": 587,
+      "line": 723,
       "object": {
         "modifier": "Activity"
       },
@@ -1377,6 +1559,11 @@
       "target": 11
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -1395,7 +1582,7 @@
       },
       "evidence": "The upregulation of alpha4beta2* nAChRs by chronic nicotine treatment has been replicated many times in numerous systems—transfected cell lines, neurons in culture, brain slices, and smokers’ brains (Albuquerque et al., 2009; Fu et al., 2009; Lester et al., 2009; Srinivasan et al., 2011",
       "key": "a66d163b6a06e09ce6213f3f1edccaf283ec1cfb22e93fbb49fe0a9b548dcec5dc7269d0654e5d51c078098a3b0d487ccbf0f89b9a95a7f8f5cd364f837e5d92",
-      "line": 595,
+      "line": 733,
       "object": {
         "modifier": "Activity"
       },
@@ -1404,6 +1591,11 @@
       "target": 11
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -1422,7 +1614,7 @@
       },
       "evidence": "(3) Nicotine activates alpha4beta2 nAChRs ~400-fold more effectively than it activates muscle-type nAChRs, because of cation-π and H-bond interactions at the agonist binding site (Xiu et al., 2009)",
       "key": "6c92ca813ebf4d5f4b80bf885e7d92c9177c258381fe6f1155862bc75b073e4ba9d2c20c55dfb1f66d68fa39ee6d2cf5a67e61adac4b6e13b9a0e463a9594806",
-      "line": 600,
+      "line": 740,
       "object": {
         "modifier": "Activity"
       },
@@ -1432,6 +1624,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Pars Compacta": true
         },
@@ -1457,13 +1652,16 @@
       },
       "evidence": "While chronic nicotine does not change the abundance or function of alpha4* nAChRs in the somata of substantia nigra pars compacta dopaminergic neurons, it does suppress baseline firing rates of these DA neurons.",
       "key": "b33fedc34d107a382420d9c3ec16493e472624e4c4514a8283ce15c354e1367fd897abb534257f7960793c0838547bbe11acc95c374350243e969413d4cfe37f",
-      "line": 615,
+      "line": 758,
       "relation": "causesNoChange",
       "source": 8,
       "target": 12
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "GABAergic Neurons": true
         }
@@ -1486,7 +1684,7 @@
       },
       "evidence": "These contrasting effects on GABA and DA neurons are due to upregulated alpha4* nAChR responses in GABA neurons, at both somata and synaptic terminals",
       "key": "d962fa6e7179da9af4f96f8048c782e44cd224741b9d7f1f6e98660713d3446c586b395a22b829fd1eb553c2527bef9d876eb51ac6f1653af4ff900f7e332062",
-      "line": 631,
+      "line": 777,
       "object": {
         "modifier": "Activity"
       },
@@ -1496,6 +1694,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Dopaminergic Neurons": true,
           "Presynaptic Terminals": true
@@ -1519,7 +1720,7 @@
       },
       "evidence": "Chronic nicotine upregulates alpha4* nAChRs in dopaminergic presynaptic terminals, apparently leading to increased resting dopamine release from those terminals",
       "key": "cfc6e3b5e30526b1f5f3a153149edff6318fbf18788c9421b9e97745d580d56e684caa892d5d01718be26e219c2e747da5bafcd1fce9811b1c6e58054e7deb00",
-      "line": 638,
+      "line": 786,
       "object": {
         "modifier": "Activity"
       },
@@ -1528,6 +1729,11 @@
       "target": 12
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -1546,7 +1752,7 @@
       },
       "evidence": "The chaperoning of nAChRs by nicotine enhances the export of alpha4beta2 nAChRs from the endoplasmic reticulum (ER), and this leads to a general increase in ER exit sites (Srinivasan et al., 2011)",
       "key": "f18bc9d79ed88deabd0f12706fc1c88681343f66397628937131b28b5d08a67907a601b01acaceb8c130332835c21f4c109b004e2a946bc59a926c464fb96f89",
-      "line": 646,
+      "line": 796,
       "object": {
         "effect": {
           "fromLoc": {
@@ -1566,6 +1772,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Pars Compacta": true
         },
@@ -1591,7 +1800,7 @@
       },
       "evidence": "While chronic nicotine does not change the abundance or function of alpha4* nAChRs in the somata of substantia nigra pars compacta dopaminergic neurons, it does suppress baseline firing rates of these DA neurons.",
       "key": "9536ffb66fd0f595c1b5c21607b5205129060974ef5e74c73987c8f76deb168324af4da934f44d730a0a468aa537f8e05532fe472a6ff1cbded985ba53100312",
-      "line": 616,
+      "line": 759,
       "object": {
         "modifier": "Activity"
       },
@@ -1601,6 +1810,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Pars Reticulata": true
         },
@@ -1626,7 +1838,7 @@
       },
       "evidence": "In mice exposed to chronic nicotine, GABA neurons in substantia nigra pars reticulata have increased baseline firing rates, both in brain slices and in anesthetized animals",
       "key": "b7884f57317bc2c078dbf9b194ee6d93058a205d8c52b7b20006096ca564c82499ba320938eb81cc32075daf754325717599a9fae6068feceb15888f3e43fece",
-      "line": 623,
+      "line": 768,
       "object": {
         "modifier": "Activity"
       },
@@ -1635,6 +1847,11 @@
       "target": 19
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -1653,7 +1870,7 @@
       },
       "evidence": "ADNFLE patients who use a nicotine patch or tobacco have fewer seizures (Willoughby et al., 2003; Brodtkorb and Picard, 2006)",
       "key": "5c1f1a33853dfd0d02bf4195c5755e017611da7eb08e9640c6cb54c90ae8797fb5298369a570f735e86e111bf0d87f8dfbaa907562617be49bc16a9bf949f538",
-      "line": 655,
+      "line": 809,
       "relation": "decreases",
       "source": 8,
       "target": 86
@@ -1683,6 +1900,11 @@
       "target": 71
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -1701,7 +1923,7 @@
       },
       "evidence": "alpha7 nAChRs also respond to nicotine concentrations roughly an order of magnitude higher than alpha42beta23, and alpha7 nAChRs have high Ca2+ permeability resembling that of NMDA receptors",
       "key": "5fa9bcfe825d546edf6b6f80b13a7e6674f6d62d314805990519205f1ed0bbf7fd9001ff50030202db72b602531f432e538a26a0d1ac20bd1b909dbe6ce0ca4d",
-      "line": 108,
+      "line": 115,
       "relation": "association",
       "source": 21,
       "subject": {
@@ -1711,6 +1933,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Species": {
           "10090": true
         }
@@ -1733,7 +1958,7 @@
       },
       "evidence": "Evidence thus far indicates that the lynx family is regulated in response to relatively strong perturbations: downregulation in NKCC1 knockout mice (Pfeffer et al., 2009), in adenylyl cyclase mutant mice (Wieczorek et al., 2010), and by alpha7 nAChR blockade (Hruska et al., 2009), whereas it is upregulated at the close of the critical period in the visual cortex, and by nicotine in the lung (Sekhon et al., 2005)",
       "key": "28c2652f5bf81416efbf075b934bff8cc083b2c5ee4bf505ca0639d581ecf58d34ea9ce81ee8535896e6d05d57833d1e959d165a40a4d2224681bb64cd03969a",
-      "line": 276,
+      "line": 326,
       "object": {
         "modifier": "Activity"
       },
@@ -1745,6 +1970,11 @@
       "target": 84
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -1763,7 +1993,7 @@
       },
       "evidence": "The neurodevelopmental program depends in part on alpha7 signaling (Liu et al.,2006)",
       "key": "525be0542d7f8ebf4aeb8c0fb2f22faad01c58766a66d885c8012232524ba0e14fd7792d77fe860b1398105da916f3587f8ab25d2b21ff9ae20009b2bd22a4e9",
-      "line": 304,
+      "line": 362,
       "relation": "association",
       "source": 21,
       "subject": {
@@ -1773,6 +2003,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Dentate Gyrus": true,
           "Hippocampus": true
@@ -1796,13 +2029,16 @@
       },
       "evidence": "alpha7 nAChRs on inhibitory interneurons throughout the hippocampus and presynaptic alpha7 nAChRs on mossy fiber terminals in the dentate gyrus participate in the control of sensory response in the hippocampus (Gray et al., 1996; Alkondon et al., 1999",
       "key": "05a69de82af5541bfefe80b9b51b59bdd625fbf1ced00a295d621d5c74e174f745d37801eae4d6629cc90bd374fad333509aef75b65319a2e0d3b4df8754e04b",
-      "line": 345,
+      "line": 415,
       "relation": "regulates",
       "source": 21,
       "target": 33
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Schizophrenia": true
         }
@@ -1825,13 +2061,16 @@
       },
       "evidence": "Three lines of evidence support the possibility that the failure of sensory inhibition in schizophrenia results from decreased expression of alpha7 nAChRs",
       "key": "5f158d58960b0d9ba5559f34bb2d438987647724347b3945bccfb8e3197e96d1f2c5a4393d64ed82a2f72203af9c221ecaa5971511457ba54ded65e50ff5e8a5",
-      "line": 381,
+      "line": 461,
       "relation": "increases",
       "source": 21,
       "target": 33
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Hippocampus": true
         }
@@ -1854,13 +2093,16 @@
       },
       "evidence": "Although alpha7 nAChRs have both presynaptic and postsynaptic expression (Frazier et al., 1998), their postsynaptic expression in humans is especially marked on inhibitory neurons of the hippocampus (Alkondon et al., 2000)",
       "key": "9aa6b712fed8595e27d3fded7ce5ca54849c338a98db42be3600a76283f5bd891d0e3efbd901b57a20b95a7333e8d45f3ce3e2fb5a3658d54f8ec429a269242f",
-      "line": 374,
+      "line": 452,
       "relation": "association",
       "source": 21,
       "target": 15
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "MeSHDisease": {
           "Schizophrenia": true
         }
@@ -1883,13 +2125,16 @@
       },
       "evidence": "First, postmortem studies of the hippocampus and thalamus show diminished labeling of putative inhibitory neurons by alpha-bungarotoxin, an antagonist of alpha7 nAChRs (Court et al., 1999)",
       "key": "87fc7f772000239bce8e700c63e9f555c7783fc21ad1a9a817ed3b717fa5589b5c93eb5fc4107d079c00ce8c77cc37104388c4c5e1f1dd373e3a572d48df464c",
-      "line": 388,
+      "line": 471,
       "relation": "increases",
       "source": 21,
       "target": 15
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Schizophrenia": true
         }
@@ -1912,12 +2157,17 @@
       },
       "evidence": "Yet some of the other genes identified, such as NRG1, are involved in the assembly of alpha7 nAChRs, further supporting a potential link between alpha7 nAChRs and schizophrenia (Mathew et al., 2007)",
       "key": "908399f50d32c65ac5e5c1b25aea7bd50e8ea8c39594cffb703715853e76c881690f03c7d3d0f9fe04c787a4cde9e0576920d6f659750530d7dd36ed1e0a88a6",
-      "line": 401,
+      "line": 488,
       "relation": "association",
       "source": 21,
       "target": 104
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -1936,7 +2186,7 @@
       },
       "evidence": "alpha7 nAChRs also respond to nicotine concentrations roughly an order of magnitude higher than alpha42beta23, and alpha7 nAChRs have high Ca2+ permeability resembling that of NMDA receptors",
       "key": "14e749c0afa473b842f024a28276d68ad1b824ff8607fd562344245a9c98ae59773d3a2cee22d51fc8f1aaa1ed5a376c1d448482fc333121ef0f7e3b6856b05b",
-      "line": 108,
+      "line": 115,
       "object": {
         "modifier": "Activity"
       },
@@ -1945,6 +2195,11 @@
       "target": 21
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -1963,7 +2218,7 @@
       },
       "evidence": "The ‘‘volume transmission’’ hypothesis states that ACh released from presynaptic terminals spreads to more distant areas, reaching concentrations < 1 mM (Descarries et al., 1997), but that multiple presynaptic impulses produce enough summed release to activate receptors (Lester, 2004)",
       "key": "bb11ff0ec1020a516c85ec288bc4154763262c454c31bf1d8f4fb0e0ab402e56e7f4a1eb75101d1fc4f9e6af455025f6a626a0e0e81bbd1d4dcabfb1984f3a21",
-      "line": 122,
+      "line": 133,
       "object": {
         "effect": {
           "fromLoc": {
@@ -1982,6 +2237,11 @@
       "target": 3
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -2000,7 +2260,7 @@
       },
       "evidence": "In most regions that receive cholinergic innervation, the high density of acetylcholinesterase (which can hydrolyze ACh at a rate of one per 100 ms!) might vitiate the volume transmission mechanism",
       "key": "b83e21fa7ea452a4916e57b7e4daa325353646114f0c0b2ccd33d4900dbf12f3c87b9fd9852e2d577a0a3c668b012705f307fc8ccfc20a85e6f00f7fbfeeb1d8",
-      "line": 127,
+      "line": 140,
       "object": {
         "modifier": "Degradation"
       },
@@ -2009,6 +2269,11 @@
       "target": 3
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -2027,7 +2292,7 @@
       },
       "evidence": "Indeed, cholinergic enhancement (via cholinesterase inhibition) reopens the critical period for visual acuity in adult wild-type mice (Morishita et al., 2010), indicating that cellular mechanisms for robust plasticity are maintained in adulthood through the cholinergic system but are suppressed by the action of lynx.",
       "key": "de711498500b5c69a6d69e2dd919a2c7c1d495550f877a12c02f4491aed84fe5f4f0646b6e7ed73624056487be0e4a21d84782be710749f286d6af850c29f6f8",
-      "line": 245,
+      "line": 287,
       "relation": "decreases",
       "source": 61,
       "subject": {
@@ -2036,6 +2301,11 @@
       "target": 35
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -2054,7 +2324,7 @@
       },
       "evidence": "As we will see below, the mystery of somatodendritic nAChRs can also be resolved by the sensitivity of alpha7 nAChRs to constant levels of another agonist, choline",
       "key": "5a8f6689df6839fb2cd70825cc272e3c4e8ee9672c8fbcc17dd644bd570051149314c332f48eb1c58d38d36f026b11bafd35313c1b72e10e746cff424940828d",
-      "line": 132,
+      "line": 147,
       "object": {
         "modifier": "Activity"
       },
@@ -2063,6 +2333,11 @@
       "target": 21
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -2081,7 +2356,7 @@
       },
       "evidence": "A possible candidate is choline, which, in addition to its other development roles, activates alpha7 nAChRs at levels several fold higher than acetylcholine",
       "key": "924025cdf8f35a07ae72191dbfa4ab1ed263fd77839a5cd37fdae4e984f9be8239b917d238c9a9161763dd3d70faac3ef6b13f9928ce97597a7edf04413064c0",
-      "line": 458,
+      "line": 562,
       "object": {
         "modifier": "Activity"
       },
@@ -2090,6 +2365,11 @@
       "target": 13
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -2108,12 +2388,17 @@
       },
       "evidence": "Mutations in nicotinic receptor subunits are linked to human disease, alpha4 and beta2 in some epilepsies, alpha7 in schizophrenia, and alpha5 in nicotine addiction; and each mutation ultimately manifests itself as an imbalance in the properties of neuronal circuits",
       "key": "0dfb4e6df7ae4916eeb8c9ca4027fec08f4d616ff8b7a8821bf7c223ae363a86ed9b78af1649ba4c3a47726a3116363b245fd8a8f5f64186b70d7a6c35eff28b",
-      "line": 138,
+      "line": 155,
       "relation": "positiveCorrelation",
       "source": 65,
       "target": 102
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -2132,12 +2417,17 @@
       },
       "evidence": "Autosomal-dominant nocturnal frontal lobe epilepsy (ADNFLE) is caused by missense mutations in either the alpha4 or the beta2 subunit",
       "key": "95179e6564abd6ba6f51e429479d5454bdeed000902e1466b70dfb7ecf5e1ca81fbf1db8c6889f6cce27a5f4e5d28b09d92d6bbf0aaebb8744e323f6bceef06e",
-      "line": 650,
+      "line": 802,
       "relation": "increases",
       "source": 65,
       "target": 86
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -2156,12 +2446,17 @@
       },
       "evidence": "Mutations in nicotinic receptor subunits are linked to human disease, alpha4 and beta2 in some epilepsies, alpha7 in schizophrenia, and alpha5 in nicotine addiction; and each mutation ultimately manifests itself as an imbalance in the properties of neuronal circuits",
       "key": "72bc5ff97a48d8093a166b0f36a6323a085b0f99a5e12ff06c8473e896f394aad5b7ac802db5f35f2e7e5f3add6d881a4db363cf460aa79b724900aa681292c0",
-      "line": 138,
+      "line": 155,
       "relation": "positiveCorrelation",
       "source": 102,
       "target": 65
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -2180,12 +2475,17 @@
       },
       "evidence": "Mutations in nicotinic receptor subunits are linked to human disease, alpha4 and beta2 in some epilepsies, alpha7 in schizophrenia, and alpha5 in nicotine addiction; and each mutation ultimately manifests itself as an imbalance in the properties of neuronal circuits",
       "key": "5bdea8ac866fdf7688453b27ad8dcf2bb6ed55a1da6c9b9efdde11c473156a8ab9ce9fc6265340beecb6d876b1ffb0b7c7d65db367395956ca8b93aa91b16d81",
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       "relation": "positiveCorrelation",
       "source": 102,
       "target": 71
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -2204,12 +2504,17 @@
       },
       "evidence": "Mutations in nicotinic receptor subunits are linked to human disease, alpha4 and beta2 in some epilepsies, alpha7 in schizophrenia, and alpha5 in nicotine addiction; and each mutation ultimately manifests itself as an imbalance in the properties of neuronal circuits",
       "key": "e2dcbbced73939c21b23acb0a34b457055161aa01d25e35e554d648cb8828d7d4969be590857c1afa3f8c8adf78fea06422c4ebe968430258cad9670a5719044",
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       "relation": "positiveCorrelation",
       "source": 71,
       "target": 102
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -2228,12 +2533,17 @@
       },
       "evidence": "Autosomal-dominant nocturnal frontal lobe epilepsy (ADNFLE) is caused by missense mutations in either the alpha4 or the beta2 subunit",
       "key": "ad689d8011ac2895d8adf752177ca501f583a4c70c2692a66432875486e311d685e9c14087d828689edfd5c8144ee98406fed71ada88a1bb8d68ab694625415b",
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       "relation": "increases",
       "source": 71,
       "target": 86
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -2252,7 +2562,7 @@
       },
       "evidence": "Mutations in nicotinic receptor subunits are linked to human disease, alpha4 and beta2 in some epilepsies, alpha7 in schizophrenia, and alpha5 in nicotine addiction; and each mutation ultimately manifests itself as an imbalance in the properties of neuronal circuits",
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       "relation": "positiveCorrelation",
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@@ -2264,6 +2574,11 @@
       "target": 69
     },
     {
+      "annotations": {
+        "Confidence": {
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       "citation": {
         "authors": [
           "Freedman R",
@@ -2282,12 +2597,17 @@
       },
       "evidence": "Mutations in nicotinic receptor subunits are linked to human disease, alpha4 and beta2 in some epilepsies, alpha7 in schizophrenia, and alpha5 in nicotine addiction; and each mutation ultimately manifests itself as an imbalance in the properties of neuronal circuits",
       "key": "3cc2a778b8eb2b39e3a59c3c081d04a826b8ea41a297697237a94a124950401dc402cfc23d90f2b47b71c9d0dcb10a0cdc93cd9cb56a644a8030f4dc55c88812",
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       "relation": "positiveCorrelation",
       "source": 104,
       "target": 69
     },
     {
+      "annotations": {
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       "citation": {
         "authors": [
           "Freedman R",
@@ -2306,12 +2626,17 @@
       },
       "evidence": "Nicotinic receptor control over GABAergic neuronal development and mature activity may represent a point of convergence for diseases such as schizophrenia (see next section), some amblyopias (Bavelier et al., 2010), and some epilepsies (Klaassen et al., 2006), which distort the excitatory-inhibitory balance in general and implicate GABAergic signaling defects in particular",
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       "relation": "association",
       "source": 104,
       "target": 25
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     {
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+        "Confidence": {
+          "High": true
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+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -2330,7 +2655,7 @@
       },
       "evidence": "In many persons with schizophrenia, cerebral evoked potential recording shows diminished inhibition of the response to repeated stimuli (Adler et al., 1982) (Figure 2A), and animal models of this phenomenon point to a defect in hippocampal inhibition",
       "key": "099eb3b076c862e590e3ead3cf2a4ab2bc4d2c2e4cf09bc384b803a77af8fe59c4896a9b6142ccaed5ec8fc1258ceb1121bcf56d3ffb4c472355bb444962a527",
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       "object": {
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@@ -2339,6 +2664,11 @@
       "target": 23
     },
     {
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+          "High": true
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       "citation": {
         "authors": [
           "Freedman R",
@@ -2357,7 +2687,7 @@
       },
       "evidence": "Recent studies provide evidence both that nicotinic signaling partially underlies these schizophrenia-related inhibitory defects and that nicotinic drugs have possible therapeutic roles",
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       "object": {
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@@ -2367,6 +2697,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Schizophrenia": true
         }
@@ -2389,13 +2722,16 @@
       },
       "evidence": "Polymorphisms in the alpha7 5' promoter and in a nearby partial duplication of the gene, FAM7A, are associated with both schizophrenia and the defect in inhibition (Leonard et al., 2002)",
       "key": "9c47d016fb3d21183d2b7481a4378a1cc312d65ba47031eef892e99848cb4f69ffe0211c300eaa71fc9655b8a4d1e1ddeae64120cfd0649464667c2d54f991af",
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       "relation": "association",
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       "target": 54
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
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         "MeSHDisease": {
           "Schizophrenia": true
         }
@@ -2418,13 +2754,16 @@
       },
       "evidence": "Yet some of the other genes identified, such as NRG1, are involved in the assembly of alpha7 nAChRs, further supporting a potential link between alpha7 nAChRs and schizophrenia (Mathew et al., 2007)",
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       "relation": "association",
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       "target": 21
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     {
       "annotations": {
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         "MeSHDisease": {
           "Schizophrenia": true
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@@ -2447,12 +2786,17 @@
       },
       "evidence": "Third, persons with schizophrenia have the greatest rate and intensity of cigarette smoking of any identifiable subgroup in the population",
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       "relation": "positiveCorrelation",
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     {
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       "citation": {
         "authors": [
           "Freedman R",
@@ -2471,12 +2815,17 @@
       },
       "evidence": "Variants in the gene for phosphatidylethanolamine methyl transferase, which synthesizes phosphatidylcholine and thus provides a source of choline, are also associated with choline deficiency and with schizophrenia",
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     {
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       "citation": {
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           "Freedman R",
@@ -2495,12 +2844,17 @@
       },
       "evidence": "Mutations in nicotinic receptor subunits are linked to human disease, alpha4 and beta2 in some epilepsies, alpha7 in schizophrenia, and alpha5 in nicotine addiction; and each mutation ultimately manifests itself as an imbalance in the properties of neuronal circuits",
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       "relation": "positiveCorrelation",
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     {
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       "citation": {
         "authors": [
           "Freedman R",
@@ -2519,12 +2873,17 @@
       },
       "evidence": "Single-nucleotide polymorphisms found in the human alpha5, alpha3, beta4 gene cluster are associated with nicotine dependence and its age-dependent onset; number of cigarettes smoked per day and ‘‘pleasurable buzz’’ elicited by smoking; alcoholism, sensitivity to the depressant effects of alcohol, and age of alcohol initiation; cocaine dependence; opioid dependence; lung cancer; and cognitive flexibility (Erlich et al., 2010; Hansen et al., 2010; Improgo et al., 2010; Saccone et al., 2010; Zhang et al., 2010)",
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     {
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       "citation": {
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           "Freedman R",
@@ -2543,12 +2902,17 @@
       },
       "evidence": "Single-nucleotide polymorphisms found in the human alpha5, alpha3, beta4 gene cluster are associated with nicotine dependence and its age-dependent onset; number of cigarettes smoked per day and ‘‘pleasurable buzz’’ elicited by smoking; alcoholism, sensitivity to the depressant effects of alcohol, and age of alcohol initiation; cocaine dependence; opioid dependence; lung cancer; and cognitive flexibility (Erlich et al., 2010; Hansen et al., 2010; Improgo et al., 2010; Saccone et al., 2010; Zhang et al., 2010)",
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       "relation": "positiveCorrelation",
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     {
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       "citation": {
         "authors": [
           "Freedman R",
@@ -2567,12 +2931,17 @@
       },
       "evidence": "Single-nucleotide polymorphisms found in the human alpha5, alpha3, beta4 gene cluster are associated with nicotine dependence and its age-dependent onset; number of cigarettes smoked per day and ‘‘pleasurable buzz’’ elicited by smoking; alcoholism, sensitivity to the depressant effects of alcohol, and age of alcohol initiation; cocaine dependence; opioid dependence; lung cancer; and cognitive flexibility (Erlich et al., 2010; Hansen et al., 2010; Improgo et al., 2010; Saccone et al., 2010; Zhang et al., 2010)",
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       "relation": "positiveCorrelation",
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     {
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       "citation": {
         "authors": [
           "Freedman R",
@@ -2591,12 +2960,17 @@
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       "evidence": "Single-nucleotide polymorphisms found in the human alpha5, alpha3, beta4 gene cluster are associated with nicotine dependence and its age-dependent onset; number of cigarettes smoked per day and ‘‘pleasurable buzz’’ elicited by smoking; alcoholism, sensitivity to the depressant effects of alcohol, and age of alcohol initiation; cocaine dependence; opioid dependence; lung cancer; and cognitive flexibility (Erlich et al., 2010; Hansen et al., 2010; Improgo et al., 2010; Saccone et al., 2010; Zhang et al., 2010)",
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       "relation": "positiveCorrelation",
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     {
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       "citation": {
         "authors": [
           "Freedman R",
@@ -2615,12 +2989,17 @@
       },
       "evidence": "Single-nucleotide polymorphisms found in the human alpha5, alpha3, beta4 gene cluster are associated with nicotine dependence and its age-dependent onset; number of cigarettes smoked per day and ‘‘pleasurable buzz’’ elicited by smoking; alcoholism, sensitivity to the depressant effects of alcohol, and age of alcohol initiation; cocaine dependence; opioid dependence; lung cancer; and cognitive flexibility (Erlich et al., 2010; Hansen et al., 2010; Improgo et al., 2010; Saccone et al., 2010; Zhang et al., 2010)",
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       "relation": "positiveCorrelation",
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       "target": 90
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     {
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       "citation": {
         "authors": [
           "Freedman R",
@@ -2639,7 +3018,7 @@
       },
       "evidence": "Single-nucleotide polymorphisms found in the human alpha5, alpha3, beta4 gene cluster are associated with nicotine dependence and its age-dependent onset; number of cigarettes smoked per day and ‘‘pleasurable buzz’’ elicited by smoking; alcoholism, sensitivity to the depressant effects of alcohol, and age of alcohol initiation; cocaine dependence; opioid dependence; lung cancer; and cognitive flexibility (Erlich et al., 2010; Hansen et al., 2010; Improgo et al., 2010; Saccone et al., 2010; Zhang et al., 2010)",
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       "relation": "positiveCorrelation",
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@@ -2651,6 +3030,11 @@
       "target": 67
     },
     {
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       "citation": {
         "authors": [
           "Freedman R",
@@ -2669,12 +3053,17 @@
       },
       "evidence": "Mutations in nicotinic receptor subunits are linked to human disease, alpha4 and beta2 in some epilepsies, alpha7 in schizophrenia, and alpha5 in nicotine addiction; and each mutation ultimately manifests itself as an imbalance in the properties of neuronal circuits",
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       "relation": "positiveCorrelation",
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       "target": 67
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     {
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       "citation": {
         "authors": [
           "Freedman R",
@@ -2693,12 +3082,17 @@
       },
       "evidence": "Single-nucleotide polymorphisms found in the human alpha5, alpha3, beta4 gene cluster are associated with nicotine dependence and its age-dependent onset; number of cigarettes smoked per day and ‘‘pleasurable buzz’’ elicited by smoking; alcoholism, sensitivity to the depressant effects of alcohol, and age of alcohol initiation; cocaine dependence; opioid dependence; lung cancer; and cognitive flexibility (Erlich et al., 2010; Hansen et al., 2010; Improgo et al., 2010; Saccone et al., 2010; Zhang et al., 2010)",
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       "relation": "positiveCorrelation",
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     {
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       "citation": {
         "authors": [
           "Freedman R",
@@ -2717,7 +3111,7 @@
       },
       "evidence": "Developmental changes in nAChR functions may play a role in nicotine addiction, as a central question in tobacco control is young adult smokers’ marked sensitivity to developing nicotine dependence (DSM-V Nicotine Workgroup, 2010; DiFranza et al., 2000; Difranza, 2010)",
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       "object": {
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@@ -2727,6 +3121,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Schizophrenia": true
         }
@@ -2749,14 +3146,19 @@
       },
       "evidence": "Third, persons with schizophrenia have the greatest rate and intensity of cigarette smoking of any identifiable subgroup in the population",
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       "relation": "positiveCorrelation",
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     {
-      "citation": {
-        "authors": [
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
+      "citation": {
+        "authors": [
           "Freedman R",
           "Lester HA",
           "Miwa JM"
@@ -2773,12 +3175,17 @@
       },
       "evidence": "Single-nucleotide polymorphisms found in the human alpha5, alpha3, beta4 gene cluster are associated with nicotine dependence and its age-dependent onset; number of cigarettes smoked per day and ‘‘pleasurable buzz’’ elicited by smoking; alcoholism, sensitivity to the depressant effects of alcohol, and age of alcohol initiation; cocaine dependence; opioid dependence; lung cancer; and cognitive flexibility (Erlich et al., 2010; Hansen et al., 2010; Improgo et al., 2010; Saccone et al., 2010; Zhang et al., 2010)",
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       "relation": "positiveCorrelation",
       "source": 93,
       "target": 63
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     {
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+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -2797,12 +3204,17 @@
       },
       "evidence": "Single-nucleotide polymorphisms found in the human alpha5, alpha3, beta4 gene cluster are associated with nicotine dependence and its age-dependent onset; number of cigarettes smoked per day and ‘‘pleasurable buzz’’ elicited by smoking; alcoholism, sensitivity to the depressant effects of alcohol, and age of alcohol initiation; cocaine dependence; opioid dependence; lung cancer; and cognitive flexibility (Erlich et al., 2010; Hansen et al., 2010; Improgo et al., 2010; Saccone et al., 2010; Zhang et al., 2010)",
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       "relation": "positiveCorrelation",
       "source": 93,
       "target": 73
     },
     {
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+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -2821,7 +3233,7 @@
       },
       "evidence": "Because alpha4beta2 nAChRs are the most susceptible to nicotine-induced upregulation, the data again seem consistent with the idea that selective upregulation of alpha4beta2 nAChRs underlies nicotine dependence",
       "key": "90aff8c4c985e1f0f1db480c0e94465ba03eeb643ff671e83f28c9805bff08bac3150c539ca8874775a5dc42aa82ac9d70836b2e003ca6e746af1a01af660f2e",
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       "object": {
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       },
@@ -2837,6 +3249,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Brain": true
         }
@@ -2859,13 +3274,16 @@
       },
       "evidence": "Finally, nAChRs exist in complexes in the brain; interacting proteins engage in complexes with nAChRs and aid in the assembly and trafficking of nAChR to the plasma membrane; examples are RIC-3 (Lansdell et al., 2005), 14-3-3 proteins (Jeanclos et al., 2001), neurexins (Cheng et al., 2009), and VILIP-1 (Lin et al., 2002)",
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       "relation": "increases",
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       "target": 59
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Brain": true
         }
@@ -2888,7 +3306,7 @@
       },
       "evidence": "Finally, nAChRs exist in complexes in the brain; interacting proteins engage in complexes with nAChRs and aid in the assembly and trafficking of nAChR to the plasma membrane; examples are RIC-3 (Lansdell et al., 2005), 14-3-3 proteins (Jeanclos et al., 2001), neurexins (Cheng et al., 2009), and VILIP-1 (Lin et al., 2002)",
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       "object": {
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@@ -2916,6 +3334,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Brain": true
         }
@@ -2938,13 +3359,16 @@
       },
       "evidence": "Finally, nAChRs exist in complexes in the brain; interacting proteins engage in complexes with nAChRs and aid in the assembly and trafficking of nAChR to the plasma membrane; examples are RIC-3 (Lansdell et al., 2005), 14-3-3 proteins (Jeanclos et al., 2001), neurexins (Cheng et al., 2009), and VILIP-1 (Lin et al., 2002)",
       "key": "f3b8d6923aa9e60679c233b5cd5dc568953e77ab223a762c0e63ca4bcff6f1edfafe9bfa21ebcc7a7f779ddecff39e6cb9ff0de51b8890ec2889eda24c56606a",
-      "line": 151,
+      "line": 170,
       "relation": "increases",
       "source": 45,
       "target": 59
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Brain": true
         }
@@ -2967,7 +3391,7 @@
       },
       "evidence": "Finally, nAChRs exist in complexes in the brain; interacting proteins engage in complexes with nAChRs and aid in the assembly and trafficking of nAChR to the plasma membrane; examples are RIC-3 (Lansdell et al., 2005), 14-3-3 proteins (Jeanclos et al., 2001), neurexins (Cheng et al., 2009), and VILIP-1 (Lin et al., 2002)",
       "key": "0b5a5210755a3f18eca5f79c7e67e68076de89e35ca5d159217d0e2d691ba3576f7df88cced2458741929b34435233b0f3edcd4f16262c1b99245c42a30c9918",
-      "line": 152,
+      "line": 171,
       "object": {
         "modifier": "Activity"
       },
@@ -2983,6 +3407,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Brain": true
         }
@@ -3005,13 +3432,16 @@
       },
       "evidence": "Finally, nAChRs exist in complexes in the brain; interacting proteins engage in complexes with nAChRs and aid in the assembly and trafficking of nAChR to the plasma membrane; examples are RIC-3 (Lansdell et al., 2005), 14-3-3 proteins (Jeanclos et al., 2001), neurexins (Cheng et al., 2009), and VILIP-1 (Lin et al., 2002)",
       "key": "f5686cf4f2f70d214e7a357d1de1fa810736a1f8976783bdb581011147a4e54e9b9792ed19673e9ecc0be2599aefcd35b1b480e1c21295a2e68ad6177ec40f8e",
-      "line": 153,
+      "line": 172,
       "relation": "increases",
       "source": 49,
       "target": 59
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Brain": true
         }
@@ -3034,7 +3464,7 @@
       },
       "evidence": "Finally, nAChRs exist in complexes in the brain; interacting proteins engage in complexes with nAChRs and aid in the assembly and trafficking of nAChR to the plasma membrane; examples are RIC-3 (Lansdell et al., 2005), 14-3-3 proteins (Jeanclos et al., 2001), neurexins (Cheng et al., 2009), and VILIP-1 (Lin et al., 2002)",
       "key": "1735aeab1bef2f97d5185521c4cfb6c8a5d481ed56b3ade1e3db15bf507e7a806b123670fad509429aca6972cbd86a1680639c4fe2c987f9eebb68284dd70a61",
-      "line": 154,
+      "line": 173,
       "object": {
         "modifier": "Activity"
       },
@@ -3056,6 +3486,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Brain": true
         }
@@ -3078,13 +3511,16 @@
       },
       "evidence": "Finally, nAChRs exist in complexes in the brain; interacting proteins engage in complexes with nAChRs and aid in the assembly and trafficking of nAChR to the plasma membrane; examples are RIC-3 (Lansdell et al., 2005), 14-3-3 proteins (Jeanclos et al., 2001), neurexins (Cheng et al., 2009), and VILIP-1 (Lin et al., 2002)",
       "key": "0e56b0700853f76c5026655e5fcbe261d7c1a3d9de33943473f1ae7ea67cd9a80c650d256c2ddf4528d1e667c39ab35db97f056c4d367bf41faafa4b7a36f01f",
-      "line": 155,
+      "line": 174,
       "relation": "increases",
       "source": 48,
       "target": 59
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Brain": true
         }
@@ -3107,7 +3543,7 @@
       },
       "evidence": "Finally, nAChRs exist in complexes in the brain; interacting proteins engage in complexes with nAChRs and aid in the assembly and trafficking of nAChR to the plasma membrane; examples are RIC-3 (Lansdell et al., 2005), 14-3-3 proteins (Jeanclos et al., 2001), neurexins (Cheng et al., 2009), and VILIP-1 (Lin et al., 2002)",
       "key": "4f3fa515a4f13c6c5fb9fa6fbba9726ba92996cc7801dd0ded287cea5e7e1c67314bcd21795439d158831d8037c4c36fd9e61b4ca6ec9f1fd45337b631c336ea",
-      "line": 156,
+      "line": 175,
       "object": {
         "modifier": "Activity"
       },
@@ -3128,6 +3564,11 @@
       "target": 59
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -3146,7 +3587,7 @@
       },
       "evidence": "Proteins that engage nAChRs within stable complexes, such as lynx family members, provide a homeostatic influence over nicotinic receptor systems",
       "key": "cdf613b39dd4467471000d875e08097ecabe6a53d6e0596563220e36c6151ff8abc45a02c8a4b5fafb2404ebd036bc0c9630a2ed5085b518c1ade7ae9c7ae196",
-      "line": 162,
+      "line": 183,
       "object": {
         "modifier": "Activity"
       },
@@ -3155,6 +3596,11 @@
       "target": 59
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -3173,7 +3619,7 @@
       },
       "evidence": "As GPI-anchored proteins can bind to transmembrane receptors intracellularly, the interactions of lynx with nAChRs could potentially alter receptor trafficking, stoichiometry, and surface number (Lester et al., 2009)",
       "key": "0fe2e242002f11a6629242813a0860ad2ae8dc91aa32ea8f67d7b6c67b996522399a62c7aaadab34e01c12522809d8f7ad3a8b03033f9f178906eae4bca587a5",
-      "line": 174,
+      "line": 199,
       "object": {
         "modifier": "Activity"
       },
@@ -3182,6 +3628,11 @@
       "target": 59
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -3200,7 +3651,7 @@
       },
       "evidence": "As GPI-anchored proteins can bind to transmembrane receptors intracellularly, the interactions of lynx with nAChRs could potentially alter receptor trafficking, stoichiometry, and surface number (Lester et al., 2009)",
       "key": "aec9c33318ade57604b13dd853d92296bb4a90ce7755adf1f4cc612d0b1709f78716f27afa1ff173bed629bfecb53c154425836a220a429079e342d5e8e3123c",
-      "line": 175,
+      "line": 200,
       "object": {
         "effect": {
           "fromLoc": {
@@ -3225,6 +3676,11 @@
       "target": 76
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -3243,7 +3699,7 @@
       },
       "evidence": "Therefore, the evolutionary relationship between lynx modulators and the alpha-neurotoxins agrees with the view that lynx modulators govern critical control points in the pathway of nicotinic receptor signaling",
       "key": "67f2115eae294b2b4c6f58be6b0045ace979a15207e226b11660e05bdf65ada48ee9851f9f64301c47b59a157e25d88b29fc2f75e3cff04c6f4e2197aff8fd92",
-      "line": 181,
+      "line": 208,
       "object": {
         "modifier": "Activity"
       },
@@ -3253,6 +3709,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Brain": true
         }
@@ -3275,7 +3734,7 @@
       },
       "evidence": "Lynx1, the first discovered member of this family expressed in the brain (Miwa et al., 1999), has an overall inhibitory effect on nAChR function",
       "key": "6343526d3a7d25e55241b19ea4d6c6bd19a5b0278167f28301decdd840e0af7cf1f7b7da905c646c17840e2a1203a2c54c40bc2a26784033ac0c04e79a1883f5",
-      "line": 186,
+      "line": 215,
       "object": {
         "modifier": "Activity"
       },
@@ -3284,6 +3743,11 @@
       "target": 59
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -3302,7 +3766,7 @@
       },
       "evidence": "Removal of the molecular brake provided by lynx proteins can lead to nicotinic receptor hypersensitivity—larger direct nicotinic responses, slowed desensitization kinetics (Miwa et al., 2006), and enhanced sensitivity of the EPSC frequency in the cortex to nicotine (Tekinay et al., 2009)",
       "key": "200e7da55a219ec18809fc2844af99f4d5a8b013317a594804da3d05d6e26b94904cba9eb188e8abe09235dca05bfe5c4f2d94d67a4e35bd3c501f6aa7bca378",
-      "line": 211,
+      "line": 246,
       "object": {
         "modifier": "Activity"
       },
@@ -3311,6 +3775,11 @@
       "target": 59
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -3329,7 +3798,7 @@
       },
       "evidence": "This indicates that lynx proteins exist, genetically, as upstream modulators of nicotinic receptor function and cholinergic signaling and can exert control over cholinergic-dependent processes",
       "key": "e58a5e9652c9dd15e4939e0889990281391780476fc95458a0e9bf3507028d921fc017212523170f06d48cf6882f3a1fd77b4100129dec36d7e334ae4fd8db20",
-      "line": 258,
+      "line": 304,
       "object": {
         "modifier": "Activity"
       },
@@ -3338,6 +3807,11 @@
       "target": 59
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -3356,12 +3830,17 @@
       },
       "evidence": "Indeed, cholinergic enhancement (via cholinesterase inhibition) reopens the critical period for visual acuity in adult wild-type mice (Morishita et al., 2010), indicating that cellular mechanisms for robust plasticity are maintained in adulthood through the cholinergic system but are suppressed by the action of lynx.",
       "key": "5af37924b3ac9aa195a22a7a2a149d94d4d1fab7c293913b2fc07030c537e92fa4011ec008fb32da1a7c829a821dd675c02369a34e761a73df7cb361cb2c9c16",
-      "line": 246,
+      "line": 288,
       "relation": "decreases",
       "source": 76,
       "target": 35
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -3380,12 +3859,17 @@
       },
       "evidence": "While genetic linkages of lynx family members to neurological disorders have not been found, evidence for cholinergic dysregulation has been linked to a lynx family member expressed in nonneuronal tissues and involved in human disease (Chimienti et al., 2003), and as such, alterations in lynx dosage may be useful in ameliorating cognitive decline associated with neuropsychiatric disorders.",
       "key": "2d6c8840ffe58d3500e89c10711e9b85bd7af968f0f4f86af5560fef74576d6ffbb1d65b53996989758652e9f5c178ef572a6e52ff2ca3c26a821a1857e41082",
-      "line": 288,
+      "line": 340,
       "relation": "association",
       "source": 76,
       "target": 35
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -3404,12 +3888,17 @@
       },
       "evidence": "While genetic linkages of lynx family members to neurological disorders have not been found, evidence for cholinergic dysregulation has been linked to a lynx family member expressed in nonneuronal tissues and involved in human disease (Chimienti et al., 2003), and as such, alterations in lynx dosage may be useful in ameliorating cognitive decline associated with neuropsychiatric disorders.",
       "key": "f2cfb22e8b9d6eb0fb80b5481f8cbdef1b7bf6a4508399bb3031b9c1beac72e674f8af3352595218bc8c5ef6b44e6f00f9c54b4564b2dd9deb2beee979cc9c36",
-      "line": 289,
+      "line": 341,
       "relation": "association",
       "source": 76,
       "target": 89
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -3428,12 +3917,17 @@
       },
       "evidence": "Neuronal maturation and loss of synaptic lability appear to be correlated with the onset of lynx1 expression",
       "key": "3ee7c4015514536784460b9c9dfc39de7ee9adc2e19e8e43bbd926bdd0273fa3054bdcedc53c00e7d4f1f93828c327b97dc1038bf258a945fe4b37dcf77acfc9",
-      "line": 300,
+      "line": 356,
       "relation": "positiveCorrelation",
       "source": 76,
       "target": 30
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -3452,12 +3946,17 @@
       },
       "evidence": "Neuronal maturation and loss of synaptic lability appear to be correlated with the onset of lynx1 expression",
       "key": "e3717810360b30eb3fa0385b61a0247faa302a324c0c1ae79f1a933ea70f752469c95dd3eae81a9bf88f2d8158525972cfcaa9d1d4ee4ab86d6dfe78e1343638",
-      "line": 301,
+      "line": 357,
       "relation": "negativeCorrelation",
       "source": 76,
       "target": 34
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -3476,7 +3975,7 @@
       },
       "evidence": "Lynx1 upregulation during a critical neurodevelopmental period, the switch in the sign of GABAergic signaling, and coexpression of lynx with GABAergic subsets all indicate a possible role of lynx mediating the timing of such developmental transitions",
       "key": "e3d01ea0daa5a5444145e9cb7dbf6b7174bc267633f6d4d526e15b383294e6bb3567ce27179c686d2dc94a6ef06a567d142256caba1a075b969b4c6a3d751bcd",
-      "line": 310,
+      "line": 370,
       "relation": "regulates",
       "source": 76,
       "target": 27
@@ -3495,6 +3994,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "MeSHDisease": {
           "Schizophrenia": true
         }
@@ -3516,12 +4018,12 @@
         "volume": "70"
       },
       "evidence": "First, postmortem studies of the hippocampus and thalamus show diminished labeling of putative inhibitory neurons by alpha-bungarotoxin, an antagonist of alpha7 nAChRs (Court et al., 1999)",
-      "key": "bacef5e3222aa631842a5c5dc77cc70ba1f915a64bcf30dc074f466023acf8a89b093ded831fe958974e3e980cf8b0ac53acb4ca907827f3245aa41c94e70c2e",
-      "line": 387,
+      "key": "5cd194550dd21df0dcd539f812d7e19be817385211bd956f989a6021030f1038fe1514ad5171dc4d07ee990cebbe7e6a161de096fb012fbab8606a0c969a7687",
+      "line": 469,
       "object": {
         "modifier": "Activity"
       },
-      "relation": "increases",
+      "relation": "decreases",
       "source": 14,
       "target": 21
     },
@@ -3538,6 +4040,11 @@
       "target": 76
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -3556,7 +4063,7 @@
       },
       "evidence": "In an alpha4beta2* nAChR-expressing cell, coexpression of lynx1 results in reduced agonist sensitivity, accelerated onset of desensitization, and slower recovery from desensitization (Ibanez-Tallon et al., 2002)",
       "key": "49aebdfc1d9eb26141cc05bb81e51c05c32e2a474bda3abbfe7ee8d584a11207ca3cca1e947041cbff56a771f10595753b14a4a4e5cb16d4eaa144720db0922b",
-      "line": 193,
+      "line": 224,
       "object": {
         "modifier": "Activity"
       },
@@ -3565,6 +4072,11 @@
       "target": 59
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -3583,13 +4095,16 @@
       },
       "evidence": "In rodents and humans, the hippocampus is importantly implicated in cognitive sensitization, and alpha4beta2* nAChRs play key roles (Levin et al., 2006; Davis and Gould, 2009)",
       "key": "841bc04841ed122d3208c7ec1687d6c74ccfbd5675a559e673807f4bf6df63c5c238f02df17b40d6441a5e911354b32f395b41464143e066d4f901f685fceb1a",
-      "line": 496,
+      "line": 610,
       "relation": "positiveCorrelation",
       "source": 11,
       "target": 36
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Mesencephalon": true,
           "Pars Compacta": true,
@@ -3614,13 +4129,16 @@
       },
       "evidence": "In the midbrain, both DA neurons (in substantia nigra pars compacta and ventral tegmental area [VTA]) and GABAergic neurons (in substantia nigra pars reticulata and VTA) express high levels of alpha4beta2* nAChRs on their somata, but only GABAergic neurons display somatic upregulation (Nashmi et al., 2007; Xiao et al., 2009)",
       "key": "2cd97665d0f11892e57f1eb650ce3042ade6a53421b49011d22c3012a29073e339cbabc77d3da3fcd1522e00e0d5a21c31c1be22d1d53ed78a00ce774d02b2d3",
-      "line": 538,
+      "line": 664,
       "relation": "positiveCorrelation",
       "source": 11,
       "target": 18
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Mesencephalon": true,
           "Pars Reticulata": true,
@@ -3645,7 +4163,7 @@
       },
       "evidence": "In the midbrain, both DA neurons (in substantia nigra pars compacta and ventral tegmental area [VTA]) and GABAergic neurons (in substantia nigra pars reticulata and VTA) express high levels of alpha4beta2* nAChRs on their somata, but only GABAergic neurons display somatic upregulation (Nashmi et al., 2007; Xiao et al., 2009)",
       "key": "d125c25043d922a72b92878f0abb7fea3d83f12c0ad95e6763cab7a8c72bdbafea1e079d938d2b192bf70749c780c37ca7cb3e9fd67bc0e4cb78384503926d25",
-      "line": 540,
+      "line": 668,
       "relation": "positiveCorrelation",
       "source": 11,
       "target": 19
@@ -3657,6 +4175,11 @@
       "target": 11
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -3675,7 +4198,7 @@
       },
       "evidence": "Each lynx paralog has a relative binding specificity and modulatory capability on alpha4beta2 (Miwa et al., 1999; Iban˜ ez-Tallon et al., 2002; Levitin et al., 2008), alpha3 (Arredondo et al., 2006), and alpha7 (Chimienti et al., 2003; Levitin et al., 2008; Hruska et al., 2009) nAChR subtypes; some interactions actually enhance nicotinic responses (Chimienti et al., 2003; Levitin et al., 2008), or their Ca2+ components (Darvas et al., 2009)",
       "key": "2fb895c790575bd85c8cc53c6fbd959d68f909e12998834495dd46264430a7d4aa001274a71fc98301cc95484c6dd5b739a01d0fcf8f1db4ed69de9682635272",
-      "line": 202,
+      "line": 235,
       "object": {
         "modifier": "Activity"
       },
@@ -3696,6 +4219,11 @@
       "target": 62
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -3714,7 +4242,7 @@
       },
       "evidence": "Each lynx paralog has a relative binding specificity and modulatory capability on alpha4beta2 (Miwa et al., 1999; Iban˜ ez-Tallon et al., 2002; Levitin et al., 2008), alpha3 (Arredondo et al., 2006), and alpha7 (Chimienti et al., 2003; Levitin et al., 2008; Hruska et al., 2009) nAChR subtypes; some interactions actually enhance nicotinic responses (Chimienti et al., 2003; Levitin et al., 2008), or their Ca2+ components (Darvas et al., 2009)",
       "key": "54fecec9e06bd1cca89a675507eaca292c5a6848248fd1c2ec988ffca078209d001645f0a7ac491aaf0350670b18c9d55d9c01d12a91cd2614970072570218e2",
-      "line": 203,
+      "line": 236,
       "object": {
         "modifier": "Activity"
       },
@@ -3741,6 +4269,11 @@
       "target": 13
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -3759,7 +4292,7 @@
       },
       "evidence": "Each lynx paralog has a relative binding specificity and modulatory capability on alpha4beta2 (Miwa et al., 1999; Iban˜ ez-Tallon et al., 2002; Levitin et al., 2008), alpha3 (Arredondo et al., 2006), and alpha7 (Chimienti et al., 2003; Levitin et al., 2008; Hruska et al., 2009) nAChR subtypes; some interactions actually enhance nicotinic responses (Chimienti et al., 2003; Levitin et al., 2008), or their Ca2+ components (Darvas et al., 2009)",
       "key": "7359ba10ad2cbf2a833a51f180e0dae41ea8b726340fc59253b486c98bf9ded24f918f3b2ad497008b237c8b885456bfd834e1b606778405ed0021fe851e8840",
-      "line": 204,
+      "line": 237,
       "object": {
         "modifier": "Activity"
       },
@@ -3775,6 +4308,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Pyramidal Cells": true
         }
@@ -3797,12 +4333,17 @@
       },
       "evidence": "One important role for alpha7 nAChRs, in conjunction with alpha3-containing nAChRs, is the induction of the KCC2 chloride transporter in pyramidal neurons (Liu et al., 2006)",
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       "relation": "increases",
       "source": 13,
       "target": 81
     },
     {
+      "annotations": {
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+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -3821,12 +4362,17 @@
       },
       "evidence": "A specific role of alpha7 nAChRs was demonstrated by failure of the induction of KCC2 by treatment with alpha7 nAChR antagonists and in a7 KO mice (Zhang and Berg, 2007)",
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       "relation": "increases",
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       "target": 81
     },
     {
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+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -3845,13 +4391,16 @@
       },
       "evidence": "alpha7 nAChRs are involved in the macrophage and placental cytokine response, which may be an additional role for genetic variants in these receptors in the pathogenesis of schizophrenia (Wang et al., 2003)",
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       "target": 29
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Placenta": true
         }
@@ -3874,13 +4423,16 @@
       },
       "evidence": "alpha7 nAChRs are involved in the macrophage and placental cytokine response, which may be an additional role for genetic variants in these receptors in the pathogenesis of schizophrenia (Wang et al., 2003)",
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       "target": 32
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     {
       "annotations": {
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         "MeSHAnatomy": {
           "Neurons": true
         },
@@ -3906,13 +4458,16 @@
       },
       "evidence": "As a consequence of nAChR hypersensitivity, lynx1 knockout mice display increased levels of Ca2+ in neurons, enhancements in synaptic efficacy, and improved learning and memory functions (Miwa et al., 2006; Darvas et al., 2009; Tekinay et al., 2009)",
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       "relation": "decreases",
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       "target": 0
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     {
       "annotations": {
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         "Species": {
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@@ -3935,13 +4490,16 @@
       },
       "evidence": "As a consequence of nAChR hypersensitivity, lynx1 knockout mice display increased levels of Ca2+ in neurons, enhancements in synaptic efficacy, and improved learning and memory functions (Miwa et al., 2006; Darvas et al., 2009; Tekinay et al., 2009)",
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       "relation": "decreases",
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       "target": 41
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     {
       "annotations": {
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         "Species": {
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@@ -3964,13 +4522,16 @@
       },
       "evidence": "As a consequence of nAChR hypersensitivity, lynx1 knockout mice display increased levels of Ca2+ in neurons, enhancements in synaptic efficacy, and improved learning and memory functions (Miwa et al., 2006; Darvas et al., 2009; Tekinay et al., 2009)",
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       "relation": "decreases",
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       "target": 37
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     {
       "annotations": {
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         "Species": {
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@@ -3993,13 +4554,16 @@
       },
       "evidence": "As a consequence of nAChR hypersensitivity, lynx1 knockout mice display increased levels of Ca2+ in neurons, enhancements in synaptic efficacy, and improved learning and memory functions (Miwa et al., 2006; Darvas et al., 2009; Tekinay et al., 2009)",
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       "relation": "decreases",
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       "target": 38
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     {
       "annotations": {
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         "Species": {
           "10090": true
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@@ -4022,13 +4586,16 @@
       },
       "evidence": "For instance, adult lynx1KO mice display heightened ocular dominance plasticity after the normal close of the critical period (Morishita et al., 2010)",
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       "relation": "decreases",
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       "target": 39
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     {
       "annotations": {
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+        },
         "Species": {
           "10090": true
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@@ -4051,13 +4618,16 @@
       },
       "evidence": "These findings indicate that suppression of the cholinergic system by lynx proteins stabilizes neural circuitry",
       "key": "e78a9edcc24b94c6c8f006a6060f860b01b10efdaededf407ab719a9494a4adc965087f1f36001868acf79f630d3aa6158fea0fa2c2f797427c327c4bb10d88e",
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       "relation": "decreases",
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       "target": 35
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     {
       "annotations": {
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+        },
         "Species": {
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@@ -4080,12 +4650,17 @@
       },
       "evidence": "These findings indicate that suppression of the cholinergic system by lynx proteins stabilizes neural circuitry",
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       "relation": "increases",
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       "target": 24
     },
     {
+      "annotations": {
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+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -4104,7 +4679,7 @@
       },
       "evidence": "Because excess activation of nAChRs damages neuronal health and brain function, organisms have a clear need to restrict the degree of nAChR activation",
       "key": "b1b74729a076433c827d887e9ce0c40f168f38423e8c7de8f794f801a30d8095b0fb33279c40f8954124b8526edbbd49609e6734ce1209a524151ef914fe11ae",
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       "object": {
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@@ -4113,6 +4688,11 @@
       "target": 59
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -4131,7 +4711,7 @@
       },
       "evidence": "The neurons release additional GABA, activating presynaptic GABAB receptors on the excitatory inputs to pyramidal neurons, which diminish the release of glutamate onto the pyramidal neurons (Figure 2)",
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@@ -4150,6 +4730,11 @@
       "target": 1
     },
     {
+      "annotations": {
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+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -4168,7 +4753,7 @@
       },
       "evidence": "Because excess activation of nAChRs damages neuronal health and brain function, organisms have a clear need to restrict the degree of nAChR activation",
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@@ -4181,6 +4766,9 @@
     },
     {
       "annotations": {
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+          "High": true
+        },
         "Species": {
           "10090": true
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@@ -4203,7 +4791,7 @@
       },
       "evidence": "Evidence thus far indicates that the lynx family is regulated in response to relatively strong perturbations: downregulation in NKCC1 knockout mice (Pfeffer et al., 2009), in adenylyl cyclase mutant mice (Wieczorek et al., 2010), and by alpha7 nAChR blockade (Hruska et al., 2009), whereas it is upregulated at the close of the critical period in the visual cortex, and by nicotine in the lung (Sekhon et al., 2005)",
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@@ -4213,6 +4801,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Species": {
           "10090": true
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@@ -4235,7 +4826,7 @@
       },
       "evidence": "Evidence thus far indicates that the lynx family is regulated in response to relatively strong perturbations: downregulation in NKCC1 knockout mice (Pfeffer et al., 2009), in adenylyl cyclase mutant mice (Wieczorek et al., 2010), and by alpha7 nAChR blockade (Hruska et al., 2009), whereas it is upregulated at the close of the critical period in the visual cortex, and by nicotine in the lung (Sekhon et al., 2005)",
       "key": "25fa593e255710a931bc48cbd90667c01d8f7f6946e4a5cada9dd80d6d58aa7cb8468e12e7932e61dce0d3d8d81d37164b6ae8c3685595da24cda97cb4dd4e09",
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@@ -4250,6 +4841,11 @@
       "target": 57
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     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -4268,7 +4864,7 @@
       },
       "evidence": "While genetic linkages of lynx family members to neurological disorders have not been found, evidence for cholinergic dysregulation has been linked to a lynx family member expressed in nonneuronal tissues and involved in human disease (Chimienti et al., 2003), and as such, alterations in lynx dosage may be useful in ameliorating cognitive decline associated with neuropsychiatric disorders.",
       "key": "f450896e45067e2cbd6ae45782d7d82b674a02448a5242bbebf4c8178fcba63db7816575d0e32d73fb63e7d95e15e822a476b58978c84a60bcc19179b39f8842",
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       "relation": "association",
       "source": 89,
       "target": 76
@@ -4277,6 +4873,9 @@
       "annotations": {
         "Cell": {
           "parasympathetic neuron": true
+        },
+        "Confidence": {
+          "High": true
         }
       },
       "citation": {
@@ -4297,12 +4896,17 @@
       },
       "evidence": "For instance, early expression of lynx1 family member, PSCA, prevents programmed cell death of parasympathetic neurons (Hruska et al., 2009)",
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       "relation": "decreases",
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       "target": 31
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     {
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+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -4321,12 +4925,17 @@
       },
       "evidence": "Neuronal maturation and loss of synaptic lability appear to be correlated with the onset of lynx1 expression",
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+      "line": 356,
       "relation": "positiveCorrelation",
       "source": 30,
       "target": 76
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -4345,12 +4954,17 @@
       },
       "evidence": "Neuronal maturation and loss of synaptic lability appear to be correlated with the onset of lynx1 expression",
       "key": "768dc0f269314f30f4a9d77ae1f80b415d50cda64834581d59b1e55c4aac64e314eb1d2157a4c5c5f13ffe2eed6eb8702d4199ee15608b8eab25dc6b720fe31c",
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       "relation": "negativeCorrelation",
       "source": 34,
       "target": 76
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -4369,7 +4983,7 @@
       },
       "evidence": "The neurodevelopmental program depends in part on alpha7 signaling (Liu et al.,2006)",
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@@ -4378,6 +4992,11 @@
       "target": 21
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -4396,12 +5015,17 @@
       },
       "evidence": "Nicotinic receptor control over GABAergic neuronal development and mature activity may represent a point of convergence for diseases such as schizophrenia (see next section), some amblyopias (Bavelier et al., 2010), and some epilepsies (Klaassen et al., 2006), which distort the excitatory-inhibitory balance in general and implicate GABAergic signaling defects in particular",
       "key": "989a56832a8cdddf79a7d0ff2857fa9e1ffa1bd1ce22f4693a97a591a3f8b07a9277b09d7ef5440191d5e130503f75fe36cbb59ca78e59139fd170a946bc5c43",
-      "line": 319,
+      "line": 381,
       "relation": "association",
       "source": 25,
       "target": 104
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -4420,12 +5044,17 @@
       },
       "evidence": "Nicotinic receptor control over GABAergic neuronal development and mature activity may represent a point of convergence for diseases such as schizophrenia (see next section), some amblyopias (Bavelier et al., 2010), and some epilepsies (Klaassen et al., 2006), which distort the excitatory-inhibitory balance in general and implicate GABAergic signaling defects in particular",
       "key": "8d344aceb0e64a4ea8d361adf6ed6ff70e19aed11b366aee176aecc1500a5b0ae4a7dfddd0bca9d56a196abd210c58f36b5fe3aedb3905b4547c048830767330",
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+      "line": 382,
       "relation": "association",
       "source": 25,
       "target": 96
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -4444,13 +5073,16 @@
       },
       "evidence": "Nicotinic receptor control over GABAergic neuronal development and mature activity may represent a point of convergence for diseases such as schizophrenia (see next section), some amblyopias (Bavelier et al., 2010), and some epilepsies (Klaassen et al., 2006), which distort the excitatory-inhibitory balance in general and implicate GABAergic signaling defects in particular",
       "key": "a3020019a0522bea2c5fd88819ca32cf79fa6f7fe6c80d37daa597eee1398ca3b27033613d2c2feef4f46ed5d178551b6719fcb2098521338754642953eb72fa",
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+      "line": 382,
       "relation": "association",
       "source": 96,
       "target": 25
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Dentate Gyrus": true,
           "Hippocampus": true
@@ -4474,12 +5106,17 @@
       },
       "evidence": "alpha7 nAChRs on inhibitory interneurons throughout the hippocampus and presynaptic alpha7 nAChRs on mossy fiber terminals in the dentate gyrus participate in the control of sensory response in the hippocampus (Gray et al., 1996; Alkondon et al., 1999",
       "key": "12c6fa73f7bed3f0cde9da29769eb3c614540164e05b4fa73501f31ecad10e0acfe17eccf1cfaaeb73d30924da7df25d7a7f2c5841f88d805da0d37ea70d0fe5",
-      "line": 346,
+      "line": 416,
       "relation": "regulates",
       "source": 15,
       "target": 33
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -4498,7 +5135,7 @@
       },
       "evidence": "Nicotinic activation of inhibitory interneurons increases their activity and activates nitric oxide synthetase",
       "key": "d4afcc4482d2208eca1ae5f1d99d452b84db1c9317eb7fa2692297f2f99f87850590efec53896b9b570c94f63bafa91ad0c51c192bd0166f7374797b9ce24738",
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       "object": {
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       },
@@ -4511,6 +5148,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Hippocampus": true
         }
@@ -4533,13 +5173,16 @@
       },
       "evidence": "Although alpha7 nAChRs have both presynaptic and postsynaptic expression (Frazier et al., 1998), their postsynaptic expression in humans is especially marked on inhibitory neurons of the hippocampus (Alkondon et al., 2000)",
       "key": "7d187250160a763ac53a5aa59949bde44daf28d4a998cefc937c13f22d06384ceb60b62fa5bb07c4421e8749c863d2707ad7e1f406d6ed6ba0e14dcaee6b04a7",
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       "relation": "association",
       "source": 15,
       "target": 21
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Schizophrenia": true
         }
@@ -4562,7 +5205,7 @@
       },
       "evidence": "Polymorphisms in the alpha7 5' promoter and in a nearby partial duplication of the gene, FAM7A, are associated with both schizophrenia and the defect in inhibition (Leonard et al., 2002)",
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       "relation": "negativeCorrelation",
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       "subject": {
@@ -4572,6 +5215,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Pyramidal Cells": true
         }
@@ -4594,7 +5240,7 @@
       },
       "evidence": "The neurons release additional GABA, activating presynaptic GABAB receptors on the excitatory inputs to pyramidal neurons, which diminish the release of glutamate onto the pyramidal neurons (Figure 2)",
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       "object": {
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@@ -4604,6 +5250,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Pyramidal Cells": true
         }
@@ -4626,7 +5275,7 @@
       },
       "evidence": "The neurons release additional GABA, activating presynaptic GABAB receptors on the excitatory inputs to pyramidal neurons, which diminish the release of glutamate onto the pyramidal neurons (Figure 2)",
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@@ -4636,6 +5285,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Pyramidal Cells": true
         }
@@ -4658,7 +5310,7 @@
       },
       "evidence": "The neurons release additional GABA, activating presynaptic GABAB receptors on the excitatory inputs to pyramidal neurons, which diminish the release of glutamate onto the pyramidal neurons (Figure 2)",
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         "effect": {
           "fromLoc": {
@@ -4677,6 +5329,11 @@
       "target": 2
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -4695,7 +5352,7 @@
       },
       "evidence": "Thus, the brainstem can regulate hippocampal response in the presence of high sensory input.",
       "key": "56e804b323e448e3b13d379e108173758ffceb03595ae8409dc357d240173bc2e459bef48727ed6de4e0364842891549c1c95eecbe3064222185ab3802c8b05c",
-      "line": 367,
+      "line": 443,
       "object": {
         "modifier": "Activity"
       },
@@ -4705,6 +5362,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Schizophrenia": true
         }
@@ -4727,13 +5387,16 @@
       },
       "evidence": "Polymorphisms in the alpha7 5' promoter and in a nearby partial duplication of the gene, FAM7A, are associated with both schizophrenia and the defect in inhibition (Leonard et al., 2002)",
       "key": "ae2d39bf71fcaa14d24d81d08ba8d52601df0208cf39c6ca51a058b1e192d3edb061ff0fd202ecf428d76ec3fe1e591dcfc0dafbe7ae7825ca28300e8ab66c2b",
-      "line": 394,
+      "line": 479,
       "relation": "association",
       "source": 54,
       "target": 104
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Schizophrenia": true
         }
@@ -4756,7 +5419,7 @@
       },
       "evidence": "Polymorphisms in the alpha7 5' promoter and in a nearby partial duplication of the gene, FAM7A, are associated with both schizophrenia and the defect in inhibition (Leonard et al., 2002)",
       "key": "47a19eed68ae0a7d764560d4df397aba2a799b8b81763527302f2add7ecd0e42595c774ad819ca38c5d927b9ab2eb9d0dfa3d7f6159a28bdb19ff9718b194d41",
-      "line": 395,
+      "line": 480,
       "object": {
         "modifier": "Activity"
       },
@@ -4772,6 +5435,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Schizophrenia": true
         }
@@ -4794,13 +5460,16 @@
       },
       "evidence": "Yet some of the other genes identified, such as NRG1, are involved in the assembly of alpha7 nAChRs, further supporting a potential link between alpha7 nAChRs and schizophrenia (Mathew et al., 2007)",
       "key": "25055574e0bd5594175168da8c6550bf8cb12562b3bd3c3bebb34d7e60335cf899e43c9cf96757bab301a893a564771fe76e1178a3fc2993edbd35c78c649de8",
-      "line": 400,
+      "line": 487,
       "relation": "increases",
       "source": 55,
       "target": 21
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Schizophrenia": true
         }
@@ -4823,7 +5492,7 @@
       },
       "evidence": "3-(2,4 dimethoxy)-benzylidene-anabaseine, derived from an alkaloid produced by nemertine worms, is a partial agonist at alpha7 nAChRs",
       "key": "58e4b397c5e61310819f97d519f46c87e89f5e1467cff1bb00f3ed8eab1ee73eefdbb2eb72b66927a7f38c39b1ca743bca8f659689c9a1e6735355373bc59910",
-      "line": 416,
+      "line": 509,
       "object": {
         "modifier": "Activity"
       },
@@ -4833,6 +5502,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Schizophrenia": true
         }
@@ -4855,13 +5527,16 @@
       },
       "evidence": "It improves sensory inhibition in schizophrenics and also moderately improves their neuropsychological deficits in attention (Olincy et al., 2006)",
       "key": "28acbc19dc7a5a9e84787dfc3804242839b8c203bdff749b9706081076770675751452961e53a814321aa05faf60f8d484887f3250c148d7ccbade2d765a05d4",
-      "line": 422,
+      "line": 517,
       "relation": "increases",
       "source": 10,
       "target": 100
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Schizophrenia": true
         }
@@ -4884,13 +5559,16 @@
       },
       "evidence": "It improves sensory inhibition in schizophrenics and also moderately improves their neuropsychological deficits in attention (Olincy et al., 2006)",
       "key": "2c79d053c9565aaa8e06b65899eebafb27eca79ba2d7e06a0cc07176d281125f531515ba302deb3d27ddc9498ea3badd791ce447269744b540177d2e752f86b5",
-      "line": 423,
+      "line": 518,
       "relation": "increases",
       "source": 10,
       "target": 33
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Schizophrenia": true
         }
@@ -4913,13 +5591,16 @@
       },
       "evidence": "Clinical ratings of their negative symptoms, particularly anhedonia (absence of a sense of pleasure) and alogia (poverty of content in their speech), also improve during treatment",
       "key": "be3aae08df7cea5e34bc7e6c27059da855b0cd3d9aa9fa5bca9dc6667a36734cef18f92fac597abbe79c6f91bec51cc33735a4d4ec0d1d6b5e3c92472dde76d6",
-      "line": 429,
+      "line": 526,
       "relation": "decreases",
       "source": 10,
       "target": 97
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Schizophrenia": true
         }
@@ -4942,13 +5623,16 @@
       },
       "evidence": "Clinical ratings of their negative symptoms, particularly anhedonia (absence of a sense of pleasure) and alogia (poverty of content in their speech), also improve during treatment",
       "key": "75a3433ed0f3d480a36b17e5c17eed4d471d784fd977574d0228f32002cc549e3aba715a8db160439515072e9f0ee532724ec9bd8672299819e86f330ec245a7",
-      "line": 430,
+      "line": 527,
       "relation": "decreases",
       "source": 10,
       "target": 99
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Neurons": true
         }
@@ -4971,13 +5655,16 @@
       },
       "evidence": "This transporter lowers the internal Cl- concentration of the neuron and changes GABA from a depolarizing to a hyperpolarizing or inhibitory neurotransmitter",
       "key": "596ee06835f509801b3bd6ec3fe0fa61a45e24d160a2bfb3fe1c2cc5e2035fbc75bfc2e60a11bcabeaf348f2fd3a101e01fc9632f3dd57f017ea48c3899e94af",
-      "line": 445,
+      "line": 545,
       "relation": "decreases",
       "source": 81,
       "target": 4
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Neurons": true
         }
@@ -5000,7 +5687,7 @@
       },
       "evidence": "This transporter lowers the internal Cl- concentration of the neuron and changes GABA from a depolarizing to a hyperpolarizing or inhibitory neurotransmitter",
       "key": "c2a57d42bb1518d3d1523d1a8047d67ea870bbd69d336d843b06e2b5ebf4f151de950c9b02538c3503c0e597e20c6e9b00c1b8189a66db78a4aa7113e9205dcf",
-      "line": 446,
+      "line": 546,
       "object": {
         "modifier": "Activity"
       },
@@ -5009,6 +5696,11 @@
       "target": 1
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -5027,7 +5719,7 @@
       },
       "evidence": "Variants in the gene for phosphatidylethanolamine methyl transferase, which synthesizes phosphatidylcholine and thus provides a source of choline, are also associated with choline deficiency and with schizophrenia",
       "key": "6a354b77f99c6bf0b00b66ecd5353c1f2d65730fe65646d82148fdefeb32da2224e4937cd2fea028598f1b26ea83341b8d808b981bd37a30a8d8eca9ba5706b9",
-      "line": 463,
+      "line": 569,
       "relation": "increases",
       "source": 77,
       "target": 9
@@ -5039,6 +5731,11 @@
       "target": 78
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -5057,12 +5754,17 @@
       },
       "evidence": "Variants in the gene for phosphatidylethanolamine methyl transferase, which synthesizes phosphatidylcholine and thus provides a source of choline, are also associated with choline deficiency and with schizophrenia",
       "key": "915642a74462fd9e171e593397319a90f5731b27101a97a3c9e5010ab0afb347e895ac35f847881bbf7b015708152f95eb1013cb7bb790be504a71711dcd2002",
-      "line": 464,
+      "line": 570,
       "relation": "increases",
       "source": 9,
       "target": 5
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -5081,12 +5783,17 @@
       },
       "evidence": "Variants in the gene for phosphatidylethanolamine methyl transferase, which synthesizes phosphatidylcholine and thus provides a source of choline, are also associated with choline deficiency and with schizophrenia",
       "key": "2088aaa07dc5075b7d9f7842c8008d924dd9ae26b4c6e3063ad3e55ba88759a0c204824880b5a6379efddf980637b88ddbed6ce93bf21f38fc0baa0d46f0b0d5",
-      "line": 465,
+      "line": 571,
       "relation": "association",
       "source": 78,
       "target": 87
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -5105,12 +5812,17 @@
       },
       "evidence": "Variants in the gene for phosphatidylethanolamine methyl transferase, which synthesizes phosphatidylcholine and thus provides a source of choline, are also associated with choline deficiency and with schizophrenia",
       "key": "2246d042a96b8fdc187726d3eec8593a8cbd78a17ca78bbf986403c58d00c3bc2ba83b25289c60259c47c8cca2564b0e48ecac441f995deed7556079e4be015c",
-      "line": 466,
+      "line": 572,
       "relation": "association",
       "source": 78,
       "target": 104
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -5129,12 +5841,17 @@
       },
       "evidence": "Variants in the gene for phosphatidylethanolamine methyl transferase, which synthesizes phosphatidylcholine and thus provides a source of choline, are also associated with choline deficiency and with schizophrenia",
       "key": "eef85ed024d8e6cfe57d50524ba5872d7198f50f32964bd080ff600b1cb7f6f45ac8966fe00e88f85e8e911538f5ee121c28cb04239fd4391c69d2ddea544567",
-      "line": 465,
+      "line": 571,
       "relation": "association",
       "source": 87,
       "target": 78
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -5153,13 +5870,16 @@
       },
       "evidence": "alpha7 nAChRs are involved in the macrophage and placental cytokine response, which may be an additional role for genetic variants in these receptors in the pathogenesis of schizophrenia (Wang et al., 2003)",
       "key": "36e11608a0b39b23d5e1a9ef163d169ff1d8e437ef18e99d9a2f021f2e5a0e8c5baf66ac3400c405a3a224b51006add6304c4c972ea83f6dd8e6b0cd415a704a",
-      "line": 472,
+      "line": 580,
       "relation": "association",
       "source": 29,
       "target": 13
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Placenta": true
         }
@@ -5182,13 +5902,16 @@
       },
       "evidence": "alpha7 nAChRs are involved in the macrophage and placental cytokine response, which may be an additional role for genetic variants in these receptors in the pathogenesis of schizophrenia (Wang et al., 2003)",
       "key": "9e96ae073789ab6f3c278bb6cce1b8645eb25edecd8d251d2c089786fde67be3eab750a8c5776bad8653a7e027a036f35dbab88a43c5feb54addf4115ce596b9",
-      "line": 474,
+      "line": 582,
       "relation": "association",
       "source": 32,
       "target": 13
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Amygdala": true
         }
@@ -5211,13 +5934,16 @@
       },
       "evidence": "For instance, dopamine increases in the extended amygdala during stress, fear, and nicotine withdrawal (Inglis and Moghaddam, 1999; Pape, 2005; Grace et al., 2007; Gallagher et al., 2008; Koob, 2009; Marcinkiewcz et al., 2009)",
       "key": "8dbeff29fe25d50a31f7c17417372e8cf79c5f453a92748f6539ef74e1a7483cb0e788490386ad460cb48991c7e49d5bb88b87aadc3826bd3f0ca97df36c0318",
-      "line": 510,
+      "line": 628,
       "relation": "increases",
       "source": 40,
       "target": 6
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Amygdala": true
         }
@@ -5240,13 +5966,16 @@
       },
       "evidence": "For instance, dopamine increases in the extended amygdala during stress, fear, and nicotine withdrawal (Inglis and Moghaddam, 1999; Pape, 2005; Grace et al., 2007; Gallagher et al., 2008; Koob, 2009; Marcinkiewcz et al., 2009)",
       "key": "63285734306287926d1d5602bb7a428336e90ec2706edb307b78d5b6b7be66d176afff0562d91442ea6ba839e4724105861946a517c2aba3b4bfb92f4d1a7de4",
-      "line": 511,
+      "line": 629,
       "relation": "increases",
       "source": 103,
       "target": 6
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Mesencephalon": true,
           "Pars Compacta": true,
@@ -5271,13 +6000,16 @@
       },
       "evidence": "In the midbrain, both DA neurons (in substantia nigra pars compacta and ventral tegmental area [VTA]) and GABAergic neurons (in substantia nigra pars reticulata and VTA) express high levels of alpha4beta2* nAChRs on their somata, but only GABAergic neurons display somatic upregulation (Nashmi et al., 2007; Xiao et al., 2009)",
       "key": "fc6970cdcc79c5cc3d2f4302cd2ba1cb1f4dd85a2cc7bb390106eb69de69d081fa1500532954e95dea73940361f3c6ff31e8913f02b01362aac05b744ea14512",
-      "line": 538,
+      "line": 664,
       "relation": "positiveCorrelation",
       "source": 18,
       "target": 11
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Mesencephalon": true,
           "Pars Reticulata": true,
@@ -5302,12 +6034,17 @@
       },
       "evidence": "In the midbrain, both DA neurons (in substantia nigra pars compacta and ventral tegmental area [VTA]) and GABAergic neurons (in substantia nigra pars reticulata and VTA) express high levels of alpha4beta2* nAChRs on their somata, but only GABAergic neurons display somatic upregulation (Nashmi et al., 2007; Xiao et al., 2009)",
       "key": "eff357813eefe7e0f5ab45309bee07f39a36b114c7c9982f6018a4b0a38dad95e8938cf04d7bae67a9795ad559d5548525fbc84dc0092f5de495d2ed70a14951",
-      "line": 540,
+      "line": 668,
       "relation": "positiveCorrelation",
       "source": 19,
       "target": 11
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -5326,12 +6063,17 @@
       },
       "evidence": "Single-nucleotide polymorphisms found in the human alpha5, alpha3, beta4 gene cluster are associated with nicotine dependence and its age-dependent onset; number of cigarettes smoked per day and ‘‘pleasurable buzz’’ elicited by smoking; alcoholism, sensitivity to the depressant effects of alcohol, and age of alcohol initiation; cocaine dependence; opioid dependence; lung cancer; and cognitive flexibility (Erlich et al., 2010; Hansen et al., 2010; Improgo et al., 2010; Saccone et al., 2010; Zhang et al., 2010)",
       "key": "af3e5730971bd79ca7f79ccb0466a2a4357aa88a77e90c09671b582b0359f4c4ac5c5731f3275f92e63ea91c0f36ac7a33ee2719068daa75028e0e33fc044611",
-      "line": 565,
+      "line": 699,
       "relation": "positiveCorrelation",
       "source": 95,
       "target": 67
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -5350,12 +6092,17 @@
       },
       "evidence": "Single-nucleotide polymorphisms found in the human alpha5, alpha3, beta4 gene cluster are associated with nicotine dependence and its age-dependent onset; number of cigarettes smoked per day and ‘‘pleasurable buzz’’ elicited by smoking; alcoholism, sensitivity to the depressant effects of alcohol, and age of alcohol initiation; cocaine dependence; opioid dependence; lung cancer; and cognitive flexibility (Erlich et al., 2010; Hansen et al., 2010; Improgo et al., 2010; Saccone et al., 2010; Zhang et al., 2010)",
       "key": "3572fd12190577907fc0af21960126319853aa8a5e0ed25bd5eacf99ae9c10b484c119aa34ff033887f5a2a642b07e71ca704469cc7bd0e3ba4edbaac9a08b66",
-      "line": 571,
+      "line": 705,
       "relation": "positiveCorrelation",
       "source": 95,
       "target": 63
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -5374,12 +6121,17 @@
       },
       "evidence": "Single-nucleotide polymorphisms found in the human alpha5, alpha3, beta4 gene cluster are associated with nicotine dependence and its age-dependent onset; number of cigarettes smoked per day and ‘‘pleasurable buzz’’ elicited by smoking; alcoholism, sensitivity to the depressant effects of alcohol, and age of alcohol initiation; cocaine dependence; opioid dependence; lung cancer; and cognitive flexibility (Erlich et al., 2010; Hansen et al., 2010; Improgo et al., 2010; Saccone et al., 2010; Zhang et al., 2010)",
       "key": "ffc7b8b509fd7163159dd0396bf595f7a404161fb51b536d02a4f855d2d5f1635da4276b799c4caa469e9cc285069885e8f9b8e921eb53e01e3bfee92d8d609e",
-      "line": 577,
+      "line": 711,
       "relation": "positiveCorrelation",
       "source": 95,
       "target": 73
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -5398,12 +6150,17 @@
       },
       "evidence": "Single-nucleotide polymorphisms found in the human alpha5, alpha3, beta4 gene cluster are associated with nicotine dependence and its age-dependent onset; number of cigarettes smoked per day and ‘‘pleasurable buzz’’ elicited by smoking; alcoholism, sensitivity to the depressant effects of alcohol, and age of alcohol initiation; cocaine dependence; opioid dependence; lung cancer; and cognitive flexibility (Erlich et al., 2010; Hansen et al., 2010; Improgo et al., 2010; Saccone et al., 2010; Zhang et al., 2010)",
       "key": "9a3fe2b6b93aff8a0c9fab3a4aaee6aa53af64f374a47a361121fe94f1195d022b17e92bfaf0dfca70c99b49fc386b978953b78a40ca9aa7cc2d9321104a0cc4",
-      "line": 566,
+      "line": 700,
       "relation": "positiveCorrelation",
       "source": 88,
       "target": 67
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -5422,12 +6179,17 @@
       },
       "evidence": "Single-nucleotide polymorphisms found in the human alpha5, alpha3, beta4 gene cluster are associated with nicotine dependence and its age-dependent onset; number of cigarettes smoked per day and ‘‘pleasurable buzz’’ elicited by smoking; alcoholism, sensitivity to the depressant effects of alcohol, and age of alcohol initiation; cocaine dependence; opioid dependence; lung cancer; and cognitive flexibility (Erlich et al., 2010; Hansen et al., 2010; Improgo et al., 2010; Saccone et al., 2010; Zhang et al., 2010)",
       "key": "27ff2a8eea7390c1f07be627f7f31f189906b9f0a20ec4497dc5c68214499a31b144059d2203e038e1815be87dd945ba0dc3d0c82e9d440df63f49fb574732e0",
-      "line": 572,
+      "line": 706,
       "relation": "positiveCorrelation",
       "source": 88,
       "target": 63
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -5446,12 +6208,17 @@
       },
       "evidence": "Single-nucleotide polymorphisms found in the human alpha5, alpha3, beta4 gene cluster are associated with nicotine dependence and its age-dependent onset; number of cigarettes smoked per day and ‘‘pleasurable buzz’’ elicited by smoking; alcoholism, sensitivity to the depressant effects of alcohol, and age of alcohol initiation; cocaine dependence; opioid dependence; lung cancer; and cognitive flexibility (Erlich et al., 2010; Hansen et al., 2010; Improgo et al., 2010; Saccone et al., 2010; Zhang et al., 2010)",
       "key": "9f9532531a7ddc166b33ccb7e637cb1c969a974659cb7ca98497dc6f5453363af8c3cfbdadf951387f6a61bf97004d48497135c5001b2940ce8e3c24ccc45a5b",
-      "line": 578,
+      "line": 712,
       "relation": "positiveCorrelation",
       "source": 88,
       "target": 73
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Freedman R",
@@ -5470,12 +6237,17 @@
       },
       "evidence": "Single-nucleotide polymorphisms found in the human alpha5, alpha3, beta4 gene cluster are associated with nicotine dependence and its age-dependent onset; number of cigarettes smoked per day and ‘‘pleasurable buzz’’ elicited by smoking; alcoholism, sensitivity to the depressant effects of alcohol, and age of alcohol initiation; cocaine dependence; opioid dependence; lung cancer; and cognitive flexibility (Erlich et al., 2010; Hansen et al., 2010; Improgo et al., 2010; Saccone et al., 2010; Zhang et al., 2010)",
       "key": "f96ea1b157e66dffb2c8addd89dc35920036cb1540f527e301edc7b77c65f1c107b9178b6accb0dd370f71129fd45c802b5881ae6b1e4c95a1a01b932c176f1b",
-      "line": 567,
+      "line": 701,
       "relation": "positiveCorrelation",
       "source": 91,
       "target": 67
     },
     {
+      "annotations": {
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@@ -5494,12 +6266,17 @@
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       "evidence": "Single-nucleotide polymorphisms found in the human alpha5, alpha3, beta4 gene cluster are associated with nicotine dependence and its age-dependent onset; number of cigarettes smoked per day and ‘‘pleasurable buzz’’ elicited by smoking; alcoholism, sensitivity to the depressant effects of alcohol, and age of alcohol initiation; cocaine dependence; opioid dependence; lung cancer; and cognitive flexibility (Erlich et al., 2010; Hansen et al., 2010; Improgo et al., 2010; Saccone et al., 2010; Zhang et al., 2010)",
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           "Freedman R",
@@ -5518,12 +6295,17 @@
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       "evidence": "Single-nucleotide polymorphisms found in the human alpha5, alpha3, beta4 gene cluster are associated with nicotine dependence and its age-dependent onset; number of cigarettes smoked per day and ‘‘pleasurable buzz’’ elicited by smoking; alcoholism, sensitivity to the depressant effects of alcohol, and age of alcohol initiation; cocaine dependence; opioid dependence; lung cancer; and cognitive flexibility (Erlich et al., 2010; Hansen et al., 2010; Improgo et al., 2010; Saccone et al., 2010; Zhang et al., 2010)",
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     {
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@@ -5542,12 +6324,17 @@
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       "evidence": "Single-nucleotide polymorphisms found in the human alpha5, alpha3, beta4 gene cluster are associated with nicotine dependence and its age-dependent onset; number of cigarettes smoked per day and ‘‘pleasurable buzz’’ elicited by smoking; alcoholism, sensitivity to the depressant effects of alcohol, and age of alcohol initiation; cocaine dependence; opioid dependence; lung cancer; and cognitive flexibility (Erlich et al., 2010; Hansen et al., 2010; Improgo et al., 2010; Saccone et al., 2010; Zhang et al., 2010)",
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     {
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       "citation": {
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@@ -5566,12 +6353,17 @@
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       "evidence": "Single-nucleotide polymorphisms found in the human alpha5, alpha3, beta4 gene cluster are associated with nicotine dependence and its age-dependent onset; number of cigarettes smoked per day and ‘‘pleasurable buzz’’ elicited by smoking; alcoholism, sensitivity to the depressant effects of alcohol, and age of alcohol initiation; cocaine dependence; opioid dependence; lung cancer; and cognitive flexibility (Erlich et al., 2010; Hansen et al., 2010; Improgo et al., 2010; Saccone et al., 2010; Zhang et al., 2010)",
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@@ -5590,12 +6382,17 @@
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       "evidence": "Single-nucleotide polymorphisms found in the human alpha5, alpha3, beta4 gene cluster are associated with nicotine dependence and its age-dependent onset; number of cigarettes smoked per day and ‘‘pleasurable buzz’’ elicited by smoking; alcoholism, sensitivity to the depressant effects of alcohol, and age of alcohol initiation; cocaine dependence; opioid dependence; lung cancer; and cognitive flexibility (Erlich et al., 2010; Hansen et al., 2010; Improgo et al., 2010; Saccone et al., 2010; Zhang et al., 2010)",
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@@ -5614,12 +6411,17 @@
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       "evidence": "Single-nucleotide polymorphisms found in the human alpha5, alpha3, beta4 gene cluster are associated with nicotine dependence and its age-dependent onset; number of cigarettes smoked per day and ‘‘pleasurable buzz’’ elicited by smoking; alcoholism, sensitivity to the depressant effects of alcohol, and age of alcohol initiation; cocaine dependence; opioid dependence; lung cancer; and cognitive flexibility (Erlich et al., 2010; Hansen et al., 2010; Improgo et al., 2010; Saccone et al., 2010; Zhang et al., 2010)",
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@@ -5638,12 +6440,17 @@
       },
       "evidence": "Single-nucleotide polymorphisms found in the human alpha5, alpha3, beta4 gene cluster are associated with nicotine dependence and its age-dependent onset; number of cigarettes smoked per day and ‘‘pleasurable buzz’’ elicited by smoking; alcoholism, sensitivity to the depressant effects of alcohol, and age of alcohol initiation; cocaine dependence; opioid dependence; lung cancer; and cognitive flexibility (Erlich et al., 2010; Hansen et al., 2010; Improgo et al., 2010; Saccone et al., 2010; Zhang et al., 2010)",
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@@ -5662,12 +6469,17 @@
       },
       "evidence": "Single-nucleotide polymorphisms found in the human alpha5, alpha3, beta4 gene cluster are associated with nicotine dependence and its age-dependent onset; number of cigarettes smoked per day and ‘‘pleasurable buzz’’ elicited by smoking; alcoholism, sensitivity to the depressant effects of alcohol, and age of alcohol initiation; cocaine dependence; opioid dependence; lung cancer; and cognitive flexibility (Erlich et al., 2010; Hansen et al., 2010; Improgo et al., 2010; Saccone et al., 2010; Zhang et al., 2010)",
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@@ -5686,12 +6498,17 @@
       },
       "evidence": "Single-nucleotide polymorphisms found in the human alpha5, alpha3, beta4 gene cluster are associated with nicotine dependence and its age-dependent onset; number of cigarettes smoked per day and ‘‘pleasurable buzz’’ elicited by smoking; alcoholism, sensitivity to the depressant effects of alcohol, and age of alcohol initiation; cocaine dependence; opioid dependence; lung cancer; and cognitive flexibility (Erlich et al., 2010; Hansen et al., 2010; Improgo et al., 2010; Saccone et al., 2010; Zhang et al., 2010)",
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@@ -5710,12 +6527,17 @@
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       "evidence": "Single-nucleotide polymorphisms found in the human alpha5, alpha3, beta4 gene cluster are associated with nicotine dependence and its age-dependent onset; number of cigarettes smoked per day and ‘‘pleasurable buzz’’ elicited by smoking; alcoholism, sensitivity to the depressant effects of alcohol, and age of alcohol initiation; cocaine dependence; opioid dependence; lung cancer; and cognitive flexibility (Erlich et al., 2010; Hansen et al., 2010; Improgo et al., 2010; Saccone et al., 2010; Zhang et al., 2010)",
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@@ -5734,12 +6556,17 @@
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       "evidence": "Single-nucleotide polymorphisms found in the human alpha5, alpha3, beta4 gene cluster are associated with nicotine dependence and its age-dependent onset; number of cigarettes smoked per day and ‘‘pleasurable buzz’’ elicited by smoking; alcoholism, sensitivity to the depressant effects of alcohol, and age of alcohol initiation; cocaine dependence; opioid dependence; lung cancer; and cognitive flexibility (Erlich et al., 2010; Hansen et al., 2010; Improgo et al., 2010; Saccone et al., 2010; Zhang et al., 2010)",
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@@ -5758,12 +6585,17 @@
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       "evidence": "Single-nucleotide polymorphisms found in the human alpha5, alpha3, beta4 gene cluster are associated with nicotine dependence and its age-dependent onset; number of cigarettes smoked per day and ‘‘pleasurable buzz’’ elicited by smoking; alcoholism, sensitivity to the depressant effects of alcohol, and age of alcohol initiation; cocaine dependence; opioid dependence; lung cancer; and cognitive flexibility (Erlich et al., 2010; Hansen et al., 2010; Improgo et al., 2010; Saccone et al., 2010; Zhang et al., 2010)",
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@@ -5782,12 +6614,17 @@
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       "evidence": "Single-nucleotide polymorphisms found in the human alpha5, alpha3, beta4 gene cluster are associated with nicotine dependence and its age-dependent onset; number of cigarettes smoked per day and ‘‘pleasurable buzz’’ elicited by smoking; alcoholism, sensitivity to the depressant effects of alcohol, and age of alcohol initiation; cocaine dependence; opioid dependence; lung cancer; and cognitive flexibility (Erlich et al., 2010; Hansen et al., 2010; Improgo et al., 2010; Saccone et al., 2010; Zhang et al., 2010)",
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       "citation": {
         "authors": [
           "Freedman R",
@@ -5806,12 +6643,17 @@
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       "evidence": "Single-nucleotide polymorphisms found in the human alpha5, alpha3, beta4 gene cluster are associated with nicotine dependence and its age-dependent onset; number of cigarettes smoked per day and ‘‘pleasurable buzz’’ elicited by smoking; alcoholism, sensitivity to the depressant effects of alcohol, and age of alcohol initiation; cocaine dependence; opioid dependence; lung cancer; and cognitive flexibility (Erlich et al., 2010; Hansen et al., 2010; Improgo et al., 2010; Saccone et al., 2010; Zhang et al., 2010)",
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@@ -5830,12 +6672,17 @@
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       "evidence": "Single-nucleotide polymorphisms found in the human alpha5, alpha3, beta4 gene cluster are associated with nicotine dependence and its age-dependent onset; number of cigarettes smoked per day and ‘‘pleasurable buzz’’ elicited by smoking; alcoholism, sensitivity to the depressant effects of alcohol, and age of alcohol initiation; cocaine dependence; opioid dependence; lung cancer; and cognitive flexibility (Erlich et al., 2010; Hansen et al., 2010; Improgo et al., 2010; Saccone et al., 2010; Zhang et al., 2010)",
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         "authors": [
           "Freedman R",
@@ -5854,12 +6701,17 @@
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       "evidence": "Single-nucleotide polymorphisms found in the human alpha5, alpha3, beta4 gene cluster are associated with nicotine dependence and its age-dependent onset; number of cigarettes smoked per day and ‘‘pleasurable buzz’’ elicited by smoking; alcoholism, sensitivity to the depressant effects of alcohol, and age of alcohol initiation; cocaine dependence; opioid dependence; lung cancer; and cognitive flexibility (Erlich et al., 2010; Hansen et al., 2010; Improgo et al., 2010; Saccone et al., 2010; Zhang et al., 2010)",
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       "citation": {
         "authors": [
           "Freedman R",
@@ -5878,7 +6730,7 @@
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       "evidence": "Single-nucleotide polymorphisms found in the human alpha5, alpha3, beta4 gene cluster are associated with nicotine dependence and its age-dependent onset; number of cigarettes smoked per day and ‘‘pleasurable buzz’’ elicited by smoking; alcoholism, sensitivity to the depressant effects of alcohol, and age of alcohol initiation; cocaine dependence; opioid dependence; lung cancer; and cognitive flexibility (Erlich et al., 2010; Hansen et al., 2010; Improgo et al., 2010; Saccone et al., 2010; Zhang et al., 2010)",
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@@ -5890,6 +6742,11 @@
       "target": 73
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     {
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       "citation": {
         "authors": [
           "Freedman R",
@@ -5908,12 +6765,17 @@
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       "evidence": "However, when all genetic factors are eliminated by studying monozygotic twins who are discordant for both tobacco use and Parkinson’s disease, tobacco smoking and chewing still decrease the risk of Parkinson’s disease (Tanner et al., 2002; Wirdefeldt et al., 2005)",
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     {
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       "citation": {
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           "Freedman R",
@@ -5932,7 +6794,7 @@
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       "evidence": "However, when all genetic factors are eliminated by studying monozygotic twins who are discordant for both tobacco use and Parkinson’s disease, tobacco smoking and chewing still decrease the risk of Parkinson’s disease (Tanner et al., 2002; Wirdefeldt et al., 2005)",
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diff --git a/hbp_knowledge/receptors/nordberg2001.bel.json b/hbp_knowledge/receptors/nordberg2001.bel.json
index 5e5188419..fd482873c 100644
--- a/hbp_knowledge/receptors/nordberg2001.bel.json
+++ b/hbp_knowledge/receptors/nordberg2001.bel.json
@@ -55,6 +55,14 @@
   },
   "links": [
     {
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       "citation": {
         "authors": [
           "Nordberg A"
@@ -71,12 +79,17 @@
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       "evidence": "Experimental data suggest that the nAChRs might act as neuromodulators in communicative processes in the brain (Kaiser et al 2000; Lindstro¨m 1997; Wonnacott 1997)",
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           "Nordberg A"
@@ -93,13 +106,16 @@
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       "evidence": "The nAChRs are found to be involved in a complex range of central nervous system disorders including Alzheimer’s disease (AD), Parkinson’s disease, schizophrenia, Tourette’s syndrome, anxiety, depression, and epilepsy (Newhouse and Kelton 2000; Newhouse et al 1997; Paterson and Nordberg 2000)",
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         "MeSHAnatomy": {
           "Cerebral Cortex": true
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@@ -123,12 +139,17 @@
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       "evidence": "A consistent, significant loss of nAChRs has been observed in cortical autopsy brain tissue from AD patients relative to age-matched healthy subjects (Nordberg and Winblad 1986)",
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@@ -145,12 +166,17 @@
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@@ -167,12 +193,17 @@
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@@ -189,12 +220,17 @@
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@@ -211,12 +247,17 @@
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       "evidence": "The nAChRs are found to be involved in a complex range of central nervous system disorders including Alzheimer’s disease (AD), Parkinson’s disease, schizophrenia, Tourette’s syndrome, anxiety, depression, and epilepsy (Newhouse and Kelton 2000; Newhouse et al 1997; Paterson and Nordberg 2000)",
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@@ -233,12 +274,17 @@
       },
       "evidence": "The nAChRs are found to be involved in a complex range of central nervous system disorders including Alzheimer’s disease (AD), Parkinson’s disease, schizophrenia, Tourette’s syndrome, anxiety, depression, and epilepsy (Newhouse and Kelton 2000; Newhouse et al 1997; Paterson and Nordberg 2000)",
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@@ -255,12 +301,17 @@
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       "evidence": "The nAChRs are found to be involved in a complex range of central nervous system disorders including Alzheimer’s disease (AD), Parkinson’s disease, schizophrenia, Tourette’s syndrome, anxiety, depression, and epilepsy (Newhouse and Kelton 2000; Newhouse et al 1997; Paterson and Nordberg 2000)",
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@@ -277,12 +328,17 @@
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       "evidence": "Interestingly enough, a considerable body of evidence exists to suggest that the nAChRs are involved in cognitive and memory functions (Levin 2000; Newhouse and Kelton 2000; Newhouse et al 1997; Sahakian and Coull 1994)",
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@@ -299,13 +355,16 @@
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@@ -329,13 +388,16 @@
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@@ -356,12 +418,17 @@
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       "evidence": "Significant reductions in the number of nAChRs were measured in cortical regions of Swedish APP 670/ 671 mutation (273% to 287%) (Marutle et al 1999)",
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@@ -378,12 +445,17 @@
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@@ -400,12 +472,17 @@
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@@ -422,12 +499,17 @@
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@@ -444,7 +526,7 @@
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@@ -482,12 +572,17 @@
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@@ -504,13 +599,16 @@
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@@ -534,13 +632,16 @@
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       "evidence": "A consistent, significant loss of nAChRs has been observed in cortical autopsy brain tissue from AD patients relative to age-matched healthy subjects (Nordberg and Winblad 1986)",
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@@ -564,13 +665,16 @@
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       "evidence": "When the laminar binding distribution of [3H]nicotine, [3H]epibatidine, and [3H]cytisine was measured in AD cortical autopsy tissue, marked reductions were observed relative to control brains (Sihver et al 1999c) (Figure 1)",
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     {
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         "MeSHAnatomy": {
           "Temporal Lobe": true
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@@ -591,13 +695,43 @@
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       "evidence": "A decrease in the protein levels of the alpha3 and alpha4 nAChR subunits was recently measured in the temporal cortex and of the alpha3, alpha4, and alpha7 nAChR subtypes in the hippocampi of AD brains relative to age-matched control subjects (Guan et al 2000b)",
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         "MeSHAnatomy": {
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@@ -618,13 +752,16 @@
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       "evidence": "A decrease in the protein levels of the alpha3 and alpha4 nAChR subunits was recently measured in the temporal cortex and of the alpha3, alpha4, and alpha7 nAChR subtypes in the hippocampi of AD brains relative to age-matched control subjects (Guan et al 2000b)",
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         "MeSHAnatomy": {
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@@ -645,12 +782,17 @@
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       "evidence": "A decrease in the protein levels of the alpha3 and alpha4 nAChR subunits was recently measured in the temporal cortex and of the alpha3, alpha4, and alpha7 nAChR subtypes in the hippocampi of AD brains relative to age-matched control subjects (Guan et al 2000b)",
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@@ -666,14 +808,44 @@
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+        "first": "Nordberg A",
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+        "title": "Nicotinic receptor abnormalities of Alzheimer's disease: therapeutic implications.",
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         "MeSHAnatomy": {
           "Hippocampus": true
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@@ -693,14 +865,17 @@
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       "evidence": "Lee et al (2000) recently also reported a significant decrease in the alpha7 nAChR protein level of the AD hippocampus",
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@@ -721,13 +896,16 @@
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       "evidence": "Examination of the regional expression of mRNA of the nAChR alpha4 and alpha3 subunits has shown no difference in autopsy AD brain tissue in any region analyzed (Hellstro ¨m-Lindahl et al 1999; Terzano et al 1998), whereas the level of the alpha7 mRNA was significantly higher in the hippocampus (Hellstro¨m-Lindahl et al 1999)",
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@@ -748,13 +926,16 @@
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       "evidence": "Examination of the regional expression of mRNA of the nAChR alpha4 and alpha3 subunits has shown no difference in autopsy AD brain tissue in any region analyzed (Hellstro ¨m-Lindahl et al 1999; Terzano et al 1998), whereas the level of the alpha7 mRNA was significantly higher in the hippocampus (Hellstro¨m-Lindahl et al 1999)",
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@@ -775,13 +956,16 @@
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       "evidence": "Examination of the regional expression of mRNA of the nAChR alpha4 and alpha3 subunits has shown no difference in autopsy AD brain tissue in any region analyzed (Hellstro ¨m-Lindahl et al 1999; Terzano et al 1998), whereas the level of the alpha7 mRNA was significantly higher in the hippocampus (Hellstro¨m-Lindahl et al 1999)",
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         "MeSHAnatomy": {
           "Cerebral Cortex": true
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@@ -802,16 +986,19 @@
       },
       "evidence": "Positron emission tomography studies have revealed a reduced cortical acetylcholinesteserase activity in AD patients (Iyo et al 1997; Kuhl et al 1999)",
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     {
       "annotations": {
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         "MeSHAnatomy": {
           "Cerebral Cortex": true
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@@ -832,15 +1019,20 @@
       },
       "evidence": "A progressive loss of cortical acetylcholinesterase activity has been observed in AD patients with cognitive decline (Shinotoh et al 2000)",
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       "citation": {
         "authors": [
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@@ -857,16 +1049,19 @@
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       "evidence": "The loss in cortical acetylcholinesterase activity was less pronounced in mildly demented AD patients relative to autopsy material and did not strictly correlate with cerebral glucose metabolism impairment (Kuhl et al 1999)",
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       "object": {
         "modifier": "Activity"
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       "relation": "decreases",
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-      "target": 37
+      "source": 47,
+      "target": 39
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Cerebral Cortex": true
         }
@@ -887,12 +1082,17 @@
       },
       "evidence": "A progressive loss of cortical acetylcholinesterase activity has been observed in AD patients with cognitive decline (Shinotoh et al 2000)",
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     {
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       "citation": {
         "authors": [
           "Nordberg A"
@@ -909,12 +1109,17 @@
       },
       "evidence": "Selective cortical deficits in [11C]nicotine binding are often observed by PET early in the course of the AD disease (Figure 3A)",
       "key": "397cea3eab4a973bd33b25a4b0962fd64f73fddc35d465c1bbdf7be496f79933678ac40e39cb0554fd16d2f85e3d6c41456e52505708fb6b8425dfb85ebe5ac7",
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       "relation": "decreases",
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       "target": 33
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     {
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       "citation": {
         "authors": [
           "Nordberg A"
@@ -931,12 +1136,17 @@
       },
       "evidence": "A ligand with a selectivity for the alpha4beta2 nAChRs would be particularly preferable because the alpha4beta2 has been recognized as the predominant subtype that is deficient in AD (for a review, see Sihver et al 2000)",
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       "relation": "decreases",
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       "target": 13
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     {
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       "citation": {
         "authors": [
           "Nordberg A"
@@ -953,12 +1163,17 @@
       },
       "evidence": "The nAChRs are found to be involved in a complex range of central nervous system disorders including Alzheimer’s disease (AD), Parkinson’s disease, schizophrenia, Tourette’s syndrome, anxiety, depression, and epilepsy (Newhouse and Kelton 2000; Newhouse et al 1997; Paterson and Nordberg 2000)",
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       "relation": "association",
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       "target": 36
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     {
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       "citation": {
         "authors": [
           "Nordberg A"
@@ -975,13 +1190,16 @@
       },
       "evidence": "The nAChRs are found to be involved in a complex range of central nervous system disorders including Alzheimer’s disease (AD), Parkinson’s disease, schizophrenia, Tourette’s syndrome, anxiety, depression, and epilepsy (Newhouse and Kelton 2000; Newhouse et al 1997; Paterson and Nordberg 2000)",
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       "relation": "association",
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       "target": 36
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Frontal Lobe": true
         }
@@ -1002,13 +1220,16 @@
       },
       "evidence": "Interestingly, a reduction in the protein level of alpha7 has also been measured in the frontal cortex of patients with schizophrenia (Guan et al 1999), whereas no decrease was measured in the alpha4 nAChR protein level (Guan et al 1999)",
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       "target": 15
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     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Frontal Lobe": true
         }
@@ -1029,12 +1250,17 @@
       },
       "evidence": "Interestingly, a reduction in the protein level of alpha7 has also been measured in the frontal cortex of patients with schizophrenia (Guan et al 1999), whereas no decrease was measured in the alpha4 nAChR protein level (Guan et al 1999)",
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       "relation": "causesNoChange",
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       "target": 14
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     {
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       "citation": {
         "authors": [
           "Nordberg A"
@@ -1051,12 +1277,17 @@
       },
       "evidence": "The nAChRs are found to be involved in a complex range of central nervous system disorders including Alzheimer’s disease (AD), Parkinson’s disease, schizophrenia, Tourette’s syndrome, anxiety, depression, and epilepsy (Newhouse and Kelton 2000; Newhouse et al 1997; Paterson and Nordberg 2000)",
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       "relation": "association",
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       "target": 36
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     {
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       "citation": {
         "authors": [
           "Nordberg A"
@@ -1073,12 +1304,17 @@
       },
       "evidence": "The nAChRs are found to be involved in a complex range of central nervous system disorders including Alzheimer’s disease (AD), Parkinson’s disease, schizophrenia, Tourette’s syndrome, anxiety, depression, and epilepsy (Newhouse and Kelton 2000; Newhouse et al 1997; Paterson and Nordberg 2000)",
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       "relation": "association",
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       "target": 36
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     {
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       "citation": {
         "authors": [
           "Nordberg A"
@@ -1095,12 +1331,17 @@
       },
       "evidence": "The nAChRs are found to be involved in a complex range of central nervous system disorders including Alzheimer’s disease (AD), Parkinson’s disease, schizophrenia, Tourette’s syndrome, anxiety, depression, and epilepsy (Newhouse and Kelton 2000; Newhouse et al 1997; Paterson and Nordberg 2000)",
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       "target": 36
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     {
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       "citation": {
         "authors": [
           "Nordberg A"
@@ -1117,12 +1358,17 @@
       },
       "evidence": "The nAChRs are found to be involved in a complex range of central nervous system disorders including Alzheimer’s disease (AD), Parkinson’s disease, schizophrenia, Tourette’s syndrome, anxiety, depression, and epilepsy (Newhouse and Kelton 2000; Newhouse et al 1997; Paterson and Nordberg 2000)",
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       "target": 36
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     {
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       "citation": {
         "authors": [
           "Nordberg A"
@@ -1139,13 +1385,16 @@
       },
       "evidence": "Interestingly enough, a considerable body of evidence exists to suggest that the nAChRs are involved in cognitive and memory functions (Levin 2000; Newhouse and Kelton 2000; Newhouse et al 1997; Sahakian and Coull 1994)",
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       "target": 36
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     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Cerebral Cortex": true
         }
@@ -1166,12 +1415,17 @@
       },
       "evidence": "A progressive loss of cortical acetylcholinesterase activity has been observed in AD patients with cognitive decline (Shinotoh et al 2000)",
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     {
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+      },
       "citation": {
         "authors": [
           "Nordberg A"
@@ -1188,13 +1442,16 @@
       },
       "evidence": "A significant correlation can be observed between cognitive function and nicotinic receptor binding (k2*) (Figure 3A)",
       "key": "851c9272487097c768dbb07b53618de0da8c2aa806732c4c61a34292fe8986edc90c3eaa9c2e9bdaf7e48217f8bb5fcd69b48cc4005bb0b707f8f2e61fd4eccf",
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       "target": 33
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     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -1215,13 +1472,18 @@
       },
       "evidence": "Cholinergic therapy is based on the assumption that low levels of acetylcholine are responsible for the cognitive decline associated with AD",
       "key": "b4c7694090afaff30e702cf8020a40937727068b507efb66285d7385cc48f96b0f09671bff7e7b21f0480bc1aed3f58995caf32071803afb9ab34b92e4ca088a",
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       "target": 3
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     {
-      "citation": {
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+        }
+      },
+      "citation": {
         "authors": [
           "Nordberg A"
         ],
@@ -1237,12 +1499,17 @@
       },
       "evidence": "Activation of the nAChR modulates the release of several neurotransmitters (Kaiser et al 2000; Wonnacott 1997) that mediate important physiologic mechanisms including cognitive functions",
       "key": "40b455db89e476a7a316cf9bd43d0a4eb88feb538fc66cbdf0eabaebab482a15a8710fe13368474a4109ead9481efa53800101e8a097366a42ba206cd4f64573",
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       "relation": "association",
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       "target": 9
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     {
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+      },
       "citation": {
         "authors": [
           "Nordberg A"
@@ -1259,7 +1526,7 @@
       },
       "evidence": "Interestingly enough, a considerable body of evidence exists to suggest that the nAChRs are involved in cognitive and memory functions (Levin 2000; Newhouse and Kelton 2000; Newhouse et al 1997; Sahakian and Coull 1994)",
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@@ -1274,10 +1541,13 @@
       "key": "5d1286f15777868d62ba0fee295b4f1a4bd0ebb379469dce0c7f11babb5fe4dac752f4260ac2e4f4d4836dc68cc024a853b15bae190833d9d52f5bcc49b220a7",
       "relation": "hasComponent",
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-      "target": 41
+      "target": 43
     },
     {
       "annotations": {
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+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -1298,13 +1568,16 @@
       },
       "evidence": "The potential therapeutic benefit of nAChR stimulation in AD is based upon the fact that nicotine improves memory in animals, healthy subjects, and AD patients (Levin 2000; Newhouse and Kelton 2000; Newhouse et al 1997; Rusted and Warburton 1992)",
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       "relation": "increases",
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       "target": 27
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     {
       "annotations": {
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+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -1325,13 +1598,16 @@
       },
       "evidence": "Acute administration of nicotine to AD patients has resulted in a measurable short-term improvement in learning, memory, and attentional performance (Jones et al 1992)",
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       "relation": "increases",
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       "target": 27
     },
     {
       "annotations": {
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+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -1352,13 +1628,16 @@
       },
       "evidence": "Acute administration of nicotine to AD patients has resulted in a measurable short-term improvement in learning, memory, and attentional performance (Jones et al 1992)",
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       "relation": "increases",
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       "target": 26
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -1379,13 +1658,16 @@
       },
       "evidence": "Acute administration of nicotine to AD patients has resulted in a measurable short-term improvement in learning, memory, and attentional performance (Jones et al 1992)",
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       "relation": "increases",
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-      "target": 52
+      "target": 54
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Cerebral Cortex": true
         },
@@ -1409,13 +1691,16 @@
       },
       "evidence": "When the laminar binding distribution of [3H]nicotine, [3H]epibatidine, and [3H]cytisine was measured in AD cortical autopsy tissue, marked reductions were observed relative to control brains (Sihver et al 1999c) (Figure 1)",
       "key": "c0d710abe8c600f81c5c7e0bf0782a90c0395d5e8e8ee8de5b87ec543895fe7f793b3abd2d486cf59ecf3e1cd028c01d1618439015371e6e950e708928fb36ba",
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       "relation": "decreases",
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+      "source": 43,
       "target": 29
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     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Temporal Lobe": true
         }
@@ -1436,10 +1721,10 @@
       },
       "evidence": "A decrease in the protein levels of the alpha3 and alpha4 nAChR subunits was recently measured in the temporal cortex and of the alpha3, alpha4, and alpha7 nAChR subtypes in the hippocampi of AD brains relative to age-matched control subjects (Guan et al 2000b)",
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@@ -1451,7 +1736,7 @@
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@@ -1463,7 +1748,7 @@
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@@ -1478,6 +1763,11 @@
       "target": 36
     },
     {
+      "annotations": {
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+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Nordberg A"
@@ -1494,7 +1784,7 @@
       },
       "evidence": "A significant correlation can be observed between cognitive function and nicotinic receptor binding (k2*) (Figure 3A)",
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       "target": 25
@@ -1513,6 +1803,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Cerebellum": true,
           "Cerebral Cortex": true
@@ -1534,13 +1827,16 @@
       },
       "evidence": "A significant decrease in [3H]epibatidine binding has been observed with aging in the human cortical brain regions and cerebellum (Marutle et al 1998)",
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       "relation": "negativeCorrelation",
       "source": 31,
       "target": 24
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Cerebral Cortex": true
         }
@@ -1561,7 +1857,7 @@
       },
       "evidence": "In addition, a marked reduction in the laminar distribution of [3H]epibatidine binding was observed in control cortical tissue with aging (Figure 1)",
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@@ -1588,10 +1884,13 @@
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       "relation": "hasComponent",
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-      "target": 42
+      "target": 44
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Hippocampus": true
         }
@@ -1612,13 +1911,16 @@
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         "MeSHAnatomy": {
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@@ -1747,14 +2061,17 @@
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@@ -1774,13 +2091,21 @@
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@@ -2015,14 +2453,22 @@
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     {
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+          "High": true
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+        "MeSHAnatomy": {
+          "Hippocampus": true
+        }
+      },
       "citation": {
         "authors": [
           "Nordberg A"
@@ -2062,15 +2516,132 @@
         "type": "PubMed",
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         "MeSHAnatomy": {
           "Cerebral Cortex": true
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@@ -2089,20 +2660,49 @@
         "type": "PubMed",
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+        "MeSHDisease": {
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@@ -2147,14 +2747,19 @@
         "type": "PubMed",
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     {
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+          "Cerebrospinal Fluid": true
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+      },
       "citation": {
         "authors": [
           "Nordberg A"
@@ -2191,20 +2807,22 @@
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+      "evidence": "Since an enhanced activity of acetylcholinesterase has been measured in cerebrospinal fluid following long-term treatment with tacrine (Nordberg et al 1999), possibly as a result of an increased acetylcholinesterase gene expression, it might be an advantage to use drugs interacting with nAChRs",
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@@ -2241,17 +2867,20 @@
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-          "Cerebral Cortex": true
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+        "MeSHDisease": {
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@@ -2268,17 +2897,19 @@
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+      "evidence": "In addition, PET studies also have revealed an improvement in nAChRs in AD patients during long-term treatment with cholinesterase inhibitors such as tacrine and NXX- 066 (Nordberg 2000; Nordberg et al 1992, 1998)",
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@@ -2293,14 +2924,22 @@
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@@ -2315,17 +2954,20 @@
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@@ -2342,14 +2984,19 @@
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-      "target": 25
+      "evidence": "It is likely that the therapeutic benefit of cholinesterase inhibitors occurs at least in part through activation of the nAChRs, by the direct action of increased levels and/or through a direct activation of the allosteric site on the nAChR (Maelicke et al 1995, 2000)",
+      "key": "1ea15cc3f4a1b3c586e5e8582a76c5893c07507000c1141411bbbff5e6f3be856f695e71f40e841d2a6ea5dfacad79261c59e0eef6a1784a047d1ced82e5d177",
+      "line": 382,
+      "relation": "increases",
+      "source": 5,
+      "target": 36
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "Nordberg A"
@@ -2365,19 +3012,19 @@
         "volume": "49"
       },
       "evidence": "It is likely that the therapeutic benefit of cholinesterase inhibitors occurs at least in part through activation of the nAChRs, by the direct action of increased levels and/or through a direct activation of the allosteric site on the nAChR (Maelicke et al 1995, 2000)",
-      "key": "e68ab608b68069b19e55eb1811f265e27f0c988a766d37e240cb017af2300a458b63d0fea9b7534b747f05e50d17382332df380d4ed664690aa2e61cebfdf7aa",
-      "line": 303,
+      "key": "a7f693655988b1aa2e55214e1ba95366a78f84d8ad645a39f7c637296a5590f2d9be4ecfb97d9b321ad0a1e5e38ffe30968f5ac82d7da35bd9e342cc5219fb33",
+      "line": 375,
       "object": {
         "modifier": "Activity"
       },
-      "relation": "increases",
-      "source": 12,
-      "target": 37
+      "relation": "decreases",
+      "source": 11,
+      "target": 39
     },
     {
       "annotations": {
-        "MeSHAnatomy": {
-          "Cerebrospinal Fluid": true
+        "Confidence": {
+          "Medium": true
         }
       },
       "citation": {
@@ -2394,20 +3041,20 @@
         "type": "PubMed",
         "volume": "49"
       },
-      "evidence": "Since an enhanced activity of acetylcholinesterase has been measured in cerebrospinal fluid following long-term treatment with tacrine (Nordberg et al 1999), possibly as a result of an increased acetylcholinesterase gene expression, it might be an advantage to use drugs interacting with nAChRs",
-      "key": "188b575de0dd12895a76b490695d9466d898eba6d725d114c4df69b6c6ca8a21f0f8a1d0c8562584f438300e7a64ff2d7691f65b272c6594023b2e4e7ac74cb4",
-      "line": 325,
+      "evidence": "It is likely that the therapeutic benefit of cholinesterase inhibitors occurs at least in part through activation of the nAChRs, by the direct action of increased levels and/or through a direct activation of the allosteric site on the nAChR (Maelicke et al 1995, 2000)",
+      "key": "84838a4df7528bd9a51e067f86aed942b01cec89ffe52daa8fbf70e6d0c3bcc094737164dcc330bea08d3bb3edd3cf962c00e8645f87c7fdecf6f527c3101aba",
+      "line": 379,
       "object": {
         "modifier": "Activity"
       },
       "relation": "increases",
-      "source": 12,
-      "target": 37
+      "source": 11,
+      "target": 36
     },
     {
       "annotations": {
-        "MeSHDisease": {
-          "Alzheimer Disease": true
+        "Confidence": {
+          "Medium": true
         }
       },
       "citation": {
@@ -2424,14 +3071,19 @@
         "type": "PubMed",
         "volume": "49"
       },
-      "evidence": "In addition, PET studies also have revealed an improvement in nAChRs in AD patients during long-term treatment with cholinesterase inhibitors such as tacrine and NXX- 066 (Nordberg 2000; Nordberg et al 1992, 1998)",
-      "key": "8788b7c92ee3ccb733a3a621efb37289671eaa1f3015422da39447cd392a4d0328febe93902a6e63daa7f1994577c9c9edd40ef583b2a374c595216f98763ca7",
-      "line": 314,
+      "evidence": "It is likely that the therapeutic benefit of cholinesterase inhibitors occurs at least in part through activation of the nAChRs, by the direct action of increased levels and/or through a direct activation of the allosteric site on the nAChR (Maelicke et al 1995, 2000)",
+      "key": "cb70f5634ced692ea9d2195fa6bb31b6010b86ee6ce7227a3e0b202941232c82a41bc41aed7a2943ed66d6cc2f07812e88944078d7d455382b1ab5b149725e01",
+      "line": 383,
       "relation": "increases",
-      "source": 12,
+      "source": 11,
       "target": 36
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "Nordberg A"
@@ -2447,16 +3099,21 @@
         "volume": "49"
       },
       "evidence": "It is likely that the therapeutic benefit of cholinesterase inhibitors occurs at least in part through activation of the nAChRs, by the direct action of increased levels and/or through a direct activation of the allosteric site on the nAChR (Maelicke et al 1995, 2000)",
-      "key": "7f071e0914b1c43f81ef6452416862b826bd8c4c37ef5ae81b1918c5d699defeb25ec779da7c755bb4b6a1b33f57feb9bcfe4c733803f763505e6f7c2d62ff81",
-      "line": 304,
+      "key": "23752bc11f1d28ca2b153c8500d0032738dd22a5454cb746d435d275263626d407adefc08478b887230595cd32efb401faf318fedf59d1a288e0d8f4c92ea1eb",
+      "line": 376,
       "object": {
         "modifier": "Activity"
       },
-      "relation": "increases",
-      "source": 5,
-      "target": 37
+      "relation": "decreases",
+      "source": 8,
+      "target": 39
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "Nordberg A"
@@ -2472,16 +3129,21 @@
         "volume": "49"
       },
       "evidence": "It is likely that the therapeutic benefit of cholinesterase inhibitors occurs at least in part through activation of the nAChRs, by the direct action of increased levels and/or through a direct activation of the allosteric site on the nAChR (Maelicke et al 1995, 2000)",
-      "key": "0a50dd67231289c5440558dbd01cbd42b91cb2287a02bb75084fddd2530c281c2f69ad712b25f9f972e49af79245e02bac823d83c34dc20262c44a2b487c7f5d",
-      "line": 305,
+      "key": "7dfb787b5690955b20a0823676c4f386d2e92c364c8c3ea048f695fc15f424ff3c6d023ccbb6856652572370e03c83c934726f88905c0f969a3b899cc45090f7",
+      "line": 380,
       "object": {
         "modifier": "Activity"
       },
       "relation": "increases",
-      "source": 11,
-      "target": 37
+      "source": 8,
+      "target": 36
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "Nordberg A"
@@ -2497,17 +3159,17 @@
         "volume": "49"
       },
       "evidence": "It is likely that the therapeutic benefit of cholinesterase inhibitors occurs at least in part through activation of the nAChRs, by the direct action of increased levels and/or through a direct activation of the allosteric site on the nAChR (Maelicke et al 1995, 2000)",
-      "key": "d21b6eaa21e996d332eb1d1f364bd44066cc2c868624cf183d9cbcf9361d100c27c064af328bdcad350a5509b25f6be395ab88ffcb9eac7812728f1f2a2f6d53",
-      "line": 306,
-      "object": {
-        "modifier": "Activity"
-      },
+      "key": "cd6d12e097bc07dce5a2ff5eadf30bb9d9c79bb847108eb03f4ca7192730efa4ba4e2ee429038f70cf516355bc11337c2fbedca1eb4ccbd2666ed2a441441ed3",
+      "line": 384,
       "relation": "increases",
       "source": 8,
-      "target": 37
+      "target": 36
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -2528,13 +3190,16 @@
       },
       "evidence": "In addition, PET studies also have revealed an improvement in nAChRs in AD patients during long-term treatment with cholinesterase inhibitors such as tacrine and NXX- 066 (Nordberg 2000; Nordberg et al 1992, 1998)",
       "key": "3d869817883ebc0bfb2b1ebbae62e15e499983c3fef29a959b49f4caf2d15f22752cd5b1557f364f2c17e7f41706eb5d53c7e40db2eec3f2542a36e1f0721c28",
-      "line": 315,
+      "line": 397,
       "relation": "increases",
       "source": 20,
       "target": 36
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -2555,13 +3220,16 @@
       },
       "evidence": "Nerve growth factor intraventricularly administered to AD patients for 3 months resulted in an increased [11C]nicotine binding (Eriksdotter-Jo¨nhagen et al 1998), whereas treatment with the 5-HT3 blocker ondansetron showed a decreased number of cortical nAChRs (Nordberg et al 1997)",
       "key": "36536e474fe15f9580eda87472264944c6e27bbdee66a1331f1c6ec03dabb6800e0055d624c5af5c4ba405861faff5166220c46063902cc50dffa80ca7d48f4d",
-      "line": 335,
+      "line": 421,
       "relation": "increases",
       "source": 17,
       "target": 33
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Cerebral Cortex": true
         },
@@ -2585,12 +3253,17 @@
       },
       "evidence": "Nerve growth factor intraventricularly administered to AD patients for 3 months resulted in an increased [11C]nicotine binding (Eriksdotter-Jo¨nhagen et al 1998), whereas treatment with the 5-HT3 blocker ondansetron showed a decreased number of cortical nAChRs (Nordberg et al 1997)",
       "key": "9265d39d8c91bf281b35c631f675c24341785a89833075005449c3c748467c7872115a91e726f9f5f734f8e195fabb2f477f79f593c5d6f4c2c4d48d0f78bf7c",
-      "line": 337,
+      "line": 423,
       "relation": "decreases",
       "source": 2,
       "target": 36
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Nordberg A"
@@ -2607,13 +3280,16 @@
       },
       "evidence": "Activation of the nAChR modulates the release of several neurotransmitters (Kaiser et al 2000; Wonnacott 1997) that mediate important physiologic mechanisms including cognitive functions",
       "key": "79f3058c34caa0ec30269aa177e52357bfdb312c3cd610e3452b41289a41c3aef443a820802de58af2f022e16e1207e540466e35590d3b6e0a72c62f568209f7",
-      "line": 353,
+      "line": 442,
       "relation": "association",
       "source": 9,
       "target": 25
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -2634,13 +3310,16 @@
       },
       "evidence": "Administration of the nicotinic antagonist mecamylamine to elderly subjects and AD patients has produced cognitive impairment (Newhouse and Kelton 2000)",
       "key": "4accaee3a229ef8b438a26326a8a77e8f347407a6cdf8624dc5829848a9b2b192a8692f5db1178690777a30f9ebc9bc98087d4bd9d8cbe594159ac4222c97e07",
-      "line": 361,
+      "line": 452,
       "relation": "decreases",
       "source": 1,
       "target": 25
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -2661,13 +3340,16 @@
       },
       "evidence": "Recently, the nicotinic agonist ABT- 418 improved verbal learning and memory on a selective reminding task in AD patients (Potter et al 1999)",
       "key": "72617438f19146aafd3a7f12b00230c632acfe015eb1d2864dbe9b6e0f6339617787c950cc917717011e0325edf672d5e47f995aaeca3fd4c8fb115792ee883f",
-      "line": 374,
+      "line": 469,
       "relation": "increases",
       "source": 19,
-      "target": 50
+      "target": 52
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -2688,13 +3370,16 @@
       },
       "evidence": "Recently, the nicotinic agonist ABT- 418 improved verbal learning and memory on a selective reminding task in AD patients (Potter et al 1999)",
       "key": "b697a5bd4ec9230e98e1ef7464e6152fd12824065fd67da372f6420da2a326cf0108c264e2dcad58b3b870b71409dcfae3b131f65bc1a0e356faba98c49dcd2c",
-      "line": 375,
+      "line": 470,
       "relation": "increases",
       "source": 19,
       "target": 27
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -2715,13 +3400,16 @@
       },
       "evidence": "Estrogen, which in epidemiologic studies has been shown to reduce the risk of AD (Henderson 1997), has in experimental studies in PC 12 cells shown neuroprotective effects against Abeta toxicity that are at least partly mediated by the alpha7 subtype nAChR (Svensson and Nordberg 1998)",
       "key": "8ea34e721c66f66d7cef371d68d80a2da6aeec3699e8719b59a418e211b724f30fd415468285f44ef593a63befac0cc0ad7fcf5fa97de89ed7a3d68c0b40d71c",
-      "line": 382,
+      "line": 479,
       "relation": "decreases",
       "source": 7,
-      "target": 45
+      "target": 47
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -2742,7 +3430,7 @@
       },
       "evidence": "Estrogen, which in epidemiologic studies has been shown to reduce the risk of AD (Henderson 1997), has in experimental studies in PC 12 cells shown neuroprotective effects against Abeta toxicity that are at least partly mediated by the alpha7 subtype nAChR (Svensson and Nordberg 1998)",
       "key": "8da05810b8c1b3b9366ae9d83d202d274005d29f86fcba3a8bbc3faedb2c7c5fb4d45ef549d75b3faabbf663f79fcca28b8be8954f1c5832153b7f453d491c21",
-      "line": 383,
+      "line": 480,
       "object": {
         "modifier": "Activity"
       },
@@ -3110,6 +3798,20 @@
       "name": "CHRN",
       "namespace": "FPLX"
     },
+    {
+      "bel": "p(HBP:\"alpha-4-containing nAChR\")",
+      "function": "Protein",
+      "id": "57423d68dc052d4eab305f9c87c79173281ef083223a485c6e5638ac43b23831616fb5b702bd611a2853a43e13eca03cc16728f2a9777ac1404ed2af8ed82a73",
+      "name": "alpha-4-containing nAChR",
+      "namespace": "HBP"
+    },
+    {
+      "bel": "p(HBP:\"alpha-7-containing nAChR\")",
+      "function": "Protein",
+      "id": "5dc50e54e00b4b491c24782efdcdda83df476da69e2a1d2e2455c5c6adaff7c0e5dc12f29b6d7ff7bb4003fdc654ec2bafa1adf0e5af954dc2145de78eb474c6",
+      "name": "alpha-7-containing nAChR",
+      "namespace": "HBP"
+    },
     {
       "bel": "p(HGNC:ACHE)",
       "function": "Protein",
@@ -3262,6 +3964,20 @@
       "name": "Schizophrenia",
       "namespace": "MESH"
     },
+    {
+      "bel": "r(HBP:\"alpha-4-containing nAChR\")",
+      "function": "RNA",
+      "id": "21c1085a0c0cbf5913d9c1e5303a925fbc09333f49b165e9187579e2605bdaa107d9bdb94df2327c6645cb5128ac4f7dd559d22482fb445adae38c2758025705",
+      "name": "alpha-4-containing nAChR",
+      "namespace": "HBP"
+    },
+    {
+      "bel": "r(HBP:\"alpha-7-containing nAChR\")",
+      "function": "RNA",
+      "id": "7565b665de5e498ad3c12eb196a5bd1360f7114fee8e96038ec4caf4f8eaa38d984b5e6203278e83fb6d4aac7f84c6df367a36fca3534e917dd2b16ea7002426",
+      "name": "alpha-7-containing nAChR",
+      "namespace": "HBP"
+    },
     {
       "bel": "r(HGNC:CHRNA3)",
       "function": "RNA",
diff --git a/hbp_knowledge/receptors/post-munson2017.bel.json b/hbp_knowledge/receptors/post-munson2017.bel.json
index 71fd79d0b..2b3303aa9 100644
--- a/hbp_knowledge/receptors/post-munson2017.bel.json
+++ b/hbp_knowledge/receptors/post-munson2017.bel.json
@@ -55,6 +55,11 @@
   },
   "links": [
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Ahlijanian MK",
@@ -84,7 +89,7 @@
       },
       "evidence": "Peak current was increased 2-fold and 6-fold relative to 3 mM acetylcholine in 300 nM and 1 μM B-973, respectively (Fig. 1C)",
       "key": "2f9211d8d15d377bd2faab61bfa813b28e1b97525325f3babe6aee165d463241299726df267b29231a0c1dddf25dea66dd6385e3c47e4737affe93f5141c3bf3",
-      "line": 82,
+      "line": 83,
       "object": {
         "modifier": "Activity"
       },
@@ -93,6 +98,11 @@
       "target": 5
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Ahlijanian MK",
@@ -122,7 +132,7 @@
       },
       "evidence": "B-973 slows receptor deactivation dramatically (Fig. 4A)",
       "key": "512f62c543ffbd2afe419e9a0842af594a37e75e42044eba885cbf261d6c24b3c4738f2a38477504279ca509a4cf7c30853bf9e6de3dc8074430344ce3a81ecb",
-      "line": 91,
+      "line": 98,
       "object": {
         "modifier": "Activity"
       },
@@ -131,6 +141,11 @@
       "target": 5
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Ahlijanian MK",
@@ -160,7 +175,7 @@
       },
       "evidence": "The amplitude of currents were dose dependent, reaching levels at 30 μM B-973 larger than control currents in response to 3 mM acetylcholine (Fig. 7A)",
       "key": "6f9ad524d1c23c1219e93a9743603bea32764c8bb265e2ce940eb85c6d219af6cb9bcd13d41db4c2fa19d31f314563d21edfb5b5fc993c418a75b1f4e3cb257b",
-      "line": 121,
+      "line": 138,
       "object": {
         "modifier": "Activity"
       },
@@ -169,6 +184,11 @@
       "target": 5
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Ahlijanian MK",
@@ -198,7 +218,7 @@
       },
       "evidence": "The currents induced by B-973 alone arise from the α7 receptor since methyllycaconitine blocks them nearly completely (Fig. 7C and Fig. S6)",
       "key": "be210ce9a524d35f3490564242a747ca4dedd11f684daed65ba42a8d0c6038482c5cc94ebb8c5cbd7367576870c9888e2aadcc0ec29fd731960e422a5ba85f9f",
-      "line": 125,
+      "line": 144,
       "object": {
         "modifier": "Activity"
       },
@@ -207,6 +227,11 @@
       "target": 5
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "Ahlijanian MK",
@@ -236,7 +261,7 @@
       },
       "evidence": "Over the concentration range studied, B-973 increased the potency of acetylcholine at the α7 receptor 70-fold (control acetylcholine EC50=0.49 mM; acetylcholine EC50 at 1 μM B-973=0.007 mM)",
       "key": "d018f84c8a46781d38cc89e81149333330e71cf929e9279d3020a13f7ae9887e91b6e931db47e702b03d571fb1571fc7efa8c0b1a0b8063de082eaf28d33b77c",
-      "line": 87,
+      "line": 90,
       "object": {
         "modifier": "Activity"
       },
@@ -246,6 +271,52 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Ahlijanian MK",
+          "Bristow LJ",
+          "Graef JD",
+          "Hendricson AW",
+          "Herrington J",
+          "Kiss L",
+          "Knox RJ",
+          "Macor JE",
+          "McDonald IM",
+          "Molski TF",
+          "Olson RE",
+          "Pieschl RL",
+          "Post-Munson DJ",
+          "Weed MR"
+        ],
+        "date": "2017-03-15",
+        "first": "Post-Munson DJ",
+        "last": "Herrington J",
+        "name": "European journal of pharmacology",
+        "pages": "16-25",
+        "reference": "28132910",
+        "title": "B-973, a novel piperazine positive allosteric modulator of the α7 nicotinic acetylcholine receptor.",
+        "type": "PubMed",
+        "volume": "799"
+      },
+      "evidence": "Over the concentration range studied, B-973 increased the potency of acetylcholine at the α7 receptor 70-fold (control acetylcholine EC50=0.49 mM; acetylcholine EC50 at 1 μM B-973=0.007 mM)",
+      "key": "7131c1d5b5d6d409fec32880ca3fd6f3af4e73cd0653a247e931adb8906a2a0f2611b3939c32427a412afdfcca9c6cbc1c063ddef791b9e3e5595bb75f4b2b8d",
+      "line": 91,
+      "object": {
+        "modifier": "Activity"
+      },
+      "relation": "increases",
+      "source": 4,
+      "target": 11
+    },
+    {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Brain": true
         }
@@ -279,12 +350,17 @@
       },
       "evidence": "PNU-120596 and B-973 enhanced [3H]A-585539 binding to rat brain membranes (Fig. 5B,C)",
       "key": "d87420773fca10f7205ba10ad9a1d4f5d13b9fd353833901149651f6b7d303cee750f2af5bd4dcfffd0e1fc245983b9ba24b764fc2d60cc258fd5a9dfd4d3e7d",
-      "line": 103,
+      "line": 114,
       "relation": "increases",
       "source": 4,
       "target": 8
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Ahlijanian MK",
@@ -314,12 +390,17 @@
       },
       "evidence": "[3H]A-585539 saturation binding revealed that B-973 and PNU-120596 increased the affinity of the receptor for [3H]A-585539 approximately 4-fold without changing the apparent Bmax (Fig. 5D)",
       "key": "57e99078b5aa89d8276f65053910a23ca5ac8aeb83707d958f9fece4a77db42e61527c38312d8b964f0070bc4c1aa7e3243299f47df0f28859f3130a14806907",
-      "line": 111,
+      "line": 124,
       "relation": "increases",
       "source": 4,
       "target": 9
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Ahlijanian MK",
@@ -349,12 +430,17 @@
       },
       "evidence": "At the highest PAM concentration tested (10 μM), the percent increase in [3H]A-585539 binding was much greater for recombinant α7 than that observed with rat brain membranes",
       "key": "ddb8f5842eb5ce6ff3b5ec6b4aebab5ddd9dbffd3029f25927dead6bcabef7ed48bdf5955c05cf48d06129c5290d5daa64b75a4611a716352a3b1f9a70173f35",
-      "line": 116,
+      "line": 131,
       "relation": "increases",
       "source": 4,
       "target": 10
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Ahlijanian MK",
@@ -384,7 +470,7 @@
       },
       "evidence": "B-973 slows receptor deactivation dramatically (Fig. 4A)",
       "key": "2fc25a8b2f5d32f942eec8c987111e65af9131591297a55d4660d5097f3954d473e2eb295124b2447b869ca9b0b5a3d29d7d1b3a50d5af3f0cba29ac2f3c3823",
-      "line": 91,
+      "line": 98,
       "relation": "negativeCorrelation",
       "source": 5,
       "subject": {
@@ -393,6 +479,11 @@
       "target": 4
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Ahlijanian MK",
@@ -422,7 +513,7 @@
       },
       "evidence": "As expected, binding was inhibited by epibatidine (Fig. 5A)",
       "key": "07cde71d7e44d0b1088a23204e7bca6a7bdb3fdd4aa0e99a74e12ac7eaa60bb28f8b3929b9d989ebb046eda1f4bb63bdaeafb1a62142eb6b52c9970833e62573",
-      "line": 96,
+      "line": 105,
       "relation": "decreases",
       "source": 2,
       "target": 9
@@ -441,6 +532,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Brain": true
         }
@@ -474,12 +568,17 @@
       },
       "evidence": "PNU-120596 and B-973 enhanced [3H]A-585539 binding to rat brain membranes (Fig. 5B,C)",
       "key": "35b7888d0a4deb6353c7d42e1ba145ddbca144f70701127a4c70a033221d23fb20b96a1e59bf3a25f6c706247dbded376f450dc1c5e227cf51e28f0751bf5835",
-      "line": 102,
+      "line": 113,
       "relation": "increases",
       "source": 0,
       "target": 8
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Ahlijanian MK",
@@ -509,7 +608,7 @@
       },
       "evidence": "[3H]A-585539 saturation binding revealed that B-973 and PNU-120596 increased the affinity of the receptor for [3H]A-585539 approximately 4-fold without changing the apparent Bmax (Fig. 5D)",
       "key": "3315159a65d028e15c46ce127cb88185117b937b86e01d6a10b64c6d150f0d7c614fdc13f660f29e39d59ff9bda125476e12414960e84bed46dca5661dcb8c2a",
-      "line": 110,
+      "line": 123,
       "relation": "increases",
       "source": 0,
       "target": 9
@@ -536,9 +635,14 @@
       "key": "9462de75ae3ea0afb65518e2e7f9dc8b398d803fb927f2eb96615e215394e8129072a3de7ed1824b21668e6d5777400ed3d9eb7381a360b488e2e149ed535a49",
       "relation": "hasComponent",
       "source": 10,
-      "target": 11
+      "target": 12
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Ahlijanian MK",
@@ -568,7 +672,7 @@
       },
       "evidence": "The currents induced by B-973 alone arise from the α7 receptor since methyllycaconitine blocks them nearly completely (Fig. 7C and Fig. S6)",
       "key": "08a1635798eb2e79fd7f1509b41ca787f22a0f59f5639c18d0e257c15c6b1484b2caaf0e29dc7d4304b479ef37bd4fedd10d38a5fddec7a4d19d08c3b2617a02",
-      "line": 126,
+      "line": 145,
       "object": {
         "modifier": "Activity"
       },
@@ -698,6 +802,13 @@
         }
       ]
     },
+    {
+      "bel": "p(HGNC:CHRNA7)",
+      "function": "Protein",
+      "id": "6f517aad2a254d42d4e0bd5118246057049b85324ab857629d0caa2da5e997bfcc08f9a0a2cd83bbb2b536c048ce402c0d521604c43b1b9c720f4e20b4dacd99",
+      "name": "CHRNA7",
+      "namespace": "HGNC"
+    },
     {
       "bel": "p(MGI:Chrna7)",
       "function": "Protein",
diff --git a/hbp_knowledge/receptors/ren2007.bel.json b/hbp_knowledge/receptors/ren2007.bel.json
index a3cc36b0d..863401504 100644
--- a/hbp_knowledge/receptors/ren2007.bel.json
+++ b/hbp_knowledge/receptors/ren2007.bel.json
@@ -56,6 +56,9 @@
   "links": [
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Species": {
           "10090": true
         }
@@ -83,13 +86,16 @@
       },
       "evidence": "Treatment with 4OH-GTS-21 improved performance in both of these paradigms, with drug-induced improvements seen at a lower dose (0.3 mg/kg) in avoidance behavior than in the spatial memory–related task",
       "key": "d8e9a14b8a306fe820d02f34d33508c18c66edcbcd50e97af10da1c41b8ae1e2558002b330ab1a1ec7274ec71ea40a67741c1c936d11cdd6115741b2130bd6a1",
-      "line": 86,
+      "line": 87,
       "relation": "increases",
       "source": 2,
       "target": 11
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Species": {
           "10090": true
         }
@@ -117,13 +123,16 @@
       },
       "evidence": "Improved performance was seen each day in the Morris water task at the 2 mg/kg drug dose compared with saline-injected, lesioned animals",
       "key": "884acfc7930024ea713b772c17539951c1d9c7b1f11e71a7f8b32dfadab0c88e88edd7c9d70e6162e5399a740dad99dd97cae722f3410a9df20a7d2662079403",
-      "line": 91,
+      "line": 94,
       "relation": "increases",
       "source": 2,
       "target": 12
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Species": {
           "10090": true
         }
@@ -151,13 +160,16 @@
       },
       "evidence": "4OH-GTS-21 had no effect on the latency to enter the dark chamber during avoidance training (Fig. 1 ) or on swim speed in the Morris water task (data not shown), indicating that it had no discernible effect on locomotor function",
       "key": "eb7afd8eab110f8e88a80e4292d5da0ebfa949a42ef9059f4c553f56afc08aec3aad440878f439b1c8d89cdd8dac37af0f43bcaf7bfe706f605159a66150a0fe",
-      "line": 97,
+      "line": 102,
       "relation": "causesNoChange",
       "source": 2,
       "target": 5
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Species": {
           "10090": true
         }
@@ -185,13 +197,16 @@
       },
       "evidence": "FFX lesions also reduced the size of the septal cholinergic perikarya in saline-injected wild type mice in a manner that was largely prevented by treatment with 4OH-GTS-21 (Fig. 5)",
       "key": "bd6d575ff49d38d38b9dbe10dc320819bed8f42f142f0aaf1d779417db35a7b572a486112e580fffa5d9d39341308a18baec7d0da32ec72e1caf7e2a03546786",
-      "line": 103,
+      "line": 110,
       "relation": "increases",
       "source": 2,
       "target": 1
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Species": {
           "10090": true
         }
@@ -219,13 +234,16 @@
       },
       "evidence": "4OH-GTS-21 had no effect on cholinergic cell size in the unlesioned sides of the septa of the wild type or PS1 mice, but did cause atrophy of these neurons in the APP/PS1 mice",
       "key": "6c7e775d13fecbe204af91ee6659fb425309568262d381f1ff857229539da7b47f8235d06d0935b66c3fc10098ce90aaba256f9956fbff381490d6bbde16769a",
-      "line": 109,
+      "line": 118,
       "relation": "causesNoChange",
       "source": 2,
       "target": 3
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         },
@@ -256,13 +274,16 @@
       },
       "evidence": "4OH-GTS-21 had no effect on cholinergic cell size in the unlesioned sides of the septa of the wild type or PS1 mice, but did cause atrophy of these neurons in the APP/PS1 mice",
       "key": "a8143447c7dd2586f33a0e3cc4f737e47c33240602bc702d3e8e20f285caa572fdaacd185e707979c756ef65f81e1b40e2016279b138cd92f508aaa5009fed07",
-      "line": 111,
+      "line": 120,
       "relation": "decreases",
       "source": 2,
       "target": 3
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Species": {
           "10090": true
         }
@@ -290,13 +311,16 @@
       },
       "evidence": "4OH-GTS-21 had no protective effect on GABAergic neuronal number in this strain, with FFX lesions causing a 34±9% reduction compared with contralateral controls (n=10; P<0.05 compared with unlesioned side, one-way ANOVA).",
       "key": "d666ef2241a654eca9b2ac5542d494a858ff4ac8866f372436744244ce111c6f9a4672327e8e4cfdd928438a98ae5795e4aff90f3557f4abee651e32a6e3546c",
-      "line": 118,
+      "line": 129,
       "relation": "causesNoChange",
       "source": 2,
       "target": 4
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Species": {
           "10090": true
         }
@@ -324,7 +348,7 @@
       },
       "evidence": "The density of this deposition was not affected by 2 weeks of twice per day injections of 1 mg/kg 4OH-GTS-21 (27\u00035 deposits/section) or by FFX lesions (37±0.4 deposits/section)",
       "key": "ffde61c81dbb174ed1f99f5265cd3972842d2fce1415eed5a4a8be9d2f45f193c31cfa525a0cee4fd6beee7156eada7a629319d355b873ad0ed9f7dfeb612f39",
-      "line": 128,
+      "line": 143,
       "relation": "causesNoChange",
       "source": 2,
       "target": 0
@@ -343,6 +367,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Species": {
           "10090": true
         }
@@ -370,7 +397,7 @@
       },
       "evidence": "Nine-month-old APP/PS1 mice had significant 6E10- staining amyloid deposition (32±5 deposits/section)",
       "key": "deffc08a8aa25de006a41ba7678ed3392cf83369b428623e2b171237d0dad94e8b753875c4433da0276c274d2986f01bcffae02ad4a9ddf56611ad11793fe414",
-      "line": 122,
+      "line": 135,
       "relation": "increases",
       "source": 6,
       "target": 0
diff --git a/hbp_knowledge/receptors/sadigh-eteghad2015.bel.json b/hbp_knowledge/receptors/sadigh-eteghad2015.bel.json
index ef7ed9616..1467225db 100644
--- a/hbp_knowledge/receptors/sadigh-eteghad2015.bel.json
+++ b/hbp_knowledge/receptors/sadigh-eteghad2015.bel.json
@@ -56,6 +56,9 @@
   "links": [
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Species": {
           "10090": true
         }
@@ -87,6 +90,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Species": {
           "10090": true
         }
@@ -111,13 +117,16 @@
       },
       "evidence": "Time spent in target quadrant in probe trials. On the probe trial, there was a statistically significant difference between groups as determined by a one-way ANOVA (F(4,70)=35.21, p<0.001). Post hoc analysis revealed a significant effect of Ab injection on the time spent in the target quadrant, indicating that the Ab decreased the searching time in the target quadrant on comparing with the control (p<0.001).",
       "key": "6d5e95eb263d572c8b827697aabf14f957067fb84bbd45e6456d5118fc8581a11e9b4eccbc7d06749c8e878ee9a341a00ab90947edac382c903ad7d6d08e1404",
-      "line": 138,
+      "line": 141,
       "relation": "decreases",
       "source": 6,
       "target": 9
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Brain": true
         },
@@ -145,7 +154,7 @@
       },
       "evidence": "In contrast, brain sections of animals treated with 10-nmol-aged Ab25–35 peptide demonstrated the presence of numerous and distinct extracellular amyloid deposits, widely disseminated throughout the brain (Fig. 5).",
       "key": "39e1a7a71cbbe4f4e10be89f92be7495c956557a3b21dc71dc034b0e94a9d024e99c97091420c9c079a9f36a6204834d1a8644be832a9d606fb65282e007cbe1",
-      "line": 206,
+      "line": 213,
       "object": {
         "location": {
           "name": "extracellular region",
@@ -158,6 +167,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Cerebral Cortex": true,
           "Hippocampus": true
@@ -186,7 +198,7 @@
       },
       "evidence": "mRNA levels of a7 nAChR subunit. Relative quantification by using a real-time RT-PCR did not reveal any significant differences in the levels of mRNA for the a7 nAChR subunits either in the hippocampus or in the cortex of various groups (p>0.05). The groups showed results in the cortex (data not shown) similar to those observed in the hippocampus (Fig. 6).",
       "key": "10bf6912ed9c9b49caa3acf0e13e561a04f13825019cd3036c3901f41dd2de5bad718f3f93241e62d529b71d7b85056838e4ff7ce482bac7321fab6a243083ca",
-      "line": 222,
+      "line": 230,
       "relation": "causesNoChange",
       "source": 6,
       "target": 10
@@ -199,6 +211,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Species": {
           "10090": true
         }
@@ -223,7 +238,7 @@
       },
       "evidence": "Moreover in Ab-received mice, treatment with PHA and Gal improved the acquisition performance on comparing with the normal saline group (p<0.001)",
       "key": "0c9e8894618cfe6cb06781565f6cf2bcdf12d0b4a86f4155d989d37fda1e8bcc4765ed06bef012b2fc9ea00b55cca3f2bc983cab19c98fce6b11932f366566a0",
-      "line": 99,
+      "line": 100,
       "object": {
         "modifier": "Activity"
       },
@@ -233,6 +248,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Species": {
           "10090": true
         }
@@ -257,7 +275,7 @@
       },
       "evidence": "Notably, PHA could completely block the Ab-impaired task acquisition and reduce escape-latency to the normal level. Furthermore, the effect of PHA against the Ab-impaired task acquisition could be abolished by the pre-treatment of the a7 nAChR antagonist MLA (p<0.001). It was also noted that blockade of a7 nAChR by MLA in the Gal-treated group resulted in a significant prolongation of the escape-latency on comparing with the Gal group (p<0.001) (Fig. 2).",
       "key": "cd6ca747c6dee8543f389d27436d40f423087cd57ccddf3243bbbb4f868b8f5c82ff89a3413f78b17ffd2a8786784a8732e7c38ee5b9c6de00e4a0b702aebdcd",
-      "line": 118,
+      "line": 120,
       "object": {
         "modifier": "Activity"
       },
@@ -267,6 +285,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Species": {
           "10090": true
         }
@@ -291,13 +312,16 @@
       },
       "evidence": "Moreover in Ab-received mice, treatment with PHA and Gal improved the acquisition performance on comparing with the normal saline group (p<0.001)",
       "key": "0b3b7456356ed10a07574a984f8dd6224782fcc399b820cc86d601b949ce37b36ba947227b20f276a9555961d14af7289950cbee44c0ed695d3d1e33b40d072e",
-      "line": 100,
+      "line": 101,
       "relation": "increases",
       "source": 2,
       "target": 4
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Species": {
           "10090": true
         }
@@ -322,13 +346,16 @@
       },
       "evidence": "Notably, PHA could completely block the Ab-impaired task acquisition and reduce escape-latency to the normal level. Furthermore, the effect of PHA against the Ab-impaired task acquisition could be abolished by the pre-treatment of the a7 nAChR antagonist MLA (p<0.001). It was also noted that blockade of a7 nAChR by MLA in the Gal-treated group resulted in a significant prolongation of the escape-latency on comparing with the Gal group (p<0.001) (Fig. 2).",
       "key": "8ac870e2d124023edc0482f2d244f673e57e7f7deeb553486785a5497ae39ac58b82851b1631b114d616ec402c953385fbcb4bf37d64d05de474840eb9ba9b26",
-      "line": 119,
+      "line": 121,
       "relation": "increases",
       "source": 2,
       "target": 4
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         },
@@ -356,13 +383,16 @@
       },
       "evidence": "The analysis also showed significant enhancing effects of PHA and Gal on the time spent in the target quadrant on comparing with the normal saline in AD mice (p<0.001). Also, in comparison with the control group, PHA-treated AD animals did not have a significant difference (p>0.05) on the time spent in the target quadrant, but in the Gal group it was significantly lower (p<0.001) (Fig. 3).",
       "key": "60ede0ce10b90bda4e46f8eee17d59e5ce1a53069f5f8aab156feb29469a1c52db892a46459e7adfbb5a56a3722a68eabb9d320a24abd8b75fa2e79376abe932",
-      "line": 154,
+      "line": 158,
       "relation": "increases",
       "source": 2,
       "target": 9
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Species": {
           "10090": true
         }
@@ -387,13 +417,16 @@
       },
       "evidence": "MLA could completely block the PHA-induced spatial memory improvement (p<0.001). Furthermore, the effect of Gal against the Ab-impaired reference memory could be abolished by the pre-treatment of the a7 nAChR antagonist MLA (p<0.001). However, a7 nAChR blockage in the Gal group has a lesser effect on reference memory in comparison of blockage of that receptor in the PHA group (p<0.05) (Fig. 4).",
       "key": "47d085660d8c224c90b23c561b6b2e64e56da1e0a598e195a84b85f999db0f6ac2367b57c205790dcb8d76c657b8954aab1542430c177343ba5f15120e3d4c32",
-      "line": 191,
+      "line": 197,
       "relation": "increases",
       "source": 2,
       "target": 9
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Cerebral Cortex": true,
           "Hippocampus": true
@@ -422,13 +455,16 @@
       },
       "evidence": "Also, no alterations in the expression of a7 nAChR mRNA were observed in pretreatment with normal saline or MLA in PHA- or Gal-treated groups (p>0.05). In the same way, the pattern of mRNA expression in the cortex (data not shown) was similar to the hippocampus (Fig. 7).",
       "key": "3d30cd74089499d47fd545b78cd89af914c2cfa67d1654d812c33702c46c5cf34e5ccc87e5743f2a7d74d47fc6376a33cfe77358fceecd040302b92e354f407f",
-      "line": 239,
+      "line": 248,
       "relation": "causesNoChange",
       "source": 2,
       "target": 10
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Cerebral Cortex": true,
           "Hippocampus": true
@@ -457,13 +493,16 @@
       },
       "evidence": "The analysis also showed significant effects of PHA and Gal on the protein levels on comparing with normal saline in AD mice (p<0.001). Moreover, Gal could not completely protect the a7 nAChR protein level in AD animals. This group has a lesser a7 nAChR protein level in comparison with the control group (p<0.001) (Fig. 8). The groups showed results in the cortex similar to those observed in the hippocampus (data not shown)",
       "key": "060b6df430061702c2ff9769ed516a9d20a572d8a7d3e35752c94f3453ae95c51da15b6742596fb66f2a7fb979dc20e410f424691dd46ebb2c6cac690a5c553b",
-      "line": 268,
+      "line": 279,
       "relation": "increases",
       "source": 2,
       "target": 7
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Cerebral Cortex": true,
           "Hippocampus": true
@@ -492,13 +531,16 @@
       },
       "evidence": "Inter-group analysis showed that the protein level decreased by pretreatment with selective a7 nAChR antagonist MLA (p<0.001). PHA and Gal prevent receptor destroying in AD animals, but this effect is completely abolished by MLA (p<0.001) (Fig. 9). The groups showed results in the cortex similar to those observed in the hippocampus (data not shown).",
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+      "line": 298,
       "relation": "increases",
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       "target": 7
     },
     {
       "annotations": {
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         "Species": {
           "10090": true
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@@ -523,7 +565,7 @@
       },
       "evidence": "Moreover in Ab-received mice, treatment with PHA and Gal improved the acquisition performance on comparing with the normal saline group (p<0.001)",
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@@ -533,6 +575,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
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+        },
         "Species": {
           "10090": true
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@@ -557,13 +602,16 @@
       },
       "evidence": "Moreover in Ab-received mice, treatment with PHA and Gal improved the acquisition performance on comparing with the normal saline group (p<0.001)",
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       "relation": "increases",
       "source": 0,
       "target": 4
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         },
@@ -591,13 +639,16 @@
       },
       "evidence": "The analysis also showed significant enhancing effects of PHA and Gal on the time spent in the target quadrant on comparing with the normal saline in AD mice (p<0.001). Also, in comparison with the control group, PHA-treated AD animals did not have a significant difference (p>0.05) on the time spent in the target quadrant, but in the Gal group it was significantly lower (p<0.001) (Fig. 3).",
       "key": "69179c05b2359d073f0857955b7d013d9362c57ff82ceda379adf64fdb73c0e59a96fc3d2b89932dca6bd8dc5699e6d0ccd2b2c55e3bf84b26a5749b947e1470",
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       "relation": "increases",
       "source": 0,
       "target": 9
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Cerebral Cortex": true,
           "Hippocampus": true
@@ -626,13 +677,16 @@
       },
       "evidence": "Also, no alterations in the expression of a7 nAChR mRNA were observed in pretreatment with normal saline or MLA in PHA- or Gal-treated groups (p>0.05). In the same way, the pattern of mRNA expression in the cortex (data not shown) was similar to the hippocampus (Fig. 7).",
       "key": "2d37129003e77df6d84e9cd288e290b3d92066dd1089079bc37c74989b2b190c6a95261b1f5e18b1a363bad663c0175bcbbd22645aa633ba81161471cc480411",
-      "line": 238,
+      "line": 247,
       "relation": "causesNoChange",
       "source": 0,
       "target": 10
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Cerebral Cortex": true,
           "Hippocampus": true
@@ -661,13 +715,16 @@
       },
       "evidence": "The analysis also showed significant effects of PHA and Gal on the protein levels on comparing with normal saline in AD mice (p<0.001). Moreover, Gal could not completely protect the a7 nAChR protein level in AD animals. This group has a lesser a7 nAChR protein level in comparison with the control group (p<0.001) (Fig. 8). The groups showed results in the cortex similar to those observed in the hippocampus (data not shown)",
       "key": "ceabb9043ba7fcb967e0048e8d982b2c7df22d77273459ac550c4cf10a0407259a53d35b324b1dc27454d8797bc01cabd46299312c02408468e1beb24862effc",
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       "relation": "increases",
       "source": 0,
       "target": 7
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Cerebral Cortex": true,
           "Hippocampus": true
@@ -696,13 +753,16 @@
       },
       "evidence": "Inter-group analysis showed that the protein level decreased by pretreatment with selective a7 nAChR antagonist MLA (p<0.001). PHA and Gal prevent receptor destroying in AD animals, but this effect is completely abolished by MLA (p<0.001) (Fig. 9). The groups showed results in the cortex similar to those observed in the hippocampus (data not shown).",
       "key": "2415e52b227b7d6af0f2cc2cb0f51c3c9e558f00fafbd6ae2bc3a2c59a6438ac0a32f1a446ba9ef846e80e9c7a53d36afcbdbc58be80f31f2087806ef4fe6f73",
-      "line": 287,
+      "line": 299,
       "relation": "increases",
       "source": 0,
       "target": 7
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Species": {
           "10090": true
         }
@@ -727,7 +787,7 @@
       },
       "evidence": "Notably, PHA could completely block the Ab-impaired task acquisition and reduce escape-latency to the normal level. Furthermore, the effect of PHA against the Ab-impaired task acquisition could be abolished by the pre-treatment of the a7 nAChR antagonist MLA (p<0.001). It was also noted that blockade of a7 nAChR by MLA in the Gal-treated group resulted in a significant prolongation of the escape-latency on comparing with the Gal group (p<0.001) (Fig. 2).",
       "key": "587b1c08664278d5726f4ee87aa3f6a5701ee77b8b72dda89c454c915383ba17f5a18e692e09d98643c0ed16d0afa50e01f8c735e79748333917de9f1c78f489",
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       "object": {
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@@ -737,6 +797,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Species": {
           "10090": true
         }
@@ -761,7 +824,7 @@
       },
       "evidence": "MLA could completely block the PHA-induced spatial memory improvement (p<0.001). Furthermore, the effect of Gal against the Ab-impaired reference memory could be abolished by the pre-treatment of the a7 nAChR antagonist MLA (p<0.001). However, a7 nAChR blockage in the Gal group has a lesser effect on reference memory in comparison of blockage of that receptor in the PHA group (p<0.05) (Fig. 4).",
       "key": "6508acf8cf25780c047759bce5391092dd6efd0a4eecb1b331de2dbb20d5e8a6513be795378cdadfefd4f63ee43d604e619ef52685ee9e077411da969c98be72",
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       "object": {
         "modifier": "Activity"
       },
@@ -771,6 +834,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Cerebral Cortex": true,
           "Hippocampus": true
@@ -799,7 +865,7 @@
       },
       "evidence": "Inter-group analysis showed that the protein level decreased by pretreatment with selective a7 nAChR antagonist MLA (p<0.001). PHA and Gal prevent receptor destroying in AD animals, but this effect is completely abolished by MLA (p<0.001) (Fig. 9). The groups showed results in the cortex similar to those observed in the hippocampus (data not shown).",
       "key": "26bdf8ee4838ff6670c2d793b3723df2f6b001362414614072b10bad519e37d600ee9224d7cd6b9b8323aa20c82c1934979cb0027d30b7250a3a3cebd44f9d96",
-      "line": 289,
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       "object": {
         "modifier": "Activity"
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@@ -809,6 +875,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Species": {
           "10090": true
         }
@@ -833,7 +902,7 @@
       },
       "evidence": "Notably, PHA could completely block the Ab-impaired task acquisition and reduce escape-latency to the normal level. Furthermore, the effect of PHA against the Ab-impaired task acquisition could be abolished by the pre-treatment of the a7 nAChR antagonist MLA (p<0.001). It was also noted that blockade of a7 nAChR by MLA in the Gal-treated group resulted in a significant prolongation of the escape-latency on comparing with the Gal group (p<0.001) (Fig. 2).",
       "key": "35d5cfb0a73757eec8917acc1da85e96a760b68af57fbc9269124c0735d37ca4301703efbaaffed02e028e0bbe03a2bafd761d7b56bdd4ec37d472901cb8f69b",
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       "object": {
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@@ -843,6 +912,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Species": {
           "10090": true
         }
@@ -867,7 +939,7 @@
       },
       "evidence": "MLA could completely block the PHA-induced spatial memory improvement (p<0.001). Furthermore, the effect of Gal against the Ab-impaired reference memory could be abolished by the pre-treatment of the a7 nAChR antagonist MLA (p<0.001). However, a7 nAChR blockage in the Gal group has a lesser effect on reference memory in comparison of blockage of that receptor in the PHA group (p<0.05) (Fig. 4).",
       "key": "95441f53eadaa6764375b3c48a9b6d9cdb618320b1c2ef6074abaad92e4aacac5690af647248f0438f5e3d2aa9591b53918350bd180aa96c9c0bdcd3d899c1ba",
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       "object": {
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@@ -877,6 +949,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Cerebral Cortex": true,
           "Hippocampus": true
@@ -905,7 +980,7 @@
       },
       "evidence": "Inter-group analysis showed that the protein level decreased by pretreatment with selective a7 nAChR antagonist MLA (p<0.001). PHA and Gal prevent receptor destroying in AD animals, but this effect is completely abolished by MLA (p<0.001) (Fig. 9). The groups showed results in the cortex similar to those observed in the hippocampus (data not shown).",
       "key": "a885a1e3e61587df27f509dae7ae77d8fb2ce0cc7cd2a941c5900d56ca3b5b30820a7f95f6b7fbdb66cad93667881526cb2781d3426738b7b88efb84f76e3895",
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       "object": {
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@@ -915,6 +990,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Species": {
           "10090": true
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@@ -939,7 +1017,7 @@
       },
       "evidence": "Notably, PHA could completely block the Ab-impaired task acquisition and reduce escape-latency to the normal level. Furthermore, the effect of PHA against the Ab-impaired task acquisition could be abolished by the pre-treatment of the a7 nAChR antagonist MLA (p<0.001). It was also noted that blockade of a7 nAChR by MLA in the Gal-treated group resulted in a significant prolongation of the escape-latency on comparing with the Gal group (p<0.001) (Fig. 2).",
       "key": "e7dce432b04bd9aaf599fc502677b8274169400b41bf5cbd1375cd4ce06730fa5b910869cc62bc79269ece6274032a43987de20b4626a917e21cddb32816caad",
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@@ -949,6 +1027,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Species": {
           "10090": true
         }
@@ -973,7 +1054,7 @@
       },
       "evidence": "Effect of a7 nAChRs blockage on time spent in target quadrant in probe trials. The implications of the a7 nAChRs on PHA- or Gal-induced spatial memory enhancement were investigated by pretreatment with normal saline or MLA. A two-way ANOVA revealed significant differences of treatment [F(1,56)=4.24, p<0.05], pretreatment [F(1,56)=96.87, p<0.001] and treatment \u0003 pretreatment interaction [F(1,32)=10.69, p<0.01]. Inter-group analysis showed that this effect was blocked by the selective a7 nAChR antagonist MLA (p<0.001).",
       "key": "072da8ab0df1d723566849004df2fcc2668ebe9bc5fc576bade3ac2e7c6b05848836e10c48e527405a7f267913145df27218d35e1ee02e2b58b6e1a4cba65b78",
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       "object": {
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       },
@@ -983,6 +1064,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Cerebral Cortex": true,
           "Hippocampus": true
@@ -1011,13 +1095,16 @@
       },
       "evidence": "Inter-group analysis showed that the protein level decreased by pretreatment with selective a7 nAChR antagonist MLA (p<0.001). PHA and Gal prevent receptor destroying in AD animals, but this effect is completely abolished by MLA (p<0.001) (Fig. 9). The groups showed results in the cortex similar to those observed in the hippocampus (data not shown).",
       "key": "d2a36f126e68c0d356b3c30b297480384b3be059fb3bc47fc2f26febadfb5227393b2ee6a49ab6bc900575b512efb73ecd793f812dbf33eee189652de780369a",
-      "line": 288,
+      "line": 300,
       "relation": "decreases",
       "source": 3,
       "target": 7
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Species": {
           "10090": true
         }
@@ -1042,13 +1129,16 @@
       },
       "evidence": "MLA could completely block the PHA-induced spatial memory improvement (p<0.001). Furthermore, the effect of Gal against the Ab-impaired reference memory could be abolished by the pre-treatment of the a7 nAChR antagonist MLA (p<0.001). However, a7 nAChR blockage in the Gal group has a lesser effect on reference memory in comparison of blockage of that receptor in the PHA group (p<0.05) (Fig. 4).",
       "key": "39f4cc54e3d0fc1c58f24fb9a6b95834c9b589510e8e2983a406b93ffb14db8b6c8de1936d31e8b7119a09a5caee5ab4aca752cb9167df705faa00aaf6187fae",
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+      "line": 198,
       "relation": "decreases",
       "source": 3,
       "target": 9
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Cerebral Cortex": true,
           "Hippocampus": true
@@ -1077,13 +1167,16 @@
       },
       "evidence": "Also, no alterations in the expression of a7 nAChR mRNA were observed in pretreatment with normal saline or MLA in PHA- or Gal-treated groups (p>0.05). In the same way, the pattern of mRNA expression in the cortex (data not shown) was similar to the hippocampus (Fig. 7).",
       "key": "1f7d8529bc3ad3053f03515ea206b5af966e9f9765290ffa1a3500043e65d25c091b55ddc7bdea5f88222a55b7bbecf2f836daa21b1aaa6a8ab2453c82a72fb7",
-      "line": 237,
+      "line": 246,
       "relation": "causesNoChange",
       "source": 3,
       "target": 10
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Species": {
           "10090": true
         }
@@ -1108,7 +1201,7 @@
       },
       "evidence": "Notably, PHA could completely block the Ab-impaired task acquisition and reduce escape-latency to the normal level. Furthermore, the effect of PHA against the Ab-impaired task acquisition could be abolished by the pre-treatment of the a7 nAChR antagonist MLA (p<0.001). It was also noted that blockade of a7 nAChR by MLA in the Gal-treated group resulted in a significant prolongation of the escape-latency on comparing with the Gal group (p<0.001) (Fig. 2).",
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+      "line": 125,
       "relation": "increases",
       "source": 7,
       "subject": {
@@ -1118,6 +1211,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Species": {
           "10090": true
         }
@@ -1142,7 +1238,7 @@
       },
       "evidence": "Effect of a7 nAChRs blockage on time spent in target quadrant in probe trials. The implications of the a7 nAChRs on PHA- or Gal-induced spatial memory enhancement were investigated by pretreatment with normal saline or MLA. A two-way ANOVA revealed significant differences of treatment [F(1,56)=4.24, p<0.05], pretreatment [F(1,56)=96.87, p<0.001] and treatment \u0003 pretreatment interaction [F(1,32)=10.69, p<0.01]. Inter-group analysis showed that this effect was blocked by the selective a7 nAChR antagonist MLA (p<0.001).",
       "key": "1c8071d716c639273143803df8afbfa38d97aa6aec013780e10b114167e78072cd61b1b22dfa216fd52b8be8f3b54130d3cbdd20a5ba23b2e28f1b11cc6b1656",
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+      "line": 180,
       "relation": "increases",
       "source": 7,
       "subject": {
@@ -1152,6 +1248,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Species": {
           "10090": true
         }
@@ -1176,13 +1275,16 @@
       },
       "evidence": "Post hoc analysis revealed that, levels of the a7 nAChR protein in normal saline-treated AD mice were significantly lower than its level in the control animals (p<0.001).",
       "key": "eee5204d4a641943d863384026ed31b31f52cfa0ec1f16a4ec786cd7397f68dc3c64e200b627b2741be111ea23f01c33a4b18607da922274954598c61f36a861",
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+      "line": 261,
       "relation": "negativeCorrelation",
       "source": 7,
       "target": 8
     },
     {
       "annotations": {
+        "Confidence": {
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+        },
         "Species": {
           "10090": true
         }
@@ -1207,7 +1309,7 @@
       },
       "evidence": "Post hoc analysis revealed that, levels of the a7 nAChR protein in normal saline-treated AD mice were significantly lower than its level in the control animals (p<0.001).",
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diff --git a/hbp_knowledge/receptors/taly2009.bel.json b/hbp_knowledge/receptors/taly2009.bel.json
index bf492308d..7f9ae91b3 100644
--- a/hbp_knowledge/receptors/taly2009.bel.json
+++ b/hbp_knowledge/receptors/taly2009.bel.json
@@ -56,6 +56,9 @@
   "links": [
     {
       "annotations": {
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         "TextLocation": {
           "Review": true
         }
@@ -82,11 +85,14 @@
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@@ -111,13 +117,118 @@
       },
       "evidence": "The acute effect of ACh consists of the fast opening (microsecond to millisecond range) of a cationic channel that is permeable to Na+, K+ and sometimes Ca2+ ions.",
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+          "Corringer PJ",
+          "Guedin D",
+          "Lestage P",
+          "Taly A"
+        ],
+        "date": "2009-09-01",
+        "first": "Taly A",
+        "last": "Changeux JP",
+        "name": "Nature reviews. Drug discovery",
+        "pages": "733-50",
+        "reference": "19721446",
+        "title": "Nicotinic receptors: allosteric transitions and therapeutic targets in the nervous system.",
+        "type": "PubMed",
+        "volume": "8"
+      },
+      "evidence": "The acute effect of ACh consists of the fast opening (microsecond to millisecond range) of a cationic channel that is permeable to Na+, K+ and sometimes Ca2+ ions.",
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+        }
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+        "authors": [
+          "Changeux JP",
+          "Corringer PJ",
+          "Guedin D",
+          "Lestage P",
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+        "first": "Taly A",
+        "last": "Changeux JP",
+        "name": "Nature reviews. Drug discovery",
+        "pages": "733-50",
+        "reference": "19721446",
+        "title": "Nicotinic receptors: allosteric transitions and therapeutic targets in the nervous system.",
+        "type": "PubMed",
+        "volume": "8"
+      },
+      "evidence": "The acute effect of ACh consists of the fast opening (microsecond to millisecond range) of a cationic channel that is permeable to Na+, K+ and sometimes Ca2+ ions.",
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+      "annotations": {
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+          "Medium": true
+        },
+        "TextLocation": {
+          "Review": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Changeux JP",
+          "Corringer PJ",
+          "Guedin D",
+          "Lestage P",
+          "Taly A"
+        ],
+        "date": "2009-09-01",
+        "first": "Taly A",
+        "last": "Changeux JP",
+        "name": "Nature reviews. Drug discovery",
+        "pages": "733-50",
+        "reference": "19721446",
+        "title": "Nicotinic receptors: allosteric transitions and therapeutic targets in the nervous system.",
+        "type": "PubMed",
+        "volume": "8"
+      },
+      "evidence": "The acute effect of ACh consists of the fast opening (microsecond to millisecond range) of a cationic channel that is permeable to Na+, K+ and sometimes Ca2+ ions.",
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       "target": 47
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     {
       "annotations": {
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         "TextLocation": {
           "Review": true
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@@ -147,11 +258,14 @@
         "modifier": "Activity"
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       "relation": "increases",
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       "target": 6
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     {
       "annotations": {
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@@ -181,11 +295,14 @@
         "modifier": "Activity"
       },
       "relation": "increases",
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       "target": 6
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     {
       "annotations": {
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           "Review": true
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@@ -210,13 +327,16 @@
       },
       "evidence": "The nAChRs are ligand-gated ion channels that are present in both the PNS (at the skeletal neuromuscular junction and in the autonomic nervous system) and the CNS.",
       "key": "6a57903e4e83c7d5aec49457bcbc2a742a3f0a7881ebf8075fb917e3f5d49ea8f36aa08acad309fa17368d9c95632b27bd8f6eb6ef6d17f16cdd89123f05f3c6",
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       "relation": "association",
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     {
       "annotations": {
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@@ -241,13 +361,16 @@
       },
       "evidence": "The nAChRs are ligand-gated ion channels that are present in both the PNS (at the skeletal neuromuscular junction and in the autonomic nervous system) and the CNS.",
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     {
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@@ -272,7 +395,7 @@
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       "evidence": "Typically, activation of brain nAChRs results in enhanced release of various key neurotransmitters, including dopamine, serotonin, glutamate and GABA (gamma-aminobutyric acid).",
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@@ -287,7 +410,7 @@
         "modifier": "Translocation"
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       "relation": "increases",
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       "subject": {
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@@ -295,6 +418,9 @@
     },
     {
       "annotations": {
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@@ -319,7 +445,7 @@
       },
       "evidence": "Typically, activation of brain nAChRs results in enhanced release of various key neurotransmitters, including dopamine, serotonin, glutamate and GABA (gamma-aminobutyric acid).",
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@@ -334,7 +460,7 @@
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@@ -342,6 +468,9 @@
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     {
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@@ -366,7 +495,7 @@
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@@ -381,7 +510,7 @@
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@@ -389,6 +518,9 @@
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     {
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@@ -413,7 +545,7 @@
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@@ -436,6 +568,9 @@
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     {
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@@ -460,9 +595,9 @@
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       "evidence": "Cholesterol is known to be crucial to nAChR function, and it interacts within the transmembrane domain between TM1, TM3 and TM4 (ReF. 57).",
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@@ -470,6 +605,9 @@
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     {
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@@ -494,31 +632,34 @@
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       "evidence": "nAChRs are known to control sensory gating, and studies investigating the role of nAChRs in schizophrenia have focused primarily on alpha7 nAChRs. Sensory-gating deficits in patients with schizophrenia174 have been linked to chromosome 15q14, proximal to the alpha7 locus175,176.",
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+      "target": 87
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     {
       "annotations": {
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+          "High": true
+        },
         "MeSHAnatomy": {
           "Hippocampus": true
         },
@@ -549,13 +690,16 @@
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       "evidence": "in the cerebral cortex, the massive reduction in nAChRs in Alzheimer’s disease128–130 involves predominantly the alpha4beta2 subtype, sparing the alpha7 subtype131. By contrast, in the hippocampus, a loss of alpha7 nAChRs seems to predominate and to correlate with the progressive loss of cognitive function132–136.",
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       "relation": "positiveCorrelation",
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+      "target": 51
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     {
       "annotations": {
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         "MeSHDisease": {
           "Alzheimer Disease": true
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@@ -583,16 +727,19 @@
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@@ -617,13 +764,16 @@
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       "evidence": "First, there is a high level of expression of alpha7 nAChRs in the hippocampus, a region that is known to be involved in memory formation. Second, gene knockout and antisense studies have shown a role for alpha7 nAChRs in learning and memory144–146, and specifically in attention and working–episodic memory147,148. Third, pharmacological studies have shown that a range of structurally diverse alpha7 nAChR-selective agonists or positive allosteric modulators improve the cognitive deficits that are associated with Alzheimer’s disease.",
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@@ -648,13 +798,16 @@
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       "evidence": "First, there is a high level of expression of alpha7 nAChRs in the hippocampus, a region that is known to be involved in memory formation. Second, gene knockout and antisense studies have shown a role for alpha7 nAChRs in learning and memory144–146, and specifically in attention and working–episodic memory147,148. Third, pharmacological studies have shown that a range of structurally diverse alpha7 nAChR-selective agonists or positive allosteric modulators improve the cognitive deficits that are associated with Alzheimer’s disease.",
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     {
       "annotations": {
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+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
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@@ -685,16 +838,19 @@
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       "evidence": "By contrast, deleting the alpha7 nAChR subunit in a mouse model of Alzheimer’s disease that overexpresses a mutated form of the human amyloid precursor protein confers protection against memory loss and synaptic dysfunction, supporting a crucial role for alpha7 nAChR as a target288.",
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@@ -719,16 +875,19 @@
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     {
       "annotations": {
         "CellLine": {
           "PC12": true
         },
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@@ -753,13 +912,16 @@
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       "evidence": "The alpha7 nAChR has previously been implicated in the in vitro neuroprotective effects of nicotine, using PC12 cells151.",
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     {
       "annotations": {
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         "MeSHDisease": {
           "Alzheimer Disease": true
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@@ -790,16 +952,19 @@
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       "evidence": "By contrast, deleting the alpha7 nAChR subunit in a mouse model of Alzheimer’s disease that overexpresses a mutated form of the human amyloid precursor protein confers protection against memory loss and synaptic dysfunction, supporting a crucial role for alpha7 nAChR as a target288.",
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     {
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         "Species": {
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@@ -827,13 +992,16 @@
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       "evidence": "in addition, a decrease in alpha7 nAChR density in the hippocampus of patients with schizophrenia has been reported177. Similarly, a low density of alpha7 nAChRs in inbred strains of mice is associated with poor gating178. Recently, the expression of a novel variant of alpha7 nAChR, CHRNA7-2 (cholinergic receptor, nicotinic, alpha7, variant 2), was found to be reduced below control levels in the prefrontal cortex of patients with schizophrenia179.",
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@@ -858,13 +1026,16 @@
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       "evidence": "However, the atypical antipsychotic drug clozapine normalizes auditory gating in DBA/2 mice — an effect which involves an alpha7 nAChR mechanism181.",
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@@ -889,13 +1060,16 @@
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@@ -920,13 +1094,16 @@
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@@ -951,13 +1128,16 @@
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       "evidence": "The acute effect of ACh consists of the fast opening (microsecond to millisecond range) of a cationic channel that is permeable to Na+, K+ and sometimes Ca2+ ions.",
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@@ -982,13 +1162,16 @@
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       "evidence": "Chronic exposure to nicotine causes a striking increase, typically by twofold, in the total number of high-affinity receptors — a process termed upregulation8.",
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@@ -1013,7 +1196,7 @@
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       "evidence": "Regardless of the exact effect of Abeta1–42 on receptor activity, it does seem to block the activation by nicotine and, consistent with the cytoprotective nature of this interaction, amyloid deposition limits neuroprotection151. This phenomenon may explain at least part of the neurotoxicity that is associated with Abeta1–42 (ReF. 156).",
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@@ -1022,10 +1205,13 @@
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-      "target": 93
+      "target": 96
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     {
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         "MeSHDisease": {
           "Alzheimer Disease": true
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@@ -1053,16 +1239,19 @@
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       "evidence": "early studies indicated that acute nicotine administration improved performance of patients with Alzheimer’s disease in cognitive tasks, whereas acute administration of the non-competitive (channel blocker) antagonist mecamylamine resulted in dose-dependent impairment of performance in a battery of cognitive tasks137–141",
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     {
       "annotations": {
         "CellLine": {
           "PC12": true
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@@ -1087,13 +1276,16 @@
       },
       "evidence": "The alpha7 nAChR has previously been implicated in the in vitro neuroprotective effects of nicotine, using PC12 cells151.",
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     {
       "annotations": {
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         "MeSHDisease": {
           "Alzheimer Disease": true
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@@ -1121,13 +1313,16 @@
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       "evidence": "Amyloid plaques form in the entorhinal cortex of patients with Alzheimer’s disease and this region, which connects the neocortex and the hippocampus, plays a crucial part in memory. it has been suggested that plaques in this region represent the lytic remnants of degenerated, Abeta1–42-burdened pyramidal neurons, and that amyloid internalization depends on alpha7 nAChR mediated Ca2+ entry162. Of interest, chronic nicotine treatment has been shown to reduce the plaque burden in animal models of Alzheimer’s disease123.",
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     {
       "annotations": {
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         "MeSHDisease": {
           "Schizophrenia": true
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@@ -1155,89 +1350,15 @@
       },
       "evidence": "Patients with schizophrenia174 and DBA/2 mouse models180,181 respond to nicotine administration with improved sensory gating, presumably through alpha7 nAChR activation182,183.",
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@@ -1261,52 +1382,21 @@
         "type": "PubMed",
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       "evidence": "Also, α7- and non-α7-containing nicotinic receptors directly or indirectly (through GABAergic interneurons) modulate serotonin release in spinal cord slices230. However, the identity of the receptors that are responsible for the spinal control of nociception is currently unknown. in this process, the nicotine-induced antinociception seems to be mediated primarily by activation of calcium– calmodulin-dependent protein kinase 2, but this is not the case for supraspinal nociception control229.",
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@@ -1331,7 +1421,7 @@
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       "evidence": "Nicotine facilitates dopamine release by acting at both somatodendritic and presynaptic nAChRs on mesolimbic246,247 and nigrostriatal247 neurons.",
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@@ -1351,6 +1441,9 @@
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     {
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@@ -1375,16 +1468,19 @@
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@@ -1409,16 +1505,19 @@
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@@ -1443,16 +1542,19 @@
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@@ -1477,16 +1579,19 @@
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@@ -1511,16 +1616,19 @@
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@@ -1545,16 +1653,19 @@
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@@ -1579,16 +1690,19 @@
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@@ -1613,16 +1727,19 @@
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@@ -1647,16 +1764,19 @@
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       "evidence": "The binding site on alpha7 nAChRs63,64 for the positive allosteric modulators PNu-120596 and lY-2087101, has been tentatively identified within the transmembrane domain. it comprises five amino acids within TM1, TM2 and TM4 which, when mutated, substantially reduce the potentiation of alpah7 nAChRs by allosteric modulators",
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@@ -1681,16 +1801,19 @@
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       "evidence": "The binding site on alpha7 nAChRs63,64 for the positive allosteric modulators PNu-120596 and lY-2087101, has been tentatively identified within the transmembrane domain. it comprises five amino acids within TM1, TM2 and TM4 which, when mutated, substantially reduce the potentiation of alpah7 nAChRs by allosteric modulators",
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@@ -1715,16 +1838,19 @@
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       "evidence": "The binding site on alpha7 nAChRs63,64 for the positive allosteric modulators PNu-120596 and lY-2087101, has been tentatively identified within the transmembrane domain. it comprises five amino acids within TM1, TM2 and TM4 which, when mutated, substantially reduce the potentiation of alpah7 nAChRs by allosteric modulators",
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@@ -1749,16 +1875,19 @@
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       "evidence": "The binding site on alpha7 nAChRs63,64 for the positive allosteric modulators PNu-120596 and lY-2087101, has been tentatively identified within the transmembrane domain. it comprises five amino acids within TM1, TM2 and TM4 which, when mutated, substantially reduce the potentiation of alpah7 nAChRs by allosteric modulators",
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@@ -1783,16 +1912,19 @@
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       "evidence": "The binding site on alpha7 nAChRs63,64 for the positive allosteric modulators PNu-120596 and lY-2087101, has been tentatively identified within the transmembrane domain. it comprises five amino acids within TM1, TM2 and TM4 which, when mutated, substantially reduce the potentiation of alpah7 nAChRs by allosteric modulators",
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@@ -1817,16 +1949,19 @@
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       "evidence": "The binding site on alpha7 nAChRs63,64 for the positive allosteric modulators PNu-120596 and lY-2087101, has been tentatively identified within the transmembrane domain. it comprises five amino acids within TM1, TM2 and TM4 which, when mutated, substantially reduce the potentiation of alpah7 nAChRs by allosteric modulators",
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@@ -1851,16 +1986,19 @@
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@@ -1885,16 +2023,19 @@
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@@ -1919,16 +2060,19 @@
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       "evidence": "The binding site on alpha7 nAChRs63,64 for the positive allosteric modulators PNu-120596 and lY-2087101, has been tentatively identified within the transmembrane domain. it comprises five amino acids within TM1, TM2 and TM4 which, when mutated, substantially reduce the potentiation of alpah7 nAChRs by allosteric modulators",
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       "annotations": {
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@@ -1953,13 +2097,16 @@
       },
       "evidence": "The cytoplasmic domain of the alpha4 nAChR subunit binds the scaffold protein 14-3-3η and the Ca2+ sensor visinin-like protein 1 (ReF. 69), and the beta2 subunit interacts with several cytoskeletal proteins, such as tubulin, dynamin and clathrin, and with G protein systems that are involved in intracellular signalling pathways70.",
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@@ -1984,19 +2131,22 @@
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       "evidence": "The cytoplasmic domain of the alpha4 nAChR subunit binds the scaffold protein 14-3-3η and the Ca2+ sensor visinin-like protein 1 (ReF. 69), and the beta2 subunit interacts with several cytoskeletal proteins, such as tubulin, dynamin and clathrin, and with G protein systems that are involved in intracellular signalling pathways70.",
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@@ -2021,16 +2171,19 @@
       },
       "evidence": "in α4- and β2-knockout mice, the responses of raphe neurons to nicotine is abolished, together with nicotine-elicited antinociception228, and α4-hypersensitive knock-in mice show nicotine hypersensitivity in the supraspinal control (hot-plate assay), but not in the spinal control (tail flick assay)229.",
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     {
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@@ -2055,13 +2208,16 @@
       },
       "evidence": "The cytoplasmic domain of the alpha4 nAChR subunit binds the scaffold protein 14-3-3η and the Ca2+ sensor visinin-like protein 1 (ReF. 69), and the beta2 subunit interacts with several cytoskeletal proteins, such as tubulin, dynamin and clathrin, and with G protein systems that are involved in intracellular signalling pathways70.",
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@@ -2086,13 +2242,16 @@
       },
       "evidence": "The cytoplasmic domain of the alpha4 nAChR subunit binds the scaffold protein 14-3-3η and the Ca2+ sensor visinin-like protein 1 (ReF. 69), and the beta2 subunit interacts with several cytoskeletal proteins, such as tubulin, dynamin and clathrin, and with G protein systems that are involved in intracellular signalling pathways70.",
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@@ -2117,13 +2276,16 @@
       },
       "evidence": "The cytoplasmic domain of the alpha4 nAChR subunit binds the scaffold protein 14-3-3η and the Ca2+ sensor visinin-like protein 1 (ReF. 69), and the beta2 subunit interacts with several cytoskeletal proteins, such as tubulin, dynamin and clathrin, and with G protein systems that are involved in intracellular signalling pathways70.",
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     {
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@@ -2148,13 +2310,16 @@
       },
       "evidence": "The cytoplasmic domain of the alpha4 nAChR subunit binds the scaffold protein 14-3-3η and the Ca2+ sensor visinin-like protein 1 (ReF. 69), and the beta2 subunit interacts with several cytoskeletal proteins, such as tubulin, dynamin and clathrin, and with G protein systems that are involved in intracellular signalling pathways70.",
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     {
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@@ -2179,13 +2344,16 @@
       },
       "evidence": "The cytoplasmic domain of the alpha4 nAChR subunit binds the scaffold protein 14-3-3η and the Ca2+ sensor visinin-like protein 1 (ReF. 69), and the beta2 subunit interacts with several cytoskeletal proteins, such as tubulin, dynamin and clathrin, and with G protein systems that are involved in intracellular signalling pathways70.",
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     {
       "annotations": {
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@@ -2210,16 +2378,19 @@
       },
       "evidence": "in α4- and β2-knockout mice, the responses of raphe neurons to nicotine is abolished, together with nicotine-elicited antinociception228, and α4-hypersensitive knock-in mice show nicotine hypersensitivity in the supraspinal control (hot-plate assay), but not in the spinal control (tail flick assay)229.",
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       "target": 15
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     {
       "annotations": {
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@@ -2244,13 +2415,16 @@
       },
       "evidence": "The cytoplasmic domain of the alpha4 nAChR subunit binds the scaffold protein 14-3-3η and the Ca2+ sensor visinin-like protein 1 (ReF. 69), and the beta2 subunit interacts with several cytoskeletal proteins, such as tubulin, dynamin and clathrin, and with G protein systems that are involved in intracellular signalling pathways70.",
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     {
       "annotations": {
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           "Review": true
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@@ -2275,13 +2449,16 @@
       },
       "evidence": "The cytoplasmic domain of the alpha4 nAChR subunit binds the scaffold protein 14-3-3η and the Ca2+ sensor visinin-like protein 1 (ReF. 69), and the beta2 subunit interacts with several cytoskeletal proteins, such as tubulin, dynamin and clathrin, and with G protein systems that are involved in intracellular signalling pathways70.",
       "key": "02b044b1687e40a5130d53e252fdd6fbe032abf690392f23608dc4523a25b983f8ac1b9d97a30eb628bd155668b58938d3d074f4b4caa964a1680764ee684707",
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       "relation": "association",
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     {
       "annotations": {
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@@ -2306,13 +2483,16 @@
       },
       "evidence": "The cytoplasmic domain of the alpha4 nAChR subunit binds the scaffold protein 14-3-3η and the Ca2+ sensor visinin-like protein 1 (ReF. 69), and the beta2 subunit interacts with several cytoskeletal proteins, such as tubulin, dynamin and clathrin, and with G protein systems that are involved in intracellular signalling pathways70.",
       "key": "180a8d90e49e8a5087f08cd82754fc78132faa69ca1ca2ee2a2b29ca8220133600f8f1933a0cbea40450432dc67e3ce65e3c9a1dc796287cab27ec510c2551af",
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     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Basal Forebrain": true,
           "Cerebral Cortex": true,
@@ -2342,13 +2522,16 @@
       },
       "evidence": "Alzheimer’s disease is characterized by progressive cognitive decline, accompanied by a loss of neurons and synapses — especially cholinergic synapses — in the basal forebrain, cerebral cortex and hippocampus126 and by a substantial reduction in both muscarinic and nicotinic AChR expression127.",
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+      "target": 51
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Basal Forebrain": true,
           "Cerebral Cortex": true,
@@ -2378,13 +2561,16 @@
       },
       "evidence": "Alzheimer’s disease is characterized by progressive cognitive decline, accompanied by a loss of neurons and synapses — especially cholinergic synapses — in the basal forebrain, cerebral cortex and hippocampus126 and by a substantial reduction in both muscarinic and nicotinic AChR expression127.",
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       "target": 43
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     {
       "annotations": {
+        "Confidence": {
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         "MeSHAnatomy": {
           "Basal Forebrain": true,
           "Cerebral Cortex": true,
@@ -2414,13 +2600,16 @@
       },
       "evidence": "Alzheimer’s disease is characterized by progressive cognitive decline, accompanied by a loss of neurons and synapses — especially cholinergic synapses — in the basal forebrain, cerebral cortex and hippocampus126 and by a substantial reduction in both muscarinic and nicotinic AChR expression127.",
       "key": "0f6ba6a3f179659ee91ffa2b01739aac3183c79d351113bb03a119f91b61f5a7dcb50967e5c8e35d56faed220251597b41802cc2388ebcd7b18780b8c13749f6",
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+      "target": 95
     },
     {
       "annotations": {
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+          "High": true
+        },
         "MeSHAnatomy": {
           "Basal Forebrain": true,
           "Cerebral Cortex": true,
@@ -2450,13 +2639,16 @@
       },
       "evidence": "Alzheimer’s disease is characterized by progressive cognitive decline, accompanied by a loss of neurons and synapses — especially cholinergic synapses — in the basal forebrain, cerebral cortex and hippocampus126 and by a substantial reduction in both muscarinic and nicotinic AChR expression127.",
       "key": "ff311d9e2aa5e1b8813721eadc3c16bb0f96a5454cf9517f9ce54e9731db2a271a63ee94abe1138ed1aa3e5cf12d0f07eccd6397025a08bed804a0277974029f",
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       "relation": "decreases",
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+      "target": 96
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Cerebral Cortex": true
         },
@@ -2484,13 +2676,16 @@
       },
       "evidence": "in the cerebral cortex, the massive reduction in nAChRs in Alzheimer’s disease128–130 involves predominantly the alpha4beta2 subtype, sparing the alpha7 subtype131. By contrast, in the hippocampus, a loss of alpha7 nAChRs seems to predominate and to correlate with the progressive loss of cognitive function132–136.",
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     {
       "annotations": {
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         "TextLocation": {
           "Review": true
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@@ -2515,13 +2710,16 @@
       },
       "evidence": "Similarly, MeM-3454 improved the ‘quality of episodic secondary memory’ score, which is a measure of episodic memory. As for episodic memory, working memory is impaired in Alzheimer’s disease. MeM-3454 significantly improved the quality of working memory score in patients with Alzheimer’s disease in Phase i trials. in a Phase ii trial, the quality of working memory scores were also improved by MeM-3454, as was the ADAS–cog (Alzheimer’s disease assessment scale–cognitive subscale) score.",
       "key": "6fa9ad1e6ac871dbe631ab342d3cb2caa0f57262ab5b877be501e4ebf8ffd220fa6a21f6b50a8f7258348cb64ea1e711e3edc88bc64d505d8619650dcdfa1c38",
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       "relation": "decreases",
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-      "target": 100
+      "source": 100,
+      "target": 103
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Entorhinal Cortex": true
         },
@@ -2549,13 +2747,16 @@
       },
       "evidence": "Amyloid plaques form in the entorhinal cortex of patients with Alzheimer’s disease and this region, which connects the neocortex and the hippocampus, plays a crucial part in memory. it has been suggested that plaques in this region represent the lytic remnants of degenerated, Abeta1–42-burdened pyramidal neurons, and that amyloid internalization depends on alpha7 nAChR mediated Ca2+ entry162. Of interest, chronic nicotine treatment has been shown to reduce the plaque burden in animal models of Alzheimer’s disease123.",
       "key": "6134678570785e7b8c6b32452ad2c36c31eb589bb658eb38502b5c70e2f362860c03aa25f11ba1ceba303a0b73d08f70b9fe7d9f8f46c3b87f7894805d0b3a49",
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-      "target": 101
+      "source": 100,
+      "target": 104
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Hippocampus": true
         },
@@ -2586,13 +2787,16 @@
       },
       "evidence": "in the cerebral cortex, the massive reduction in nAChRs in Alzheimer’s disease128–130 involves predominantly the alpha4beta2 subtype, sparing the alpha7 subtype131. By contrast, in the hippocampus, a loss of alpha7 nAChRs seems to predominate and to correlate with the progressive loss of cognitive function132–136.",
       "key": "2662f269972058b23fa42371c7064664e2e702fea9d9fb767bc0007816bee1dfca508e4ba9ae397eb0862a823c0f6c0cf411a89feb9bc1ebf31fffba5edb794f",
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       "relation": "positiveCorrelation",
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-      "target": 81
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+      "target": 84
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     {
       "annotations": {
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         "TextLocation": {
           "Review": true
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@@ -2617,13 +2821,16 @@
       },
       "evidence": "in addition to the obvious symptoms of hallucinations and delusions, patients with schizophrenia frequently suffer from cognitive symptoms, such as the inability to focus attention173.",
       "key": "702c4405c15d43c9cd256f73664b3d7edcc8ee6d07ca565eed24fc09a26cfadd22bae6262ca37c1596b6566cad1917737b0fa8d56089346612ae3afe51e7e9d0",
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       "relation": "association",
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+      "target": 115
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         },
@@ -2651,13 +2858,16 @@
       },
       "evidence": "early studies indicated that acute nicotine administration improved performance of patients with Alzheimer’s disease in cognitive tasks, whereas acute administration of the non-competitive (channel blocker) antagonist mecamylamine resulted in dose-dependent impairment of performance in a battery of cognitive tasks137–141",
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     {
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@@ -2682,13 +2892,16 @@
       },
       "evidence": "First, there is a high level of expression of alpha7 nAChRs in the hippocampus, a region that is known to be involved in memory formation. Second, gene knockout and antisense studies have shown a role for alpha7 nAChRs in learning and memory144–146, and specifically in attention and working–episodic memory147,148. Third, pharmacological studies have shown that a range of structurally diverse alpha7 nAChR-selective agonists or positive allosteric modulators improve the cognitive deficits that are associated with Alzheimer’s disease.",
       "key": "2da2dce40f1047392320f459e6de1d67578ed13e9680de5a3ef4844eb5c32364310a2d5f7cec1414faae5747fd356ba9d0083c494e8197e279e63da35852eda0",
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       "relation": "association",
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     {
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@@ -2713,13 +2926,16 @@
       },
       "evidence": "First, there is a high level of expression of alpha7 nAChRs in the hippocampus, a region that is known to be involved in memory formation. Second, gene knockout and antisense studies have shown a role for alpha7 nAChRs in learning and memory144–146, and specifically in attention and working–episodic memory147,148. Third, pharmacological studies have shown that a range of structurally diverse alpha7 nAChR-selective agonists or positive allosteric modulators improve the cognitive deficits that are associated with Alzheimer’s disease.",
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       "relation": "association",
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     {
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@@ -2744,13 +2960,16 @@
       },
       "evidence": "First, there is a high level of expression of alpha7 nAChRs in the hippocampus, a region that is known to be involved in memory formation. Second, gene knockout and antisense studies have shown a role for alpha7 nAChRs in learning and memory144–146, and specifically in attention and working–episodic memory147,148. Third, pharmacological studies have shown that a range of structurally diverse alpha7 nAChR-selective agonists or positive allosteric modulators improve the cognitive deficits that are associated with Alzheimer’s disease.",
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       "target": 41
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     {
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@@ -2775,13 +2994,16 @@
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       "evidence": "First, there is a high level of expression of alpha7 nAChRs in the hippocampus, a region that is known to be involved in memory formation. Second, gene knockout and antisense studies have shown a role for alpha7 nAChRs in learning and memory144–146, and specifically in attention and working–episodic memory147,148. Third, pharmacological studies have shown that a range of structurally diverse alpha7 nAChR-selective agonists or positive allosteric modulators improve the cognitive deficits that are associated with Alzheimer’s disease.",
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       "annotations": {
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@@ -2809,13 +3031,16 @@
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       "evidence": "Amyloid plaques form in the entorhinal cortex of patients with Alzheimer’s disease and this region, which connects the neocortex and the hippocampus, plays a crucial part in memory. it has been suggested that plaques in this region represent the lytic remnants of degenerated, Abeta1–42-burdened pyramidal neurons, and that amyloid internalization depends on alpha7 nAChR mediated Ca2+ entry162. Of interest, chronic nicotine treatment has been shown to reduce the plaque burden in animal models of Alzheimer’s disease123.",
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       "evidence": "First, there is a high level of expression of alpha7 nAChRs in the hippocampus, a region that is known to be involved in memory formation. Second, gene knockout and antisense studies have shown a role for alpha7 nAChRs in learning and memory144–146, and specifically in attention and working–episodic memory147,148. Third, pharmacological studies have shown that a range of structurally diverse alpha7 nAChR-selective agonists or positive allosteric modulators improve the cognitive deficits that are associated with Alzheimer’s disease.",
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       "evidence": "As expected, AR-R17779 — a selective partial alpha7 nAChR agonist — improved scopolamine-elicited deficits in social recognition, and the 24-hour memory retention interval in unimpaired animals. Repeated doses of AR-R17779 enhanced long-term learning and attenuated working-memory deficits in rats.",
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       "evidence": "As expected, AR-R17779 — a selective partial alpha7 nAChR agonist — improved scopolamine-elicited deficits in social recognition, and the 24-hour memory retention interval in unimpaired animals. Repeated doses of AR-R17779 enhanced long-term learning and attenuated working-memory deficits in rats.",
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       "evidence": "As expected, AR-R17779 — a selective partial alpha7 nAChR agonist — improved scopolamine-elicited deficits in social recognition, and the 24-hour memory retention interval in unimpaired animals. Repeated doses of AR-R17779 enhanced long-term learning and attenuated working-memory deficits in rats.",
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       "evidence": "Two partial agonists of alpha7 nAChRs, GTS-21 (also a strong alpha4beta2 antagonist) and MeM-3454 (also a strong 5-hydroxytryptamine type 3 receptor (5HT3) antagonist)149 (TABLe 1), further showed a procognitive action and, in preclinical studies, MeM-3454 enhanced episodic, spatial and working memory.",
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       "evidence": "As with nicotine, the weak alpha7 nAChR agonist GTS-21 is neuroprotective, specifically protecting against Abeta1–42-elicited neurotoxicity154. This effect is probably due to small, protracted increases in receptor-mediated Ca2+ influx. importantly, high concentrations of GTS-21 reduced cell survival, underlining the possible risk of over-stimulation152",
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       "evidence": "As with nicotine, the weak alpha7 nAChR agonist GTS-21 is neuroprotective, specifically protecting against Abeta1–42-elicited neurotoxicity154. This effect is probably due to small, protracted increases in receptor-mediated Ca2+ influx. importantly, high concentrations of GTS-21 reduced cell survival, underlining the possible risk of over-stimulation152",
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@@ -3125,13 +3377,16 @@
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       "evidence": "GTS-21, one of a series of compounds derived from anabaseine, an alkaloid found in marine worms, is a partial agonist of alpha7 nAChRs that improves memory-related behaviours in various paradigms and normalizes auditory gating186. it is the leading clinical candidate in the field of alpha7 nAChRs.",
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@@ -3156,13 +3411,16 @@
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       "evidence": "initially evaluated in normal subjects, GTS-21 was found to significantly improve attention and memory. in a second Phase i trial187, GTS-21 normalized P50 auditory gating in patients with schizophrenia.",
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@@ -3221,13 +3482,16 @@
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@@ -3283,13 +3550,16 @@
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       "evidence": "Two partial agonists of alpha7 nAChRs, GTS-21 (also a strong alpha4beta2 antagonist) and MeM-3454 (also a strong 5-hydroxytryptamine type 3 receptor (5HT3) antagonist)149 (TABLe 1), further showed a procognitive action and, in preclinical studies, MeM-3454 enhanced episodic, spatial and working memory.",
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@@ -3314,13 +3584,16 @@
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       "evidence": "Two partial agonists of alpha7 nAChRs, GTS-21 (also a strong alpha4beta2 antagonist) and MeM-3454 (also a strong 5-hydroxytryptamine type 3 receptor (5HT3) antagonist)149 (TABLe 1), further showed a procognitive action and, in preclinical studies, MeM-3454 enhanced episodic, spatial and working memory.",
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@@ -3345,13 +3618,16 @@
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       "evidence": "Similarly, MeM-3454 improved the ‘quality of episodic secondary memory’ score, which is a measure of episodic memory. As for episodic memory, working memory is impaired in Alzheimer’s disease. MeM-3454 significantly improved the quality of working memory score in patients with Alzheimer’s disease in Phase i trials. in a Phase ii trial, the quality of working memory scores were also improved by MeM-3454, as was the ADAS–cog (Alzheimer’s disease assessment scale–cognitive subscale) score.",
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@@ -3376,7 +3652,7 @@
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       "evidence": "The procognitive effect of MeM-3454 on episodic memory was completely blocked by the alpha7-specific antagonist methyllycaconitine, establishing that the efficacy of MeM-3454 can be attributed to alpha7 nAChR binding.",
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@@ -3389,6 +3665,9 @@
         "CellLine": {
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@@ -3413,16 +3692,19 @@
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       "evidence": "The alpha7 nAChR has previously been implicated in the in vitro neuroprotective effects of nicotine, using PC12 cells151.",
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@@ -3447,13 +3729,16 @@
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       "evidence": "The alpha7 nAChR has previously been implicated in the in vitro neuroprotective effects of nicotine, using PC12 cells151.",
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@@ -3478,13 +3763,16 @@
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       "evidence": "Choline, like nicotine, can protect neural cells from cytotoxicity that is induced by growth factor deprivation152 or exposure to the glutamate analogue AMPA (alpha-amino-3-hydroxy-5-methyl-4- isoxazole propionic acid)153.",
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@@ -3509,7 +3797,7 @@
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       "evidence": "Choline, like nicotine, can protect neural cells from cytotoxicity that is induced by growth factor deprivation152 or exposure to the glutamate analogue AMPA (alpha-amino-3-hydroxy-5-methyl-4- isoxazole propionic acid)153.",
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@@ -3519,6 +3807,9 @@
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@@ -3543,13 +3834,16 @@
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       "evidence": "Choline, like nicotine, can protect neural cells from cytotoxicity that is induced by growth factor deprivation152 or exposure to the glutamate analogue AMPA (alpha-amino-3-hydroxy-5-methyl-4- isoxazole propionic acid)153.",
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@@ -3574,13 +3868,16 @@
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       "evidence": "As with nicotine, the weak alpha7 nAChR agonist GTS-21 is neuroprotective, specifically protecting against Abeta1–42-elicited neurotoxicity154. This effect is probably due to small, protracted increases in receptor-mediated Ca2+ influx. importantly, high concentrations of GTS-21 reduced cell survival, underlining the possible risk of over-stimulation152",
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@@ -3605,13 +3902,16 @@
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@@ -3636,7 +3936,7 @@
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@@ -3646,6 +3946,9 @@
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@@ -3670,13 +3973,16 @@
       },
       "evidence": "Regardless of the exact effect of Abeta1–42 on receptor activity, it does seem to block the activation by nicotine and, consistent with the cytoprotective nature of this interaction, amyloid deposition limits neuroprotection151. This phenomenon may explain at least part of the neurotoxicity that is associated with Abeta1–42 (ReF. 156).",
       "key": "a5e9f48d17b1c11af4df5e78ae1f1780bd72b739381fdbee2f937a3d435874b75f5bc182ee46423c4ccec84a49d0fbc83f164d91782d54654535e03883ad5104",
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+      "line": 452,
       "relation": "decreases",
       "source": 0,
-      "target": 53
+      "target": 56
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Entorhinal Cortex": true
         },
@@ -3704,13 +4010,16 @@
       },
       "evidence": "Amyloid plaques form in the entorhinal cortex of patients with Alzheimer’s disease and this region, which connects the neocortex and the hippocampus, plays a crucial part in memory. it has been suggested that plaques in this region represent the lytic remnants of degenerated, Abeta1–42-burdened pyramidal neurons, and that amyloid internalization depends on alpha7 nAChR mediated Ca2+ entry162. Of interest, chronic nicotine treatment has been shown to reduce the plaque burden in animal models of Alzheimer’s disease123.",
       "key": "e39cd9d90591f836b3abb01e9577285f314a6bf18d4f0a7993bc30719fc6105304cd1d8dd4e8e217ff9a99c1b2ee130c1185b76208dedcfece344553c833de5e",
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       "relation": "association",
       "source": 35,
-      "target": 50
+      "target": 53
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -3735,13 +4044,16 @@
       },
       "evidence": "ABT-418, discussed above, has also been found to be active in a limited human trial in attention deficit hyperactivity disorder (ADHD)171. A second compound, ABT-089, which is a partial agonist at alpha4beta2 nAChRs, was also efficacious in ADHD172",
       "key": "01a1e92cde5e2bb591398374267439a785791206f9141b82a084b93c43cef103137271a6439c46f20f4e1c229f5e602154bb575bfff4fdf5081485438f4624f3",
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       "relation": "association",
       "source": 29,
-      "target": 98
+      "target": 101
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -3766,13 +4078,16 @@
       },
       "evidence": "ABT-418, discussed above, has also been found to be active in a limited human trial in attention deficit hyperactivity disorder (ADHD)171. A second compound, ABT-089, which is a partial agonist at alpha4beta2 nAChRs, was also efficacious in ADHD172",
       "key": "3ab93cc992852d0d0666260936e4add28149d2aa9930e272e8026bacef51ab7c4358585d7a31e39dd27edb7ec1a97c64b1479e0355fd6a3602db40632f636592",
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       "relation": "association",
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+      "source": 101,
       "target": 29
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -3797,13 +4112,16 @@
       },
       "evidence": "ABT-418, discussed above, has also been found to be active in a limited human trial in attention deficit hyperactivity disorder (ADHD)171. A second compound, ABT-089, which is a partial agonist at alpha4beta2 nAChRs, was also efficacious in ADHD172",
       "key": "2dc4b183c02bcb7f9bb4b8ef5a22823139a7a4df8e9d2f0d8318326dd0bfdf72a9629476a01e8c99a60bfc8f218638f57076dbf7e099d0eb3d86b14b4799575c",
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       "relation": "association",
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       "target": 45
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     {
       "annotations": {
+        "Confidence": {
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         "TextLocation": {
           "Review": true
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@@ -3828,13 +4146,16 @@
       },
       "evidence": "ABT-418, discussed above, has also been found to be active in a limited human trial in attention deficit hyperactivity disorder (ADHD)171. A second compound, ABT-089, which is a partial agonist at alpha4beta2 nAChRs, was also efficacious in ADHD172",
       "key": "753e301fb21a345dd6283f51553b8a44857e5972437512c6d71a8ab385127cd3fb77d4abf500e6888d5b9997364aa03535341c82c6a8d77c0c3848d1a9fb2137",
-      "line": 459,
+      "line": 490,
       "relation": "association",
       "source": 45,
-      "target": 98
+      "target": 101
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     {
       "annotations": {
+        "Confidence": {
+          "High": true
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         "TextLocation": {
           "Review": true
         }
@@ -3859,13 +4180,16 @@
       },
       "evidence": "in addition to the obvious symptoms of hallucinations and delusions, patients with schizophrenia frequently suffer from cognitive symptoms, such as the inability to focus attention173.",
       "key": "471fa616a7ffd74847e1b5dd73c766e01666a74f5ce8ac051211ebfe87ce159708f0c69ffbf6a74787d1fd90fa9ac3f4e4d54793037a2f67c1e01386fb890794",
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       "relation": "association",
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-      "target": 107
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+      "target": 110
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     {
       "annotations": {
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         "TextLocation": {
           "Review": true
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@@ -3890,13 +4214,16 @@
       },
       "evidence": "in addition to the obvious symptoms of hallucinations and delusions, patients with schizophrenia frequently suffer from cognitive symptoms, such as the inability to focus attention173.",
       "key": "f3f9689cf87daeb0f8575ea07a25c238d356bd55bc4cc5c83649a98ddd2064d60ac76b4de1a217e53194ee5b07fa1d3e252117747550e6a2f8bf7b6941434994",
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       "relation": "association",
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-      "target": 105
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+      "target": 108
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     {
       "annotations": {
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         "TextLocation": {
           "Review": true
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@@ -3921,13 +4248,16 @@
       },
       "evidence": "in addition to the obvious symptoms of hallucinations and delusions, patients with schizophrenia frequently suffer from cognitive symptoms, such as the inability to focus attention173.",
       "key": "ec61eb0b89262188e07ff5fbd9aa877b6501bec970aa253b248d32fbd8873f9a530bdd5b9ab6bee2b634a382cd0457a07aeb0caf72dbcf7e43fb41bfb7ad5ce7",
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       "relation": "association",
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-      "target": 48
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+      "target": 51
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     {
       "annotations": {
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         "TextLocation": {
           "Review": true
         }
@@ -3952,13 +4282,16 @@
       },
       "evidence": "nAChRs are known to control sensory gating, and studies investigating the role of nAChRs in schizophrenia have focused primarily on alpha7 nAChRs. Sensory-gating deficits in patients with schizophrenia174 have been linked to chromosome 15q14, proximal to the alpha7 locus175,176.",
       "key": "2d17696e6f7bc0873ee202167b59089ea732eaa7ab963d4b288b98a894324f8ab69e2b9e133c1701e6424ff9fcd79017e57480604473ce414d01ab54d9bb6085",
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       "relation": "association",
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-      "target": 52
+      "source": 115,
+      "target": 55
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHAnatomy": {
           "Hippocampus": true
         },
@@ -3986,13 +4319,16 @@
       },
       "evidence": "in addition, a decrease in alpha7 nAChR density in the hippocampus of patients with schizophrenia has been reported177. Similarly, a low density of alpha7 nAChRs in inbred strains of mice is associated with poor gating178. Recently, the expression of a novel variant of alpha7 nAChR, CHRNA7-2 (cholinergic receptor, nicotinic, alpha7, variant 2), was found to be reduced below control levels in the prefrontal cortex of patients with schizophrenia179.",
       "key": "43a822b312b124720ff2a0ac6589c5cd79dec59ee7cddfe08c5f6a619304a1332c01bee449b1f68b5ef550590078a8f1ce2186395814db6c056ebf3fdaac845f",
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       "relation": "decreases",
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-      "target": 81
+      "source": 115,
+      "target": 84
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     {
       "annotations": {
+        "Confidence": {
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         "TextLocation": {
           "Review": true
         }
@@ -4017,13 +4353,16 @@
       },
       "evidence": "in addition to the obvious symptoms of hallucinations and delusions, patients with schizophrenia frequently suffer from cognitive symptoms, such as the inability to focus attention173.",
       "key": "f662d5008b04ede61a1b12c168cbf729bf8e95ab194a3bf95c57484044384104ed3385e0221edbe69bb1849063d7ac4a7f8bbc05c89b55f6232ae7ee535caf5f",
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       "relation": "association",
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-      "target": 112
+      "source": 110,
+      "target": 115
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     {
       "annotations": {
+        "Confidence": {
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+        },
         "TextLocation": {
           "Review": true
         }
@@ -4048,13 +4387,16 @@
       },
       "evidence": "in addition to the obvious symptoms of hallucinations and delusions, patients with schizophrenia frequently suffer from cognitive symptoms, such as the inability to focus attention173.",
       "key": "3a9faab656923dff085fc94d9a1d60cc9e30a40f991b75c70809e3ebf64f82e29d850d80899d4b3171d565a22e275db53e26282cb1190a1d138e1a6d56ea580c",
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       "relation": "association",
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-      "target": 112
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+      "target": 115
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     {
       "annotations": {
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         "TextLocation": {
           "Review": true
         }
@@ -4079,13 +4421,16 @@
       },
       "evidence": "nAChRs are known to control sensory gating, and studies investigating the role of nAChRs in schizophrenia have focused primarily on alpha7 nAChRs. Sensory-gating deficits in patients with schizophrenia174 have been linked to chromosome 15q14, proximal to the alpha7 locus175,176.",
       "key": "2f9cc01be92f495e7250f96efc939387533fcfdfa02f4d7cf998c2d3e63646b16357e2bbecf71c86fe5cf3b5581d1753833ee7a8ea14db5c9843284214a3c056",
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       "relation": "association",
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-      "target": 112
+      "source": 55,
+      "target": 115
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Species": {
           "10090": true
         },
@@ -4113,13 +4458,16 @@
       },
       "evidence": "in addition, a decrease in alpha7 nAChR density in the hippocampus of patients with schizophrenia has been reported177. Similarly, a low density of alpha7 nAChRs in inbred strains of mice is associated with poor gating178. Recently, the expression of a novel variant of alpha7 nAChR, CHRNA7-2 (cholinergic receptor, nicotinic, alpha7, variant 2), was found to be reduced below control levels in the prefrontal cortex of patients with schizophrenia179.",
       "key": "8e760e60a4b5037933c661272932f11e4864be04e1b375af790412183da53618148872b647eff1fdbf0279c959dabc61f33969309df431efef719d6f8f3a595e",
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       "relation": "association",
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-      "target": 81
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     {
       "annotations": {
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+        },
         "TextLocation": {
           "Review": true
         }
@@ -4144,13 +4492,16 @@
       },
       "evidence": "However, the atypical antipsychotic drug clozapine normalizes auditory gating in DBA/2 mice — an effect which involves an alpha7 nAChR mechanism181.",
       "key": "ff29ac01a1daaedfe519021bd4da3bdab0d9c9c492126d6a27de6a808498dcbecfe17f7187e69014213bf74e96cf104d171f9ecb2e474b11d6abdbb85c8e1266",
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       "relation": "increases",
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-      "target": 52
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     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -4175,13 +4526,16 @@
       },
       "evidence": "However, the atypical antipsychotic drug clozapine normalizes auditory gating in DBA/2 mice — an effect which involves an alpha7 nAChR mechanism181.",
       "key": "8226874b260dccbc7bcb229cc3899ace77baf212b14467577e871f38e91510d55d4d4755f1555317a7052d2e4e5b79d12692ddd63633ab61d3d6ccdcddae8fee",
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       "relation": "association",
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-      "target": 81
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     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -4206,13 +4560,16 @@
       },
       "evidence": "Two compounds that are currently in clinical use might have direct effects on the alpha7 nAChR. The anticholinesterase inhibitor galantamine has modulatory effects on alpha7 nAChR and was reportedly beneficial for patients with schizophrenia in a case study184",
       "key": "53c5889b24635906bcae2c37a0a16d548206de1b30dfc80e475c90a4a8e1dc129bd31c20fdd18b8b5d36854f9fbd6a11c2c95e047086c2d2af9ad23c0d172f2e",
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       "relation": "regulates",
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-      "target": 81
+      "target": 84
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -4237,13 +4594,16 @@
       },
       "evidence": "Two compounds that are currently in clinical use might have direct effects on the alpha7 nAChR. The anticholinesterase inhibitor galantamine has modulatory effects on alpha7 nAChR and was reportedly beneficial for patients with schizophrenia in a case study184",
       "key": "41cfee24f1bdbf7e3ad336203f8bd580184f81dbc96797149d9c4e6cab69457e2e076155aa948909dc825248777e2ac8e5d01826452f2d9bbcd0f8c5c0ad084c",
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       "relation": "decreases",
       "source": 12,
-      "target": 112
+      "target": 115
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Schizophrenia": true
         },
@@ -4271,16 +4631,19 @@
       },
       "evidence": "Similarly, topisetron, a 5HT3 antagonist marketed outside the united States as an anti-nausea drug, also has efficacy as an alpha7 nAChR agonist and increases the inhibition of P50 auditory gating in schizophrenia185.",
       "key": "2b17b568e2e4d219b845d1cedcc2a34c6ba43bcaf7db5f21cf9ec896ca6e190719f066bb8833964af81eed9482dfb19d9906818803c8f15e1c47349a8a7d4925",
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       "object": {
         "modifier": "Activity"
       },
       "relation": "increases",
       "source": 22,
-      "target": 81
+      "target": 84
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Schizophrenia": true
         },
@@ -4308,13 +4671,16 @@
       },
       "evidence": "Similarly, topisetron, a 5HT3 antagonist marketed outside the united States as an anti-nausea drug, also has efficacy as an alpha7 nAChR agonist and increases the inhibition of P50 auditory gating in schizophrenia185.",
       "key": "6cdaa8e1aa2edd0e85c485ce24a275317dda5198df7b56a51de958b31fe81d7509965514e9b73828c1e4e6aad5a46e8ddc9ee5a5e104a33a929d2c137e08cb74",
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       "relation": "decreases",
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-      "target": 52
+      "target": 55
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -4339,7 +4705,7 @@
       },
       "evidence": "Nicotine self administration is also reduced in rats by dihydro-beta erythroidine (DHbetae), a selective alpha4beta2 antagonist199. in this context, partial agonists may substitute for the desired effects of nicotine and antagonize its reinforcing properties163,200.",
       "key": "3d613c35818dccb8b8a9f47c20400b49ea9402ba43e620b068a9070976da11d15e64a955ee30f9b581cbd1d5ea711f7b36f48a729e9745116631060eada40a4f",
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       "object": {
         "modifier": "Activity"
       },
@@ -4349,6 +4715,9 @@
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -4373,16 +4742,19 @@
       },
       "evidence": "Nicotine self administration is also reduced in rats by dihydro-beta erythroidine (DHbetae), a selective alpha4beta2 antagonist199. in this context, partial agonists may substitute for the desired effects of nicotine and antagonize its reinforcing properties163,200.",
       "key": "04f2aff3226cf1cae712cc8f461c96d6ade4add53add7a8dce207381b2a2dc018f86db3a9391310fb02fb4472f7e3b8595e735896ad4761e3b2a6b3ac6df6a15",
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       "object": {
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       },
       "relation": "decreases",
       "source": 33,
-      "target": 70
+      "target": 73
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -4407,13 +4779,16 @@
       },
       "evidence": "varenicline (Chantix/Champix; Pfizer), the most recently approved drug for smoking cessation which is now on the market, is a partial agonist at alpha4beta2 nAChRs, and a full agonist at alpha7 nAChRs (ReF. 200).",
       "key": "7e5f8b53e5218aab840bc32f9a333ebf11c782b3d8f732645c26c727bb3aa9f61656309a9244406bc899f16a41fa34a1f5347893cab052651b0e8d089b920c4b",
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       "relation": "increases",
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-      "target": 102
+      "target": 105
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -4438,16 +4813,19 @@
       },
       "evidence": "varenicline (Chantix/Champix; Pfizer), the most recently approved drug for smoking cessation which is now on the market, is a partial agonist at alpha4beta2 nAChRs, and a full agonist at alpha7 nAChRs (ReF. 200).",
       "key": "84e04564fd5f820ae4525d7190200ed2e2d86c1f9ca0adef61a0deeeee850ad814eca5d45114c575b4d38e7123e8ae35452e6e941d179ec29407451ca1cb1da3",
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       "relation": "increases",
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-      "target": 70
+      "target": 73
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "TextLocation": {
           "Review": true
         }
@@ -4472,16 +4850,19 @@
       },
       "evidence": "varenicline (Chantix/Champix; Pfizer), the most recently approved drug for smoking cessation which is now on the market, is a partial agonist at alpha4beta2 nAChRs, and a full agonist at alpha7 nAChRs (ReF. 200).",
       "key": "25bc0fbf1fa5c0d69adf73f70509c1ab2459ce43438f3e5f1af52e3298a58a5e028f0aaaa54ed2ea59fc74a278d2b66b0f620536b278192f594fb424c71e1630",
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         "modifier": "Activity"
       },
       "relation": "increases",
       "source": 24,
-      "target": 81
+      "target": 84
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "MeSHAnatomy": {
           "Corpus Striatum": true
         },
@@ -4509,13 +4890,16 @@
       },
       "evidence": "For example, as discussed above, at least five functional nAChR subtypes have been identified in dopaminergic terminals in the striatum: α4α6β2β3, α6β2β3 and α6β2, which have the highest sensitivity to nicotine, and α4β2 and α4α5β2, which are more numerous than the α6-containing subtypes, yet with lower affinity for nicotine105,106,204.",
       "key": "fedaef650b94ce70cc0ac58a1309932854211cc2e53a32987018f71d7b3db3a59ae3fd69f039c76527757d7aab812c70579bd5e3d7ada2039f52266fa8f0ceb2",
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       "relation": "association",
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-      "target": 57
+      "target": 60
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "MeSHAnatomy": {
           "Corpus Striatum": true
         },
@@ -4543,13 +4927,16 @@
       },
       "evidence": "For example, as discussed above, at least five functional nAChR subtypes have been identified in dopaminergic terminals in the striatum: α4α6β2β3, α6β2β3 and α6β2, which have the highest sensitivity to nicotine, and α4β2 and α4α5β2, which are more numerous than the α6-containing subtypes, yet with lower affinity for nicotine105,106,204.",
       "key": "ff745b685ccec3b6f09bd4da6415478ce1a18a6515366caf44dcf4523a88fb8fc60ea9f94a6a7eeed489fd2f410afa37a8ff2e676f18721575e19cafcc5cc347",
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       "relation": "association",
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-      "target": 60
+      "target": 63
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "MeSHAnatomy": {
           "Corpus Striatum": true
         },
@@ -4577,13 +4964,16 @@
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       "evidence": "For example, as discussed above, at least five functional nAChR subtypes have been identified in dopaminergic terminals in the striatum: α4α6β2β3, α6β2β3 and α6β2, which have the highest sensitivity to nicotine, and α4β2 and α4α5β2, which are more numerous than the α6-containing subtypes, yet with lower affinity for nicotine105,106,204.",
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@@ -5418,15 +5826,15 @@
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@@ -5452,15 +5860,15 @@
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@@ -5486,13 +5894,16 @@
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@@ -5662,13 +6085,16 @@
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       "evidence": "Meanwhile, a number of key antidepressants, such as fluoxetine (Prozac; lilly), sertraline (Zoloft; Pfizer), paroxetine (Paxil/Seroxat; Novo Nordisk/GlaxoSmithKline), nefazodone, nisoxetine, citalopram (Celexa/Cipramil/Cipram; H. lundbeck), nomifensine and vanoxerine211–216 were shown to inhibit neuronal nAChRs, in addition to inhibiting selective monoamine reuptake.",
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@@ -5733,13 +6162,16 @@
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       "evidence": "Meanwhile, a number of key antidepressants, such as fluoxetine (Prozac; lilly), sertraline (Zoloft; Pfizer), paroxetine (Paxil/Seroxat; Novo Nordisk/GlaxoSmithKline), nefazodone, nisoxetine, citalopram (Celexa/Cipramil/Cipram; H. lundbeck), nomifensine and vanoxerine211–216 were shown to inhibit neuronal nAChRs, in addition to inhibiting selective monoamine reuptake.",
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@@ -5767,16 +6199,19 @@
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       "evidence": "Meanwhile, a number of key antidepressants, such as fluoxetine (Prozac; lilly), sertraline (Zoloft; Pfizer), paroxetine (Paxil/Seroxat; Novo Nordisk/GlaxoSmithKline), nefazodone, nisoxetine, citalopram (Celexa/Cipramil/Cipram; H. lundbeck), nomifensine and vanoxerine211–216 were shown to inhibit neuronal nAChRs, in addition to inhibiting selective monoamine reuptake.",
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@@ -5804,13 +6239,16 @@
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       "evidence": "Meanwhile, a number of key antidepressants, such as fluoxetine (Prozac; lilly), sertraline (Zoloft; Pfizer), paroxetine (Paxil/Seroxat; Novo Nordisk/GlaxoSmithKline), nefazodone, nisoxetine, citalopram (Celexa/Cipramil/Cipram; H. lundbeck), nomifensine and vanoxerine211–216 were shown to inhibit neuronal nAChRs, in addition to inhibiting selective monoamine reuptake.",
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@@ -5838,16 +6276,19 @@
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       "evidence": "Meanwhile, a number of key antidepressants, such as fluoxetine (Prozac; lilly), sertraline (Zoloft; Pfizer), paroxetine (Paxil/Seroxat; Novo Nordisk/GlaxoSmithKline), nefazodone, nisoxetine, citalopram (Celexa/Cipramil/Cipram; H. lundbeck), nomifensine and vanoxerine211–216 were shown to inhibit neuronal nAChRs, in addition to inhibiting selective monoamine reuptake.",
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@@ -5875,13 +6316,16 @@
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       "evidence": "Meanwhile, a number of key antidepressants, such as fluoxetine (Prozac; lilly), sertraline (Zoloft; Pfizer), paroxetine (Paxil/Seroxat; Novo Nordisk/GlaxoSmithKline), nefazodone, nisoxetine, citalopram (Celexa/Cipramil/Cipram; H. lundbeck), nomifensine and vanoxerine211–216 were shown to inhibit neuronal nAChRs, in addition to inhibiting selective monoamine reuptake.",
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@@ -5909,16 +6353,19 @@
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       "evidence": "Meanwhile, a number of key antidepressants, such as fluoxetine (Prozac; lilly), sertraline (Zoloft; Pfizer), paroxetine (Paxil/Seroxat; Novo Nordisk/GlaxoSmithKline), nefazodone, nisoxetine, citalopram (Celexa/Cipramil/Cipram; H. lundbeck), nomifensine and vanoxerine211–216 were shown to inhibit neuronal nAChRs, in addition to inhibiting selective monoamine reuptake.",
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@@ -5946,13 +6393,16 @@
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       "evidence": "Meanwhile, a number of key antidepressants, such as fluoxetine (Prozac; lilly), sertraline (Zoloft; Pfizer), paroxetine (Paxil/Seroxat; Novo Nordisk/GlaxoSmithKline), nefazodone, nisoxetine, citalopram (Celexa/Cipramil/Cipram; H. lundbeck), nomifensine and vanoxerine211–216 were shown to inhibit neuronal nAChRs, in addition to inhibiting selective monoamine reuptake.",
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@@ -5980,16 +6430,19 @@
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       "evidence": "Meanwhile, a number of key antidepressants, such as fluoxetine (Prozac; lilly), sertraline (Zoloft; Pfizer), paroxetine (Paxil/Seroxat; Novo Nordisk/GlaxoSmithKline), nefazodone, nisoxetine, citalopram (Celexa/Cipramil/Cipram; H. lundbeck), nomifensine and vanoxerine211–216 were shown to inhibit neuronal nAChRs, in addition to inhibiting selective monoamine reuptake.",
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@@ -6018,13 +6471,16 @@
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       "evidence": "using in vivo proton NMR imaging, levels of choline (the rate-limiting precursor to endogeneous ACh) were shown to be increased in the brains of patients with depression217 and in the prefrontal cortex of adolescents with depression218 compared with the control group.",
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@@ -6049,7 +6505,7 @@
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       "evidence": "Also, α7- and non-α7-containing nicotinic receptors directly or indirectly (through GABAergic interneurons) modulate serotonin release in spinal cord slices230. However, the identity of the receptors that are responsible for the spinal control of nociception is currently unknown. in this process, the nicotine-induced antinociception seems to be mediated primarily by activation of calcium– calmodulin-dependent protein kinase 2, but this is not the case for supraspinal nociception control229.",
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@@ -6069,6 +6525,9 @@
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@@ -6093,12 +6552,12 @@
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       "evidence": "Also, α7- and non-α7-containing nicotinic receptors directly or indirectly (through GABAergic interneurons) modulate serotonin release in spinal cord slices230. However, the identity of the receptors that are responsible for the spinal control of nociception is currently unknown. in this process, the nicotine-induced antinociception seems to be mediated primarily by activation of calcium– calmodulin-dependent protein kinase 2, but this is not the case for supraspinal nociception control229.",
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@@ -6106,6 +6565,9 @@
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@@ -6130,16 +6592,19 @@
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@@ -6164,13 +6629,16 @@
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       "evidence": "The first nicotinic receptor ligand to undergo Phase ii clinical trials for analgesic activity was the potent Abbott compound ABT-594, a nAChR agonist that preferentially targets α4β2 (ReFS 231–235). The compound allowed for the clinical proof of concept, but could not be developed further because of adverse effects such as emesis and nausea236. As these adverse effects seemed to be attributable to the activation of the ganglionic α3β4 nAChR receptors, Abbott undertook a search for more selective α4β2 agonists, independently and in cooperation with Neurosearch.",
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diff --git a/hbp_knowledge/tardbp/monahan2016.bel.json b/hbp_knowledge/tardbp/monahan2016.bel.json
new file mode 100644
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+      "bel": "p(HGNC:OPTN, pmod(Ph, Ser, 177))",
+      "function": "Protein",
+      "id": "23d6cad42a0662bd4e2116b564946f285b7f3bf493615a3a1f335aa8063e5f0a12dfafab149f2a1a3c4fbcb7c80db594557455e78bbfdf034656a135c16c17a8",
+      "name": "OPTN",
+      "namespace": "HGNC",
+      "variants": [
+        {
+          "code": "Ser",
+          "identifier": {
+            "name": "Ph",
+            "namespace": "bel"
+          },
+          "kind": "pmod",
+          "pos": 177
+        }
+      ]
+    },
+    {
+      "bel": "p(HGNC:OPTN, var(\"?\"))",
+      "function": "Protein",
+      "id": "2d3980d88740b5514ac6cc6b3666fdfc1d895029770a06b4d55c3baec886bf1857e7021567b51d6cb3c5fbb64470a7538b5dc97b1a6b6b10cc0d638f35d86418",
+      "name": "OPTN",
+      "namespace": "HGNC",
+      "variants": [
+        {
+          "identifier": "?",
+          "kind": "hgvs"
+        }
+      ]
+    },
+    {
+      "bel": "p(HGNC:OPTN, var(\"p.Glu478Gly\"))",
+      "function": "Protein",
+      "id": "897c4ce44997af36d245efef52a585650e66b20b6b4541488f1481d2d82a4c214e60a53c92b629b39dd4e788e304ec827068cd151ad63035fb4c7b37a6ef62c0",
+      "name": "OPTN",
+      "namespace": "HGNC",
+      "variants": [
+        {
+          "identifier": "p.Glu478Gly",
+          "kind": "hgvs"
+        }
+      ]
+    },
+    {
+      "bel": "p(HGNC:OPTN, var(\"p.Glu50Lys\"))",
+      "function": "Protein",
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+      "name": "OPTN",
+      "namespace": "HGNC",
+      "variants": [
+        {
+          "identifier": "p.Glu50Lys",
+          "kind": "hgvs"
+        }
+      ]
+    },
+    {
+      "bel": "p(HGNC:PRKN)",
+      "function": "Protein",
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+      "name": "PRKN",
+      "namespace": "HGNC"
+    },
+    {
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+      "function": "Protein",
+      "id": "12b7b5a9bbd7b228839c3b87cac4922538a82738d25d378e311783e258891a00d8a1345fdfec91f6825d95c491db34c4479046002cc0d76b30d60ee11019b919",
+      "name": "RAB11A",
+      "namespace": "HGNC"
+    },
+    {
+      "bel": "p(HGNC:RAB11B)",
+      "function": "Protein",
+      "id": "dbffd9d4e1e4f250bc12902427bb8b2b62919c3c09efd493cc00d7d2355d76468eda69a8852133ae36c152a2c21610a3fd3db0e07535a09c993d261a88da586e",
+      "name": "RAB11B",
+      "namespace": "HGNC"
+    },
+    {
+      "bel": "p(HGNC:RAB1A)",
+      "function": "Protein",
+      "id": "54bc7323fecdeb3ec17a7ec03afcdf2c5746c72017167baa729f2a3fd192fd4d3c54bd306b2c5e3927627015703e9462b366500a051476951b8b0a24f353bb8d",
+      "name": "RAB1A",
+      "namespace": "HGNC"
+    },
+    {
+      "bel": "p(HGNC:RAB1B)",
+      "function": "Protein",
+      "id": "f4a5c1e5240567659cee73dbf9efe2ffb5dd5a401183db78ab130c7a09d1cd074d380f031aa9f6fd3674fd0503c4a0d4eb7ff82b2791a7c1e4d3d4e65a9ba858",
+      "name": "RAB1B",
+      "namespace": "HGNC"
+    },
+    {
+      "bel": "p(HGNC:RAB5A)",
+      "function": "Protein",
+      "id": "9ed8ca3851da7f03fc1479c502d152b264193c44ab5647c073985b3fe814db730dcb15e208232900e0d007c139d4c153488fb8cf0b3e5e90389e2a1512f2c225",
+      "name": "RAB5A",
+      "namespace": "HGNC"
+    },
+    {
+      "bel": "p(HGNC:RAB7A)",
+      "function": "Protein",
+      "id": "9f81bb674b68dcd43383a0451584f530e6946aba6c5a29a2a857e20d64e7b77059be7c6812280dfd67f357d98084559a2816e28200eabfd781add947d8f42a4f",
+      "name": "RAB7A",
+      "namespace": "HGNC"
+    },
+    {
+      "bel": "p(HGNC:SNCA)",
+      "function": "Protein",
+      "id": "4345441d1f420dc0d830377737dba9467f21b1637ed3472a697534ce698f2566b780dd52cda47c96b782242b1bcfa70e9a6147fb3bb251d1f3e1e2a0bb7038f3",
+      "name": "SNCA",
+      "namespace": "HGNC"
+    },
+    {
+      "bel": "p(HGNC:SOD1)",
+      "function": "Protein",
+      "id": "7bebe84ddc870a4ceb70828bba41ec797b861126138342942eb8124edaef94657501d4b9c4a69876b38e0fba2ff4cd5a91b560173b73723f03809ed503e90e98",
+      "name": "SOD1",
+      "namespace": "HGNC"
+    },
+    {
+      "bel": "p(HGNC:SOD1, var(\"?\"))",
+      "function": "Protein",
+      "id": "489d0def821169265e7e27a156e90cfceba86c9192b2566cc767f80dfba25e8f19d858d93667e7c8280bca5e41c8b63db9c5e590b43bc6d0b9039bcb9afbba00",
+      "name": "SOD1",
+      "namespace": "HGNC",
+      "variants": [
+        {
+          "identifier": "?",
+          "kind": "hgvs"
+        }
+      ]
+    },
+    {
+      "bel": "p(HGNC:SQSTM1)",
+      "function": "Protein",
+      "id": "8cd06d93cab875a139eae92082f11af5ad651146fabba6fa298a46f2cfda5bcb2bccf9dec8cc73067f5c11595d8eeb288f5c13f6a56dd316b54d108e5e66217d",
+      "name": "SQSTM1",
+      "namespace": "HGNC"
+    },
+    {
+      "bel": "p(HGNC:SQSTM1, var(\"?\"))",
+      "function": "Protein",
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+      "namespace": "HGNC",
+      "variants": [
+        {
+          "identifier": "?",
+          "kind": "hgvs"
+        }
+      ]
+    },
+    {
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+      "function": "Protein",
+      "id": "96048ed5d196081ca480607e30326cb8bb474db3177bfdeea242002c3c7a4681b51247acdfdd0a3ae600face27455ed0e62e9c750e79b240b8e7418150b92963",
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+      "namespace": "HGNC"
+    },
+    {
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+      "function": "Protein",
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+      "name": "TARDBP",
+      "namespace": "HGNC",
+      "variants": [
+        {
+          "kind": "frag",
+          "missing": "?"
+        },
+        {
+          "identifier": {
+            "name": "protein complex oligomerization",
+            "namespace": "GO"
+          },
+          "kind": "pmod"
+        }
+      ]
+    },
+    {
+      "bel": "p(HGNC:TARDBP, frag(\"?\"), pmod(HBP:\"protein aggregation\"))",
+      "function": "Protein",
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+      "name": "TARDBP",
+      "namespace": "HGNC",
+      "variants": [
+        {
+          "kind": "frag",
+          "missing": "?"
+        },
+        {
+          "identifier": {
+            "name": "protein aggregation",
+            "namespace": "HBP"
+          },
+          "kind": "pmod"
+        }
+      ]
+    },
+    {
+      "bel": "p(HGNC:TARDBP, pmod(HBP:\"protein aggregation\"))",
+      "function": "Protein",
+      "id": "74693b94796985c176dd314319647222588ef1a6c5958db72cb622c68b50e795f20907829176664d7fa146cb6548cb90de82a28cbc7056176eb0f9366db80783",
+      "name": "TARDBP",
+      "namespace": "HGNC",
+      "variants": [
+        {
+          "identifier": {
+            "name": "protein aggregation",
+            "namespace": "HBP"
+          },
+          "kind": "pmod"
+        }
+      ]
+    },
+    {
+      "bel": "p(HGNC:TARDBP, var(\"?\"))",
+      "function": "Protein",
+      "id": "b09c7da55da5317df3a7af6133d32eb6796debcefa6ffa2b89bde80f13ae410a3bb6bbedc5dc3a3cdf6f00fbcc005ea6a9602784696780c46ea7a42b46708402",
+      "name": "TARDBP",
+      "namespace": "HGNC",
+      "variants": [
+        {
+          "identifier": "?",
+          "kind": "hgvs"
+        }
+      ]
+    },
+    {
+      "bel": "p(HGNC:TBK1)",
+      "function": "Protein",
+      "id": "f47324f7cb1a2f60144d4bd700e88b416bc18f129d19354e4a5f1be5a23054e8397da2a1cf4eee18b52286aeb373c31ffe91dae4b754abd816d22ee267277619",
+      "name": "TBK1",
+      "namespace": "HGNC"
+    },
+    {
+      "bel": "p(HGNC:TIA1)",
+      "function": "Protein",
+      "id": "1e09d03a1d49636c0a36c943ac875de40aff08193ed16da5cd248cfb8110836016e3f7efb21197b6fa8ed82229e5b49493b4c10e249f3bfe672aeeea83526781",
+      "name": "TIA1",
+      "namespace": "HGNC"
+    },
+    {
+      "bel": "p(HGNC:UBQLN2)",
+      "function": "Protein",
+      "id": "6c71f3b637844882cbe5876a99d86b275c4c520515c322345b8a26edbae8a52103272d3c5f3e91d66b36908cdaae558cb71a31b00310a67ac7da8ad85cd2f551",
+      "name": "UBQLN2",
+      "namespace": "HGNC"
+    },
+    {
+      "bel": "p(HGNC:UBQLN2, var(\"?\"))",
+      "function": "Protein",
+      "id": "80315cb8e9ad0b98a1be99b7dd7f61b72f00815edfd9e233c4021bf113a28eab459f4f09e28fb11c41c0d3bd76061055f87e727193fde56fc63698d7f838f3ce",
+      "name": "UBQLN2",
+      "namespace": "HGNC",
+      "variants": [
+        {
+          "identifier": "?",
+          "kind": "hgvs"
+        }
+      ]
+    },
+    {
+      "bel": "p(HGNC:VCP)",
+      "function": "Protein",
+      "id": "307857d01a7f0dadc6a2107652397cb1357840ad198966860f655229f5b1f374eef2ce0e8cf74787599054138963ac8cd6613577cbf8002da0b34a9a25494da5",
+      "name": "VCP",
+      "namespace": "HGNC"
+    },
+    {
+      "bel": "p(INTERPRO:\"Prion/Doppel protein, beta-ribbon domain\")",
+      "function": "Protein",
+      "id": "1e355dad42bcdacbafac227b2b03adf402f754b90b6f0484c588cf5daf588f049eae728aeefd4280a733e5ff0a44448ba621ab0e7f395889cfbef81d4a5507ec",
+      "name": "Prion/Doppel protein, beta-ribbon domain",
+      "namespace": "INTERPRO"
+    },
+    {
+      "bel": "p(MESH:Proteins)",
+      "function": "Protein",
+      "id": "20fec9748aca569e46ee2703620f548aece50dde1dd6518d2833a58da6a5fc28e70918b127d515943ad659b626fa533df7854b4887e2cab8d3a7af00dea602d0",
+      "name": "Proteins",
+      "namespace": "MESH"
+    },
+    {
+      "bel": "p(MESH:Proteins, pmod(HBP:misfolded))",
+      "function": "Protein",
+      "id": "7defcfb58615925d9b5ce72e9147cd763b639190208c4a4b3e935c69b5cad27da06ee1afdccb7eb1a3290b004e453ef4271a4952c5ab34bf5b73cb22c12103b8",
+      "name": "Proteins",
+      "namespace": "MESH",
+      "variants": [
+        {
+          "identifier": {
+            "name": "misfolded",
+            "namespace": "HBP"
+          },
+          "kind": "pmod"
+        }
+      ]
+    },
+    {
+      "bel": "p(MESH:Proteins, pmod(Ub))",
+      "function": "Protein",
+      "id": "eec7827eaf9a8c63740d8caddb124f2f9b407f08cff90cff9b204cb3886d1f03dbc8af83ba8a0c83a87b0e7d0803537125ed0137e951a2d38e656efeac1ba0f2",
+      "name": "Proteins",
+      "namespace": "MESH",
+      "variants": [
+        {
+          "identifier": {
+            "name": "Ub",
+            "namespace": "bel"
+          },
+          "kind": "pmod"
+        }
+      ]
+    },
+    {
+      "bel": "path(HBP:\"mitochondrial dysfunction\")",
+      "function": "Pathology",
+      "id": "290f620a8ca62af5c329ceed61c52205bedef0b2ba17347a57e3e26dec8a12aac110be32f0fda6061476b9745f37c4e21a45fe75b71d678f32dc6ccdf5362edd",
+      "name": "mitochondrial dysfunction",
+      "namespace": "HBP"
+    },
+    {
+      "bel": "path(HBP:Neurodegeneration)",
+      "function": "Pathology",
+      "id": "1e32e61de82d42fab0a4abcd15d32d3fa5b2f65883b2d99c828d4019591a465f11cd017eefe918bc5d066b7f3cef9d21f4e0988e5c23cc2c135313815478263a",
+      "name": "Neurodegeneration",
+      "namespace": "HBP"
+    },
+    {
+      "bel": "path(MESH:\"Amyotrophic Lateral Sclerosis\")",
+      "function": "Pathology",
+      "id": "5e56d7b5172af0ae281c2f920b132d7b2263ae5eff7b0f1c9a22347914d8c169c79314aa7738c7e68cf75fac198de894bff58cb9fd4a0cb95ab434310fa07daa",
+      "name": "Amyotrophic Lateral Sclerosis",
+      "namespace": "MESH"
+    },
+    {
+      "bel": "path(MESH:\"Glaucoma, Open-Angle\")",
+      "function": "Pathology",
+      "id": "f87bda240bfe48c91395d64ffb10d135f216b7a7e1347d7b543accb0801c33f03840dcbac302d5709ff9217cab864f6215d7ed5c9cf2c1062893e6bdfa51560f",
+      "name": "Glaucoma, Open-Angle",
+      "namespace": "MESH"
+    },
+    {
+      "bel": "path(MESH:\"Liver Diseases\")",
+      "function": "Pathology",
+      "id": "d3586f9b49ff9c9cb4adee7ac4bae55923c4c165695f88fb59967ea24e1efbfc6d7ef39dcd5d59642df2a7b893db5c3f7bef664e5e34b520711dc0c1c1188760",
+      "name": "Liver Diseases",
+      "namespace": "MESH"
+    },
+    {
+      "bel": "path(MESH:\"Motor Neuron Disease\")",
+      "function": "Pathology",
+      "id": "5bcd3747717338775c3f15a99faf9be4315edf3e6bf305ab947d7d0070052dbab6a2eb7a72c7103fad592eefaea94e15155dc784feccb9e6edd4a3ab0d75d341",
+      "name": "Motor Neuron Disease",
+      "namespace": "MESH"
+    },
+    {
+      "bel": "path(MESH:\"Parkinson Disease\")",
+      "function": "Pathology",
+      "id": "d7f039170f83b3fcc27595412f3b0352cd1fe95f8481a2b1144ce311ac81bb5f0087a0a7e682f498d193e00b8e8fb29908a6e0b8e23da5ef349aeeb4723b9be0",
+      "name": "Parkinson Disease",
+      "namespace": "MESH"
+    },
+    {
+      "bel": "path(MESH:\"Prion Diseases\")",
+      "function": "Pathology",
+      "id": "77a6a3bd7d6db2c0a0ee8814c1b00ee33162c12751e9b0f6ea90968e7e3d6756ac5b8a658b4066cc6ecbb67d7dc949f29efd5f438ba1c2bb7b638209c2420bb5",
+      "name": "Prion Diseases",
+      "namespace": "MESH"
+    },
+    {
+      "bel": "path(MESH:Death)",
+      "function": "Pathology",
+      "id": "7277084fc3a1b0e377445b9052c02ac77fa754286debbdf8cfb948a489cda1bbfabab27531dc1a81026f92c278772709598e2982fd523d37d8d9b888532f8d63",
+      "name": "Death",
+      "namespace": "MESH"
+    }
+  ]
+}
\ No newline at end of file
diff --git a/hbp_knowledge/tardbp/xia2016.bel.json b/hbp_knowledge/tardbp/xia2016.bel.json
new file mode 100644
index 000000000..73364e71f
--- /dev/null
+++ b/hbp_knowledge/tardbp/xia2016.bel.json
@@ -0,0 +1,5622 @@
+{
+  "directed": true,
+  "graph": {
+    "annotation_list": {},
+    "annotation_pattern": {
+      "Species": "^\\d+$"
+    },
+    "annotation_url": {
+      "CellLine": "https://arty.scai.fraunhofer.de/artifactory/bel/annotation/cell-line/cell-line-20170511.belanno",
+      "CellStructure": "https://arty.scai.fraunhofer.de/artifactory/bel/annotation/cell-structure/cell-structure-20170511.belanno"
+    },
+    "document_metadata": {
+      "authors": "Sandra Spalek",
+      "contact": "charles.hoyt@scai.fraunhofer.de",
+      "copyright": "Copyright © 2019 Fraunhofer Institute SCAI, All rights reserved.",
+      "description": "",
+      "licenses": "CC BY 4.0",
+      "name": "TDP-43 loss of function increases TFEB activity and blocks autophagosome–lysosome fusion",
+      "version": "1.0.0"
+    },
+    "namespace_pattern": {},
+    "namespace_url": {
+      "CHEBI": "https://raw.githubusercontent.com/pharmacome/terminology/efc856fb009a39e4d284269a6801f79ed3d3cf56/external/chebi-names.belns",
+      "GO": "https://raw.githubusercontent.com/pharmacome/terminology/efc856fb009a39e4d284269a6801f79ed3d3cf56/external/go-names.belns",
+      "HGNC": "https://raw.githubusercontent.com/pharmacome/terminology/efc856fb009a39e4d284269a6801f79ed3d3cf56/external/hgnc-names.belns",
+      "HGNCGENEFAMILY": "https://raw.githubusercontent.com/pharmacome/terminology/efc856fb009a39e4d284269a6801f79ed3d3cf56/external/hgnc.genefamily-names.belns",
+      "MESH": "https://raw.githubusercontent.com/pharmacome/terminology/efc856fb009a39e4d284269a6801f79ed3d3cf56/external/mesh-names.belns"
+    },
+    "namespaces_uncached": [],
+    "path": "tardbp/xia2016.bel",
+    "pybel_version": "0.13.3-dev"
+  },
+  "links": [
+    {
+      "citation": {
+        "authors": [
+          "Chen D",
+          "Fu C",
+          "Gao F",
+          "Han J",
+          "Hao Z",
+          "Hu Q",
+          "Ren H",
+          "Wang G",
+          "Wang H",
+          "Xia Q",
+          "Ying Z"
+        ],
+        "date": "2016-01-18",
+        "first": "Xia Q",
+        "last": "Wang G",
+        "name": "The EMBO journal",
+        "pages": "121-42",
+        "reference": "26702100",
+        "title": "TDP-43 loss of function increases TFEB activity and blocks autophagosome-lysosome fusion.",
+        "type": "PubMed",
+        "volume": "35"
+      },
+      "evidence": "Given that ALP, the critical cellular quality control system, is involved in ALS (Ling et al, 2013) and that TFEB is a master regulator of ALP and is functionally associated with neurodegenerative diseases as recently reported (Sardiello et al, 2009; Settembre et al, 2011; Tsunemi et al, 2012; Decressac et al, 2013; Spampanato et al, 2013), we wonder whether TDP-43 is able to regulate TFEB",
+      "key": "c5ddd9858221f38d5d9b3ae7372e945ddd7823236e4fc0187b06bfaa57febe9b780e64e9e3c1744d4cf6f3445157a1606d2116dc436f8ef53fc877abe3158429",
+      "line": 86,
+      "relation": "association",
+      "source": 12,
+      "target": 70
+    },
+    {
+      "citation": {
+        "authors": [
+          "Chen D",
+          "Fu C",
+          "Gao F",
+          "Han J",
+          "Hao Z",
+          "Hu Q",
+          "Ren H",
+          "Wang G",
+          "Wang H",
+          "Xia Q",
+          "Ying Z"
+        ],
+        "date": "2016-01-18",
+        "first": "Xia Q",
+        "last": "Wang G",
+        "name": "The EMBO journal",
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+        "reference": "26702100",
+        "title": "TDP-43 loss of function increases TFEB activity and blocks autophagosome-lysosome fusion.",
+        "type": "PubMed",
+        "volume": "35"
+      },
+      "evidence": "In addition, formation of autophagosomes (yellow) was also enhanced in TDP-43-depleted cells treated with bafilomycin A1 (Fig 6D and E).",
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+        "authors": [
+          "Chen D",
+          "Fu C",
+          "Gao F",
+          "Han J",
+          "Hao Z",
+          "Hu Q",
+          "Ren H",
+          "Wang G",
+          "Wang H",
+          "Xia Q",
+          "Ying Z"
+        ],
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+        "first": "Xia Q",
+        "last": "Wang G",
+        "name": "The EMBO journal",
+        "pages": "121-42",
+        "reference": "26702100",
+        "title": "TDP-43 loss of function increases TFEB activity and blocks autophagosome-lysosome fusion.",
+        "type": "PubMed",
+        "volume": "35"
+      },
+      "evidence": "Importantly, we observed significant decreased LC3/LAMP1 co-localization (autophagosome–lysosome fusion) in dynactin 1-deficient cells, and loss of TDP-43 was not able to decrease LC3/LAMP1 co-localization in dynactin 1-deficient cells (Fig 7D and E).",
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+        "authors": [
+          "Chen D",
+          "Fu C",
+          "Gao F",
+          "Han J",
+          "Hao Z",
+          "Hu Q",
+          "Ren H",
+          "Wang G",
+          "Wang H",
+          "Xia Q",
+          "Ying Z"
+        ],
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+        "first": "Xia Q",
+        "last": "Wang G",
+        "name": "The EMBO journal",
+        "pages": "121-42",
+        "reference": "26702100",
+        "title": "TDP-43 loss of function increases TFEB activity and blocks autophagosome-lysosome fusion.",
+        "type": "PubMed",
+        "volume": "35"
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+      "evidence": "Meanwhile, retransfection of dynactin 1 could increase LC3/LAMP1 co-localization in TDP-43-depleted cells (Fig 7F and G), indicating that dynactin 1 deficiency contributes to the impairment of autophagosome–lysosome fusion in TDP-43-depleted cells",
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+          "kind": "hgvs"
+        },
+        {
+          "identifier": "p.Lys11Ala",
+          "kind": "hgvs"
+        }
+      ]
+    },
+    {
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+      "name": "TFEB",
+      "namespace": "HGNC",
+      "variants": [
+        {
+          "identifier": "p.Ser211Ala",
+          "kind": "hgvs"
+        }
+      ]
+    },
+    {
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+      "name": "14-3-3 phospho-serine/phospho-threonine binding proteins",
+      "namespace": "HGNCGENEFAMILY"
+    },
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+      "namespace": "HGNCGENEFAMILY"
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+      "name": "Cathepsins",
+      "namespace": "HGNCGENEFAMILY"
+    },
+    {
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+      "function": "Pathology",
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+      "name": "Amyotrophic Lateral Sclerosis",
+      "namespace": "MESH"
+    },
+    {
+      "bel": "path(MESH:\"Neurodegenerative Diseases\")",
+      "function": "Pathology",
+      "id": "95863a6d11beb3bd993523e1c8c7e210d281b0c092553f6a4cf27dd3ecf2fa51b49c5056b8aed6f7ac7c82f99101c34bc9fc0afc3dce117fe011d159ba9e4c89",
+      "name": "Neurodegenerative Diseases",
+      "namespace": "MESH"
+    },
+    {
+      "bel": "path(MESH:Starvation)",
+      "function": "Pathology",
+      "id": "def4b2b2f8f12ec04a5a7ada344d57efed9547211133e8ca8673d264f9d8eaded37af479e4a7853c17aabc6bc66fd425d9591ed363c00a3ba326f695341b6533",
+      "name": "Starvation",
+      "namespace": "MESH"
+    },
+    {
+      "bel": "r(HGNC:ATG5)",
+      "function": "RNA",
+      "id": "6541c96a65c2d8ad6f3248d4fccf928d27b0d5e7d84f7c84de68a63c50324c37647af5bf8d079fa8ad6bad14b574ea2168b8831d7fed6ca600b6c3409c9bed30",
+      "name": "ATG5",
+      "namespace": "HGNC"
+    },
+    {
+      "bel": "r(HGNC:ATG9B)",
+      "function": "RNA",
+      "id": "c6ff518dee451e8407e81ec5a904b6f7a25a386e055fa83ffc87d7b4332f57f3e7470eab2a57e88fb34bcbe704a092a3fcddf3367e1605c66d61f5868715936b",
+      "name": "ATG9B",
+      "namespace": "HGNC"
+    },
+    {
+      "bel": "r(HGNC:BECN1)",
+      "function": "RNA",
+      "id": "3b092901566cda0f6e31876f3addfc36e16011e998f65799877207c443007dc9cfd072d41e1a96a56f1ce5ed7f4b401fbe4d32cd09a7486d99467970249e7066",
+      "name": "BECN1",
+      "namespace": "HGNC"
+    },
+    {
+      "bel": "r(HGNC:LAMP1)",
+      "function": "RNA",
+      "id": "8de6c5dbd3492eaf40b3a7178ce887f19921d831d864277da746092687158ec326dd7c9d5884697e767e8136e8cfbf80f519c4f80863991884e0e4b6c75dea52",
+      "name": "LAMP1",
+      "namespace": "HGNC"
+    },
+    {
+      "bel": "r(HGNC:RPTOR)",
+      "function": "RNA",
+      "id": "ca0523ff4578c14757d6818a3a14d9cff3205e5822469e49fc5e5bc159129e0316693d7dd80c8459401485b4506d5ace31542af08102ec98787368b387fa4ae2",
+      "name": "RPTOR",
+      "namespace": "HGNC"
+    }
+  ]
+}
\ No newline at end of file
diff --git a/hbp_knowledge/tau/kanaan2011.bel.json b/hbp_knowledge/tau/kanaan2011.bel.json
index ad8a77888..959710c6e 100644
--- a/hbp_knowledge/tau/kanaan2011.bel.json
+++ b/hbp_knowledge/tau/kanaan2011.bel.json
@@ -4,16 +4,9 @@
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       "MeSHAnatomy": "https://arty.scai.fraunhofer.de/artifactory/bel/annotation/mesh-anatomy/mesh-anatomy-20170511.belanno",
-      "MeSHDisease": "https://arty.scai.fraunhofer.de/artifactory/bel/annotation/mesh-diseases/mesh-diseases-20170511.belanno",
-      "Subgraph": "https://arty.scai.fraunhofer.de/artifactory/bel/annotation/neurommsig/neurommsig-1.0.3.belanno",
-      "TextLocation": "https://arty.scai.fraunhofer.de/artifactory/bel/annotation/text-location/text-location-1.0.1.belanno"
+      "MeSHDisease": "https://arty.scai.fraunhofer.de/artifactory/bel/annotation/mesh-diseases/mesh-diseases-20170511.belanno"
     },
     "document_metadata": {
       "authors": "Lingling Xu",
@@ -22,26 +15,14 @@
       "description": "",
       "licenses": "CC BY 4.0",
       "name": "Pathogenic forms of tau inhibit kinesin-dependent axonal transport through a mechanism involving activation of axonal phosphotransferases.",
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-    "namespace_pattern": {
-      "DNSNP": "rs[0-9]+",
-      "HBP": ".*",
-      "TAXONOMY": "^\\d+$"
+      "version": "1.0.1"
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     "namespace_url": {
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-      "INTERPRO": "https://arty.scai.fraunhofer.de/artifactory/bel/namespace/interpro/interpro-20170731.belns",
-      "MESH": "https://raw.githubusercontent.com/pharmacome/terminology/b46b65c3da259b6e86026514dfececab7c22a11b/external/mesh-names.belns",
-      "MGI": "https://arty.scai.fraunhofer.de/artifactory/bel/namespace/mgi-mouse-genes/mgi-mouse-genes-20170725.belns",
-      "NCBIGENE": "https://raw.githubusercontent.com/pharmacome/terminology/b46b65c3da259b6e86026514dfececab7c22a11b/external/entrez.belns",
-      "RGD": "https://arty.scai.fraunhofer.de/artifactory/bel/namespace/rgd-rat-genes/rgd-rat-genes-20170725.belns"
+      "GO": "https://raw.githubusercontent.com/pharmacome/terminology/c328ad964c08967a0417a887510b97b965a62fa5/external/go-names.belns",
+      "HBP": "https://raw.githubusercontent.com/pharmacome/terminology/9ebb3f418f589bca43c89915f5c29cd5b3689d0c/export/hbp-names.belns",
+      "HGNC": "https://raw.githubusercontent.com/pharmacome/terminology/c328ad964c08967a0417a887510b97b965a62fa5/external/hgnc-names.belns",
+      "MESH": "https://raw.githubusercontent.com/pharmacome/terminology/c328ad964c08967a0417a887510b97b965a62fa5/external/mesh-names.belns"
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     "namespaces_uncached": [],
     "path": "tau/kanaan2011.bel",
@@ -49,6 +30,15 @@
   },
   "links": [
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Cytoplasm": true,
+          "Neurons": true
+        }
+      },
       "citation": {
         "authors": [
           "Andreadis A",
@@ -72,23 +62,44 @@
         "type": "PubMed",
         "volume": "31"
       },
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       "relation": "causesNoChange",
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+      "source": 12,
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+      "source": 12,
+      "target": 14
+    },
+    {
+      "annotations": {
+        "Confidence": {
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+        },
+        "MeSHAnatomy": {
+          "Cytoplasm": true,
+          "Neurons": true
+        }
+      },
       "citation": {
         "authors": [
           "Andreadis A",
@@ -112,14 +123,19 @@
         "type": "PubMed",
         "volume": "31"
       },
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+      "evidence": "perfusion of full-length WT tau monomers (2 􏰊M) (Fig. 1 A) had no effect on FAT in squid axoplasm (Fig. 2 A), while 6D and 6P tau monomers (2 􏰊M) significantly inhibited anterograde FAT when compared with WT tau monomer (Fig. 2 B, C) or buffer controls (data not shown).",
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       "relation": "decreases",
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-      "target": 2
+      "source": 5,
+      "target": 1
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     {
+      "annotations": {
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+        }
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       "citation": {
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           "Andreadis A",
@@ -143,14 +159,58 @@
         "type": "PubMed",
         "volume": "31"
       },
-      "evidence": "Together, these data demonstrate that, as posited for aggregated tau (LaPointe et al., 2009), short N-terminal isoforms of tau inhibit anterograde FAT by a mech- anism involving activation of PP1 and GSK3 that is independent of microtubule binding.",
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+      "evidence": "Together, these data demonstrate that, as posited for aggregated tau (LaPointe et al., 2009), short N-terminal isoforms of tau inhibit anterograde FAT by a mechanism involving activation of PP1 and GSK3 that is independent of microtubule binding.",
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       "relation": "decreases",
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+      "source": 5,
+      "target": 1
+    },
+    {
+      "annotations": {
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+        }
+      },
+      "citation": {
+        "authors": [
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+          "Binder LI",
+          "Brady ST",
+          "Fu Y",
+          "Kanaan NM",
+          "LaPointe NE",
+          "Morfini GA",
+          "Patterson KR",
+          "Pigino GF",
+          "Song Y"
+        ],
+        "date": "2011-07-06",
+        "first": "Kanaan NM",
+        "last": "Binder LI",
+        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
+        "pages": "9858-68",
+        "reference": "21734277",
+        "title": "Pathogenic forms of tau inhibit kinesin-dependent axonal transport through a mechanism involving activation of axonal phosphotransferases.",
+        "type": "PubMed",
+        "volume": "31"
+      },
+      "evidence": "As observed with Δ2–18 tau aggregates (LaPointe et al., 2009), monomeric Δ2–18 6D tau showed no effect on FAT (Fig. 4 A, D), demonstrating that PAD is necessary for 6D tau- mediated inhibition of anterograde FAT.",
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+      "line": 107,
+      "relation": "decreases",
+      "source": 5,
+      "subject": {
+        "modifier": "Activity"
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+      "target": 1
     },
     {
+      "annotations": {
+        "Confidence": {
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+        }
+      },
       "citation": {
         "authors": [
           "Andreadis A",
@@ -175,13 +235,18 @@
         "volume": "31"
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       "evidence": " Neither 6D nor 6P tau (Fig. 2D) had an effect on retrograde FAT",
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       "relation": "causesNoChange",
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+      "source": 5,
+      "target": 3
     },
     {
+      "annotations": {
+        "Confidence": {
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+        }
+      },
       "citation": {
         "authors": [
           "Andreadis A",
@@ -205,17 +270,22 @@
         "type": "PubMed",
         "volume": "31"
       },
-      "evidence": "Together, these data demonstrate that, as posited for aggregated tau (LaPointe et al., 2009), short N-terminal isoforms of tau inhibit anterograde FAT by a mech- anism involving activation of PP1 and GSK3 that is independent of microtubule binding.",
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+      "evidence": "Together, these data demonstrate that, as posited for aggregated tau (LaPointe et al., 2009), short N-terminal isoforms of tau inhibit anterograde FAT by a mechanism involving activation of PP1 and GSK3 that is independent of microtubule binding.",
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       "object": {
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       "relation": "increases",
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-      "target": 18
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     },
     {
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       "citation": {
         "authors": [
           "Andreadis A",
@@ -239,23 +309,62 @@
         "type": "PubMed",
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-      "evidence": "Together, these data demonstrate that, as posited for aggregated tau (LaPointe et al., 2009), short N-terminal isoforms of tau inhibit anterograde FAT by a mech- anism involving activation of PP1 and GSK3 that is independent of microtubule binding.",
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+      "evidence": "Together, these data demonstrate that, as posited for aggregated tau (LaPointe et al., 2009), short N-terminal isoforms of tau inhibit anterograde FAT by a mechanism involving activation of PP1 and GSK3 that is independent of microtubule binding.",
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+        "MeSHAnatomy": {
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+          "Neurons": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Andreadis A",
+          "Binder LI",
+          "Brady ST",
+          "Fu Y",
+          "Kanaan NM",
+          "LaPointe NE",
+          "Morfini GA",
+          "Patterson KR",
+          "Pigino GF",
+          "Song Y"
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+        "first": "Kanaan NM",
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+        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
+        "pages": "9858-68",
+        "reference": "21734277",
+        "title": "Pathogenic forms of tau inhibit kinesin-dependent axonal transport through a mechanism involving activation of axonal phosphotransferases.",
+        "type": "PubMed",
+        "volume": "31"
+      },
+      "evidence": "perfusion of full-length WT tau monomers (2 􏰊M) (Fig. 1 A) had no effect on FAT in squid axoplasm (Fig. 2 A), while 6D and 6P tau monomers (2 􏰊M) significantly inhibited anterograde FAT when compared with WT tau monomer (Fig. 2 B, C) or buffer controls (data not shown).",
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       "source": 6,
-      "target": 7
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     },
     {
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+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Andreadis A",
@@ -279,17 +388,19 @@
         "type": "PubMed",
         "volume": "31"
       },
-      "evidence": "As observed with 􏰁2–18 tau aggregates (LaPointe et al., 2009), monomeric 􏰁2–18 6D tau showed no effect on FAT (Fig. 4 A, D), demonstrating that PAD is necessary for 6D tau- mediated inhibition of anterograde FAT.",
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-      "line": 88,
-      "relation": "association",
+      "evidence": " Neither 6D nor 6P tau (Fig. 2D) had an effect on retrograde FAT",
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-        "modifier": "Activity"
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-      "target": 7
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     {
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       "citation": {
         "authors": [
           "Andreadis A",
@@ -313,14 +424,22 @@
         "type": "PubMed",
         "volume": "31"
       },
-      "evidence": "As observed with 􏰁2–18 tau aggregates (LaPointe et al., 2009), monomeric 􏰁2–18 6D tau showed no effect on FAT (Fig. 4 A, D), demonstrating that PAD is necessary for 6D tau- mediated inhibition of anterograde FAT.",
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-      "relation": "association",
-      "source": 2,
-      "target": 7
+      "evidence": "Together, these data demonstrate that, as posited for aggregated tau (LaPointe et al., 2009), short N-terminal isoforms of tau inhibit anterograde FAT by a mechanism involving activation of PP1 and GSK3 that is independent of microtubule binding.",
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     {
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+        "Confidence": {
+          "Medium": true
+        }
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       "citation": {
         "authors": [
           "Andreadis A",
@@ -344,14 +463,22 @@
         "type": "PubMed",
         "volume": "31"
       },
-      "evidence": "perfusion of full-length WT tau monomers (2 􏰊M) (Fig. 1 A) had no effect on FAT in squid axoplasm (Fig. 2 A), while 6D and 6P tau monomers (2 􏰊M) significantly inhibited anterograde FAT when compared with WT tau monomer (Fig. 2 B, C) or buf- fer controls (data not shown).",
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+      "evidence": " Collectively, these data indicate that PAD is both necessary and sufficient to inhibit an-terograde FAT by activating the PP1–GSK3 cascade.",
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       "relation": "decreases",
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     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
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       "citation": {
         "authors": [
           "Andreadis A",
@@ -375,14 +502,22 @@
         "type": "PubMed",
         "volume": "31"
       },
-      "evidence": " Neither 6D nor 6P tau (Fig. 2D) had an effect on retrograde FAT",
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-      "line": 78,
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-      "target": 4
+      "evidence": "Together, these data demonstrate that, as posited for aggregated tau (LaPointe et al., 2009), short N-terminal isoforms of tau inhibit anterograde FAT by a mechanism involving activation of PP1 and GSK3 that is independent of microtubule binding.",
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     {
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+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "Andreadis A",
@@ -406,17 +541,22 @@
         "type": "PubMed",
         "volume": "31"
       },
-      "evidence": "Together, these data demonstrate that, as posited for aggregated tau (LaPointe et al., 2009), short N-terminal isoforms of tau inhibit anterograde FAT by a mech- anism involving activation of PP1 and GSK3 that is independent of microtubule binding.",
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-      "line": 84,
+      "evidence": "Again, coperfusion of the PAD peptide with either I-2 (50 nM) (Fig. 5A) or ING-135 (100 nM) (Fig. 5B) completely prevented anterograde FAT inhibition. ",
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       "relation": "decreases",
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       "subject": {
         "modifier": "Activity"
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     {
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       "citation": {
         "authors": [
           "Andreadis A",
@@ -440,17 +580,22 @@
         "type": "PubMed",
         "volume": "31"
       },
-      "evidence": "Together, these data demonstrate that, as posited for aggregated tau (LaPointe et al., 2009), short N-terminal isoforms of tau inhibit anterograde FAT by a mech- anism involving activation of PP1 and GSK3 that is independent of microtubule binding.",
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-      "line": 85,
+      "evidence": " Collectively, these data indicate that PAD is both necessary and sufficient to inhibit an-terograde FAT by activating the PP1–GSK3 cascade.",
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       "relation": "decreases",
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       "subject": {
         "modifier": "Activity"
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     {
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       "citation": {
         "authors": [
           "Andreadis A",
@@ -474,17 +619,22 @@
         "type": "PubMed",
         "volume": "31"
       },
-      "evidence": "As observed with 􏰁2–18 tau aggregates (LaPointe et al., 2009), monomeric 􏰁2–18 6D tau showed no effect on FAT (Fig. 4 A, D), demonstrating that PAD is necessary for 6D tau- mediated inhibition of anterograde FAT.",
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-      "line": 88,
+      "evidence": "As observed with Δ2–18 tau aggregates (LaPointe et al., 2009), monomeric Δ2–18 6D tau showed no effect on FAT (Fig. 4 A, D), demonstrating that PAD is necessary for 6D tau- mediated inhibition of anterograde FAT.",
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       "object": {
         "modifier": "Activity"
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-      "relation": "association",
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-      "target": 6
+      "relation": "increases",
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+      "target": 5
     },
     {
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+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "Andreadis A",
@@ -508,14 +658,19 @@
         "type": "PubMed",
         "volume": "31"
       },
-      "evidence": "As observed with 􏰁2–18 tau aggregates (LaPointe et al., 2009), monomeric 􏰁2–18 6D tau showed no effect on FAT (Fig. 4 A, D), demonstrating that PAD is necessary for 6D tau- mediated inhibition of anterograde FAT.",
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-      "line": 89,
-      "relation": "association",
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-      "target": 2
+      "evidence": "The PAD peptide selectively inhibited anterograde FAT (Fig. 4 B, D), but not retrograde FAT (Fig. 4B,E).",
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     {
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+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "Andreadis A",
@@ -539,14 +694,19 @@
         "type": "PubMed",
         "volume": "31"
       },
-      "evidence": "The PAD peptide selectively in- hibited anterograde FAT (Fig. 4 B, D), but not retrograde FAT (Fig. 4B,E).",
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-      "relation": "increases",
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-      "target": 2
+      "evidence": " Collectively, these data indicate that PAD is both necessary and sufficient to inhibit an-terograde FAT by activating the PP1–GSK3 cascade.",
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+      "relation": "decreases",
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     {
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+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "Andreadis A",
@@ -570,14 +730,19 @@
         "type": "PubMed",
         "volume": "31"
       },
-      "evidence": " Collectively, these data indicate that PAD is both necessary and sufficient to inhibit an- terograde FAT by activating the PP1–GSK3 cascade.",
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-      "relation": "increases",
-      "source": 7,
-      "target": 2
+      "evidence": "Together, these data indicate that disease- associated modifications and mutations in tau that increase exposure of PAD promote activation of the PP1–GSK3 pathway and inhibition of anterograde FAT.",
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     {
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+        }
+      },
       "citation": {
         "authors": [
           "Andreadis A",
@@ -601,14 +766,23 @@
         "type": "PubMed",
         "volume": "31"
       },
-      "evidence": "The PAD peptide selectively in- hibited anterograde FAT (Fig. 4 B, D), but not retrograde FAT (Fig. 4B,E).",
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+      "evidence": "The PAD peptide selectively inhibited anterograde FAT (Fig. 4 B, D), but not retrograde FAT (Fig. 4B,E).",
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       "relation": "causesNoChange",
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+      "target": 3
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Cytoplasm": true,
+          "Neurons": true
+        }
+      },
       "citation": {
         "authors": [
           "Andreadis A",
@@ -633,13 +807,22 @@
         "volume": "31"
       },
       "evidence": "P-c-Jun was dephosphorylated to a greater extent in PAD peptide-perfused axoplasms than their scrambled peptide- perfused counterpart (Fig. 5F ), suggesting that the PAD peptide induced activation of endogenous axoplasmic phosphatases.",
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       "relation": "decreases",
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+      "target": 11
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Cytoplasm": true,
+          "Neurons": true
+        }
+      },
       "citation": {
         "authors": [
           "Andreadis A",
@@ -663,17 +846,26 @@
         "type": "PubMed",
         "volume": "31"
       },
-      "evidence": "A trend of elevated GSK3 activity (􏰈32%) relative to PKC activity ( p 􏰄 0.28, paired t test; n 􏰄 3) was observed for axoplasms incubated with the PAD peptide (mean 􏰄 4.9 􏰉 2.5), compared with those incubated with scram- bled peptide (mean 􏰄 3.7 􏰉 1.7), which supports the results from vesicle motility assays. ",
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-      "line": 108,
+      "evidence": "P-c-Jun was dephosphorylated to a greater extent in PAD peptide-perfused axoplasms than their scrambled peptide- perfused counterpart (Fig. 5F ), suggesting that the PAD peptide induced activation of endogenous axoplasmic phosphatases.",
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       "object": {
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-      "target": 17
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+      "source": 9,
+      "target": 18
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Cytoplasm": true,
+          "Neurons": true
+        }
+      },
       "citation": {
         "authors": [
           "Andreadis A",
@@ -697,17 +889,22 @@
         "type": "PubMed",
         "volume": "31"
       },
-      "evidence": " Collectively, these data indicate that PAD is both necessary and sufficient to inhibit an- terograde FAT by activating the PP1–GSK3 cascade.",
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+      "evidence": "A trend of elevated GSK3 activity (􏰈32%) relative to PKC activity ( p 􏰄 0.28, paired t test; n 􏰄 3) was observed for axoplasms incubated with the PAD peptide (mean 􏰄 4.9 􏰉 2.5), compared with those incubated with scrambled peptide (mean 􏰄 3.7 􏰉 1.7), which supports the results from vesicle motility assays. ",
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       "object": {
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       "target": 17
     },
     {
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+        }
+      },
       "citation": {
         "authors": [
           "Andreadis A",
@@ -731,14 +928,22 @@
         "type": "PubMed",
         "volume": "31"
       },
-      "evidence": "To evaluate the relevance of these find- ings in human disease, we generated a novel monoclonal antibody, termed TNT1, which specifically recognizes PAD.",
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-      "relation": "association",
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+      "evidence": " Collectively, these data indicate that PAD is both necessary and sufficient to inhibit an-terograde FAT by activating the PP1–GSK3 cascade.",
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+      "object": {
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     },
     {
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+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "Andreadis A",
@@ -762,17 +967,22 @@
         "type": "PubMed",
         "volume": "31"
       },
-      "evidence": "These data indicated that increased PAD exposure, as revealed by TNT1 immunoreac- tivity, occurs early in AD and remains present throughout the disease process.",
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-      "relation": "association",
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-      "subject": {
+      "evidence": "Together, these data indicate that disease- associated modifications and mutations in tau that increase exposure of PAD promote activation of the PP1–GSK3 pathway and inhibition of anterograde FAT.",
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+      "target": 17
     },
     {
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+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "Andreadis A",
@@ -796,17 +1006,22 @@
         "type": "PubMed",
         "volume": "31"
       },
-      "evidence": " Together, these data suggest that increased PAD exposure represents an early event in AD pathogenesis and that AT8 may not be required for PAD ex- posure in situ.",
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-      "relation": "association",
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+      "evidence": " Collectively, these data indicate that PAD is both necessary and sufficient to inhibit an-terograde FAT by activating the PP1–GSK3 cascade.",
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         "type": "PubMed",
         "volume": "31"
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         "type": "PubMed",
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+        "authors": [
+          "Andreadis A",
+          "Binder LI",
+          "Brady ST",
+          "Fu Y",
+          "Kanaan NM",
+          "LaPointe NE",
+          "Morfini GA",
+          "Patterson KR",
+          "Pigino GF",
+          "Song Y"
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+        "date": "2011-07-06",
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+        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
+        "pages": "9858-68",
+        "reference": "21734277",
+        "title": "Pathogenic forms of tau inhibit kinesin-dependent axonal transport through a mechanism involving activation of axonal phosphotransferases.",
+        "type": "PubMed",
+        "volume": "31"
       },
+      "evidence": "Again, coperfusion of the PAD peptide with either I-2 (50 nM) (Fig. 5A) or ING-135 (100 nM) (Fig. 5B) completely prevented anterograde FAT inhibition. ",
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         "type": "PubMed",
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         "type": "PubMed",
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         "type": "PubMed",
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         "type": "PubMed",
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-        "modifier": "Activity"
+      "evidence": "These data indicated that increased PAD exposure, as revealed by TNT1 immunoreactivity, occurs early in AD and remains present throughout the disease process.",
+      "key": "5deb6ea43ace85b615c2ac82d6e5299e7cb7f35824b1f540f3e6202204e0df587e059333cbbf138a70ad4240458ed8becaf8ae98de79d87423a863b546a9e0f4",
+      "line": 184,
+      "relation": "increases",
+      "source": 20,
+      "target": 9
+    },
+    {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
       },
-      "relation": "association",
-      "source": 19,
-      "target": 7
+      "citation": {
+        "authors": [
+          "Andreadis A",
+          "Binder LI",
+          "Brady ST",
+          "Fu Y",
+          "Kanaan NM",
+          "LaPointe NE",
+          "Morfini GA",
+          "Patterson KR",
+          "Pigino GF",
+          "Song Y"
+        ],
+        "date": "2011-07-06",
+        "first": "Kanaan NM",
+        "last": "Binder LI",
+        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
+        "pages": "9858-68",
+        "reference": "21734277",
+        "title": "Pathogenic forms of tau inhibit kinesin-dependent axonal transport through a mechanism involving activation of axonal phosphotransferases.",
+        "type": "PubMed",
+        "volume": "31"
+      },
+      "evidence": " Together, these data suggest that increased PAD exposure represents an early event in AD pathogenesis and that AT8 may not be required for PAD exposure in situ.",
+      "key": "cace30e5637149eb3c449eb7c0a84bcd3bc6cb6e6c71ad9ceee81154fce9ebb6c32c97788c5281f75b7ca9b734cf6dbb80ff3fda39fa8d96a08040f8bdbc6515",
+      "line": 189,
+      "relation": "increases",
+      "source": 20,
+      "target": 9
     }
   ],
   "multigraph": true,
   "nodes": [
     {
-      "bel": "a(HBP:\"I-2\")",
+      "bel": "a(HBP:\"Tau antibody, TNT1\")",
       "function": "Abundance",
-      "id": "94ed115c12bb1b36cff4f84f41521cc451873c48265919ba553ca4e5735bd2424dc664d915f9145e747bad1f10cba0a822c43e11998330afbf02471c38b403a9",
-      "name": "I-2",
-      "namespace": "HBP"
-    },
-    {
-      "bel": "a(HBP:\"ING-135\")",
-      "function": "Abundance",
-      "id": "01a4af6caf26b61d6ec1bb7c4844b8d17e328d78ba86857c4da618d1dabeb6d1793f71756723e0f594ef3e1c197f8b8d4d519cbb9463aebbc91faca71abffe8b",
-      "name": "ING-135",
+      "id": "c796a83d992a31f44fd416a82c553ea69886271a8874826c38794337517edd3598e1d7600b8d88fccbe5d7f4b89aa744c88b53c8ef340e5a8aba804b3feda576",
+      "name": "Tau antibody, TNT1",
       "namespace": "HBP"
     },
     {
@@ -1312,73 +1663,52 @@
       "namespace": "GO"
     },
     {
-      "bel": "complex(p(HBP:\"6D tau\", frag(\"2_18\")), p(HBP:PAD))",
-      "function": "Complex",
-      "id": "afb2ed0559c44f8dd88bcafdd02f1a856ded91c6bab9f9233518e6795467afabcecb3db1343e4762ef65441d83ce967b934d1ee7158f91a70d35eff072565634",
+      "bel": "composite(p(HBP:\"phosphatase-activating domain\"), p(HGNC:PPP1R2))",
+      "function": "Composite",
+      "id": "29ff757b3e6e9a7fd0445049d7887d7bb66494fa4c4bedc60031dc871b51707975500efa70e3a61dfa6a06ebae9a65b5ee38ca2f9bc3516266f296516df2ba97",
       "members": [
         {
-          "bel": "p(HBP:\"6D tau\", frag(\"2_18\"))",
+          "bel": "p(HBP:\"phosphatase-activating domain\")",
           "function": "Protein",
-          "id": "05a177cfa46adbb0cd50be682e11092a9333ad2251e684e3fb95cd47821711c35f48acd4ff00d25ac8aa68bed1fa990e7c0cb1a353c190cc4ae7b206ea296525",
-          "name": "6D tau",
-          "namespace": "HBP",
-          "variants": [
-            {
-              "kind": "frag",
-              "start": 2,
-              "stop": 18
-            }
-          ]
+          "id": "13b79ee497a2b5239e3ade45a0755015d95761404ee260005b56b78d57a40582afa3f4758ec8271987e918bdbc8ac86349e5ce62a2de5005a88a948eecbeec43",
+          "name": "phosphatase-activating domain",
+          "namespace": "HBP"
         },
         {
-          "bel": "p(HBP:PAD)",
+          "bel": "p(HGNC:PPP1R2)",
           "function": "Protein",
-          "id": "0141ea4b99f008acb5781e2541436f974ce67711a953b21aed1fe18cbf2972ee21cbb7e73c540e72cfbd78c8af5d2f3c280d74fe5bea3e06a7eb443007b3d8f2",
-          "name": "PAD",
-          "namespace": "HBP"
+          "id": "838178b4cf6bb4321ab67c79abf10352015f11c7c5607ab40425f7f4ac6ab444be0506ba1808a8787e782edc6376b115b43f154fdf6664b1b6b1a1e9588926b3",
+          "name": "PPP1R2",
+          "namespace": "HGNC"
         }
       ]
     },
     {
-      "bel": "p(HBP:\"6D tau\")",
+      "bel": "p(HBP:\"Tau 6D\")",
       "function": "Protein",
-      "id": "b22576f7e78b628b443db98126bbcdf3a6492eff1f43aa53d2413d263754926554988a093f3bfc235de3b10005ce23711ba93eb54fcfad95d83313d3f0847a93",
-      "name": "6D tau",
+      "id": "a948c4abef2806672d16d82e3b33205d6556fe568be001ee1dcfe2a0980c22a9387094f4c92914c7e238821446dc16b1b796de5e7923b70e00a6e1182c3738dd",
+      "name": "Tau 6D",
       "namespace": "HBP"
     },
     {
-      "bel": "p(HBP:\"6D tau\", frag(\"2_18\"))",
-      "function": "Protein",
-      "id": "05a177cfa46adbb0cd50be682e11092a9333ad2251e684e3fb95cd47821711c35f48acd4ff00d25ac8aa68bed1fa990e7c0cb1a353c190cc4ae7b206ea296525",
-      "name": "6D tau",
-      "namespace": "HBP",
-      "variants": [
-        {
-          "kind": "frag",
-          "start": 2,
-          "stop": 18
-        }
-      ]
-    },
-    {
-      "bel": "p(HBP:\"6P tau\")",
+      "bel": "p(HBP:\"Tau 6P\")",
       "function": "Protein",
-      "id": "b287bad37c94c4a941c77344f43adf04ef619b51a1dc6ef71fec23a5998bc6f8f111191b4508ef009f068b81eeb6e63e27275c981d3ed8899ac62906e9d0af7f",
-      "name": "6P tau",
+      "id": "4deb784a58757d7b7441d45d895dc8589293748a81aa5298d992c681b413b808a78a8e7e518746df0d9617c1c1e0a59f0d0bb2158ea50fcd49ffefda0941d4c2",
+      "name": "Tau 6P",
       "namespace": "HBP"
     },
     {
-      "bel": "p(HBP:\"AT8 tau\")",
+      "bel": "p(HBP:\"Tau epitope, AT8\")",
       "function": "Protein",
-      "id": "90ab58611a58c3554181e20ca7cfd44a0e83b974cf634281e3894999343f486dabac3cde6957dd0ad4808010b8db7cc57ddee8e209ba31c078df8e5f6c51f053",
-      "name": "AT8 tau",
+      "id": "41962f318cfbbdc940cf240c51ccc8748ed33b59785b3f776e1cc1907c3e0b69b3340d9fa53ac1108ad1894a38c564cf329d40fbfe4a60ba76cdbd228bebf859",
+      "name": "Tau epitope, AT8",
       "namespace": "HBP"
     },
     {
-      "bel": "p(HBP:\"AT8 tau\", pmod(Ph))",
+      "bel": "p(HBP:\"Tau epitope, AT8\", pmod(Ph))",
       "function": "Protein",
-      "id": "64541a31527aae2288a7fdfde43b8120d01ee44f88f8b705beb605d5ec19432ebf43ed48c81b24924214c153d5312bc32e4e519030f1a490e51ceda5f3ce5c60",
-      "name": "AT8 tau",
+      "id": "7c5041347697308f23734268f47b8e06c7b21f7f0a4ce617a1e1602c8691501252784d7dacb7eac0e9e999862eb8e5d58de0fa535fc0ce00e2bf492c864c9294",
+      "name": "Tau epitope, AT8",
       "namespace": "HBP",
       "variants": [
         {
@@ -1391,32 +1721,34 @@
       ]
     },
     {
-      "bel": "p(HBP:\"delta 144-273 tau\")",
-      "function": "Protein",
-      "id": "f968379bebc6c0e360d27ecd8331bff8e573835d5a0356d42596da7d8772ecdfe4a11fbe0d6af365425af0d9364b688316a23e5da07a5125a86ec42db8874be3",
-      "name": "delta 144-273 tau",
-      "namespace": "HBP"
-    },
-    {
-      "bel": "p(HBP:\"endogenous axoplasmic phosphatases\")",
+      "bel": "p(HBP:\"phosphatase-activating domain\")",
       "function": "Protein",
-      "id": "3f6aa7832ebc0a4102511dab8248ed8a48878ef167fec0c0fd264d8aea1ae73aa4abcb75205cda34ece80a0c65b34e32e0835fc8bd971d54661665fd7605fb36",
-      "name": "endogenous axoplasmic phosphatases",
+      "id": "13b79ee497a2b5239e3ade45a0755015d95761404ee260005b56b78d57a40582afa3f4758ec8271987e918bdbc8ac86349e5ce62a2de5005a88a948eecbeec43",
+      "name": "phosphatase-activating domain",
       "namespace": "HBP"
     },
     {
-      "bel": "p(HBP:PAD)",
+      "bel": "p(HGNC:JUN)",
       "function": "Protein",
-      "id": "0141ea4b99f008acb5781e2541436f974ce67711a953b21aed1fe18cbf2972ee21cbb7e73c540e72cfbd78c8af5d2f3c280d74fe5bea3e06a7eb443007b3d8f2",
-      "name": "PAD",
-      "namespace": "HBP"
+      "id": "54cf70b0e3223232ffad00658dfdeacf4c42283c91f943562a4debab6c786a69bb8021b49d44ab47268272c5c0c28f47a456172e7a4ce508bb34c8b6bcb23358",
+      "name": "JUN",
+      "namespace": "HGNC"
     },
     {
-      "bel": "p(HBP:TNT1)",
+      "bel": "p(HGNC:JUN, pmod(Ph))",
       "function": "Protein",
-      "id": "4c72a7ff9320d936bcb9ce511aed3f0e41c8957bc29400abdda83cb9031fec74e1e525206ad9b3c349d86609e2aa491c1e86ea8afd3d92ce80b693bd89f386f1",
-      "name": "TNT1",
-      "namespace": "HBP"
+      "id": "b9fb0818f797ec30c2c3e13c864ad845efa3bf35ba154045862cfb22f76e67830ce0c18c0bfecd045bf0e92056780ce374fea81a4a4ffb21b6d4721672b29197",
+      "name": "JUN",
+      "namespace": "HGNC",
+      "variants": [
+        {
+          "identifier": {
+            "name": "Ph",
+            "namespace": "bel"
+          },
+          "kind": "pmod"
+        }
+      ]
     },
     {
       "bel": "p(HGNC:MAPT)",
@@ -1426,21 +1758,54 @@
       "namespace": "HGNC"
     },
     {
-      "bel": "p(HGNC:MAPT, pmod(Ph))",
+      "bel": "p(HGNC:MAPT, pmod(HBP:hyperphosphorylation))",
       "function": "Protein",
-      "id": "526bae251987f8c4f55f6e2451662fa55e087c57585beae7c389b020d73487c739834e9b8ec841783de6a5b5fb9df8b138e9eff4406a9ec5e606766575dcac0e",
+      "id": "ede67fb639f29861d91976fefa16d8279b53ae13a659f35d70ed12e01bf3f339ffcf701fc54c7c4e908fee9902c02aac3e0022dcae5a7afa217ed2d4dba133b0",
       "name": "MAPT",
       "namespace": "HGNC",
       "variants": [
         {
           "identifier": {
-            "name": "Ph",
-            "namespace": "bel"
+            "name": "hyperphosphorylation",
+            "namespace": "HBP"
           },
           "kind": "pmod"
         }
       ]
     },
+    {
+      "bel": "p(HGNC:MAPT, var(\"?\"))",
+      "function": "Protein",
+      "id": "40a1fcd2e6b4af4d7f275f7ffae5cd34aff043c40297e912ed0e45c5a645d1abe2b717042d39ef0fd11ffa06c96785d31a8c7af123db21c2162d4e6ab59b9729",
+      "name": "MAPT",
+      "namespace": "HGNC",
+      "variants": [
+        {
+          "identifier": "?",
+          "kind": "hgvs"
+        }
+      ]
+    },
+    {
+      "bel": "p(HGNC:MAPT, var(\"p.144_273del\"))",
+      "function": "Protein",
+      "id": "6a4fa02c386249f1eb95cd412dcfd768336c182d3148ca8bdd2b1e6418df45fd13e43180a6ab01025b39ee4e1c5d50de11600ac5efafcdfd2a234d294ee0e7a9",
+      "name": "MAPT",
+      "namespace": "HGNC",
+      "variants": [
+        {
+          "identifier": "p.144_273del",
+          "kind": "hgvs"
+        }
+      ]
+    },
+    {
+      "bel": "p(HGNC:PPP1R2)",
+      "function": "Protein",
+      "id": "838178b4cf6bb4321ab67c79abf10352015f11c7c5607ab40425f7f4ac6ab444be0506ba1808a8787e782edc6376b115b43f154fdf6664b1b6b1a1e9588926b3",
+      "name": "PPP1R2",
+      "namespace": "HGNC"
+    },
     {
       "bel": "p(MESH:\"Glycogen Synthase Kinase 3\")",
       "function": "Protein",
@@ -1448,6 +1813,13 @@
       "name": "Glycogen Synthase Kinase 3",
       "namespace": "MESH"
     },
+    {
+      "bel": "p(MESH:\"Phosphoprotein Phosphatases\")",
+      "function": "Protein",
+      "id": "f19230c6a48523a81980278d258d6ba9f60a233b642a767ce9beac012463e2c4e81369a919b097bdff111ebebff2092886661ca398426a555d4e240559cbd634",
+      "name": "Phosphoprotein Phosphatases",
+      "namespace": "MESH"
+    },
     {
       "bel": "p(MESH:\"Protein Phosphatase 1\")",
       "function": "Protein",
diff --git a/hbp_knowledge/tau/nestor/tau_mitochondria.bel.json b/hbp_knowledge/tau/nestor/tau_mitochondria.bel.json
index 8708a543c..4d6e68518 100644
--- a/hbp_knowledge/tau/nestor/tau_mitochondria.bel.json
+++ b/hbp_knowledge/tau/nestor/tau_mitochondria.bel.json
@@ -28,7 +28,7 @@
       "TextLocation": "https://arty.scai.fraunhofer.de/artifactory/bel/annotation/text-location/text-location-1.0.1.belanno"
     },
     "document_metadata": {
-      "authors": "Kristian Kolpeja",
+      "authors": "Kristian Kolpeja, Sandra Spalek",
       "contact": "charles.hoyt@scai.fraunhofer.de",
       "copyright": "Copyright © 2018-2019 Fraunhofer Institute SCAI, All rights reserved",
       "description": "Tau and mitochondria section of TauBase",
@@ -48,7 +48,7 @@
       "ECCODE": "https://raw.githubusercontent.com/pharmacome/terminology/b46b65c3da259b6e86026514dfececab7c22a11b/external/ec-code.belns",
       "FPLX": "https://raw.githubusercontent.com/sorgerlab/famplex/e8ae9926ff95266032cb74f77973c84939bffbeb/export/famplex.belns",
       "GO": "https://raw.githubusercontent.com/pharmacome/terminology/b46b65c3da259b6e86026514dfececab7c22a11b/external/go-names.belns",
-      "HBP": "https://raw.githubusercontent.com/pharmacome/terminology/90e1cb9e5e882703380c9db8d4915ac6f3cba137/export/hbp-names.belns",
+      "HBP": "https://raw.githubusercontent.com/pharmacome/terminology/efc856fb009a39e4d284269a6801f79ed3d3cf56/export/hbp-names.belns",
       "HGNC": "https://raw.githubusercontent.com/pharmacome/terminology/b46b65c3da259b6e86026514dfececab7c22a11b/external/hgnc-names.belns",
       "HGNCGENEFAMILY": "https://raw.githubusercontent.com/pharmacome/terminology/3074b85b858455d8eeb76cfcdef685ced19bbe11/external/hgnc.genefamily-names.belns",
       "HP": "https://arty.scai.fraunhofer.de/artifactory/bel/namespace/hp/hp-20171108.belns",
@@ -66,6 +66,52 @@
   "links": [
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "Method": {
+          "Immunoblotting": true,
+          "Imunofluorescence": true,
+          "RT-PCR": true
+        },
+        "MouseStrain": {
+          "Tau X Drp1+/-": true
+        },
+        "Species": {
+          "10090": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Fry D",
+          "Kandimalla R",
+          "Manczak M",
+          "Reddy PH",
+          "Sesaki H",
+          "Suneetha Y"
+        ],
+        "date": "2016-11-15",
+        "first": "Kandimalla R",
+        "last": "Reddy PH",
+        "name": "Human molecular genetics",
+        "pages": "4881-4897",
+        "reference": "28173111",
+        "title": "Reduced dynamin-related protein 1 protects against phosphorylated Tau-induced mitochondrial dysfunction and synaptic damage in Alzheimer's disease.",
+        "type": "PubMed",
+        "volume": "25"
+      },
+      "evidence": "Mitochondrial dysfunction found to be reduced in TauXDrp1þ/+- mice relative to Tau mice. Phosphorylated Tau levels were significantly reduced in TauXDrp1þ/+- mice relative to Tau mice. These findings suggest that a partial reduction of Drp1 decreases the levels of phosphorylated Tau, reduces mitochondrial dysfunction, and maintains mitochondrial dynamics, enhances mitochondrial biogenesis and synaptic activity in Tau mice.",
+      "key": "df9084da9500b872414a83d3674262eb391433603bd0b0ca2abf11e202b9feae76d092bfb376f3ccf44e8835f962cb6fa8768aa65a6a33e941d028dfe2e47d5d",
+      "line": 88,
+      "relation": "positiveCorrelation",
+      "source": 29,
+      "target": 26
+    },
+    {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "Method": {
           "Immunoblotting": true,
           "Imunofluorescence": true,
@@ -99,16 +145,19 @@
       },
       "evidence": "Mitochondrial dysfunction found to be reduced in TauXDrp1þ/+- mice relative to Tau mice. Phosphorylated Tau levels were significantly reduced in TauXDrp1þ/+- mice relative to Tau mice. These findings suggest that a partial reduction of Drp1 decreases the levels of phosphorylated Tau, reduces mitochondrial dysfunction, and maintains mitochondrial dynamics, enhances mitochondrial biogenesis and synaptic activity in Tau mice.",
       "key": "2197e03923ca551bdaab0186d9449b5d234f3ef545c36a76c1efdb4196e2fd7314c5108759fda871f32d23fef91670314e9425e4c82cccf24354c79f938d8ab5",
-      "line": 87,
+      "line": 89,
       "object": {
         "modifier": "Activity"
       },
       "relation": "negativeCorrelation",
-      "source": 20,
+      "source": 29,
       "target": 5
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "Method": {
           "Immunoblotting": true,
           "Imunofluorescence": true,
@@ -142,13 +191,16 @@
       },
       "evidence": "Mitochondrial dysfunction found to be reduced in TauXDrp1þ/+- mice relative to Tau mice. Phosphorylated Tau levels were significantly reduced in TauXDrp1þ/+- mice relative to Tau mice. These findings suggest that a partial reduction of Drp1 decreases the levels of phosphorylated Tau, reduces mitochondrial dysfunction, and maintains mitochondrial dynamics, enhances mitochondrial biogenesis and synaptic activity in Tau mice.",
       "key": "40a5c07a57eefce143dda8dc67c09191e37af92ab43c62921b7c3d39766ca8e01de6e21d8464d47bf9ec82fdb6f8986a413b8193ed973dc6373386f434536d9c",
-      "line": 90,
+      "line": 92,
       "relation": "negativeCorrelation",
-      "source": 20,
+      "source": 29,
       "target": 5
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "Method": {
           "Immunoblotting": true,
           "Imunofluorescence": true,
@@ -182,13 +234,16 @@
       },
       "evidence": "Mitochondrial dysfunction found to be reduced in TauXDrp1þ/+- mice relative to Tau mice. Phosphorylated Tau levels were significantly reduced in TauXDrp1þ/+- mice relative to Tau mice. These findings suggest that a partial reduction of Drp1 decreases the levels of phosphorylated Tau, reduces mitochondrial dysfunction, and maintains mitochondrial dynamics, enhances mitochondrial biogenesis and synaptic activity in Tau mice.",
       "key": "adfac06a857a6b7c67d7f53043a1e3a735fdcd5dc98389cf5bb4a06a6db687ecc6371da5cbe77c631f9caaf8c0fb9a621f06f9ee25b3abd37662d57470023277",
-      "line": 88,
+      "line": 90,
       "relation": "positiveCorrelation",
-      "source": 20,
-      "target": 9
+      "source": 29,
+      "target": 12
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "Method": {
           "Immunoblotting": true,
           "Imunofluorescence": true,
@@ -222,13 +277,16 @@
       },
       "evidence": "Mitochondrial dysfunction found to be reduced in TauXDrp1þ/+- mice relative to Tau mice. Phosphorylated Tau levels were significantly reduced in TauXDrp1þ/+- mice relative to Tau mice. These findings suggest that a partial reduction of Drp1 decreases the levels of phosphorylated Tau, reduces mitochondrial dysfunction, and maintains mitochondrial dynamics, enhances mitochondrial biogenesis and synaptic activity in Tau mice.",
       "key": "1b7cf775270fa789bb35b284fce9da3bedeb7e4b99e3717de6899384131b719c46e31f79dc76870a357fabb0be46c89883c75420712d4e682dc4b30c21be17cb",
-      "line": 89,
+      "line": 91,
       "relation": "negativeCorrelation",
-      "source": 20,
+      "source": 29,
       "target": 2
     },
     {
       "annotations": {
+        "Confidence": {
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         "Method": {
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           "Imunofluorescence": true,
@@ -262,16 +320,22 @@
       },
       "evidence": "Mitochondrial dysfunction found to be reduced in TauXDrp1þ/+- mice relative to Tau mice. Phosphorylated Tau levels were significantly reduced in TauXDrp1þ/+- mice relative to Tau mice. These findings suggest that a partial reduction of Drp1 decreases the levels of phosphorylated Tau, reduces mitochondrial dysfunction, and maintains mitochondrial dynamics, enhances mitochondrial biogenesis and synaptic activity in Tau mice.",
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     {
       "annotations": {
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         "Method": {
           "Immunoblotting": true,
           "Imunofluorescence": true,
@@ -305,13 +369,19 @@
       },
       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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     {
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           "Imunofluorescence": true,
@@ -345,13 +415,19 @@
       },
       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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     {
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         "Method": {
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           "Imunofluorescence": true,
@@ -385,13 +461,19 @@
       },
       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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     {
       "annotations": {
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         "Method": {
           "Immunoblotting": true,
           "Imunofluorescence": true,
@@ -424,14 +506,20 @@
         "volume": "25"
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       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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           "Imunofluorescence": true,
@@ -465,13 +553,19 @@
       },
       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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     {
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         "Method": {
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           "Imunofluorescence": true,
@@ -504,14 +598,20 @@
         "volume": "25"
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       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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     {
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         "Method": {
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           "Imunofluorescence": true,
@@ -545,13 +645,19 @@
       },
       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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         "Method": {
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           "Imunofluorescence": true,
@@ -585,13 +691,19 @@
       },
       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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     {
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           "Imunofluorescence": true,
@@ -625,13 +737,19 @@
       },
       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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     {
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         "Method": {
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           "Imunofluorescence": true,
@@ -664,14 +782,20 @@
         "volume": "25"
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       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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     {
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           "Imunofluorescence": true,
@@ -704,14 +828,20 @@
         "volume": "25"
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       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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     {
       "annotations": {
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         "Method": {
           "Immunoblotting": true,
           "Imunofluorescence": true,
@@ -744,14 +874,20 @@
         "volume": "25"
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       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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     {
       "annotations": {
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+        },
+        "MeSHAnatomy": {
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         "Method": {
           "Immunoblotting": true,
           "Imunofluorescence": true,
@@ -784,14 +920,20 @@
         "volume": "25"
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       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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     {
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           "Imunofluorescence": true,
@@ -824,14 +966,20 @@
         "volume": "25"
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       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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     {
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+        "MeSHAnatomy": {
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         "Method": {
           "Immunoblotting": true,
           "Imunofluorescence": true,
@@ -864,14 +1012,20 @@
         "volume": "25"
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       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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@@ -1264,14 +2226,20 @@
         "volume": "25"
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       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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@@ -1304,14 +2272,20 @@
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@@ -1343,18 +2317,21 @@
         "type": "PubMed",
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@@ -1386,15 +2363,21 @@
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@@ -1427,14 +2410,20 @@
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@@ -1467,14 +2456,20 @@
         "volume": "25"
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       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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@@ -1507,14 +2502,20 @@
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@@ -1546,21 +2547,67 @@
         "type": "PubMed",
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-      "relation": "hasVariant",
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+        "Method": {
+          "Immunoblotting": true,
+          "Imunofluorescence": true,
+          "RT-PCR": true
+        },
+        "MouseStrain": {
+          "Tau X Drp1+/-": true
+        },
+        "Species": {
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+      "citation": {
+        "authors": [
+          "Fry D",
+          "Kandimalla R",
+          "Manczak M",
+          "Reddy PH",
+          "Sesaki H",
+          "Suneetha Y"
+        ],
+        "date": "2016-11-15",
+        "first": "Kandimalla R",
+        "last": "Reddy PH",
+        "name": "Human molecular genetics",
+        "pages": "4881-4897",
+        "reference": "28173111",
+        "title": "Reduced dynamin-related protein 1 protects against phosphorylated Tau-induced mitochondrial dysfunction and synaptic damage in Alzheimer's disease.",
+        "type": "PubMed",
+        "volume": "25"
+      },
+      "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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@@ -1592,15 +2639,21 @@
         "type": "PubMed",
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-      "evidence": "Mitochondrial dysfunction found to be reduced in TauXDrp1þ/+- mice relative to Tau mice. Phosphorylated Tau levels were significantly reduced in TauXDrp1þ/+- mice relative to Tau mice. These findings suggest that a partial reduction of Drp1 decreases the levels of phosphorylated Tau, reduces mitochondrial dysfunction, and maintains mitochondrial dynamics, enhances mitochondrial biogenesis and synaptic activity in Tau mice.",
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@@ -1632,18 +2685,21 @@
         "type": "PubMed",
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-      "evidence": "Mitochondrial dysfunction found to be reduced in TauXDrp1þ/+- mice relative to Tau mice. Phosphorylated Tau levels were significantly reduced in TauXDrp1þ/+- mice relative to Tau mice. These findings suggest that a partial reduction of Drp1 decreases the levels of phosphorylated Tau, reduces mitochondrial dysfunction, and maintains mitochondrial dynamics, enhances mitochondrial biogenesis and synaptic activity in Tau mice.",
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         "volume": "25"
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       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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           "Imunofluorescence": true,
@@ -1719,17 +2778,20 @@
         "volume": "25"
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       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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           "Immunoblotting": true,
           "Imunofluorescence": true,
@@ -1762,17 +2824,66 @@
         "volume": "25"
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       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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+        },
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+        "Method": {
+          "Immunoblotting": true,
+          "Imunofluorescence": true,
+          "RT-PCR": true
+        },
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+      "citation": {
+        "authors": [
+          "Fry D",
+          "Kandimalla R",
+          "Manczak M",
+          "Reddy PH",
+          "Sesaki H",
+          "Suneetha Y"
+        ],
+        "date": "2016-11-15",
+        "first": "Kandimalla R",
+        "last": "Reddy PH",
+        "name": "Human molecular genetics",
+        "pages": "4881-4897",
+        "reference": "28173111",
+        "title": "Reduced dynamin-related protein 1 protects against phosphorylated Tau-induced mitochondrial dysfunction and synaptic damage in Alzheimer's disease.",
+        "type": "PubMed",
+        "volume": "25"
+      },
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           "Immunoblotting": true,
           "Imunofluorescence": true,
@@ -1805,17 +2916,23 @@
         "volume": "25"
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       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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@@ -1848,17 +2965,20 @@
         "volume": "25"
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       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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@@ -1891,17 +3011,20 @@
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       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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@@ -1934,17 +3057,23 @@
         "volume": "25"
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       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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           "Immunoblotting": true,
           "Imunofluorescence": true,
@@ -1977,17 +3106,20 @@
         "volume": "25"
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       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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           "Imunofluorescence": true,
@@ -2060,17 +3198,23 @@
         "volume": "25"
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       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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           "Imunofluorescence": true,
@@ -2103,14 +3247,20 @@
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       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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@@ -2143,17 +3293,20 @@
         "volume": "25"
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       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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@@ -2186,14 +3339,23 @@
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       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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@@ -2226,17 +3388,20 @@
         "volume": "25"
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       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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         "volume": "25"
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       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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@@ -2309,17 +3480,23 @@
         "volume": "25"
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@@ -2352,14 +3529,20 @@
         "volume": "25"
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       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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@@ -2392,17 +3575,20 @@
         "volume": "25"
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       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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@@ -2435,14 +3621,23 @@
         "volume": "25"
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       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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@@ -2475,17 +3670,20 @@
         "volume": "25"
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       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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@@ -2518,14 +3716,20 @@
         "volume": "25"
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       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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@@ -2558,17 +3762,23 @@
         "volume": "25"
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       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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@@ -2602,13 +3812,19 @@
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       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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@@ -2641,17 +3857,20 @@
         "volume": "25"
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       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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@@ -2684,14 +3903,23 @@
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       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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@@ -2724,14 +3952,20 @@
         "volume": "25"
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       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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         "volume": "25"
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       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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+      "target": 8
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "Method": {
           "Immunoblotting": true,
           "Imunofluorescence": true,
@@ -2804,14 +4044,20 @@
         "volume": "25"
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       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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-      "relation": "positiveCorrelation",
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     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "Method": {
           "Immunoblotting": true,
           "Imunofluorescence": true,
@@ -2844,14 +4090,20 @@
         "volume": "25"
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       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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-      "relation": "positiveCorrelation",
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-      "target": 6
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     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "Method": {
           "Immunoblotting": true,
           "Imunofluorescence": true,
@@ -2884,14 +4136,20 @@
         "volume": "25"
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       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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-      "relation": "positiveCorrelation",
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     {
       "annotations": {
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+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "Method": {
           "Immunoblotting": true,
           "Imunofluorescence": true,
@@ -2925,13 +4183,19 @@
       },
       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
       "key": "1c1494c8144a8a08bd92fde1b8812533f191c87cf678bdb4ac4082bc61d23bc81f61f9804f571577fab159a971fa2e99d5bdb5b9c17ebc8f6c1d3b9f35517b81",
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       "relation": "positiveCorrelation",
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+      "target": 29
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     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "Method": {
           "Immunoblotting": true,
           "Imunofluorescence": true,
@@ -2964,14 +4228,20 @@
         "volume": "25"
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       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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       "relation": "positiveCorrelation",
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+      "source": 20,
+      "target": 8
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     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "Method": {
           "Immunoblotting": true,
           "Imunofluorescence": true,
@@ -3004,14 +4274,20 @@
         "volume": "25"
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       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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-      "relation": "positiveCorrelation",
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       "target": 3
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     {
       "annotations": {
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+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "Method": {
           "Immunoblotting": true,
           "Imunofluorescence": true,
@@ -3044,14 +4320,20 @@
         "volume": "25"
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       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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-      "relation": "positiveCorrelation",
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-      "target": 16
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     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "Method": {
           "Immunoblotting": true,
           "Imunofluorescence": true,
@@ -3085,13 +4367,19 @@
       },
       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
       "key": "7534eda3c6141ac5bb1e182a8c63934bfd04559134882fcd805a9075a8cee2dbb6144749551c53c35fcb12923b46d2d13d615e523b486ac3bdb4c8771acdd220",
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       "relation": "negativeCorrelation",
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+      "target": 29
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "Method": {
           "Immunoblotting": true,
           "Imunofluorescence": true,
@@ -3124,14 +4412,20 @@
         "volume": "25"
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       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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       "relation": "negativeCorrelation",
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+      "source": 13,
+      "target": 8
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     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "Method": {
           "Immunoblotting": true,
           "Imunofluorescence": true,
@@ -3164,14 +4458,20 @@
         "volume": "25"
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       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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-      "relation": "positiveCorrelation",
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       "target": 1
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     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
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+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "Method": {
           "Immunoblotting": true,
           "Imunofluorescence": true,
@@ -3205,13 +4505,19 @@
       },
       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
       "key": "5df84d0d39b95fe4063eb7a7f8e6188c57e898a8b43bf0b3237bdf2ce53b63c32a1dc0fc4bb85ed33b174c52f8e89db5dbba52faf80f6dfe26833f8c9ca701e1",
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       "relation": "negativeCorrelation",
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-      "target": 20
+      "source": 33,
+      "target": 29
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "Method": {
           "Immunoblotting": true,
           "Imunofluorescence": true,
@@ -3244,14 +4550,20 @@
         "volume": "25"
       },
       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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       "relation": "negativeCorrelation",
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-      "target": 20
+      "source": 14,
+      "target": 8
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "Method": {
           "Immunoblotting": true,
           "Imunofluorescence": true,
@@ -3284,14 +4596,20 @@
         "volume": "25"
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       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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-      "relation": "positiveCorrelation",
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       "target": 1
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     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "Method": {
           "Immunoblotting": true,
           "Imunofluorescence": true,
@@ -3325,13 +4643,19 @@
       },
       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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       "relation": "negativeCorrelation",
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-      "target": 20
+      "source": 37,
+      "target": 29
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "Method": {
           "Immunoblotting": true,
           "Imunofluorescence": true,
@@ -3364,14 +4688,20 @@
         "volume": "25"
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       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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     {
       "annotations": {
+        "Confidence": {
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+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "Method": {
           "Immunoblotting": true,
           "Imunofluorescence": true,
@@ -3404,14 +4734,20 @@
         "volume": "25"
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       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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       "target": 1
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     {
       "annotations": {
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+        "MeSHAnatomy": {
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         "Method": {
           "Immunoblotting": true,
           "Imunofluorescence": true,
@@ -3444,14 +4780,20 @@
         "volume": "25"
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       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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     {
       "annotations": {
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+        "MeSHAnatomy": {
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+        },
         "Method": {
           "Immunoblotting": true,
           "Imunofluorescence": true,
@@ -3484,14 +4826,20 @@
         "volume": "25"
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       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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-      "relation": "positiveCorrelation",
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     {
       "annotations": {
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+        "MeSHAnatomy": {
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         "Method": {
           "Immunoblotting": true,
           "Imunofluorescence": true,
@@ -3524,14 +4872,20 @@
         "volume": "25"
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       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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     {
       "annotations": {
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+        "MeSHAnatomy": {
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         "Method": {
           "Immunoblotting": true,
           "Imunofluorescence": true,
@@ -3565,13 +4919,19 @@
       },
       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
       "key": "453cfc75afbb48ccc42ff9e768aaee8942ca7fff87c8773f26caec7aa82eb30e637e9b2bc93d0d3d5aec631d1639374dc8523e8d593dfd066c76d87919c18ec9",
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+      "target": 29
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     {
       "annotations": {
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+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "Method": {
           "Immunoblotting": true,
           "Imunofluorescence": true,
@@ -3604,14 +4964,20 @@
         "volume": "25"
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       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "Method": {
           "Immunoblotting": true,
           "Imunofluorescence": true,
@@ -3644,14 +5010,20 @@
         "volume": "25"
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       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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     {
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+        "MeSHAnatomy": {
+          "Brain": true
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         "Method": {
           "Immunoblotting": true,
           "Imunofluorescence": true,
@@ -3685,13 +5057,19 @@
       },
       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
       "key": "5c4ece8895510e57f6843031518f079ec7beacb4adf43d6c10822fac3a898f6c3e9bfdc7475006da9011a3cbe17fc600d82886ca8fe817dd8c1fa49d1c13d47b",
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+      "target": 29
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     {
       "annotations": {
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+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "Method": {
           "Immunoblotting": true,
           "Imunofluorescence": true,
@@ -3724,14 +5102,20 @@
         "volume": "25"
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       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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+      "target": 8
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     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "Method": {
           "Immunoblotting": true,
           "Imunofluorescence": true,
@@ -3764,14 +5148,20 @@
         "volume": "25"
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       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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-      "relation": "positiveCorrelation",
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       "target": 5
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     {
       "annotations": {
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+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "Method": {
           "Immunoblotting": true,
           "Imunofluorescence": true,
@@ -3805,13 +5195,19 @@
       },
       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
       "key": "f74fda0d94a8532501d0b54412a12cdd2d3a508f574db6d8554cf6ec1699c020c1c64d3bdad1f3ea7910872f720ef1cd2512b040050e5a0f20ebfa385f67e518",
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+      "target": 29
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     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "Method": {
           "Immunoblotting": true,
           "Imunofluorescence": true,
@@ -3844,14 +5240,20 @@
         "volume": "25"
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       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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       "relation": "negativeCorrelation",
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+      "source": 19,
+      "target": 8
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     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "Method": {
           "Immunoblotting": true,
           "Imunofluorescence": true,
@@ -3884,14 +5286,20 @@
         "volume": "25"
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       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
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-      "relation": "positiveCorrelation",
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       "target": 5
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     {
       "annotations": {
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+          "Medium": true
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+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "Method": {
           "Immunoblotting": true,
           "Imunofluorescence": true,
@@ -3925,13 +5333,19 @@
       },
       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
       "key": "c2f2ec4aebd86e1f8471ab0924a09ec868ec5a78865d8e23c257caa15450ab0af5dc53ceee633e0e2e4a6357cd7bd338030b279e79c20e29f1b1b3f89923a514",
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+      "source": 43,
+      "target": 29
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     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "Method": {
           "Immunoblotting": true,
           "Imunofluorescence": true,
@@ -3964,11 +5378,57 @@
         "volume": "25"
       },
       "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
-      "key": "4551c1b00660a819c2243979f90933c9e3351c62774a00f25c4d26b8c02518d0a64c5c78232e6e4e707b1a9171db852a2ca8e7e0fa0c6325e0f27327de52d1b7",
-      "line": 142,
+      "key": "43ee8d446367e9fa0fa435e0177c6a51323ef35caa778ae1428a296cad80e9578268789e501289d05bfe45221087ca2199695c75e16d0a799842dcbe051f6c3c",
+      "line": 155,
       "relation": "negativeCorrelation",
-      "source": 17,
-      "target": 20
+      "source": 24,
+      "target": 8
+    },
+    {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
+        "Method": {
+          "Immunoblotting": true,
+          "Imunofluorescence": true,
+          "RT-PCR": true
+        },
+        "MouseStrain": {
+          "Tau X Drp1+/-": true
+        },
+        "Species": {
+          "10090": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Fry D",
+          "Kandimalla R",
+          "Manczak M",
+          "Reddy PH",
+          "Sesaki H",
+          "Suneetha Y"
+        ],
+        "date": "2016-11-15",
+        "first": "Kandimalla R",
+        "last": "Reddy PH",
+        "name": "Human molecular genetics",
+        "pages": "4881-4897",
+        "reference": "28173111",
+        "title": "Reduced dynamin-related protein 1 protects against phosphorylated Tau-induced mitochondrial dysfunction and synaptic damage in Alzheimer's disease.",
+        "type": "PubMed",
+        "volume": "25"
+      },
+      "evidence": "Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics—Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis—Nrf1, Nrf2, PGC1a and TFAM and synaptic— synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month old Drp1þ/+-, Tau, TauXDrp1þ/+- and wild-type mice. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1þ/+- mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1þ/+- mice relative to Tau mice.",
+      "key": "efba99ea75f0d3fdd8bab0db29443b3053cb581a35ee506ea6a3d790471f764e739429abdac0aa604996d3fa42824a6f1ca31853a808ceeec7586a581d2cf1c1",
+      "line": 159,
+      "relation": "association",
+      "source": 24,
+      "target": 5
     }
   ],
   "multigraph": true,
@@ -4015,6 +5475,20 @@
       "name": "mitochondrion",
       "namespace": "GO"
     },
+    {
+      "bel": "p(HGNCGENEFAMILY:\"Vesicle associated membrane proteins\")",
+      "function": "Protein",
+      "id": "32887a1553fae1f1cac03896c6e943dbd36d0412d91a343c318812ccb7278be85ba3cbfcf989535e75c4ec91a57722c53de2a1ce16e62b53dcd1b52ed949d40d",
+      "name": "Vesicle associated membrane proteins",
+      "namespace": "HGNCGENEFAMILY"
+    },
+    {
+      "bel": "p(MGI:Dlg4)",
+      "function": "Protein",
+      "id": "efbd503487dcaffdd68be92d9adce7bc32d290ef6cc91492d0ec5611a041a0590e8de0025ef254be48d2550a5ca2c3439fbdc0ea8eb36b9f4fbb970ec12f8ce6",
+      "name": "Dlg4",
+      "namespace": "MGI"
+    },
     {
       "bel": "p(MGI:Dnm1l)",
       "function": "Protein",
@@ -4029,6 +5503,13 @@
       "name": "Fis1",
       "namespace": "MGI"
     },
+    {
+      "bel": "p(MGI:Gap43)",
+      "function": "Protein",
+      "id": "00e364fd5c27e255bf881e057bbc477b860467cc812d56aa5ae80980634b51674911c62f35ea948a7b1abf2449f298d8f19eba9159bcea2be7c2770ede2b33c9",
+      "name": "Gap43",
+      "namespace": "MGI"
+    },
     {
       "bel": "p(MGI:Mapt)",
       "function": "Protein",
@@ -4080,6 +5561,13 @@
       "name": "Nrf1",
       "namespace": "MGI"
     },
+    {
+      "bel": "p(MGI:Nrgn)",
+      "function": "Protein",
+      "id": "8eca9c90c00da8a8cbd6c96d815afb1addaa1ce4bec069ca486db919c9089dec974086cb87f2f31ba831bf93b7006c13edf6fc0124038e4b1b8e0843068561a7",
+      "name": "Nrgn",
+      "namespace": "MGI"
+    },
     {
       "bel": "p(MGI:Opa1)",
       "function": "Protein",
@@ -4101,6 +5589,27 @@
       "name": "Ppid",
       "namespace": "MGI"
     },
+    {
+      "bel": "p(MGI:Syn1)",
+      "function": "Protein",
+      "id": "c4aa3d6a8aba5d19dc3ed1ad995b3f4379839a65e02269ae04e2a55d19c4d5c055cdc6a5cdc2280c59c24df644fcd7b2d232ccc0d14fb4c0ab1cddcb3b73da9d",
+      "name": "Syn1",
+      "namespace": "MGI"
+    },
+    {
+      "bel": "p(MGI:Synpo)",
+      "function": "Protein",
+      "id": "be251291b51afe9812e2dc593db5a7786728fe1ac6617754c2060170b2f3f2a09c05409aafe667896a202383d8cf1c32ec61222774fa3323852a2c398c42d242",
+      "name": "Synpo",
+      "namespace": "MGI"
+    },
+    {
+      "bel": "p(MGI:Syp)",
+      "function": "Protein",
+      "id": "81f5125d4b52aac9a857be32b63ec0cfb4206764335f8942e31d07bc0d579e8dab81cc419d387f2d6d3913d6b219d530e68d5199d0106174a91f1824a212a736",
+      "name": "Syp",
+      "namespace": "MGI"
+    },
     {
       "bel": "p(MGI:Tfam)",
       "function": "Protein",
@@ -4108,6 +5617,20 @@
       "name": "Tfam",
       "namespace": "MGI"
     },
+    {
+      "bel": "p(MGI:Vamp1)",
+      "function": "Protein",
+      "id": "82c43f35d22b1cefa772cb31a6bcf6490fc857198bd57b975af38e91c3f5575b962a5e092b24e3e993785f9323746d2fbc5f26ac008be261a3a932cecb367dfc",
+      "name": "Vamp1",
+      "namespace": "MGI"
+    },
+    {
+      "bel": "path(HBP:\"mitochondrial dysfunction\")",
+      "function": "Pathology",
+      "id": "290f620a8ca62af5c329ceed61c52205bedef0b2ba17347a57e3e26dec8a12aac110be32f0fda6061476b9745f37c4e21a45fe75b71d678f32dc6ccdf5362edd",
+      "name": "mitochondrial dysfunction",
+      "namespace": "HBP"
+    },
     {
       "bel": "r(HGNCGENEFAMILY:\"Vesicle associated membrane proteins\")",
       "function": "RNA",
@@ -4207,17 +5730,10 @@
       "namespace": "MGI"
     },
     {
-      "bel": "r(MGI:Syn2)",
+      "bel": "r(MGI:Synpo)",
       "function": "RNA",
-      "id": "089e64c4fa3056fb98ca6e562c935d0f45edb734923a55c35dea8c83419365a00cd82c85304477a0961a42f803f0862a98b6af87f39608f23049e950dba6789e",
-      "name": "Syn2",
-      "namespace": "MGI"
-    },
-    {
-      "bel": "r(MGI:Synpo2)",
-      "function": "RNA",
-      "id": "97703a7608777d6293c7dfbc5c0db1805b8e66f491b939e3f825d8248898694523a597c88c7904ba783333f27678b93e363914cbfc103db61594bddbd3e76c17",
-      "name": "Synpo2",
+      "id": "c95b1acf983a7c8e0ac836b7c13859008310cee50c0851175c4c8550e516dadcbbb67774bec04a2c91d6cc587d4f4bf20b03897c48c2728b4ab7c3939faabba9",
+      "name": "Synpo",
       "namespace": "MGI"
     },
     {
@@ -4233,6 +5749,13 @@
       "id": "d84656a7430c3de6b942721605132688c56d05b4ad8fff4fd311cb23159b0cfe586dc44d40eab09682f798ed2516cde73075e9a35bf76b094b505421d0ff040e",
       "name": "Tfam",
       "namespace": "MGI"
+    },
+    {
+      "bel": "r(MGI:Vamp1)",
+      "function": "RNA",
+      "id": "f355cb11cfde193f4aeb0f51a5250472f3ecface833df5ad74688f0bebb1e927945242703e99f85054cf1123c1861d8d48e4f0390b967c53b82a6484ed547126",
+      "name": "Vamp1",
+      "namespace": "MGI"
     }
   ]
 }
\ No newline at end of file
diff --git a/hbp_knowledge/tau/nestor/tau_modifications.bel.json b/hbp_knowledge/tau/nestor/tau_modifications.bel.json
index 06d422a33..81c4136cf 100644
--- a/hbp_knowledge/tau/nestor/tau_modifications.bel.json
+++ b/hbp_knowledge/tau/nestor/tau_modifications.bel.json
@@ -256,17 +256,14 @@
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       "Cell": "https://arty.scai.fraunhofer.de/artifactory/bel/annotation/cell/cell-20170511.belanno",
       "CellLine": "https://arty.scai.fraunhofer.de/artifactory/bel/annotation/cell-line/cell-line-20170511.belanno",
-      "CellStructure": "https://arty.scai.fraunhofer.de/artifactory/bel/annotation/cell-structure/cell-structure-20170511.belanno",
       "Confidence": "https://arty.scai.fraunhofer.de/artifactory/bel/annotation/confidence/confidence-1.0.0.belanno",
       "Disease": "https://arty.scai.fraunhofer.de/artifactory/bel/annotation/disease/disease-20170511.belanno",
       "Gender": "https://arty.scai.fraunhofer.de/artifactory/bel/annotation/gender/gender-1.0.0.belanno",
       "MeSHAnatomy": "https://arty.scai.fraunhofer.de/artifactory/bel/annotation/mesh-anatomy/mesh-anatomy-20170511.belanno",
-      "MeSHDisease": "https://arty.scai.fraunhofer.de/artifactory/bel/annotation/mesh-diseases/mesh-diseases-20170511.belanno",
-      "Subgraph": "https://arty.scai.fraunhofer.de/artifactory/bel/annotation/neurommsig/neurommsig-1.0.3.belanno",
-      "TextLocation": "https://arty.scai.fraunhofer.de/artifactory/bel/annotation/text-location/text-location-1.0.1.belanno"
+      "MeSHDisease": "https://arty.scai.fraunhofer.de/artifactory/bel/annotation/mesh-diseases/mesh-diseases-20170511.belanno"
     },
     "document_metadata": {
-      "authors": "Kristian Kolpeja",
+      "authors": "Kristian Kolpeja, Esther Wollert, Sandra Spalek",
       "contact": "charles.hoyt@scai.fraunhofer.de",
       "copyright": "Copyright © 2018 Fraunhofer Institute SCAI, All rights reserved",
       "description": "Tau Modifications Sections of TauBase",
@@ -282,22 +279,19 @@
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     },
     "namespace_url": {
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-      "ECCODE": "https://raw.githubusercontent.com/pharmacome/terminology/b46b65c3da259b6e86026514dfececab7c22a11b/external/ec-code.belns",
+      "CHEBI": "https://raw.githubusercontent.com/pharmacome/terminology/c328ad964c08967a0417a887510b97b965a62fa5/external/chebi-names.belns",
+      "ECCODE": "https://raw.githubusercontent.com/pharmacome/terminology/c328ad964c08967a0417a887510b97b965a62fa5/external/ec-code.belns",
       "FPLX": "https://raw.githubusercontent.com/sorgerlab/famplex/e8ae9926ff95266032cb74f77973c84939bffbeb/export/famplex.belns",
-      "GO": "https://raw.githubusercontent.com/pharmacome/terminology/b46b65c3da259b6e86026514dfececab7c22a11b/external/go-names.belns",
-      "HBP": "https://raw.githubusercontent.com/pharmacome/terminology/90e1cb9e5e882703380c9db8d4915ac6f3cba137/export/hbp-names.belns",
-      "HGNC": "https://raw.githubusercontent.com/pharmacome/terminology/b46b65c3da259b6e86026514dfececab7c22a11b/external/hgnc-names.belns",
-      "HGNCGENEFAMILY": "https://raw.githubusercontent.com/pharmacome/terminology/3074b85b858455d8eeb76cfcdef685ced19bbe11/external/hgnc.genefamily-names.belns",
-      "HP": "https://arty.scai.fraunhofer.de/artifactory/bel/namespace/hp/hp-20171108.belns",
-      "INTERPRO": "https://raw.githubusercontent.com/pharmacome/terminology/f2f993e599694ab5ce989cc39d789a499f75db99/external/interpro-names.belns",
-      "MESH": "https://raw.githubusercontent.com/pharmacome/terminology/01c9daa61012b37dd0a1bc962521ba51a15b38f1/external/mesh-names.belns",
-      "MGI": "https://raw.githubusercontent.com/pharmacome/terminology/f2f993e599694ab5ce989cc39d789a499f75db99/external/mgi-names.belns",
-      "MIRBASE": "https://raw.githubusercontent.com/pharmacome/terminology/0c9853baf883545b922ff1b138a9f297a70b7951/external/mirbase-names.belns",
-      "NCBIGENE": "https://raw.githubusercontent.com/pharmacome/terminology/b46b65c3da259b6e86026514dfececab7c22a11b/external/entrez.belns",
-      "PFAM": "https://raw.githubusercontent.com/pharmacome/terminology/8ccfed235e418e4c8aa576f9a5ef0f838e794c7f/external/pfam-names.belns",
-      "RGD": "https://raw.githubusercontent.com/pharmacome/terminology/f2f993e599694ab5ce989cc39d789a499f75db99/external/rgd-names.belns"
+      "GO": "https://raw.githubusercontent.com/pharmacome/terminology/c328ad964c08967a0417a887510b97b965a62fa5/external/go-names.belns",
+      "HBP": "https://raw.githubusercontent.com/pharmacome/terminology/c328ad964c08967a0417a887510b97b965a62fa5/export/hbp-names.belns",
+      "HGNC": "https://raw.githubusercontent.com/pharmacome/terminology/c328ad964c08967a0417a887510b97b965a62fa5/external/hgnc-names.belns",
+      "HGNCGENEFAMILY": "https://raw.githubusercontent.com/pharmacome/terminology/efc856fb009a39e4d284269a6801f79ed3d3cf56/external/hgnc.genefamily-names.belns",
+      "HP": "https://raw.githubusercontent.com/pharmacome/terminology/c328ad964c08967a0417a887510b97b965a62fa5/external/hp-names.belns",
+      "INTERPRO": "https://raw.githubusercontent.com/pharmacome/terminology/c328ad964c08967a0417a887510b97b965a62fa5/external/interpro-names.belns",
+      "MESH": "https://raw.githubusercontent.com/pharmacome/terminology/efc856fb009a39e4d284269a6801f79ed3d3cf56/external/mesh-names.belns",
+      "MGI": "https://raw.githubusercontent.com/pharmacome/terminology/efc856fb009a39e4d284269a6801f79ed3d3cf56/external/mgi-names.belns",
+      "MIRBASE": "https://raw.githubusercontent.com/pharmacome/terminology/c328ad964c08967a0417a887510b97b965a62fa5/external/mirbase-names.belns",
+      "RGD": "https://raw.githubusercontent.com/pharmacome/terminology/efc856fb009a39e4d284269a6801f79ed3d3cf56/external/rgd-names.belns"
     },
     "namespaces_uncached": [],
     "path": "tau/nestor/tau_modifications.bel",
@@ -306,6 +300,9 @@
   "links": [
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Disease": {
           "Alzheimer's disease": true
         }
@@ -341,11 +338,14 @@
       "key": "4f9875a04ffbd508f492efe7fe9c532c863899681a848f8e376a4ff75546946ef37cb629a493ca24cae43e2ff33f2cd075b587ea2569941a1dd305e7c858915c",
       "line": 110,
       "relation": "partOf",
-      "source": 601,
-      "target": 80
+      "source": 686,
+      "target": 94
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Disease": {
           "Alzheimer's disease": true
         }
@@ -381,14 +381,17 @@
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       "line": 116,
       "relation": "positiveCorrelation",
-      "source": 601,
-      "target": 908
+      "source": 686,
+      "target": 1017
     },
     {
       "annotations": {
         "Anatomy": {
           "cerebral cortex": true
         },
+        "Confidence": {
+          "High": true
+        },
         "Method": {
           "Immunoprecipitation": true,
           "Liquid Chromatography": true,
@@ -429,180 +432,191 @@
       },
       "evidence": "In order to pinpoint new N-terminal truncation sites of Tau, we optimized a proteomic approach (Fig. 1C) in brain samples. The whole range of Tau species was immunoprecipitated (IP) from protein extracts with the Tau-5 antibody, which recognizes amino acid residues 218–225. As shown by WB analysis (Fig. S1), Tau-5 IP allows the purification of full-length Tau (FL-Tau) as well as N- and C-terminally truncated Tau and aggregated species, which display lower and higher molecular weights, respectively. These new N-terminal sites were scattered across the Tau sequence (Fig. 1D), and except for Ala2, have not been described before.",
       "key": "9c217f38e43d79f0ea24ee9c15484feb580ad29cf8c69e3901ef1312cd2ca24cb5ed387e54e12f3b640e7b8d3174b46fda809ebeed7cdbdc6efdd8effe758dbb",
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+      "line": 164,
       "relation": "isA",
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-      "target": 486
+      "source": 686,
+      "target": 567
     },
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-      "target": 601
+      "source": 567,
+      "target": 686
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@@ -622,21 +636,32 @@
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@@ -656,21 +681,26 @@
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@@ -690,21 +720,32 @@
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@@ -722,42 +763,69 @@
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@@ -765,11 +833,8 @@
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@@ -794,20 +859,26 @@
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@@ -815,11 +886,8 @@
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@@ -844,20 +912,26 @@
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@@ -865,11 +939,8 @@
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@@ -894,81 +965,82 @@
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-          "Maurage CA",
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-          "Sambo AV",
-          "Sergeant N",
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     {
       "key": "233175822018f00d5bba682b71d9619e69b1ffcbc798ef965753963c52979fe53377c90e3fec2a692a31e92e3e0183cf12a6286f7e77474e51b0e10554f3d71b",
       "relation": "hasVariant",
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     {
-      "citation": {
-        "authors": [
-          "Feng Y",
-          "Jiang J",
-          "Liu XH",
-          "Liu ZC",
-          "Luo HB",
-          "Shu XJ",
-          "Wang JZ",
-          "Wang XC",
-          "Xia YY",
-          "Xiong YS",
-          "Ye K",
-          "Yin G",
-          "Yu G",
-          "Zeng K"
-        ],
-        "date": "2014-11-18",
-        "first": "Luo HB",
-        "last": "Wang JZ",
-        "name": "Proceedings of the National Academy of Sciences of the United States of America",
-        "pages": "16586-91",
-        "reference": "25378699",
-        "title": "SUMOylation at K340 inhibits tau degradation through deregulating its phosphorylation and ubiquitination.",
-        "type": "PubMed",
-        "volume": "111"
-      },
-      "evidence": "Furthermore, the enhanced SUMO-immunoreactivity, costained with the hyperphosphorylated tau, is detected in cerebral cortex of the AD brains, and β-amyloid exposure of rat primary hippocampal neurons induces a dose-dependent SUMOylation of the hyperphosphorylated tau. Our findings suggest that tau SUMOylation reciprocally stimulates its phosphorylation and inhibits the ubiquitination-mediated tau degradation, which provides a new insight into the AD-like tau accumulation.",
-      "key": "bf785e3f7946efe72898b8897c4aac73bddf83f152ae446ae015717ea07c3352a43772c0834f7bbd4fa88104b0af3378a9f67f5292ebbf185a7311fa452320d2",
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-    {
-      "citation": {
-        "authors": [
-          "Albrecht F",
-          "Arendt T",
-          "Arsalan-Werner A",
-          "Flach K",
-          "Goedert M",
-          "Herrmann L",
-          "Hilbrich I",
-          "Holzer M",
-          "Ramminger E"
-        ],
-        "date": "2014-09-01",
-        "first": "Flach K",
-        "last": "Holzer M",
-        "name": "Biochimica et biophysica acta",
-        "pages": "1527-38",
-        "reference": "24905733",
-        "title": "Axotrophin/MARCH7 acts as an E3 ubiquitin ligase and ubiquitinates tau protein in vitro impairing microtubule binding.",
-        "type": "PubMed",
-        "volume": "1842"
-      },
-      "evidence": "We show that axotrophin/MARCH7, a RING-variant domain containing protein with similarity to E3 ubiquitin ligases interacts with tau. We find here that tau becomes mono-ubiquitinated by recombinant tau-interacting RING-variant domain, which diminishes its microtubule-binding. Tau becomes mono-ubiquitinated by recombinant tau-interacting RING-variant domain reducing microtubule-binding.",
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       "relation": "hasVariant",
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       "key": "758dbf2f96744f2ed36fa0683491d58ec9e2af98512023191f10fb0b013f31d68aec6b065498cbdf5408faf20e20379de4fcdc861f456f5f3c04c231f99d769b",
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       "key": "48d009066693f0c5cf1d09a48e396a171f7616a3073a7681f306857eb792aef0af1ec0f0ae3f5cce7d27d47836b23bdecd8678ba6f18c411fc7af7b5f8e7c594",
       "relation": "hasVariant",
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-        "authors": [
-          "Ando K",
-          "Blum D",
-          "Bretteville A",
-          "Buée L",
-          "Bégard S",
-          "Bélarbi K",
-          "Caillet-Boudin ML",
-          "Demey-Thomas E",
-          "Dourlen P",
-          "Drobecq H",
-          "Eddarkaoui S",
-          "Galas MC",
-          "Ghestem A",
-          "Hamdane M",
-          "Landrieu I",
-          "Lippens G",
-          "Maurage CA",
-          "Melnyk P",
-          "Sambo AV",
-          "Sergeant N",
-          "Smet C",
-          "Verdier Y",
-          "Vingtdeux V",
-          "Vinh J"
-        ],
-        "date": "2013-03-01",
-        "first": "Ando K",
-        "last": "Buée L",
-        "name": "Neurobiology of aging",
-        "pages": "757-69",
-        "reference": "22926167",
-        "title": "Tau pathology modulates Pin1 post-translational modifications and may be relevant as biomarker.",
-        "type": "PubMed",
-        "volume": "34"
-      },
-      "evidence": "Because Pin1 has at least 4 major isovariants in addition to the native polypeptide, this means that Pin1 has 4 (possibly more) posttranslational modifications including phosphorylation at 3 sites (Ser16 and Ser65/Ser71), N-acetylation (amino-terminus and Lys46) and oxidation (Met130 and 146). In all experimental conditions, including tau-overexpressing cells, tau transgenic mice and AD brains, global levels of Pin1 posttranslational modifications were decreased compared with control conditions.",
-      "key": "105c0efb8a24fe685b7cb1758376a90916c0ce3c71330c1b0132b0e3eba5146796a1286276e083db208185d30ce7911319c7c3bd978535a21621dcce5ba562f0",
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-          "Ando K",
-          "Blum D",
-          "Bretteville A",
-          "Buée L",
-          "Bégard S",
-          "Bélarbi K",
-          "Caillet-Boudin ML",
-          "Demey-Thomas E",
-          "Dourlen P",
-          "Drobecq H",
-          "Eddarkaoui S",
-          "Galas MC",
-          "Ghestem A",
-          "Hamdane M",
-          "Landrieu I",
-          "Lippens G",
-          "Maurage CA",
-          "Melnyk P",
-          "Sambo AV",
-          "Sergeant N",
-          "Smet C",
-          "Verdier Y",
-          "Vingtdeux V",
-          "Vinh J"
-        ],
-        "date": "2013-03-01",
-        "first": "Ando K",
-        "last": "Buée L",
-        "name": "Neurobiology of aging",
-        "pages": "757-69",
-        "reference": "22926167",
-        "title": "Tau pathology modulates Pin1 post-translational modifications and may be relevant as biomarker.",
-        "type": "PubMed",
-        "volume": "34"
-      },
-      "evidence": "Because Pin1 has at least 4 major isovariants in addition to the native polypeptide, this means that Pin1 has 4 (possibly more) posttranslational modifications including phosphorylation at 3 sites (Ser16 and Ser65/Ser71), N-acetylation (amino-terminus and Lys46) and oxidation (Met130 and 146). In all experimental conditions, including tau-overexpressing cells, tau transgenic mice and AD brains, global levels of Pin1 posttranslational modifications were decreased compared with control conditions.",
-      "key": "67f16cc08ce4823fc7e6e99a676be4864d0db004d29bed879377e0c6d78271b5a4bc4b6fada078267c1514ff2da3ce51d52261d031ac4b247d35737ef7f119ef",
-      "line": 3978,
-      "relation": "negativeCorrelation",
-      "source": 486,
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-    {
-      "citation": {
-        "authors": [
-          "Ando K",
-          "Blum D",
-          "Bretteville A",
-          "Buée L",
-          "Bégard S",
-          "Bélarbi K",
-          "Caillet-Boudin ML",
-          "Demey-Thomas E",
-          "Dourlen P",
-          "Drobecq H",
-          "Eddarkaoui S",
-          "Galas MC",
-          "Ghestem A",
-          "Hamdane M",
-          "Landrieu I",
-          "Lippens G",
-          "Maurage CA",
-          "Melnyk P",
-          "Sambo AV",
-          "Sergeant N",
-          "Smet C",
-          "Verdier Y",
-          "Vingtdeux V",
-          "Vinh J"
-        ],
-        "date": "2013-03-01",
-        "first": "Ando K",
-        "last": "Buée L",
-        "name": "Neurobiology of aging",
-        "pages": "757-69",
-        "reference": "22926167",
-        "title": "Tau pathology modulates Pin1 post-translational modifications and may be relevant as biomarker.",
-        "type": "PubMed",
-        "volume": "34"
-      },
-      "evidence": "Because Pin1 has at least 4 major isovariants in addition to the native polypeptide, this means that Pin1 has 4 (possibly more) posttranslational modifications including phosphorylation at 3 sites (Ser16 and Ser65/Ser71), N-acetylation (amino-terminus and Lys46) and oxidation (Met130 and 146). In all experimental conditions, including tau-overexpressing cells, tau transgenic mice and AD brains, global levels of Pin1 posttranslational modifications were decreased compared with control conditions.",
-      "key": "cb126746dd9ca1eb10ae95a8370765c85e9177cb7c0dab9405e00f1ccb718a93f97bfc283f39db8580fcea01418ffafdab45f6c4f25aadd701a46aecc595feed",
-      "line": 3980,
-      "relation": "negativeCorrelation",
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-      "target": 648
+      "source": 567,
+      "target": 704
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "ExpMethod": {
           "in vitro": true
         },
@@ -2871,17 +2143,25 @@
         "type": "PubMed",
         "volume": "36"
       },
-      "evidence": "We were prompted to carry out this study because Acr is mainly localized in the neurons [54], is found in association with NFTs and dystrophic neurites surrounding senile plaques [55], is highly toxic to neurons, is found elevated 2–5 fold in affected regions of AD brain. EC can sequester highly reactive and toxic byproducts of oxidation such as acrolein.",
-      "key": "e457c6f8f2b075ad8deec9b2d780da3df00ffa5b53b70fec614188c6cead2ea506c0a5e39152582adc7388ce847f5abc8e186ac087c0f92655ef785bc4f62d7b",
-      "line": 438,
+      "evidence": "We were prompted to carry out this study because Acr is mainly localized in the neurons [54], is found in association with NFTs and dystrophic neurites surrounding senile plaques [55], is highly toxic to neurons, is found elevated 2–5 fold in affected regions of AD brain [33], and has been shown to increase tau phosphorylation at pathological sites, attributed to activation of both GSK3beta and the stress activated kinase p38 [56], which possibly promotes tau aggregation [57].",
+      "key": "95596c9f4c34eab16d9ea7cd6bc53447e2ee337a1ece4e37196ea99de996167ece803634f1c7a4bcc75cd7f6b840097a168b8044531ebae57c1abd708ae22c93",
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       "object": {
         "modifier": "Activity"
       },
-      "relation": "positiveCorrelation",
-      "source": 80,
-      "target": 40
+      "relation": "association",
+      "source": 94,
+      "target": 48
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHDisease": {
+          "Supranuclear Palsy, Progressive": true
+        }
+      },
       "citation": {
         "authors": [
           "Halverson RA",
@@ -2903,12 +2183,20 @@
       },
       "evidence": "Protein and mRNA levels of transglutaminase 1 were increased in globus pallidus of PSP as compared to controls. There were also significantly higher mRNA levels of the short form of transglutaminase 2 in globus pallidus of PSP (974% of control). Transglutaminase 1 mRNA and the long isoform of transglutaminase 2 mRNA (2212% of control) were significantly higher in PSP in the dentate of cerebellum. Together, these findings suggest that transglutaminase 1 and 2 enzymes may be involved in the formation and/or stabilization of neurofibrillary tangles in selectively vulnerable brain regions in PSP. These transglutaminases may be potential targets for therapeutic intervention.",
       "key": "cc18e6bd74307b83e1ba331809409ad1d4fd13b74b3aed4e5ca1bdca1b24f999c392c035b322044eb0bba0472674d767013c96bb6a275252ab70d39333aedc58",
-      "line": 718,
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       "relation": "positiveCorrelation",
-      "source": 80,
-      "target": 729
+      "source": 94,
+      "target": 819
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHDisease": {
+          "Supranuclear Palsy, Progressive": true
+        }
+      },
       "citation": {
         "authors": [
           "Halverson RA",
@@ -2930,58 +2218,19 @@
       },
       "evidence": "Protein and mRNA levels of transglutaminase 1 were increased in globus pallidus of PSP as compared to controls. There were also significantly higher mRNA levels of the short form of transglutaminase 2 in globus pallidus of PSP (974% of control). Transglutaminase 1 mRNA and the long isoform of transglutaminase 2 mRNA (2212% of control) were significantly higher in PSP in the dentate of cerebellum. Together, these findings suggest that transglutaminase 1 and 2 enzymes may be involved in the formation and/or stabilization of neurofibrillary tangles in selectively vulnerable brain regions in PSP. These transglutaminases may be potential targets for therapeutic intervention.",
       "key": "8485350c0c03924e8171f9865e2bbd2e1424ef256239512a858b037671a5bf9a05929a1c6289fdd77425c52e9ebb2bf27dea7b5eb7846d5e6dfd3ee354d71c98",
-      "line": 719,
-      "relation": "positiveCorrelation",
-      "source": 80,
-      "target": 730
-    },
-    {
-      "annotations": {
-        "Anatomy": {
-          "prefrontal cortex": true
-        },
-        "Disease": {
-          "Alzheimer's disease": true
-        },
-        "Method": {
-          "Immunoblotting": true,
-          "Transglutaminase Assay": true
-        }
-      },
-      "citation": {
-        "authors": [
-          "Cox TM",
-          "Johnson GV",
-          "Lockhart JP",
-          "Miller ML",
-          "Powers RE",
-          "Zinnerman MD"
-        ],
-        "date": "1997-03-21",
-        "first": "Johnson GV",
-        "last": "Powers RE",
-        "name": "Brain research",
-        "pages": "323-9",
-        "reference": "9099822",
-        "title": "Transglutaminase activity is increased in Alzheimer's disease brain.",
-        "type": "PubMed",
-        "volume": "751"
-      },
-      "evidence": "Total transglutaminase activity was significantly higher in the Alzheimer's disease prefrontal cortex compared to control. In addition the levels of tissue transglutaminase, as determined by quantitative immunoblotting, were elevated approximately 3-fold in Alzheimer's disease prefrontal cortex compared to control. To our knowledge, this is the first demonstration that transglutaminase is increased in Alzheimer's disease brain. There were no significant differences in transglutaminase activity or levels in the cerebellum between control and Alzheimer's disease cases. Because the elevation of transglutaminase in the Alzheimer's disease samples occurred in the prefrontal cortex, where neurofibrillary pathology is usually abundant, and not in the cerebellum, which is usually spared in Alzheimer's disease, it can be suggested that transglutaminase could be a contributing factor in neurofibrillary tangle formation.",
-      "key": "ec4faa0db172566c4614e4f4886f67601ee6070039df4ed58ec492f4723948bf111a17e60277416b14d4ac65ddb396084c1d6c7fcbfe147f18ffc03710c9339f",
-      "line": 769,
-      "object": {
-        "modifier": "Activity"
-      },
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       "relation": "positiveCorrelation",
-      "source": 80,
-      "target": 730
+      "source": 94,
+      "target": 820
     },
     {
       "annotations": {
         "Anatomy": {
           "globus pallidus": true,
           "pons": true
+        },
+        "Confidence": {
+          "Medium": true
         }
       },
       "citation": {
@@ -3003,13 +2252,13 @@
       },
       "evidence": "There were significantly higher levels of epsilon-(gamma-glutamyl) lysine cross-linking of PHF-tau in globus pallidus and pons regions of PSP cases compared to barely detectable cross-links in controls. The occipital cortex, an area spared from neurofibrillary pathology in PSP, showed no detectable cross-linking of PHF-tau protein in either PSP cases or control cases. Double-label immunofluorescence demonstrated the colocalization of the cross-link and PHF-tau in NFT in pons of PSP Previous studies and present data are consistent with the hypothesis that transglutaminase-induced cross-linking may be a factor contributing to the abnormal polymerization and stabilization of tau in straight and PHFs leading to neurofibrillary tangle formation in neurodegenerative diseases, including PSP and AD.",
       "key": "90c407ab9db386668a11537f7dee78d0e2b498806c8bc03eef2ab3b2114402b10137a84870d31cc80465f307d27b041f5be8ac92280c31e3d1a3e63e84215531",
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       "object": {
         "modifier": "Activity"
       },
       "relation": "positiveCorrelation",
-      "source": 80,
-      "target": 267
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+      "target": 337
     },
     {
       "annotations": {
@@ -3017,6 +2266,9 @@
           "frontal cortex": true,
           "parietal cortex": true
         },
+        "Confidence": {
+          "High": true
+        },
         "Disease": {
           "Alzheimer's disease": true
         },
@@ -3047,19 +2299,22 @@
       },
       "evidence": "The number of neurons that are immunoreactive with an antibody directed at the epsilon-(gamma-glutamyl)lysine bond was significantly higher in AD cortex compared with age-matched controls and schizophrenics. PHF tau-directed antibodies AT8, MC-1 and PHF-1 co-localized with epsilon(gamma-glutamyl)lysine immunolabeling in AD NFT. Immunoaffinity purification and immunoblotting experiments demonstrated that PHF tau contains epsilon(gamma-glutamyl)lysine bonds in parietal and frontal cortex in AD. In control cases with NFT present in the entorhinal cortex and hippocampus, indicative of Braak and Braak stage II, epsilon(gamma-glutamyl)lysine bonds were present in PHF tau in parietal and frontal cortex, despite the lack of microscopically detectable NFT or senile plaques in these cortical regions. The presence of PHF tau with epsilon(gamma-glutamyl)lysine bonds in brain regions devoid of NFT in stage II (but regions, which would be expected to contain NFT in stage III) suggests that these bonds occur early in the formation of NFT.",
       "key": "671e03ac9b088093aa346f6c5334086601fed058e12c09ebbd02012fdb791638290954a4ba208db5e85643388770d0eee6dd4d6ddacdb1d8cf9a8834f4eaf7bf",
-      "line": 748,
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       "object": {
         "modifier": "Activity"
       },
       "relation": "positiveCorrelation",
-      "source": 80,
-      "target": 267
+      "source": 94,
+      "target": 337
     },
     {
       "annotations": {
         "Anatomy": {
           "hippocampal formation": true
         },
+        "Confidence": {
+          "High": true
+        },
         "Disease": {
           "Alzheimer's disease": true
         }
@@ -3083,43 +2338,206 @@
       },
       "evidence": "Degenerating neurons from the AD hippocampus, compared to neurons from the normal aged hippocampus, exhibited increased immunoreactivity for TGase and demonstrated co-labeling for PHF1 and anti-TGase. Our results suggest that TGase may be associated with the neurofibrillary degeneration observed in AD, thereby implicating TGase as a potential factor in the pathogenesis of Alzheimer's disease.",
       "key": "95bda13980a5fff6c945babdb5d2053ebc0aa977bb2e2a40da5bfc3ec851aeddff373042a4268ab85ea0b03e5e867c6c778eeccc2e47f0e9be92a937751a8cc6",
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       "object": {
         "modifier": "Activity"
       },
       "relation": "positiveCorrelation",
-      "source": 80,
-      "target": 267
+      "source": 94,
+      "target": 337
     },
     {
+      "annotations": {
+        "Anatomy": {
+          "globus pallidus": true,
+          "pons": true
+        },
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
-          "Kawakami F",
-          "Ohtsuki K",
-          "Suzuki K"
+          "Lee JM",
+          "Muma NA",
+          "Troncoso JC",
+          "Zemaitaitis MO"
         ],
-        "date": "2008-02-01",
-        "first": "Kawakami F",
-        "last": "Ohtsuki K",
-        "name": "Biological &amp; pharmaceutical bulletin",
-        "pages": "193-200",
-        "reference": "18239272",
-        "title": "A novel consensus phosphorylation motif in sulfatide- and cholesterol-3-sulfate-binding protein substrates for CK1 in vitro.",
+        "date": "2000-11-01",
+        "first": "Zemaitaitis MO",
+        "last": "Muma NA",
+        "name": "Journal of neuropathology and experimental neurology",
+        "pages": "983-9",
+        "reference": "11089576",
+        "title": "Transglutaminase-induced cross-linking of tau proteins in progressive supranuclear palsy.",
         "type": "PubMed",
-        "volume": "31"
+        "volume": "59"
+      },
+      "evidence": "There were significantly higher levels of epsilon-(gamma-glutamyl) lysine cross-linking of PHF-tau in globus pallidus and pons regions of PSP cases compared to barely detectable cross-links in controls. The occipital cortex, an area spared from neurofibrillary pathology in PSP, showed no detectable cross-linking of PHF-tau protein in either PSP cases or control cases. Double-label immunofluorescence demonstrated the colocalization of the cross-link and PHF-tau in NFT in pons of PSP Previous studies and present data are consistent with the hypothesis that transglutaminase-induced cross-linking may be a factor contributing to the abnormal polymerization and stabilization of tau in straight and PHFs leading to neurofibrillary tangle formation in neurodegenerative diseases, including PSP and AD.",
+      "key": "41af518dcac4d1f1e2617b2bcbadc5a453f20bf35349387daa2f2907c325f50de615df893f6ca42643520215ea6e60b7e41029db7e0f6e7e6d043a75d53fff17",
+      "line": 876,
+      "relation": "positiveCorrelation",
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+    },
+    {
+      "annotations": {
+        "Anatomy": {
+          "globus pallidus": true,
+          "pons": true
+        },
+        "Confidence": {
+          "Medium": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Lee JM",
+          "Muma NA",
+          "Troncoso JC",
+          "Zemaitaitis MO"
+        ],
+        "date": "2000-11-01",
+        "first": "Zemaitaitis MO",
+        "last": "Muma NA",
+        "name": "Journal of neuropathology and experimental neurology",
+        "pages": "983-9",
+        "reference": "11089576",
+        "title": "Transglutaminase-induced cross-linking of tau proteins in progressive supranuclear palsy.",
+        "type": "PubMed",
+        "volume": "59"
+      },
+      "evidence": "There were significantly higher levels of epsilon-(gamma-glutamyl) lysine cross-linking of PHF-tau in globus pallidus and pons regions of PSP cases compared to barely detectable cross-links in controls. The occipital cortex, an area spared from neurofibrillary pathology in PSP, showed no detectable cross-linking of PHF-tau protein in either PSP cases or control cases. Double-label immunofluorescence demonstrated the colocalization of the cross-link and PHF-tau in NFT in pons of PSP Previous studies and present data are consistent with the hypothesis that transglutaminase-induced cross-linking may be a factor contributing to the abnormal polymerization and stabilization of tau in straight and PHFs leading to neurofibrillary tangle formation in neurodegenerative diseases, including PSP and AD.",
+      "key": "2c3070ddb940fd1d9095a60aa740532715440b5e102ce559cc9b4535aa3f3e34a5f397e80bfd2249130813acde115dcbd6c36694474edb748f471aa255b4bd02",
+      "line": 877,
+      "relation": "positiveCorrelation",
+      "source": 94,
+      "target": 1017
+    },
+    {
+      "annotations": {
+        "Anatomy": {
+          "prefrontal cortex": true
+        },
+        "Confidence": {
+          "Medium": true
+        },
+        "Disease": {
+          "Alzheimer's disease": true
+        },
+        "Method": {
+          "Immunoblotting": true,
+          "Transglutaminase Assay": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Cox TM",
+          "Johnson GV",
+          "Lockhart JP",
+          "Miller ML",
+          "Powers RE",
+          "Zinnerman MD"
+        ],
+        "date": "1997-03-21",
+        "first": "Johnson GV",
+        "last": "Powers RE",
+        "name": "Brain research",
+        "pages": "323-9",
+        "reference": "9099822",
+        "title": "Transglutaminase activity is increased in Alzheimer's disease brain.",
+        "type": "PubMed",
+        "volume": "751"
+      },
+      "evidence": "Total transglutaminase activity was significantly higher in the Alzheimer's disease prefrontal cortex compared to control. In addition the levels of tissue transglutaminase, as determined by quantitative immunoblotting, were elevated approximately 3-fold in Alzheimer's disease prefrontal cortex compared to control. To our knowledge, this is the first demonstration that transglutaminase is increased in Alzheimer's disease brain. There were no significant differences in transglutaminase activity or levels in the cerebellum between control and Alzheimer's disease cases. Because the elevation of transglutaminase in the Alzheimer's disease samples occurred in the prefrontal cortex, where neurofibrillary pathology is usually abundant, and not in the cerebellum, which is usually spared in Alzheimer's disease, it can be suggested that transglutaminase could be a contributing factor in neurofibrillary tangle formation.",
+      "key": "f7ea63ba999ec15026c5d8c5153f7c4b89890601db672e098fb0e37b64ffd2e5900c78b2783efec7f918f312f0215898ce662f0e16c55f223d46fa7cfb5bdaa0",
+      "line": 918,
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+      },
+      "relation": "positiveCorrelation",
+      "source": 94,
+      "target": 845
+    },
+    {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Cowburn RF",
+          "Dahllund L",
+          "Gustafsson E",
+          "Lund H",
+          "Malinowsky D",
+          "Strömberg K",
+          "Sunnemark D",
+          "Svensson A"
+        ],
+        "date": "2013-07-01",
+        "first": "Lund H",
+        "last": "Sunnemark D",
+        "name": "Brain pathology (Zurich, Switzerland)",
+        "pages": "378-89",
+        "reference": "23088643",
+        "title": "Tau-tubulin kinase 1 expression, phosphorylation and co-localization with phospho-Ser422 tau in the Alzheimer's disease brain.",
+        "type": "PubMed",
+        "volume": "23"
       },
       "evidence": "The pSer422 antibody displayed an almost identical pattern to that of AT8, in that it stained NFTs (Figure 5A–D), neuropil threads and neuritic plaques (Figure 5E–H)",
-      "key": "6c94c15cdabcbfb71d277e9a7cca4bb919dc5a4d32d4b9b0669ebe89ac38d6d3e1e99f5bb4b54e609b75bcbf9a59457fce2704aca65f392daa6b3e8c721fd876",
-      "line": 1290,
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       "relation": "association",
-      "source": 80,
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+      "target": 415
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+      "annotations": {
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+          "Medium": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Cowburn RF",
+          "Dahllund L",
+          "Gustafsson E",
+          "Lund H",
+          "Malinowsky D",
+          "Strömberg K",
+          "Sunnemark D",
+          "Svensson A"
+        ],
+        "date": "2013-07-01",
+        "first": "Lund H",
+        "last": "Sunnemark D",
+        "name": "Brain pathology (Zurich, Switzerland)",
+        "pages": "378-89",
+        "reference": "23088643",
+        "title": "Tau-tubulin kinase 1 expression, phosphorylation and co-localization with phospho-Ser422 tau in the Alzheimer's disease brain.",
+        "type": "PubMed",
+        "volume": "23"
+      },
+      "evidence": "These data suggest a role for TTBK1 in pre-tangle formation prior to the formation of fibrillar tau and strengthen the idea that tau is phosphorylated at Ser422 at an early intermediate stage in NFT formation.",
+      "key": "5a4d5d57c06a23dd71f77005553ef4f0ee37e71a4dcecc5b8bb83e0a252bd4ddd332ac123ad078027b7a7702cc0c93b9849651e6b00492902fc4f05cf392aba9",
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+      "target": 654
     },
     {
       "annotations": {
         "Braak_Stage": {
           "Stage III": true,
           "Stage VI": true
+        },
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Neocortex": true
         }
       },
       "citation": {
@@ -3149,16 +2567,22 @@
       },
       "evidence": "In a prospective study three different synaptic protein (synaptophysin, SNAP-25 and syntaxin) were found to be progressively decreased in neocortex at Braak stages III-VI [158], NFT-bearing neurons demonstrating, for example, a 35%–57% reduction in synaptophysin mRNA in AD brain [159].",
       "key": "ac2f8c88e709f87dd4fb3b02d36346212a88e7df9968af1b83805ccde3e9f25426ab4175ad7eb0bd1d4c2ca16db70e03d558213242c79ec5caff26a855bebad7",
-      "line": 1683,
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       "relation": "negativeCorrelation",
-      "source": 80,
-      "target": 935
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+      "target": 1045
     },
     {
       "annotations": {
         "Braak_Stage": {
           "Stage III": true,
           "Stage VI": true
+        },
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Neocortex": true
         }
       },
       "citation": {
@@ -3188,16 +2612,22 @@
       },
       "evidence": "In a prospective study three different synaptic protein (synaptophysin, SNAP-25 and syntaxin) were found to be progressively decreased in neocortex at Braak stages III-VI [158], NFT-bearing neurons demonstrating, for example, a 35%–57% reduction in synaptophysin mRNA in AD brain [159].",
       "key": "4cd60e41461bc88cd184d6d00cb126d7dfcc66823bd046399c600d1c5923fdf1ccdeb7d31eb637424150eebdc6dcd76a32128af910fc282298c8864b9ed21f1f",
-      "line": 1684,
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       "relation": "negativeCorrelation",
-      "source": 80,
-      "target": 684
+      "source": 94,
+      "target": 773
     },
     {
       "annotations": {
         "Braak_Stage": {
           "Stage III": true,
           "Stage VI": true
+        },
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Neocortex": true
         }
       },
       "citation": {
@@ -3227,12 +2657,17 @@
       },
       "evidence": "In a prospective study three different synaptic protein (synaptophysin, SNAP-25 and syntaxin) were found to be progressively decreased in neocortex at Braak stages III-VI [158], NFT-bearing neurons demonstrating, for example, a 35%–57% reduction in synaptophysin mRNA in AD brain [159].",
       "key": "a23466e9a65d030c5443aeadac05ecfd0137d241cad0374baa77a36ff0090153818c9a7d2dc1bd08617469b007929cc87fa5349c6917fc94bdcdfdd976c21678",
-      "line": 1685,
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       "relation": "negativeCorrelation",
-      "source": 80,
-      "target": 762
+      "source": 94,
+      "target": 852
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "Ai J",
@@ -3263,95 +2698,192 @@
       },
       "evidence": "The accumulation of p25 involves neurofibrillary tangle (NFT) formation via regulation of tau phosphorylation (Wen et al. 2007; Su and Tsai 2011)",
       "key": "fea943038b13c8418f56411b7779694e815927397f71cf7be66bb412ad0f48b0f968522ff7e8f7d53f43f20eb0789e42c0a4d6488ccb39e2c57f8ae79b2c9eca",
-      "line": 2306,
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       "relation": "positiveCorrelation",
-      "source": 80,
-      "target": 311
+      "source": 94,
+      "target": 388
     },
     {
       "annotations": {
-        "Anatomy": {
-          "CA1 field of hippocampus": true,
-          "CA3 field of hippocampus": true,
-          "cerebral cortex": true,
-          "dentate gyrus granule cell layer": true
-        },
-        "Research_Model": {
-          "hTau E391 transgenic mice": true
+        "Cell_Line": {
+          "N2a": true,
+          "SH-SY5Y": true
         },
-        "Species": {
-          "10090": true
+        "Confidence": {
+          "Medium": true
         }
       },
       "citation": {
         "authors": [
-          "Kraemer BC",
-          "Leverenz JB",
-          "McMillan PJ",
-          "Raskind M",
-          "Robinson L",
-          "Schellenberg G"
+          "Fan SJ",
+          "Huang FI",
+          "Liou JP",
+          "Yang CR"
         ],
-        "date": "2011-11-01",
-        "first": "McMillan PJ",
-        "last": "Schellenberg G",
-        "name": "Journal of neuropathology and experimental neurology",
-        "pages": "1006-19",
-        "reference": "22002427",
-        "title": "Truncation of tau at E391 promotes early pathologic changes in transgenic mice.",
+        "date": "2018-05-29",
+        "first": "Fan SJ",
+        "last": "Yang CR",
+        "name": "Cell death &amp; disease",
+        "pages": "655",
+        "reference": "29844403",
+        "title": "The novel histone de acetylase 6 inhibitor, MPT0G211, ameliorates tau phosphorylation and cognitive deficits in an Alzheimer's disease model.",
         "type": "PubMed",
-        "volume": "70"
+        "volume": "9"
       },
-      "evidence": "E391-3610 mice (higher expressers) exhibit robust somatodendritic distribution of phospho- Ser 202/Thr 205 tau throughout the cortex, in hippocampal CA3 pyramidal neurons, CA1 apical dendrites and cell bodies and dentate granule cells.",
-      "key": "b95d2718e3f9c217747ce3bfa45ce1378fc8db43e671e2c59b1ecd53ac3f9c4a95850b0718dcaa70a7ca506e2f17caa5f00a06dd523cdab74185e0f79d696ca5",
-      "line": 2572,
+      "evidence": "This study aimed to investigate the protective effects and mechanism of the novel HDAC6 inhibitor, MPT0G211, using an AD model. Our results indicated that MPT0G211 significantly reduced tau phosphorylation and aggregation, the processes highly correlated with the formation of NFTs. This HDAC6 inhibitory activity resulted in an increase in acetylated Hsp90, which decreased Hsp90 and HDAC6 binding, causing ubiquitination of phosphorylated tau proteins. In addition, a significant increase of phospho-glycogen synthase kinase-3β (phospho-GSK3β) on Ser9 (the inactive form) through Akt phosphorylation was associated with the inhibition of phospho-tau Ser396 in response to MPT0G211 treatment.",
+      "key": "33cfa15916a6ca8ab88fbc5cc01fa11b241fdc6a7927142785f584bd8d3f42646d8c3574c3d00d30c72786d48f897be009c5430d22546cc92a1a84f15d825bfa",
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       "relation": "positiveCorrelation",
-      "source": 80,
-      "target": 544
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+      "target": 116
     },
     {
       "annotations": {
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-          "CA1 field of hippocampus": true,
-          "CA3 field of hippocampus": true,
-          "cerebral cortex": true,
-          "dentate gyrus granule cell layer": true
-        },
-        "Research_Model": {
-          "hTau E391 transgenic mice": true
-        },
-        "Species": {
-          "10090": true
-        }
+        "Confidence": {
+          "Medium": true
+        }
       },
       "citation": {
         "authors": [
-          "Kraemer BC",
-          "Leverenz JB",
-          "McMillan PJ",
-          "Raskind M",
-          "Robinson L",
-          "Schellenberg G"
+          "Andreadis A",
+          "Binder LI",
+          "Brady ST",
+          "Fu Y",
+          "Kanaan NM",
+          "LaPointe NE",
+          "Morfini GA",
+          "Patterson KR",
+          "Pigino GF",
+          "Song Y"
         ],
-        "date": "2011-11-01",
-        "first": "McMillan PJ",
-        "last": "Schellenberg G",
-        "name": "Journal of neuropathology and experimental neurology",
-        "pages": "1006-19",
-        "reference": "22002427",
-        "title": "Truncation of tau at E391 promotes early pathologic changes in transgenic mice.",
+        "date": "2011-07-06",
+        "first": "Kanaan NM",
+        "last": "Binder LI",
+        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
+        "pages": "9858-68",
+        "reference": "21734277",
+        "title": "Pathogenic forms of tau inhibit kinesin-dependent axonal transport through a mechanism involving activation of axonal phosphotransferases.",
         "type": "PubMed",
-        "volume": "70"
+        "volume": "31"
       },
-      "evidence": "E391-3610 mice (higher expressers) exhibit robust somatodendritic distribution of phospho- Ser 202/Thr 205 tau throughout the cortex, in hippocampal CA3 pyramidal neurons, CA1 apical dendrites and cell bodies and dentate granule cells.",
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-      "line": 2573,
-      "relation": "positiveCorrelation",
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+      "evidence": "Filamentous, but not soluble, forms of wild-type tau inhibit anterograde, kinesin-based fast axonal transport (FAT) by activating axonal protein phosphatase 1 (PP1) and glycogen synthase kinase 3 (GSK3), independent of microtubule binding. Amino acids 2-18 of tau, comprising a phosphatase-activating domain (PAD), are necessary and sufficient for activation of this pathway. Various pathogenic forms of tau displaying increased exposure of PAD inhibited anterograde FAT in squid axoplasm. Immunohistochemical studies using a novel PAD-specific monoclonal antibody in human postmortem tissue indicated that increased PAD exposure represents an early pathogenic event in AD that closely associates in time with AT8 immunoreactivity. We propose a model of pathogenesis in which disease-associated changes in tau conformation lead to increased exposure of PAD, activation of PP1-GSK3, and inhibition of FAT",
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+      "relation": "decreases",
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+          "Medium": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Andreadis A",
+          "Binder LI",
+          "Brady ST",
+          "Fu Y",
+          "Kanaan NM",
+          "LaPointe NE",
+          "Morfini GA",
+          "Patterson KR",
+          "Pigino GF",
+          "Song Y"
+        ],
+        "date": "2011-07-06",
+        "first": "Kanaan NM",
+        "last": "Binder LI",
+        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
+        "pages": "9858-68",
+        "reference": "21734277",
+        "title": "Pathogenic forms of tau inhibit kinesin-dependent axonal transport through a mechanism involving activation of axonal phosphotransferases.",
+        "type": "PubMed",
+        "volume": "31"
+      },
+      "evidence": "Filamentous, but not soluble, forms of wild-type tau inhibit anterograde, kinesin-based fast axonal transport (FAT) by activating axonal protein phosphatase 1 (PP1) and glycogen synthase kinase 3 (GSK3), independent of microtubule binding. Amino acids 2-18 of tau, comprising a phosphatase-activating domain (PAD), are necessary and sufficient for activation of this pathway. Various pathogenic forms of tau displaying increased exposure of PAD inhibited anterograde FAT in squid axoplasm. Immunohistochemical studies using a novel PAD-specific monoclonal antibody in human postmortem tissue indicated that increased PAD exposure represents an early pathogenic event in AD that closely associates in time with AT8 immunoreactivity. We propose a model of pathogenesis in which disease-associated changes in tau conformation lead to increased exposure of PAD, activation of PP1-GSK3, and inhibition of FAT",
+      "key": "6c06f5e132ec6d59a9a9773d13460aa670b8c6a1a948ccd6655c11b0061dbb747ab60c95ce2ebe06115e609ecf66ac6b8142c0743fd4cdd52fe2e99a5a5f7fc5",
+      "line": 4765,
+      "object": {
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+      "relation": "increases",
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+          "Medium": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Andreadis A",
+          "Binder LI",
+          "Brady ST",
+          "Fu Y",
+          "Kanaan NM",
+          "LaPointe NE",
+          "Morfini GA",
+          "Patterson KR",
+          "Pigino GF",
+          "Song Y"
+        ],
+        "date": "2011-07-06",
+        "first": "Kanaan NM",
+        "last": "Binder LI",
+        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
+        "pages": "9858-68",
+        "reference": "21734277",
+        "title": "Pathogenic forms of tau inhibit kinesin-dependent axonal transport through a mechanism involving activation of axonal phosphotransferases.",
+        "type": "PubMed",
+        "volume": "31"
+      },
+      "evidence": "Filamentous, but not soluble, forms of wild-type tau inhibit anterograde, kinesin-based fast axonal transport (FAT) by activating axonal protein phosphatase 1 (PP1) and glycogen synthase kinase 3 (GSK3), independent of microtubule binding. Amino acids 2-18 of tau, comprising a phosphatase-activating domain (PAD), are necessary and sufficient for activation of this pathway. Various pathogenic forms of tau displaying increased exposure of PAD inhibited anterograde FAT in squid axoplasm. Immunohistochemical studies using a novel PAD-specific monoclonal antibody in human postmortem tissue indicated that increased PAD exposure represents an early pathogenic event in AD that closely associates in time with AT8 immunoreactivity. We propose a model of pathogenesis in which disease-associated changes in tau conformation lead to increased exposure of PAD, activation of PP1-GSK3, and inhibition of FAT",
+      "key": "8f09965a9e5e0b00a36d894c3978578c90c4403ec288b09c41bb8080e8796de847ab6b4f146d3f7ab00fe4bb4198a4927a0f8006cabd297c7556cd4a58959de5",
+      "line": 4766,
+      "object": {
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+      "relation": "increases",
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+      "target": 537
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+    {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Ikura T",
+          "Ito N"
+        ],
+        "date": "2013-09-01",
+        "first": "Ikura T",
+        "last": "Ito N",
+        "name": "Protein engineering, design &amp; selection : PEDS",
+        "pages": "539-46",
+        "reference": "23832849",
+        "title": "Peptidyl-prolyl isomerase activity of FK506 binding protein 12 prevents tau peptide from aggregating.",
+        "type": "PubMed",
+        "volume": "26"
+      },
+      "evidence": "We then investigated the function of FK506-binding protein (FKBP) 12, which is known to accumulate in neurofibrillary tangles in vivo, on aggregation of the R3 peptide and found that FKBP12 completely prevented the peptide from aggregating at a concentration ratio of 1 : 4 (peptide:FKBP12). FKBP12 also restored the oligomer of the peptide to its monomeric status. Mutational studies on the catalytic center of FKBP12 indicated that peptidyl-prolyl isomerase activity of FKBP12 was essential for prevention of aggregation. Assuming that the propensity of aggregation of the peptide is different in each cis-/trans-isomer, we propose that the aggregation behavior of the R3 peptide can be theoretically described with a simple kinetic scheme, in which only the cis-isomer can aggregate and FKBP12 catalyzes isomerization of the peptide in both the monomeric and aggregative states.",
+      "key": "92bcd72fd6c18e28c94370a239b7eed2e9998092ebca668cd550f9c62124fe0c91fc693eb7f487de9dd527bf2e8e4854bd50eae61e2e7b6c656b9331234759a7",
+      "line": 4953,
+      "relation": "association",
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+      "target": 529
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Disease": {
           "Alzheimer's disease": true
         }
@@ -3387,11 +2919,14 @@
       "key": "ad3dcfc05f5602eca8a9c3a78fd0dac590d11bbfe56e8328a4f63df3dafca72350a8b5135383f43055949a2619e882eabc61621a8adb439cf6962cf2cd959b66",
       "line": 111,
       "relation": "partOf",
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+      "target": 94
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Disease": {
           "Alzheimer's disease": true
         }
@@ -3427,11 +2962,14 @@
       "key": "d63890ce542d2ffefb76605a5b5dc2d6294ccf64c9f348a0012408845225bea59445f1297984d23cb88fd187427f6f325bb20b8909428c2385321f59e26e4366",
       "line": 117,
       "relation": "positiveCorrelation",
-      "source": 602,
-      "target": 908
+      "source": 687,
+      "target": 1017
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Disease": {
           "Alzheimer's disease": true
         }
@@ -3467,11 +3005,14 @@
       "key": "ce08d9d1f9fa77d57b647b46d52a13e53f3efcb5597d7379229f6223121d717c5baeada982d369d2bf1732cfa1ced5d805bdea26ed500ac2b2f6db9ae36b95fc",
       "line": 112,
       "relation": "partOf",
-      "source": 603,
-      "target": 80
+      "source": 688,
+      "target": 94
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Disease": {
           "Alzheimer's disease": true
         }
@@ -3507,11 +3048,14 @@
       "key": "3a319ce8af83552ec0634eaaf77f081a486492d30dc2756e1c3aafa51f83677e290cf3aa7d9c98bff164178a63076e90f198b54c197a737f790a58ea636ee244",
       "line": 118,
       "relation": "positiveCorrelation",
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+      "target": 1017
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Disease": {
           "Alzheimer's disease": true
         }
@@ -3547,52 +3091,14 @@
       "key": "ee8e957a2e5d15c1c28eb6ae85a58f29df11b6154249050a41e48d75d0d7d9c5ccbcbff9be900c777db726f14a8d6baa2a8bb852792ab9f2afd7b3db55fd95e3",
       "line": 113,
       "relation": "partOf",
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     {
       "annotations": {
-        "Anatomy": {
-          "CA1 field of hippocampus": true,
-          "CA3 field of hippocampus": true,
-          "cerebral cortex": true,
-          "dentate gyrus granule cell layer": true
-        },
-        "Research_Model": {
-          "hTau E391 transgenic mice": true
+        "Confidence": {
+          "High": true
         },
-        "Species": {
-          "10090": true
-        }
-      },
-      "citation": {
-        "authors": [
-          "Kraemer BC",
-          "Leverenz JB",
-          "McMillan PJ",
-          "Raskind M",
-          "Robinson L",
-          "Schellenberg G"
-        ],
-        "date": "2011-11-01",
-        "first": "McMillan PJ",
-        "last": "Schellenberg G",
-        "name": "Journal of neuropathology and experimental neurology",
-        "pages": "1006-19",
-        "reference": "22002427",
-        "title": "Truncation of tau at E391 promotes early pathologic changes in transgenic mice.",
-        "type": "PubMed",
-        "volume": "70"
-      },
-      "evidence": "E391-3610 mice (higher expressers) exhibit robust somatodendritic distribution of phospho- Ser 202/Thr 205 tau throughout the cortex, in hippocampal CA3 pyramidal neurons, CA1 apical dendrites and cell bodies and dentate granule cells.",
-      "key": "2cfdd6aea28bbb3b4ac2d6271e038e63ad34220dbb22c9ba08666d017925e292573beae0171d97584f3a73e6a2ba06c4734b08528fb978804d27e26ac962396f",
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         "Disease": {
           "Alzheimer's disease": true
         }
@@ -3628,14 +3134,17 @@
       "key": "76560eadf5f0bd560ea8fcd6d15b3ed4fcf1803fecf93c0fd485206d9642346c5f3cd642d2df925653e9f7851740e06a191b6cf35b8c34e2c2c0fd2e1fccf1af",
       "line": 119,
       "relation": "positiveCorrelation",
-      "source": 608,
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     },
     {
       "annotations": {
         "Anatomy": {
           "cerebral cortex": true
         },
+        "Confidence": {
+          "High": true
+        },
         "Method": {
           "Immunoprecipitation": true,
           "Liquid Chromatography": true,
@@ -3675,12 +3184,17 @@
       },
       "evidence": "In order to pinpoint new N-terminal truncation sites of Tau, we optimized a proteomic approach (Fig. 1C) in brain samples. The whole range of Tau species was immunoprecipitated (IP) from protein extracts with the Tau-5 antibody, which recognizes amino acid residues 218–225. As shown by WB analysis (Fig. S1), Tau-5 IP allows the purification of full-length Tau (FL-Tau) as well as N- and C-terminally truncated Tau and aggregated species, which display lower and higher molecular weights, respectively. These new N-terminal sites were scattered across the Tau sequence (Fig. 1D), and except for Ala2, have not been described before.",
       "key": "efea7439d516ab5c59cdc43bf8ad31759115c8ba9c98e815fec257cb51c0d8948e88be3c945a89dc2aa41a37ebe70924fbfabe19068410a5d649a436d5140fa7",
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       "relation": "isA",
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     },
     {
+      "annotations": {
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+          "High": true
+        }
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       "citation": {
         "authors": [
           "Babić Leko M",
@@ -3708,10 +3222,10 @@
       },
       "evidence": "The tau fragment first isolated from the PHF core is approximately 100 amino acids in length. Its N-terminus was defined by sequence analysis [30,56], and its C-terminus was defined by epitope mapping of MN423. Immunoreactivity was shown to depend on a specific C-terminal trunctation at Glu391 [33,150].",
       "key": "9a0f7707051f0c221b8e44c17712a7832a0cb109a5e3b44894bd39ece8609907922b3826e4aa0fe8e5428d2687973b0c8f7d9d825073755c1a9ec3cbe9c146c7",
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     {
       "annotations": {
@@ -3721,6 +3235,9 @@
           "cerebral cortex": true,
           "dentate gyrus granule cell layer": true
         },
+        "Confidence": {
+          "Medium": true
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         "Research_Model": {
           "hTau E391 transgenic mice": true
         },
@@ -3749,10 +3266,10 @@
       },
       "evidence": "E391-3610 mice (higher expressers) exhibit robust somatodendritic distribution of phospho- Ser 202/Thr 205 tau throughout the cortex, in hippocampal CA3 pyramidal neurons, CA1 apical dendrites and cell bodies and dentate granule cells.",
       "key": "f4f54bdd83c2bf669bab3c5bcb40562447da359a76f0b3e11a3fed00cbd97b0348f43aae3c205632817470aad9c9471416cece5bc8a8d854bb22d862d44368d3",
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     {
       "annotations": {
@@ -3762,6 +3279,9 @@
           "cerebral cortex": true,
           "dentate gyrus granule cell layer": true
         },
+        "Confidence": {
+          "Medium": true
+        },
         "Research_Model": {
           "hTau E391 transgenic mice": true
         },
@@ -3790,13 +3310,16 @@
       },
       "evidence": "E391-3610 mice (higher expressers) exhibit robust somatodendritic distribution of phospho- Ser 202/Thr 205 tau throughout the cortex, in hippocampal CA3 pyramidal neurons, CA1 apical dendrites and cell bodies and dentate granule cells.",
       "key": "758e12101438d25474f92da5fbe96bc00076c4ee6f5e4491546bd4299a36c5273cc6df59b032068bf2f7fc48d31626882725717c4a2ca14969ac39822749cc7d",
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       "relation": "positiveCorrelation",
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-      "target": 547
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+      "target": 632
     },
     {
       "annotations": {
+        "Confidence": {
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         "Disease": {
           "Alzheimer's disease": true
         }
@@ -3832,11 +3355,14 @@
       "key": "eac9ddd86d0cab51c024641dd2af71e6445973eb207e81888bec65b174a524291c661f98135c3c56f9706f6589f4aaa59c6c71774262d7bfa1b470121a91992c",
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     {
       "annotations": {
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         "Disease": {
           "Alzheimer's disease": true
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@@ -3872,11 +3398,17 @@
       "key": "6dae651b7565e6eee5c2d42d6feb78b05865f9b02daa2a4565b508468a1cfa5f3acceeaea2f918c6778a81a26d1b60645ffa3442c17328eb2e6aa0c98aef71d2",
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       "relation": "positiveCorrelation",
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+      "target": 1017
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "MeSHDisease": {
           "Chronic Traumatic Encephalopathy": true
         },
@@ -3913,13 +3445,19 @@
       },
       "evidence": "We performed immunohistochemistry and immunofluorescence on fixed brain sections and biochemical analysis of fresh brain extracts to characterize the presence of PAD-exposed tau (TNT1 antibody), tau oligomers (TOC1 antibody), tau phosphorylated at S422 (pS422 antibody), and tau truncated at D421 (TauC3 antibody) in the brains of 9-11 cases with CTE and cases of nondemented aged controls and AD (Braak VI) (n = 6, each). These 4 markers are particularly useful in understanding potential posttraumatic events in CTE because PAD exposure impairs axonal transport (24), oligomers confer toxicity (28, 38–40), pS422 correlates with cognitive decline (15), and D421 truncated tau may be related to cell toxicity (41, 42). All 3 early tau markers (ie, TNT1, TOC1, and pS422) were present in CTE and displayed extensive colocalization in perivascular tau lesions that are considered diagnostic for CTE.",
       "key": "c95470205ba510a37b07761ac7893acbdf795d61b3c2b37726454799db992b5acb7650be99f5e6c9a14afb07dbbcffd39fcfd3ca9400b18e090010c723a2b661",
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       "relation": "biomarkerFor",
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-      "target": 910
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+      "target": 1019
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "MeSHDisease": {
           "Chronic Traumatic Encephalopathy": true
         },
@@ -3955,14 +3493,17 @@
         "volume": "75"
       },
       "evidence": "We performed immunohistochemistry and immunofluorescence on fixed brain sections and biochemical analysis of fresh brain extracts to characterize the presence of PAD-exposed tau (TNT1 antibody), tau oligomers (TOC1 antibody), tau phosphorylated at S422 (pS422 antibody), and tau truncated at D421 (TauC3 antibody) in the brains of 9-11 cases with CTE and cases of nondemented aged controls and AD (Braak VI) (n = 6, each). These 4 markers are particularly useful in understanding potential posttraumatic events in CTE because PAD exposure impairs axonal transport (24), oligomers confer toxicity (28, 38–40), pS422 correlates with cognitive decline (15), and D421 truncated tau may be related to cell toxicity (41, 42). All 3 early tau markers (ie, TNT1, TOC1, and pS422) were present in CTE and displayed extensive colocalization in perivascular tau lesions that are considered diagnostic for CTE.",
-      "key": "b21fe7fa6f6be8ed9376f1ab862833dd7d6e3dae2d782a18c230401ef2c0ed75c6cb22049a497beaa601b3208c4b919268f3431028cc7c5e2d8ccd9eea768954",
-      "line": 235,
-      "relation": "positiveCorrelation",
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-      "target": 368
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+      "relation": "association",
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+      "target": 1014
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     {
       "annotations": {
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+          "High": true
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         "Disease": {
           "Alzheimer's disease": true
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@@ -3998,11 +3539,14 @@
       "key": "2c9d372a6fa17347d826895992c322f7a6f1084209a3791dce11df46fef4b65b6c2d0b1d2eacad5fa2144605369de16cad1edf3483fb3e4c9271d853e89ae2ca",
       "line": 116,
       "relation": "positiveCorrelation",
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+      "target": 686
     },
     {
       "annotations": {
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         "Disease": {
           "Alzheimer's disease": true
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@@ -4038,11 +3582,14 @@
       "key": "16a2cc5583be6798308c7745bffac7500963bca8fd323bad1b2e7d13baf0b3166a1526c5891dd0b339f9c0a498fdc7f618aea1a72aaca322d21e4646a445d97f",
       "line": 117,
       "relation": "positiveCorrelation",
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-      "target": 602
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     },
     {
       "annotations": {
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         "Disease": {
           "Alzheimer's disease": true
         }
@@ -4078,11 +3625,14 @@
       "key": "370a8242545921b8416d35aa35c2541e6d5763598cfcb1e8c3a963d75eaa0a150ca96b307be932d12a0356deec618fb548a1fd13b2656306a4e8b14b74b11885",
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       "relation": "positiveCorrelation",
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-      "target": 603
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     {
       "annotations": {
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         "Disease": {
           "Alzheimer's disease": true
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@@ -4118,11 +3668,14 @@
       "key": "5b95292768d50a6abc98f1e6226be49d22b904065e6032d43bc77a2ea8c8d35fd45cda59fe31341aada363d9740da522522541e5d32f61fb1ccafd7faecfef80",
       "line": 119,
       "relation": "positiveCorrelation",
-      "source": 908,
-      "target": 608
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+      "target": 693
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Disease": {
           "Alzheimer's disease": true
         }
@@ -4158,14 +3711,64 @@
       "key": "c477f96c01470d97bc91ade47293358a99cabdadfc79a954657a44fda2766acdb603b7f8fc7893dd827c008c3a18faec288db9960a93ada6569141258224538d",
       "line": 120,
       "relation": "positiveCorrelation",
-      "source": 908,
-      "target": 604
+      "source": 1017,
+      "target": 689
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
+        "Method": {
+          "CD Spectroscopy": true,
+          "Liquid Chromatography": true,
+          "Mass Spectrometry": true,
+          "Tau aggregation assay": true,
+          "Tubulin polymerization assay, light scattering method": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Clark DJ",
+          "Cooper GL",
+          "Funk KE",
+          "Kuret J",
+          "Liao Z",
+          "Schafer KN",
+          "Thomas SN",
+          "Yang AJ"
+        ],
+        "date": "2014-08-15",
+        "first": "Funk KE",
+        "last": "Kuret J",
+        "name": "The Biochemical journal",
+        "pages": "77-88",
+        "reference": "24869773",
+        "title": "Lysine methylation is an endogenous post-translational modification of tau protein in human brain and a modulator of aggregation propensity.",
+        "type": "PubMed",
+        "volume": "462"
+      },
+      "evidence": "An example of a spectrum identifying K311 as a site of dimethylation at 2.2 ppm mass accuracy is shown in Fig. 2B. This residue was reported as a possible methylation site in AD-brain derived tau protein on the basis of Edman degradation years ago [36]. It resides within the “PHF6” motif of the MTBR, which has been reported to mediate the aggregation propensity of recombinant monomeric tau in vitro [6, 37]. Other methylation sites within the MTBR include K259, K290, and K353, each of which lies in a KXGS motif associated with AMP-activated protein kinase mediated regulation of microtubule binding [38]. Within the N-terminal projection domain, Lys methylation was detected at K24, K44, K67, and K190 (Fig. 1).",
+      "key": "6aa20043ef4cd552041169855a2411c9397331be6c37dde4ce961ccd47f5fb5b93e4301cb2fe7ff0abea48ccc88e2282fc75b47c69eb0f6b1c1eebbc696e7332",
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+      "relation": "association",
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+      "target": 617
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+    {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "ExpMethod": {
           "in vitro": true
         },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "Method": {
           "Electron Microscopy, Transmission": true,
           "Mass Spectrometry": true
@@ -4187,18 +3790,21 @@
         "type": "PubMed",
         "volume": "36"
       },
-      "evidence": "We were prompted to carry out this study because Acr is mainly localized in the neurons [54], is found in association with NFTs and dystrophic neurites surrounding senile plaques [55], is highly toxic to neurons, is found elevated 2–5 fold in affected regions of AD brain. EC can sequester highly reactive and toxic byproducts of oxidation such as acrolein.",
-      "key": "0df4bdc2426bda0b3746d0a9150880a2fb9fb7d75ed7e2cfe7898bc6924df4246a4c913ed9a75450190f24dd8e71f84a65e668f52cf6ca1895c7eebfff02de88",
-      "line": 441,
+      "evidence": "We were prompted to carry out this study because Acr is mainly localized in the neurons [54], is found in association with NFTs and dystrophic neurites surrounding senile plaques [55], is highly toxic to neurons, is found elevated 2–5 fold in affected regions of AD brain [33], and has been shown to increase tau phosphorylation at pathological sites, attributed to activation of both GSK3beta and the stress activated kinase p38 [56], which possibly promotes tau aggregation [57].",
+      "key": "073140bd0986a540759da41af2bbaf95596cbe0e2cd7ae99da6c61d738469eae0f118385935e5a3e22d9cf848b74c205dfcb6511091d14705eed720a7c4d6591",
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       "object": {
         "modifier": "Activity"
       },
       "relation": "positiveCorrelation",
-      "source": 908,
-      "target": 40
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+      "target": 48
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "Method": {
           "Atomic Force Microscopy": true,
           "Confocal Microscopy": true,
@@ -4238,17 +3844,69 @@
       },
       "evidence": "Triosephosphate isomerase (TPI) is a key enzyme in cell metabolism that controls the glycolytic flow and energy production through the interconversion of dihydroxyacetone phosphate (DHAP) and D-glyceraldehyde 3-phosphate (G3P) (Richard, 1993). Notably, TPI is the only glycolytic enzyme whose functional deficiency is associated to neurodegeneration (Eber et al., 1991; Ovadi et al., 2004). In particular, inefficient glycolysis (Hoyer et al., 1988) and ATP depletion (Keil et al., 2004) are characteristic in Alzheimer’s disease brains.",
       "key": "0512276a11d765d3c7dc5b7ced43c79746b54af59f8a6be8ad26ca74c05bb5a4f2f1384c9ed37cd350c7a2bdeac12650422e860b9e4a20c821af81c65310b951",
-      "line": 605,
+      "line": 714,
       "relation": "negativeCorrelation",
-      "source": 908,
+      "source": 1017,
       "target": 176
     },
+    {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "Method": {
+          "Atomic Force Microscopy": true,
+          "Confocal Microscopy": true,
+          "Electron Microscopy, Transmission": true,
+          "Immunofluorescence": true,
+          "Immunohistochemistry": true,
+          "Immunoprecipitation": true,
+          "Turbidometric Analysis": true,
+          "Western Blot": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Bravo R",
+          "Coma M",
+          "Fernàndez-Busquets X",
+          "Guix FX",
+          "Ill-Raga G",
+          "Miscione GP",
+          "Muñoz FJ",
+          "Nakaya T",
+          "Suzuki T",
+          "Valverde MA",
+          "Villà-Freixa J",
+          "de Fabritiis G",
+          "de Strooper B"
+        ],
+        "date": "2009-05-01",
+        "first": "Guix FX",
+        "last": "Muñoz FJ",
+        "name": "Brain : a journal of neurology",
+        "pages": "1335-45",
+        "reference": "19251756",
+        "title": "Amyloid-dependent triosephosphate isomerase nitrotyrosination induces glycation and tau fibrillation.",
+        "type": "PubMed",
+        "volume": "132"
+      },
+      "evidence": "Triosephosphate isomerase (TPI) is a key enzyme in cell metabolism that controls the glycolytic flow and energy production through the interconversion of dihydroxyacetone phosphate (DHAP) and D-glyceraldehyde 3-phosphate (G3P) (Richard, 1993). Notably, TPI is the only glycolytic enzyme whose functional deficiency is associated to neurodegeneration (Eber et al., 1991; Ovadi et al., 2004). In particular, inefficient glycolysis (Hoyer et al., 1988) and ATP depletion (Keil et al., 2004) are characteristic in Alzheimer’s disease brains.",
+      "key": "9e840faa1762c85c77c160ece1ddc129e0b21faa690f3be6403b274186bafadbeb19a8e55ab524e873b52b56faecaa6394645df27879e4f7eeb375e129a6cd6f",
+      "line": 715,
+      "relation": "negativeCorrelation",
+      "source": 1017,
+      "target": 41
+    },
     {
       "annotations": {
         "Anatomy": {
           "frontal cortex": true,
           "hippocampal formation": true
         },
+        "Confidence": {
+          "High": true
+        },
         "Disease": {
           "Alzheimer's disease": true
         },
@@ -4291,10 +3949,10 @@
       },
       "evidence": "Ab induced nitro-oxidative stress on human neuroblastoma cells, resulting in nitrotyrosination of TPI. Moreover, higher levels of nitro-TPI were also detected in extracts from hippocampus (Fig. 1F) and frontal cortex (Fig. 1G) obtained from Alzheimer’s disease brains, compared with healthy subjects.",
       "key": "b47b24d4ff2a7574be58e0815dc924e71655e4bbc53d6ef1686cdf8077f63274ecfe48d143ab62a28d0452eb9cf740120c84ebe62dd312bf68356d548d8ae453",
-      "line": 616,
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       "relation": "positiveCorrelation",
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-      "target": 765
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+      "target": 855
     },
     {
       "annotations": {
@@ -4302,6 +3960,9 @@
           "frontal cortex": true,
           "hippocampal formation": true
         },
+        "Confidence": {
+          "High": true
+        },
         "Disease": {
           "Alzheimer's disease": true
         },
@@ -4344,10 +4005,44 @@
       },
       "evidence": "Ab induced nitro-oxidative stress on human neuroblastoma cells, resulting in nitrotyrosination of TPI. Moreover, higher levels of nitro-TPI were also detected in extracts from hippocampus (Fig. 1F) and frontal cortex (Fig. 1G) obtained from Alzheimer’s disease brains, compared with healthy subjects.",
       "key": "e795c5984f47e771893dd779b32269f4bf056603208ae9616573c87c648e2d7d1a27ca0df97a4018006ce1847b2d9d40bd44aa9aedef20fd691705b7bf3d58e6",
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+      "relation": "positiveCorrelation",
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+      "target": 856
+    },
+    {
+      "annotations": {
+        "Anatomy": {
+          "globus pallidus": true,
+          "pons": true
+        },
+        "Confidence": {
+          "Medium": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Lee JM",
+          "Muma NA",
+          "Troncoso JC",
+          "Zemaitaitis MO"
+        ],
+        "date": "2000-11-01",
+        "first": "Zemaitaitis MO",
+        "last": "Muma NA",
+        "name": "Journal of neuropathology and experimental neurology",
+        "pages": "983-9",
+        "reference": "11089576",
+        "title": "Transglutaminase-induced cross-linking of tau proteins in progressive supranuclear palsy.",
+        "type": "PubMed",
+        "volume": "59"
+      },
+      "evidence": "There were significantly higher levels of epsilon-(gamma-glutamyl) lysine cross-linking of PHF-tau in globus pallidus and pons regions of PSP cases compared to barely detectable cross-links in controls. The occipital cortex, an area spared from neurofibrillary pathology in PSP, showed no detectable cross-linking of PHF-tau protein in either PSP cases or control cases. Double-label immunofluorescence demonstrated the colocalization of the cross-link and PHF-tau in NFT in pons of PSP Previous studies and present data are consistent with the hypothesis that transglutaminase-induced cross-linking may be a factor contributing to the abnormal polymerization and stabilization of tau in straight and PHFs leading to neurofibrillary tangle formation in neurodegenerative diseases, including PSP and AD.",
+      "key": "67c756f8a24490860850ba1ff1d4f22cfa949b98b208fc7c7003690a37fefe463ba88f8c5e07fb625cfc70018573e533763912375cb5981e841af4459b7b6c6b",
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       "relation": "positiveCorrelation",
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     },
     {
       "annotations": {
@@ -4355,6 +4050,9 @@
           "frontal cortex": true,
           "parietal cortex": true
         },
+        "Confidence": {
+          "High": true
+        },
         "Disease": {
           "Alzheimer's disease": true
         },
@@ -4385,19 +4083,22 @@
       },
       "evidence": "The number of neurons that are immunoreactive with an antibody directed at the epsilon-(gamma-glutamyl)lysine bond was significantly higher in AD cortex compared with age-matched controls and schizophrenics. PHF tau-directed antibodies AT8, MC-1 and PHF-1 co-localized with epsilon(gamma-glutamyl)lysine immunolabeling in AD NFT. Immunoaffinity purification and immunoblotting experiments demonstrated that PHF tau contains epsilon(gamma-glutamyl)lysine bonds in parietal and frontal cortex in AD. In control cases with NFT present in the entorhinal cortex and hippocampus, indicative of Braak and Braak stage II, epsilon(gamma-glutamyl)lysine bonds were present in PHF tau in parietal and frontal cortex, despite the lack of microscopically detectable NFT or senile plaques in these cortical regions. The presence of PHF tau with epsilon(gamma-glutamyl)lysine bonds in brain regions devoid of NFT in stage II (but regions, which would be expected to contain NFT in stage III) suggests that these bonds occur early in the formation of NFT.",
       "key": "873d1526b3e7d90425f9d4e163514a5d3a1c589ac5780e1b48ce19bb80417a80bb52e8ced6a68cb8ed2ad5572592886c3a0c38d40f42215b64a6ec69655cf71c",
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       "object": {
         "modifier": "Activity"
       },
       "relation": "positiveCorrelation",
-      "source": 908,
-      "target": 267
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+      "target": 337
     },
     {
       "annotations": {
         "Anatomy": {
           "hippocampal formation": true
         },
+        "Confidence": {
+          "High": true
+        },
         "Disease": {
           "Alzheimer's disease": true
         }
@@ -4421,19 +4122,22 @@
       },
       "evidence": "Degenerating neurons from the AD hippocampus, compared to neurons from the normal aged hippocampus, exhibited increased immunoreactivity for TGase and demonstrated co-labeling for PHF1 and anti-TGase. Our results suggest that TGase may be associated with the neurofibrillary degeneration observed in AD, thereby implicating TGase as a potential factor in the pathogenesis of Alzheimer's disease.",
       "key": "a36efe122629a7f359f605842525d7ab37aebff6f298dad19acfb2eb8950f25baab06f721db72e3af6a159c27ff5442a0d739e4ad14617ac95cf14f5863510cf",
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       "object": {
         "modifier": "Activity"
       },
       "relation": "positiveCorrelation",
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-      "target": 267
+      "source": 1017,
+      "target": 337
     },
     {
       "annotations": {
         "Anatomy": {
           "prefrontal cortex": true
         },
+        "Confidence": {
+          "Medium": true
+        },
         "Disease": {
           "Alzheimer's disease": true
         },
@@ -4462,19 +4166,25 @@
         "volume": "751"
       },
       "evidence": "Total transglutaminase activity was significantly higher in the Alzheimer's disease prefrontal cortex compared to control. In addition the levels of tissue transglutaminase, as determined by quantitative immunoblotting, were elevated approximately 3-fold in Alzheimer's disease prefrontal cortex compared to control. To our knowledge, this is the first demonstration that transglutaminase is increased in Alzheimer's disease brain. There were no significant differences in transglutaminase activity or levels in the cerebellum between control and Alzheimer's disease cases. Because the elevation of transglutaminase in the Alzheimer's disease samples occurred in the prefrontal cortex, where neurofibrillary pathology is usually abundant, and not in the cerebellum, which is usually spared in Alzheimer's disease, it can be suggested that transglutaminase could be a contributing factor in neurofibrillary tangle formation.",
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       "object": {
         "modifier": "Activity"
       },
       "relation": "increases",
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-      "target": 730
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+      "target": 845
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "Disease": {
           "Alzheimer's disease": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
         }
       },
       "citation": {
@@ -4499,160 +4209,155 @@
       },
       "evidence": "Tau-nY29 detects soluble tau and paired helical filament tau from severely affected Alzheimer's brain but fails to recognize tau from normal aged brain. This observation suggests that nitration at Tyr29 is a disease-related event that may alter the intrinsic ability of tau to self-polymerize. In Alzheimer's brain, Tau-nY29 labels the fibrillar triad of tau lesions, including neurofibrillary tangles, neuritic plaques, and, to a lesser extent, neuropil threads. Intriguingly, although Tau-nY29 stains both the neuronal and glial tau pathology of Pick disease, it detects only the neuronal pathology in corticobasal degeneration and progressive supranuclear palsy without labeling the predominant glial pathology.",
       "key": "632d9df28c77300b2ed8d438bc53463b63b7ca46f0ed66ea0870a42a6a7824c742dc186fc289dcdeccaa2fde1b7981d6270a9710c93952371ab45a6232e5515f",
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       "relation": "positiveCorrelation",
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+      "target": 604
     },
     {
       "annotations": {
-        "Study_Group": {
-          "Spanish cohort": true
+        "Confidence": {
+          "Medium": true
         }
       },
       "citation": {
         "authors": [
-          "Berciano J",
-          "Bullido MJ",
-          "Combarros O",
-          "Frank A",
-          "Martínez-García A",
-          "Mateo I",
-          "Pozueta A",
-          "Rodríguez-Rodríguez E",
-          "Sánchez-Juan P",
-          "Valdivieso F",
-          "Vázquez-Higuera JL"
+          "Cowburn RF",
+          "Dahllund L",
+          "Gustafsson E",
+          "Lund H",
+          "Malinowsky D",
+          "Strömberg K",
+          "Sunnemark D",
+          "Svensson A"
         ],
-        "date": "2011-03-01",
-        "first": "Vázquez-Higuera JL",
-        "last": "Combarros O",
-        "name": "Neurobiology of aging",
-        "pages": "550.e5-9",
-        "reference": "20096481",
-        "title": "Genetic variations in tau-tubulin kinase-1 are linked to Alzheimer's disease in a Spanish case-control cohort.",
+        "date": "2013-07-01",
+        "first": "Lund H",
+        "last": "Sunnemark D",
+        "name": "Brain pathology (Zurich, Switzerland)",
+        "pages": "378-89",
+        "reference": "23088643",
+        "title": "Tau-tubulin kinase 1 expression, phosphorylation and co-localization with phospho-Ser422 tau in the Alzheimer's disease brain.",
         "type": "PubMed",
-        "volume": "32"
+        "volume": "23"
       },
-      "evidence": "Haplotype analysis of the block formed by rs2651206, rs10807287, and rs7764257 showed that the combination of the three frequent alleles (CTA) was significantly (p = 0.02) overrepresented in the AD group (67%) compared to the control group (63%), and this result was still significant after multiple testing corrections with 10,000 permutations (p = 0.05).",
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-      "line": 1316,
-      "relation": "association",
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-      "target": 251
+      "evidence": "TTBK1 has been shown, by partial phosphopeptide mapping, to phosphorylate tau at serine residues 198, 199, 202 and 422 and at tyrosine 197 in vitro, sites that are also phosphorylated in AD PHFs (7, 12)",
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     {
       "annotations": {
-        "Study_Group": {
-          "Han chinese": true
+        "Confidence": {
+          "Medium": true
         }
       },
       "citation": {
         "authors": [
-          "Alessi DR",
-          "Begley MJ",
-          "Bouskila M",
-          "Cantley LC",
-          "Deak M",
-          "Esoof N",
-          "Fang EH",
-          "Gay L",
-          "Prescott A",
-          "Storey KG"
+          "Cowburn RF",
+          "Dahllund L",
+          "Gustafsson E",
+          "Lund H",
+          "Malinowsky D",
+          "Strömberg K",
+          "Sunnemark D",
+          "Svensson A"
         ],
-        "date": "2011-07-01",
-        "first": "Bouskila M",
-        "last": "Alessi DR",
-        "name": "The Biochemical journal",
-        "pages": "157-67",
-        "reference": "21548880",
-        "title": "TTBK2 kinase substrate specificity and the impact of spinocerebellar-ataxia-causing mutations on expression, activity, localization and development.",
+        "date": "2013-07-01",
+        "first": "Lund H",
+        "last": "Sunnemark D",
+        "name": "Brain pathology (Zurich, Switzerland)",
+        "pages": "378-89",
+        "reference": "23088643",
+        "title": "Tau-tubulin kinase 1 expression, phosphorylation and co-localization with phospho-Ser422 tau in the Alzheimer's disease brain.",
         "type": "PubMed",
-        "volume": "437"
+        "volume": "23"
       },
-      "evidence": "Significant association with a reduced risk of LOAD (odds ratio/OR=0.69). rs2651206 polymorphism was strongly associated with LOAD (OR=0.72) (age, gender, and APOE adjusted). The TG haplotype, deriving from the two minor alleles, decreases risk of LOAD (OR=0.78, P=0.037).",
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       "relation": "positiveCorrelation",
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     {
       "annotations": {
-        "Study_Group": {
-          "Spanish cohort": true
+        "Confidence": {
+          "Medium": true
         }
       },
       "citation": {
         "authors": [
-          "Berciano J",
-          "Bullido MJ",
-          "Combarros O",
-          "Frank A",
-          "Martínez-García A",
-          "Mateo I",
-          "Pozueta A",
-          "Rodríguez-Rodríguez E",
-          "Sánchez-Juan P",
-          "Valdivieso F",
-          "Vázquez-Higuera JL"
+          "Cowburn RF",
+          "Dahllund L",
+          "Gustafsson E",
+          "Lund H",
+          "Malinowsky D",
+          "Strömberg K",
+          "Sunnemark D",
+          "Svensson A"
         ],
-        "date": "2011-03-01",
-        "first": "Vázquez-Higuera JL",
-        "last": "Combarros O",
-        "name": "Neurobiology of aging",
-        "pages": "550.e5-9",
-        "reference": "20096481",
-        "title": "Genetic variations in tau-tubulin kinase-1 are linked to Alzheimer's disease in a Spanish case-control cohort.",
+        "date": "2013-07-01",
+        "first": "Lund H",
+        "last": "Sunnemark D",
+        "name": "Brain pathology (Zurich, Switzerland)",
+        "pages": "378-89",
+        "reference": "23088643",
+        "title": "Tau-tubulin kinase 1 expression, phosphorylation and co-localization with phospho-Ser422 tau in the Alzheimer's disease brain.",
         "type": "PubMed",
-        "volume": "32"
+        "volume": "23"
       },
-      "evidence": "Haplotype analysis of the block formed by rs2651206, rs10807287, and rs7764257 showed that the combination of the three frequent alleles (CTA) was significantly (p = 0.02) overrepresented in the AD group (67%) compared to the control group (63%), and this result was still significant after multiple testing corrections with 10,000 permutations (p = 0.05).",
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+      "evidence": "TTBK1 has been shown, by partial phosphopeptide mapping, to phosphorylate tau at serine residues 198, 199, 202 and 422 and at tyrosine 197 in vitro, sites that are also phosphorylated in AD PHFs (7, 12)",
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     {
       "annotations": {
-        "Study_Group": {
-          "Spanish cohort": true
+        "Confidence": {
+          "Medium": true
         }
       },
       "citation": {
         "authors": [
-          "Berciano J",
-          "Bullido MJ",
-          "Combarros O",
-          "Frank A",
-          "Martínez-García A",
-          "Mateo I",
-          "Pozueta A",
-          "Rodríguez-Rodríguez E",
-          "Sánchez-Juan P",
-          "Valdivieso F",
-          "Vázquez-Higuera JL"
+          "Cowburn RF",
+          "Dahllund L",
+          "Gustafsson E",
+          "Lund H",
+          "Malinowsky D",
+          "Strömberg K",
+          "Sunnemark D",
+          "Svensson A"
         ],
-        "date": "2011-03-01",
-        "first": "Vázquez-Higuera JL",
-        "last": "Combarros O",
-        "name": "Neurobiology of aging",
-        "pages": "550.e5-9",
-        "reference": "20096481",
-        "title": "Genetic variations in tau-tubulin kinase-1 are linked to Alzheimer's disease in a Spanish case-control cohort.",
+        "date": "2013-07-01",
+        "first": "Lund H",
+        "last": "Sunnemark D",
+        "name": "Brain pathology (Zurich, Switzerland)",
+        "pages": "378-89",
+        "reference": "23088643",
+        "title": "Tau-tubulin kinase 1 expression, phosphorylation and co-localization with phospho-Ser422 tau in the Alzheimer's disease brain.",
         "type": "PubMed",
-        "volume": "32"
+        "volume": "23"
       },
-      "evidence": "Haplotype analysis of the block formed by rs2651206, rs10807287, and rs7764257 showed that the combination of the three frequent alleles (CTA) was significantly (p = 0.02) overrepresented in the AD group (67%) compared to the control group (63%), and this result was still significant after multiple testing corrections with 10,000 permutations (p = 0.05).",
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-      "relation": "association",
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-      "target": 255
+      "evidence": "TTBK1 has been shown, by partial phosphopeptide mapping, to phosphorylate tau at serine residues 198, 199, 202 and 422 and at tyrosine 197 in vitro, sites that are also phosphorylated in AD PHFs (7, 12)",
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+      "source": 1017,
+      "target": 674
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -4683,14 +4388,54 @@
         "volume": "6"
       },
       "evidence": "3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain.",
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       "relation": "positiveCorrelation",
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-      "target": 589
+      "source": 1017,
+      "target": 674
+    },
+    {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Cowburn RF",
+          "Dahllund L",
+          "Gustafsson E",
+          "Lund H",
+          "Malinowsky D",
+          "Strömberg K",
+          "Sunnemark D",
+          "Svensson A"
+        ],
+        "date": "2013-07-01",
+        "first": "Lund H",
+        "last": "Sunnemark D",
+        "name": "Brain pathology (Zurich, Switzerland)",
+        "pages": "378-89",
+        "reference": "23088643",
+        "title": "Tau-tubulin kinase 1 expression, phosphorylation and co-localization with phospho-Ser422 tau in the Alzheimer's disease brain.",
+        "type": "PubMed",
+        "volume": "23"
+      },
+      "evidence": "TTBK1 has been shown, by partial phosphopeptide mapping, to phosphorylate tau at serine residues 198, 199, 202 and 422 and at tyrosine 197 in vitro, sites that are also phosphorylated in AD PHFs (7, 12)",
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+      "target": 654
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -4721,14 +4466,179 @@
         "volume": "6"
       },
       "evidence": "3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain.",
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       "relation": "positiveCorrelation",
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+    },
+    {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "Study_Group": {
+          "Spanish cohort": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Berciano J",
+          "Bullido MJ",
+          "Combarros O",
+          "Frank A",
+          "Martínez-García A",
+          "Mateo I",
+          "Pozueta A",
+          "Rodríguez-Rodríguez E",
+          "Sánchez-Juan P",
+          "Valdivieso F",
+          "Vázquez-Higuera JL"
+        ],
+        "date": "2011-03-01",
+        "first": "Vázquez-Higuera JL",
+        "last": "Combarros O",
+        "name": "Neurobiology of aging",
+        "pages": "550.e5-9",
+        "reference": "20096481",
+        "title": "Genetic variations in tau-tubulin kinase-1 are linked to Alzheimer's disease in a Spanish case-control cohort.",
+        "type": "PubMed",
+        "volume": "32"
+      },
+      "evidence": "Haplotype analysis of the block formed by rs2651206, rs10807287, and rs7764257 showed that the combination of the three frequent alleles (CTA) was significantly (p = 0.02) overrepresented in the AD group (67%) compared to the control group (63%), and this result was still significant after multiple testing corrections with 10,000 permutations (p = 0.05).",
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+      "source": 1017,
+      "target": 319
+    },
+    {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        },
+        "Study_Group": {
+          "Han chinese": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Alessi DR",
+          "Begley MJ",
+          "Bouskila M",
+          "Cantley LC",
+          "Deak M",
+          "Esoof N",
+          "Fang EH",
+          "Gay L",
+          "Prescott A",
+          "Storey KG"
+        ],
+        "date": "2011-07-01",
+        "first": "Bouskila M",
+        "last": "Alessi DR",
+        "name": "The Biochemical journal",
+        "pages": "157-67",
+        "reference": "21548880",
+        "title": "TTBK2 kinase substrate specificity and the impact of spinocerebellar-ataxia-causing mutations on expression, activity, localization and development.",
+        "type": "PubMed",
+        "volume": "437"
+      },
+      "evidence": "Significant association with a reduced risk of LOAD (odds ratio/OR=0.69). rs2651206 polymorphism was strongly associated with LOAD (OR=0.72) (age, gender, and APOE adjusted). The TG haplotype, deriving from the two minor alleles, decreases risk of LOAD (OR=0.78, P=0.037).",
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     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "Study_Group": {
+          "Spanish cohort": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Berciano J",
+          "Bullido MJ",
+          "Combarros O",
+          "Frank A",
+          "Martínez-García A",
+          "Mateo I",
+          "Pozueta A",
+          "Rodríguez-Rodríguez E",
+          "Sánchez-Juan P",
+          "Valdivieso F",
+          "Vázquez-Higuera JL"
+        ],
+        "date": "2011-03-01",
+        "first": "Vázquez-Higuera JL",
+        "last": "Combarros O",
+        "name": "Neurobiology of aging",
+        "pages": "550.e5-9",
+        "reference": "20096481",
+        "title": "Genetic variations in tau-tubulin kinase-1 are linked to Alzheimer's disease in a Spanish case-control cohort.",
+        "type": "PubMed",
+        "volume": "32"
+      },
+      "evidence": "Haplotype analysis of the block formed by rs2651206, rs10807287, and rs7764257 showed that the combination of the three frequent alleles (CTA) was significantly (p = 0.02) overrepresented in the AD group (67%) compared to the control group (63%), and this result was still significant after multiple testing corrections with 10,000 permutations (p = 0.05).",
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+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "Study_Group": {
+          "Spanish cohort": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Berciano J",
+          "Bullido MJ",
+          "Combarros O",
+          "Frank A",
+          "Martínez-García A",
+          "Mateo I",
+          "Pozueta A",
+          "Rodríguez-Rodríguez E",
+          "Sánchez-Juan P",
+          "Valdivieso F",
+          "Vázquez-Higuera JL"
+        ],
+        "date": "2011-03-01",
+        "first": "Vázquez-Higuera JL",
+        "last": "Combarros O",
+        "name": "Neurobiology of aging",
+        "pages": "550.e5-9",
+        "reference": "20096481",
+        "title": "Genetic variations in tau-tubulin kinase-1 are linked to Alzheimer's disease in a Spanish case-control cohort.",
+        "type": "PubMed",
+        "volume": "32"
+      },
+      "evidence": "Haplotype analysis of the block formed by rs2651206, rs10807287, and rs7764257 showed that the combination of the three frequent alleles (CTA) was significantly (p = 0.02) overrepresented in the AD group (67%) compared to the control group (63%), and this result was still significant after multiple testing corrections with 10,000 permutations (p = 0.05).",
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+    {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -4759,14 +4669,20 @@
         "volume": "6"
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       "evidence": "3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain.",
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     {
       "annotations": {
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+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -4797,14 +4713,20 @@
         "volume": "6"
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       "evidence": "3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain.",
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     {
       "annotations": {
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+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -4835,14 +4757,20 @@
         "volume": "6"
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       "evidence": "3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain.",
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     {
       "annotations": {
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+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
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@@ -4873,14 +4801,20 @@
         "volume": "6"
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     {
       "annotations": {
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+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -4911,14 +4845,20 @@
         "volume": "6"
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       "evidence": "3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain.",
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     {
       "annotations": {
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+          "Medium": true
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+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -4949,14 +4889,20 @@
         "volume": "6"
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       "evidence": "3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain.",
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     {
       "annotations": {
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+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
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@@ -4987,14 +4933,20 @@
         "volume": "6"
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       "evidence": "3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain.",
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     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
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@@ -5025,14 +4977,20 @@
         "volume": "6"
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     {
       "annotations": {
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+        },
+        "MeSHAnatomy": {
+          "Brain": true
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         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -5063,14 +5021,20 @@
         "volume": "6"
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       "evidence": "3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain.",
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     {
       "annotations": {
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+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
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@@ -5101,14 +5065,20 @@
         "volume": "6"
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       "evidence": "3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain.",
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     {
       "annotations": {
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+        },
+        "MeSHAnatomy": {
+          "Brain": true
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         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -5139,14 +5109,20 @@
         "volume": "6"
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     {
       "annotations": {
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+          "Medium": true
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+        "MeSHAnatomy": {
+          "Brain": true
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         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -5177,14 +5153,20 @@
         "volume": "6"
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       "evidence": "3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain.",
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     {
       "annotations": {
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+          "Medium": true
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+        "MeSHAnatomy": {
+          "Brain": true
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         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -5215,14 +5197,20 @@
         "volume": "6"
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       "evidence": "3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain.",
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     {
       "annotations": {
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+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
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         "MeSHDisease": {
           "Alzheimer Disease": true
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@@ -5253,14 +5241,20 @@
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     {
       "annotations": {
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+        "MeSHAnatomy": {
+          "Brain": true
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         "MeSHDisease": {
           "Alzheimer Disease": true
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@@ -5291,14 +5285,20 @@
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     {
       "annotations": {
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+        "MeSHAnatomy": {
+          "Brain": true
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         "MeSHDisease": {
           "Alzheimer Disease": true
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@@ -5329,14 +5329,20 @@
         "volume": "6"
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     {
       "annotations": {
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+          "Brain": true
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         "MeSHDisease": {
           "Alzheimer Disease": true
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@@ -5367,14 +5373,20 @@
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     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -5405,14 +5417,20 @@
         "volume": "6"
       },
       "evidence": "3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain.",
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     {
       "annotations": {
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+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -5443,14 +5461,20 @@
         "volume": "6"
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       "evidence": "3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain.",
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     {
       "annotations": {
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+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -5481,14 +5505,20 @@
         "volume": "6"
       },
       "evidence": "3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain.",
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     {
       "annotations": {
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+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -5519,14 +5549,20 @@
         "volume": "6"
       },
       "evidence": "3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain.",
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+      "target": 677
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     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -5557,14 +5593,20 @@
         "volume": "6"
       },
       "evidence": "3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain.",
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     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -5595,14 +5637,20 @@
         "volume": "6"
       },
       "evidence": "3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain.",
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     {
       "annotations": {
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+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -5633,14 +5681,20 @@
         "volume": "6"
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       "evidence": "3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain.",
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+      "target": 656
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     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -5671,14 +5725,20 @@
         "volume": "6"
       },
       "evidence": "3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain.",
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       "relation": "positiveCorrelation",
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+      "target": 670
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -5709,13 +5769,49 @@
         "volume": "6"
       },
       "evidence": "3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain.",
-      "key": "9925ef0a7b74f27240339dc89a30fcb37dc698a2a5fdc40b840184e6a77f8c7fe362683ce33cfeb89901ea83a6f5ef0f1d2f91b238a1009eb438e6c117bd5824",
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       "relation": "positiveCorrelation",
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-      "target": 569
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+      "target": 655
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+    {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "Disease": {
+          "Alzheimer's disease": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Buée-Scherrer V",
+          "Goedert M"
+        ],
+        "date": "2002-03-27",
+        "first": "Buée-Scherrer V",
+        "last": "Goedert M",
+        "name": "FEBS letters",
+        "pages": "151-4",
+        "reference": "11943212",
+        "title": "Phosphorylation of microtubule-associated protein tau by stress-activated protein kinases in intact cells.",
+        "type": "PubMed",
+        "volume": "515"
+      },
+      "evidence": "Immunohistochemical analyses using isoform-selective antibodies demonstrated that MARK4 in a phosphorylated form colocalizes with p-tau Ser262 in granulovacuolar degeneration bodies (GVDs) that progressively accumulate in AD.",
+      "key": "433fbef0ae674bb1b49da44e6c7cae6ccd6934e1a0a84172872bcb6bc01ec4d48eeeb0fcbe24deb30c2cd470561be0f53797427abfe83d8fe686e6d935a4745f",
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+      "target": 1006
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     {
+      "annotations": {
+        "Confidence": {
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+        }
+      },
       "citation": {
         "authors": [
           "Blokzijl A",
@@ -5740,12 +5836,84 @@
       },
       "evidence": "In cells, a CagA peptide inhibited tau phosphorylation at Ser²6² mediated by MARK4 but not other MARK isoforms. A strong and significant elevation of MARK4 expression and MARK4-tau interactions in AD brains correlated with the Braak stages of the disease.",
       "key": "ea625f646f4e3ac3d84037067bab260ccda4063920340e3e5777cd75d67c6ce965e5a8db4c113d456eb7504ee3b4477e3dc346cf3ac76a51cdd56e7e1bcbe796",
-      "line": 1846,
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       "relation": "positiveCorrelation",
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-      "target": 635
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+      "target": 722
+    },
+    {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Blokzijl A",
+          "Classon C",
+          "Gu GJ",
+          "Kamali-Moghaddam M",
+          "Landegren U",
+          "Lund H",
+          "Sunnemark D",
+          "Wu D",
+          "von Euler G"
+        ],
+        "date": "2013-09-01",
+        "first": "Gu GJ",
+        "last": "Kamali-Moghaddam M",
+        "name": "Neuromolecular medicine",
+        "pages": "458-69",
+        "reference": "23666762",
+        "title": "Role of individual MARK isoforms in phosphorylation of tau at Ser²⁶² in Alzheimer's disease.",
+        "type": "PubMed",
+        "volume": "15"
+      },
+      "evidence": "In cells, a CagA peptide inhibited tau phosphorylation at Ser²6² mediated by MARK4 but not other MARK isoforms. A strong and significant elevation of MARK4 expression and MARK4-tau interactions in AD brains correlated with the Braak stages of the disease.",
+      "key": "dcded1f7bda000716f64398f05d1c9dfe23ed28fe8f83342b53fd8aa39a1481e1385492374bba4bc71487b73ee12489f360c5c089686fe32e502d05d80aec009",
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+      "relation": "positiveCorrelation",
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+      "target": 287
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+    {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Cavallaro RA",
+          "Ciraci V",
+          "Ferrer I",
+          "Fuso A",
+          "Nicolia V",
+          "Scarpa S"
+        ],
+        "date": "2017-01-01",
+        "first": "Nicolia V",
+        "last": "Fuso A",
+        "name": "Current Alzheimer research",
+        "pages": "753-759",
+        "reference": "28176663",
+        "title": "GSK3β 5'-flanking DNA Methylation and Expression in Alzheimer's Disease Patients.",
+        "type": "PubMed",
+        "volume": "14"
+      },
+      "evidence": "We found that GSK3β mRNA was overexpressed only in patients with initial AD, with no effect on the levels of the protein. On the other hand, we unexpectedly observed the decrease of the inactive GSK3β in cortex from AD patients at Braak stages I-II, whereas considerable increase was observed in AD patients at stages V-VI compared to the control subjects.",
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+      "relation": "increases",
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     {
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+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "Ai J",
@@ -5776,13 +5944,16 @@
       },
       "evidence": "To perform its function, Cdk5 must bind to the neuron-specific regulatory subunit protein p35, which is beneficial for neuronal development (Tsai et al. 1994; Chae et al. 1997). However, truncation of p35 and conversion to p25 (Patrick et al. 1999) is found in the forebrain of rats after focal cerebral ischemia and in AD patients, and these alterations are deleterious to the brain",
       "key": "64bc2e6cab2cf48144b64e0a2e05228a4bb3a502b897d167a8f4e71a50fdadf622a4b414744f56349cd22fe510f433a6f62bbadd4d392c4d81e2710bccf3de5d",
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       "relation": "positiveCorrelation",
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-      "target": 311
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+      "target": 388
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Disease_Progression": {
           "Early Stage": true
         },
@@ -5812,10 +5983,10 @@
       },
       "evidence": "This sequence (Fig. 3G–N) is supported by Western blot analysis, phosphorylated Thr231 in three AD cases and their age-matched controls, suggesting that tau phosphorylation at Thr231 occurs before the formation of oligomers (Fig. 3O).",
       "key": "2647cdb4a17ca840e3cb385ae9d6e7d29da3f3027833221ad43a3536f60fb907b3373478a812f48375785d6e2d2b9ef5e4d71ea7beb8c3a88f95a07725b1cf34",
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       "relation": "positiveCorrelation",
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-      "target": 583
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+      "target": 667
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     {
       "annotations": {
@@ -5826,6 +5997,9 @@
           "Stage I": true,
           "Stage II": true
         },
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -5851,16 +6025,19 @@
       },
       "evidence": "The highly vulnerable CA1 pyramidal neurons were characterized by age- and disease-unrelated increases in PRCKB levels and by age- and disease-related increases in MAPK1 levels. In contrast, low PRKCB levels were found in CA2 pyramidal neurons, and MAPK1 levels were elevated in controls and intermediate AD stages. Both PRKCB and MAPK1 were increased in the late AD stages. MAPK1 and PRKCB levels were low in the brainstem and cerebellum.",
       "key": "9a8c7d1eb6f920f98e6b5ac4fe6f2bd00ae2155473ab83514cc3de2a86e3f5ba3914b32db23a5d7fa354cdcaa7fbcead89588ad0894b6b467bd65d5c2c7878e2",
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       "relation": "increases",
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-      "target": 477
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+      "target": 558
     },
     {
       "annotations": {
         "Anatomy": {
           "pyramidal layer of CA1": true
         },
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -5886,16 +6063,19 @@
       },
       "evidence": "The highly vulnerable CA1 pyramidal neurons were characterized by age- and disease-unrelated increases in PRCKB levels and by age- and disease-related increases in MAPK1 levels. In contrast, low PRKCB levels were found in CA2 pyramidal neurons, and MAPK1 levels were elevated in controls and intermediate AD stages. Both PRKCB and MAPK1 were increased in the late AD stages. MAPK1 and PRKCB levels were low in the brainstem and cerebellum.",
       "key": "161a6332dde3705cbdf7934bd1f37c8993aafe3c47e5d7fde3843cb966154863fc819b294df84e42f0aae0274fad6bd89e81859c157ea912a54b9f18fa184f9e",
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       "relation": "increases",
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-      "target": 661
+      "source": 1017,
+      "target": 752
     },
     {
       "annotations": {
         "Anatomy": {
           "cerebral cortex": true
         },
+        "Confidence": {
+          "Medium": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -5926,15 +6106,18 @@
       },
       "evidence": "We show here that ITPKB protein level was increased 3-fold in the cerebral cortex of most patients with Alzheimer's disease compared with control subjects, and accumulated in dystrophic neurites associated to amyloid plaques. In mouse Neuro-2a neuroblastoma cells, Itpkb overexpression was associated with increased cell apoptosis and increased β-secretase 1 activity leading to overproduction of amyloid-β peptides. In this cellular model, an inhibitor of mitogen-activated kinase kinases 1/2 completely prevented overproduction of amyloid-β peptides. Transgenic overexpression of ITPKB in mouse forebrain neurons was not sufficient to induce amyloid plaque formation or tau hyperphosphorylation. However, in the 5X familial Alzheimer's disease mouse model, neuronal ITPKB overexpression significantly increased extracellular signal-regulated kinases 1/2 activation and β-secretase 1 activity, resulting in exacerbated Alzheimer's disease pathology as shown by increased astrogliosis, amyloid-β40 peptide production and tau hyperphosphorylation.",
       "key": "4f2e94cd2d11f59e73924ed05f76619302e3c021d9eda9264c964af7757d61cfcf6680a7612f25095661c333cc403fede248a7f2cca0c659bc47380666c1ce58",
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       "relation": "increases",
-      "source": 908,
-      "target": 460
+      "source": 1017,
+      "target": 541
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "Research_Model": {
-          "P301S mice": true
+          "5xFAD mice": true
         },
         "Species": {
           "10090": true
@@ -5942,33 +6125,120 @@
       },
       "citation": {
         "authors": [
-          "Devidze N",
-          "Gan L",
-          "Gestwicki JE",
-          "Johnson JR",
-          "Krogan NJ",
-          "Li Y",
-          "Masliah E",
-          "Min SW",
-          "Mok SA",
-          "Sohn PD"
+          "Ando K",
+          "Brion JP",
+          "D'Amico E",
+          "Duyckaerts C",
+          "Erneux C",
+          "Jia Y",
+          "Leroy K",
+          "Luo HR",
+          "Pouillon V",
+          "Schurmans S",
+          "Stygelbout V"
         ],
-        "date": "2018-04-11",
-        "first": "Min SW",
-        "last": "Gan L",
-        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
-        "pages": "3680-3688",
-        "reference": "29540553",
-        "title": "SIRT1 Deacetylates Tau and Reduces Pathogenic Tau Spread in a Mouse Model of Tauopathy.",
+        "date": "2014-02-01",
+        "first": "Stygelbout V",
+        "last": "Brion JP",
+        "name": "Brain : a journal of neurology",
+        "pages": "537-52",
+        "reference": "24401760",
+        "title": "Inositol trisphosphate 3-kinase B is increased in human Alzheimer brain and exacerbates mouse Alzheimer pathology.",
         "type": "PubMed",
-        "volume": "38"
+        "volume": "137"
       },
-      "evidence": "Here we show that the protein deacetylase SIRT1 reduces tau acetylation in a mouse model of neurodegeneration. SIRT1 deficiency in the brain aggravates synapse loss and behavioral disinhibition, and SIRT1 overexpression ameliorates propagation of tau pathology.",
-      "key": "d901aca3ddfbabeec2989593dff3ec51f2b47394a214f3d5ed70150b87b5f8915679079a02967131cd55f1470b13b9a66965c7028f5270451d31b548d5348bb3",
-      "line": 3036,
-      "relation": "negativeCorrelation",
-      "source": 908,
-      "target": 847
+      "evidence": "We show here that ITPKB protein level was increased 3-fold in the cerebral cortex of most patients with Alzheimer's disease compared with control subjects, and accumulated in dystrophic neurites associated to amyloid plaques. In mouse Neuro-2a neuroblastoma cells, Itpkb overexpression was associated with increased cell apoptosis and increased β-secretase 1 activity leading to overproduction of amyloid-β peptides. In this cellular model, an inhibitor of mitogen-activated kinase kinases 1/2 completely prevented overproduction of amyloid-β peptides. Transgenic overexpression of ITPKB in mouse forebrain neurons was not sufficient to induce amyloid plaque formation or tau hyperphosphorylation. However, in the 5X familial Alzheimer's disease mouse model, neuronal ITPKB overexpression significantly increased extracellular signal-regulated kinases 1/2 activation and β-secretase 1 activity, resulting in exacerbated Alzheimer's disease pathology as shown by increased astrogliosis, amyloid-β40 peptide production and tau hyperphosphorylation.",
+      "key": "77a66c0c5d9f6a709dd912e0a63972c444e4ca7ebb7fef19ceb24a87d2b5be4f01758cb5ea7bdda0be629f4bb0df178c0a56a2155651974887d65f7d468dc79d",
+      "line": 3529,
+      "relation": "positiveCorrelation",
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+      "target": 1009
+    },
+    {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "Research_Model": {
+          "5xFAD mice": true
+        },
+        "Species": {
+          "10090": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Ando K",
+          "Brion JP",
+          "D'Amico E",
+          "Duyckaerts C",
+          "Erneux C",
+          "Jia Y",
+          "Leroy K",
+          "Luo HR",
+          "Pouillon V",
+          "Schurmans S",
+          "Stygelbout V"
+        ],
+        "date": "2014-02-01",
+        "first": "Stygelbout V",
+        "last": "Brion JP",
+        "name": "Brain : a journal of neurology",
+        "pages": "537-52",
+        "reference": "24401760",
+        "title": "Inositol trisphosphate 3-kinase B is increased in human Alzheimer brain and exacerbates mouse Alzheimer pathology.",
+        "type": "PubMed",
+        "volume": "137"
+      },
+      "evidence": "We show here that ITPKB protein level was increased 3-fold in the cerebral cortex of most patients with Alzheimer's disease compared with control subjects, and accumulated in dystrophic neurites associated to amyloid plaques. In mouse Neuro-2a neuroblastoma cells, Itpkb overexpression was associated with increased cell apoptosis and increased β-secretase 1 activity leading to overproduction of amyloid-β peptides. In this cellular model, an inhibitor of mitogen-activated kinase kinases 1/2 completely prevented overproduction of amyloid-β peptides. Transgenic overexpression of ITPKB in mouse forebrain neurons was not sufficient to induce amyloid plaque formation or tau hyperphosphorylation. However, in the 5X familial Alzheimer's disease mouse model, neuronal ITPKB overexpression significantly increased extracellular signal-regulated kinases 1/2 activation and β-secretase 1 activity, resulting in exacerbated Alzheimer's disease pathology as shown by increased astrogliosis, amyloid-β40 peptide production and tau hyperphosphorylation.",
+      "key": "cf8b7d44c1fcb9ab31ef2e866cb659a2aa65eec582e50cf24bdae111c6c2bd85e1c9f03c8c5e2c4fb40cfea8dcbedb33abb929676a5b4a8b26795c30fb63e019",
+      "line": 3530,
+      "relation": "positiveCorrelation",
+      "source": 1017,
+      "target": 454
+    },
+    {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "Research_Model": {
+          "5xFAD mice": true
+        },
+        "Species": {
+          "10090": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Ando K",
+          "Brion JP",
+          "D'Amico E",
+          "Duyckaerts C",
+          "Erneux C",
+          "Jia Y",
+          "Leroy K",
+          "Luo HR",
+          "Pouillon V",
+          "Schurmans S",
+          "Stygelbout V"
+        ],
+        "date": "2014-02-01",
+        "first": "Stygelbout V",
+        "last": "Brion JP",
+        "name": "Brain : a journal of neurology",
+        "pages": "537-52",
+        "reference": "24401760",
+        "title": "Inositol trisphosphate 3-kinase B is increased in human Alzheimer brain and exacerbates mouse Alzheimer pathology.",
+        "type": "PubMed",
+        "volume": "137"
+      },
+      "evidence": "We show here that ITPKB protein level was increased 3-fold in the cerebral cortex of most patients with Alzheimer's disease compared with control subjects, and accumulated in dystrophic neurites associated to amyloid plaques. In mouse Neuro-2a neuroblastoma cells, Itpkb overexpression was associated with increased cell apoptosis and increased β-secretase 1 activity leading to overproduction of amyloid-β peptides. In this cellular model, an inhibitor of mitogen-activated kinase kinases 1/2 completely prevented overproduction of amyloid-β peptides. Transgenic overexpression of ITPKB in mouse forebrain neurons was not sufficient to induce amyloid plaque formation or tau hyperphosphorylation. However, in the 5X familial Alzheimer's disease mouse model, neuronal ITPKB overexpression significantly increased extracellular signal-regulated kinases 1/2 activation and β-secretase 1 activity, resulting in exacerbated Alzheimer's disease pathology as shown by increased astrogliosis, amyloid-β40 peptide production and tau hyperphosphorylation.",
+      "key": "5200d4cc9b3a817f7a0d09238574a47cf47e31b8c81233837838015c2325f5aa1e9f935a470d18cedd9ffd9463970b30c1cd7d87739b9bf6cba424b57b7c40fa",
+      "line": 3531,
+      "relation": "positiveCorrelation",
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+      "target": 599
     },
     {
       "annotations": {
@@ -5976,6 +6246,9 @@
           "entorhinal cortex": true,
           "middle temporal gyrus": true,
           "superior frontal gyrus": true
+        },
+        "Confidence": {
+          "High": true
         }
       },
       "citation": {
@@ -6003,16 +6276,19 @@
       },
       "evidence": "Sirt3 levels were reduced in the entorhinal cortex, the middle temporal gyrus, and the superior frontal gyrus of AD subjects compared to those of CN and was associated with poorer test scores of neuropsychological evaluation and the severity of tau pathology.",
       "key": "caf018b5c469092327716d6f0707d4407eb8704ee7bff695d93959dd3c24d5cde3b20d70527924bd8ec1a7c33091f860643ffb2abd90f311cc3ca05bafa12cad",
-      "line": 3053,
+      "line": 3765,
       "relation": "negativeCorrelation",
-      "source": 908,
-      "target": 849
+      "source": 1017,
+      "target": 940
     },
     {
       "annotations": {
         "Braak_Stage": {
           "Stage I": true
         },
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -6039,12 +6315,17 @@
       },
       "evidence": "We also tested for ac-tau 280 in early stage Alzheimer's disease (Braak stage 1). Histopathological examination using the ac tau 280 antibody was performed in three Alzheimer's cases and three CTE patients. Presence of ac-tau 280 was confirmed in all cases at early sites of disease manifestation. These findings suggest that tau acetylation may precede tau phosphorylation and could be the first ",
       "key": "12d449a1ffb7620845498c1e6b5928cdb054e54ae295d1af953188e446d25866245726f01ddddc26436a82f8314ecd3d0de76d85b173a4861e69ecb9d8961440",
-      "line": 3064,
+      "line": 3779,
       "relation": "positiveCorrelation",
-      "source": 908,
-      "target": 498
+      "source": 1017,
+      "target": 580
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "Cohen TJ",
@@ -6067,12 +6348,48 @@
       },
       "evidence": "Thus, K280 acetylation is a feature found in a variety of human 4R or 3R/4R tauopathies including AD, but not 3R-tauopathies such as PiD.",
       "key": "d729fc3abb3248782db8e0317e68b7000f12fd392804226daaf9eab49128aba2364d4b15275c8cae2222a71512e601fa768365a5192f96ee5fdf0a966c06cbc8",
-      "line": 3270,
+      "line": 4056,
       "relation": "positiveCorrelation",
-      "source": 908,
-      "target": 498
+      "source": 1017,
+      "target": 580
+    },
+    {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Saha P",
+          "Sen N",
+          "Sen T"
+        ],
+        "date": "2018-03-20",
+        "first": "Sen T",
+        "last": "Sen N",
+        "name": "Science signaling",
+        "reference": "29559585",
+        "title": "Nitrosylation of GAPDH augments pathological tau acetylation upon exposure to amyloid-β.",
+        "type": "PubMed",
+        "volume": "11"
+      },
+      "evidence": "We found that NO production and tau acetylation at Lys280 occurred in the brain tissue in mice and in cultured mouse cortical neurons in response to exposure to amyloid-β1-42 (Aβ1-42), a peptide that is also implicated in AD. An increased abundance of NO facilitated the S-nitrosylation (SNO) of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). S-nitrosylated GAPDH (GAPDH-SNO) promoted the acetylation and activation of the acetyltransferase p300 and facilitated the nitrosylation and inactivation of the deacetylase sirtuin 1 (SIRT1). The abundance of GAPDH-SNO was increased in postmortem brain samples from AD patients. Preventing the increase in GAPDH-SNO abundance in both cultured neurons and mice, either by overexpression of the nitrosylation mutant of GAPDH (GAPDH C150S) or by treatment with the GAPDH nitrosylation inhibitor CGP3466B (also known as omigapil), abrogated Aβ1-42-induced tau acetylation, memory impairment, and locomotor dysfunction in mice, suggesting that this drug might be repurposed to treat patients with AD.",
+      "key": "8ceba96729cce4e8ffda9b406d810ca8c82f2b34e92667e15f9deb1086a78cf7e94c60cee82dd87f23283a2fca34ee701cc0eaf9e947b4d39ed41e17455bcad1",
+      "line": 3833,
+      "relation": "positiveCorrelation",
+      "source": 1017,
+      "target": 533
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "Cohen TJ",
@@ -6095,46 +6412,52 @@
       },
       "evidence": "Thus, K280 acetylation is a feature found in a variety of human 4R or 3R/4R tauopathies including AD, but not 3R-tauopathies such as PiD.",
       "key": "1ab3acad4fca5f9112dcf459ec9e907049bae23c55e971a49735aee4ff40cf96440f1b724c5570c27c8f7be868ac5042ccac724494fd3a9bd423f0944131c296",
-      "line": 3272,
+      "line": 4058,
       "relation": "isA",
-      "source": 908,
-      "target": 903
+      "source": 1017,
+      "target": 999
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
-          "Devidze N",
-          "Gan L",
-          "Gestwicki JE",
-          "Johnson JR",
-          "Krogan NJ",
-          "Li Y",
-          "Masliah E",
-          "Min SW",
-          "Mok SA",
-          "Sohn PD"
+          "Dehennaut V",
+          "Drougat L",
+          "Guinez C",
+          "Lefebvre T",
+          "Michalski JC",
+          "Mir AM",
+          "Mortuaire M",
+          "Olivier S",
+          "Vercoutter-Edouart AS"
         ],
-        "date": "2018-04-11",
-        "first": "Min SW",
-        "last": "Gan L",
-        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
-        "pages": "3680-3688",
-        "reference": "29540553",
-        "title": "SIRT1 Deacetylates Tau and Reduces Pathogenic Tau Spread in a Mouse Model of Tauopathy.",
+        "date": "2010-02-01",
+        "first": "Lefebvre T",
+        "last": "Michalski JC",
+        "name": "Biochimica et biophysica acta",
+        "pages": "67-79",
+        "reference": "19732809",
+        "title": "Dysregulation of the nutrient/stress sensor O-GlcNAcylation is involved in the etiology of cardiovascular disorders, type-2 diabetes and Alzheimer's disease.",
         "type": "PubMed",
-        "volume": "38"
-      },
-      "evidence": "SIRT1 activation or elevation ameliorates pathology and neurodegeneration in AD (Qin et al., 2006; Kim et al., 2007). Loss of SIRT1 induces impairment of learning and memory (Gao et al., 2010; Michán et al., 2010).",
-      "key": "b1ac9987550af5d8d78ddf464f0fb292a353f4258f216cb7d9759765b0ded233e4a42f80afd529df32d37af743b138620d597a0740e941120dcfaf7561f7e6f7",
-      "line": 3332,
-      "object": {
-        "modifier": "Activity"
+        "volume": "1800"
       },
+      "evidence": " This post-translational modification is likely an indicator of good health since its intracellular level correlates with the availability of extracellular glucose. From a more practical point of view, it has been shown that O-GlcNAcylation impairments contribute to the etiology of cardiovascular diseases, type-2 diabetes and Alzheimer's disease (AD), three illnesses common in occidental societies.",
+      "key": "ff57fe8b0ffebfcee28ad35e87d39605f9472806044c3cf160039eada0a569359917bba5daca50a3d649362a62c74f4575456ada81282d4b40e323913a23d845",
+      "line": 4234,
       "relation": "negativeCorrelation",
-      "source": 908,
-      "target": 677
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+      "target": 859
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "Dehennaut V",
@@ -6157,14 +6480,19 @@
         "type": "PubMed",
         "volume": "1800"
       },
-      "evidence": " This post-translational modification is likely an indicator of good health since its intracellular level correlates with the availability of extracellular glucose. From a more practical point of view, it has been shown that O-GlcNAcylation impairments contribute to the etiology of cardiovascular diseases, type-2 diabetes and Alzheimer's disease (AD), three illnesses common in occidental societies.",
-      "key": "a508a0d7adeb8a26496d805bd2337b7a76ad727883fe26ba2a9c8e3ce65798848526d9d17244a0acf74a33ddda7ba58aea0e88c764574a2ffc67f041e81e2493",
-      "line": 3408,
-      "relation": "negativeCorrelation",
-      "source": 908,
-      "target": 106
+      "evidence": "It has been reported that the proteasomal machinery is modified by O-GlcNAcylation [53,126] and that after modification by OGT, the proteasome is inhibited [53]. Intriguingly, it has been proposed that a genetic impairment in the OGA gene results in proteasomal dysfunction through a lack of hydrolysis of the inhibitory O-GlcNAc residues of the 19S regulatory cap. Indeed, the OGA gene is located in the 10q locus [127,128], a chromosomal region frequently mutated in AD. The impairment of OGA in AD and the subsequent static OGlcNAcylation of the proteasome may explain why the latter fails to degrade neuronal aggregates. In addition, it has been reported that OGlcNAcylation reduces the sensitivity of intracellular proteins to proteasomal degradation by directly modifying them [43,129,130]. The two phenomena could thus act synergistically: a protein could escape degradation by means of its own O-GlcNAcylation and by the inhibitory effect of glycosylation on the proteasome, leading to a considerable decrease in the turnover of proteins that in turn may aggregate and cause neuronal death.",
+      "key": "06d6f9f733d28eda3cdb0d3b65e2269ce9e42e358dd0ee15ab2819e4c5da40919c34bd15ba9b2d0c266a44f06b815fdc07d50ae8dc47658fc0971f2e17f2635a",
+      "line": 4250,
+      "relation": "positiveCorrelation",
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+      "target": 329
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Barton Whittle T",
@@ -6191,13 +6519,16 @@
       },
       "evidence": "The plasma level of SUMO1 was significantly increased in dementia patients, as compared to control groups. The levels of SUMO1 correlated to decreased Mini-Mental State Examination (r =-0.123, p = 0.029). These results suggest that elevated plasma SUMO1 levels may be associated with AD.",
       "key": "8a1a5012496e665b797068000473d86cae81076dbc739569702446e210dfb79d4b24522d83735a10bc7eba6082eb44eaff440545fd2b86be70a108984aa8e8d0",
-      "line": 3613,
+      "line": 4483,
       "relation": "positiveCorrelation",
-      "source": 908,
-      "target": 692
+      "source": 1017,
+      "target": 781
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Study_Group": {
           "Korean population": true
         }
@@ -6223,67 +6554,143 @@
       },
       "evidence": "The genotype distribution of a polymorphism in intron 7 (rs761059) differed between AD cases and controls, with an adjusted odds ratio (OR) of 1.45 (p=0.046, 95% CI: 1.01-2.08). One haplotype (ht2 CAGAG) was found in 14.0% of the AD patients and in 11.1% of the controls (p=0.04, OR=1.43. 95% CI; 1.01-2.01). Stratification by the ApoE gave no significant difference between the groups but when stratified by gender, two SNPs (rs8052688, rs8063) were significantly associated with the risk of MCI among women.",
       "key": "884afa56903cdb4e820da5190583b398db2309ab76ef7195fcdde9da4a43ef755c351b19624e96e9fd9a6e13f4dcfae2f158875f376831239e7840be4b079ff8",
-      "line": 3622,
+      "line": 4494,
       "relation": "positiveCorrelation",
-      "source": 908,
-      "target": 254
+      "source": 1017,
+      "target": 321
     },
     {
       "annotations": {
-        "Method": {
-          "Western Blot": true
+        "Confidence": {
+          "Medium": true
         }
       },
       "citation": {
         "authors": [
-          "Adler CH",
-          "Beach TG",
-          "Braithwaite SP",
-          "Lee KW",
-          "Mouradian MM",
-          "Oh S",
-          "Park HJ",
-          "Stock JB",
-          "Voronkov M",
-          "Yan R",
-          "Zhang J"
+          "Ehninger D",
+          "Hettich MM",
+          "Kickstein E",
+          "Krauß S",
+          "Matthes F",
+          "Pfurtscheller S",
+          "Posey K",
+          "Schneider R",
+          "Schweiger S",
+          "Weber S"
         ],
-        "date": "2018-02-01",
-        "first": "Park HJ",
-        "last": "Mouradian MM",
-        "name": "Journal of neuropathology and experimental neurology",
-        "pages": "139-148",
-        "reference": "29281045",
-        "title": "Protein Phosphatase 2A and Its Methylation Modulating Enzymes LCMT-1 and PME-1 Are Dysregulated in Tauopathies of Progressive Supranuclear Palsy and Alzheimer Disease.",
+        "date": "2017-10-23",
+        "first": "Schweiger S",
+        "last": "Krauß S",
+        "name": "Scientific reports",
+        "pages": "13753",
+        "reference": "29062069",
+        "title": "Resveratrol induces dephosphorylation of Tau by interfering with the MID1-PP2A complex.",
         "type": "PubMed",
-        "volume": "77"
+        "volume": "7"
       },
-      "evidence": "Western blot analyses showed a decrease of methyl-PP2A and an increase of demethyl-PP2A with a concomitant reduction in the methyl/demethyl PP2A ratio in both PSP (74%) and AD (76%) brains, associated with an LCMT-1 decrease and a demethylating enzyme increase, protein phosphatase methylesterase (PME-1), in both diseases.",
-      "key": "8b9f5668aedda52da704420f97221f8d32b6bdb709a76d1dc145f4b6adc1d18cbffd7740a15320bbe72f74498dd934eb64e25e8c26d7739740fc75960eca5a93",
-      "line": 3913,
-      "relation": "decreases",
-      "source": 908,
-      "target": 468
+      "evidence": "Here we show that resveratrol treatment directly interferes with the MID1-α4-PP2A degradation complex by reducing MID1 protein expression in vitro and in vivo. This leads to an increase of microtubule-associated PP2A activity and a time- and dose-dependent dephosphorylation of Tau. Interestingly, we further show that MID1 expression is elevated in AD tissue.",
+      "key": "4bd740a742387846b53604c26e20a6d1abeba49d729cae033115ecd95aac3d15b1078d53197da26d96609308d3fd947306363359ae3da1aad1a4c0cec603b9e0",
+      "line": 4702,
+      "relation": "positiveCorrelation",
+      "source": 1017,
+      "target": 726
     },
     {
       "annotations": {
-        "Method": {
-          "Western Blot": true
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
         }
       },
       "citation": {
         "authors": [
-          "Adler CH",
-          "Beach TG",
-          "Braithwaite SP",
-          "Lee KW",
-          "Mouradian MM",
-          "Oh S",
-          "Park HJ",
-          "Stock JB",
-          "Voronkov M",
-          "Yan R",
-          "Zhang J"
+          "Arzberger T",
+          "Banzhaf-Strathmann J",
+          "Benito E",
+          "Edbauer D",
+          "Fischer A",
+          "Kretzschmar H",
+          "May S",
+          "Tahirovic S"
+        ],
+        "date": "2014-08-01",
+        "first": "Banzhaf-Strathmann J",
+        "last": "Edbauer D",
+        "name": "The EMBO journal",
+        "pages": "1667-80",
+        "reference": "25001178",
+        "title": "MicroRNA-125b induces tau hyperphosphorylation and cognitive deficits in Alzheimer's disease.",
+        "type": "PubMed",
+        "volume": "33"
+      },
+      "evidence": "In primary neurons, overexpression of miR-125b causes tau hyperphosphorylation and an upregulation of p35, cdk5, and p44/42-MAPK signaling. In parallel, the phosphatases DUSP6 and PPP1CA and the anti-apoptotic factor Bcl-W are downregulated as direct targets of miR-125b. Knockdown of these phosphatases induces tau hyperphosphorylation, and overexpression of PPP1CA and Bcl-W prevents miR-125b-induced tau phosphorylation, suggesting that they mediate the effects of miR-125b on tau. Conversely, suppression of miR-125b in neurons by tough decoys reduces tau phosphorylation and kinase expression/activity. Injecting miR-125b into the hippocampus of mice impairs associative learning and is accompanied by downregulation of Bcl-W, DUSP6, and PPP1CA, resulting in increased tau phosphorylation in vivo. Importantly, DUSP6 and PPP1CA are also reduced in AD brains.",
+      "key": "2ef9e358c9da65b77a9a21b0b4877b8c61d496e5360df7c80e4e764471af479f62b2d46747538e25d8d0bffbce9f067ce7cd0d0a94b22c6d68f88eb519790bf1",
+      "line": 4861,
+      "relation": "negativeCorrelation",
+      "source": 1017,
+      "target": 519
+    },
+    {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Arzberger T",
+          "Banzhaf-Strathmann J",
+          "Benito E",
+          "Edbauer D",
+          "Fischer A",
+          "Kretzschmar H",
+          "May S",
+          "Tahirovic S"
+        ],
+        "date": "2014-08-01",
+        "first": "Banzhaf-Strathmann J",
+        "last": "Edbauer D",
+        "name": "The EMBO journal",
+        "pages": "1667-80",
+        "reference": "25001178",
+        "title": "MicroRNA-125b induces tau hyperphosphorylation and cognitive deficits in Alzheimer's disease.",
+        "type": "PubMed",
+        "volume": "33"
+      },
+      "evidence": "In primary neurons, overexpression of miR-125b causes tau hyperphosphorylation and an upregulation of p35, cdk5, and p44/42-MAPK signaling. In parallel, the phosphatases DUSP6 and PPP1CA and the anti-apoptotic factor Bcl-W are downregulated as direct targets of miR-125b. Knockdown of these phosphatases induces tau hyperphosphorylation, and overexpression of PPP1CA and Bcl-W prevents miR-125b-induced tau phosphorylation, suggesting that they mediate the effects of miR-125b on tau. Conversely, suppression of miR-125b in neurons by tough decoys reduces tau phosphorylation and kinase expression/activity. Injecting miR-125b into the hippocampus of mice impairs associative learning and is accompanied by downregulation of Bcl-W, DUSP6, and PPP1CA, resulting in increased tau phosphorylation in vivo. Importantly, DUSP6 and PPP1CA are also reduced in AD brains.",
+      "key": "1fbb26a59536a9b35ee83c8f0a7df09a7c15bdac66489eda0e3fbc7c5e367155cd2647deeda499cbc817900cf103b2b72f644f63efef693fc3bc1101493432f7",
+      "line": 4862,
+      "relation": "negativeCorrelation",
+      "source": 1017,
+      "target": 742
+    },
+    {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "Method": {
+          "Western Blot": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Adler CH",
+          "Beach TG",
+          "Braithwaite SP",
+          "Lee KW",
+          "Mouradian MM",
+          "Oh S",
+          "Park HJ",
+          "Stock JB",
+          "Voronkov M",
+          "Yan R",
+          "Zhang J"
         ],
         "date": "2018-02-01",
         "first": "Park HJ",
@@ -6296,13 +6703,136 @@
         "volume": "77"
       },
       "evidence": "Western blot analyses showed a decrease of methyl-PP2A and an increase of demethyl-PP2A with a concomitant reduction in the methyl/demethyl PP2A ratio in both PSP (74%) and AD (76%) brains, associated with an LCMT-1 decrease and a demethylating enzyme increase, protein phosphatase methylesterase (PME-1), in both diseases.",
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+        "Method": {
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+      "citation": {
+        "authors": [
+          "Adler CH",
+          "Beach TG",
+          "Braithwaite SP",
+          "Lee KW",
+          "Mouradian MM",
+          "Oh S",
+          "Park HJ",
+          "Stock JB",
+          "Voronkov M",
+          "Yan R",
+          "Zhang J"
+        ],
+        "date": "2018-02-01",
+        "first": "Park HJ",
+        "last": "Mouradian MM",
+        "name": "Journal of neuropathology and experimental neurology",
+        "pages": "139-148",
+        "reference": "29281045",
+        "title": "Protein Phosphatase 2A and Its Methylation Modulating Enzymes LCMT-1 and PME-1 Are Dysregulated in Tauopathies of Progressive Supranuclear Palsy and Alzheimer Disease.",
+        "type": "PubMed",
+        "volume": "77"
+      },
+      "evidence": "Western blot analyses showed a decrease of methyl-PP2A and an increase of demethyl-PP2A with a concomitant reduction in the methyl/demethyl PP2A ratio in both PSP (74%) and AD (76%) brains, associated with an LCMT-1 decrease and a demethylating enzyme increase, protein phosphatase methylesterase (PME-1), in both diseases.",
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+        "Method": {
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+      },
+      "citation": {
+        "authors": [
+          "Adler CH",
+          "Beach TG",
+          "Braithwaite SP",
+          "Lee KW",
+          "Mouradian MM",
+          "Oh S",
+          "Park HJ",
+          "Stock JB",
+          "Voronkov M",
+          "Yan R",
+          "Zhang J"
+        ],
+        "date": "2018-02-01",
+        "first": "Park HJ",
+        "last": "Mouradian MM",
+        "name": "Journal of neuropathology and experimental neurology",
+        "pages": "139-148",
+        "reference": "29281045",
+        "title": "Protein Phosphatase 2A and Its Methylation Modulating Enzymes LCMT-1 and PME-1 Are Dysregulated in Tauopathies of Progressive Supranuclear Palsy and Alzheimer Disease.",
+        "type": "PubMed",
+        "volume": "77"
+      },
+      "evidence": "Western blot analyses showed a decrease of methyl-PP2A and an increase of demethyl-PP2A with a concomitant reduction in the methyl/demethyl PP2A ratio in both PSP (74%) and AD (76%) brains, associated with an LCMT-1 decrease and a demethylating enzyme increase, protein phosphatase methylesterase (PME-1), in both diseases.",
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+        "Confidence": {
+          "Medium": true
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+        "MeSHAnatomy": {
+          "Cell Nucleus": true
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+      },
+      "citation": {
+        "authors": [
+          "Arendt T",
+          "Brückner MK",
+          "Gruschka H",
+          "Hilbrich I",
+          "Holzer M",
+          "Rohn S",
+          "Ueberham E",
+          "Ueberham U",
+          "Wodischeck S"
+        ],
+        "date": "2014-12-01",
+        "first": "Ueberham U",
+        "last": "Arendt T",
+        "name": "Neuropathology and applied neurobiology",
+        "pages": "815-32",
+        "reference": "24964035",
+        "title": "Pin1 promotes degradation of Smad proteins and their interaction with phosphorylated tau in Alzheimer's disease.",
+        "type": "PubMed",
+        "volume": "40"
+      },
+      "evidence": "Alltogether, this provides evidence for a negative feed-back regulation of Pin1 by Smad. A similar mechanism might be instrumental in AD, where nuclear Smad concentrations are significantly reduced , which potentially contributes to increased levels of Pin1 [16]",
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     {
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       "citation": {
         "authors": [
           "Lu KP",
@@ -6320,17 +6850,20 @@
         "volume": "13"
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       "evidence": "Pin1 accelerates cis to trans conversion to prevent accumulation of pathogenic cis p-tau conformation in AD, providing the first structural evidence for how Pin1 protects against AD.",
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     {
       "annotations": {
         "Anatomy": {
           "cerebral cortex": true
         },
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         "Method": {
           "Immunoprecipitation": true,
           "Liquid Chromatography": true,
@@ -6373,16 +6906,19 @@
       },
       "evidence": "In order to pinpoint new N-terminal truncation sites of Tau, we optimized a proteomic approach (Fig. 1C) in brain samples. The whole range of Tau species was immunoprecipitated (IP) from protein extracts with the Tau-5 antibody, which recognizes amino acid residues 218–225. As shown by WB analysis (Fig. S1), Tau-5 IP allows the purification of full-length Tau (FL-Tau) as well as N- and C-terminally truncated Tau and aggregated species, which display lower and higher molecular weights, respectively. These new N-terminal sites were scattered across the Tau sequence (Fig. 1D), and except for Ala2, have not been described before.",
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         "Method": {
           "Immunoprecipitation": true,
           "Liquid Chromatography": true,
@@ -6422,16 +6958,19 @@
       },
       "evidence": "In order to pinpoint new N-terminal truncation sites of Tau, we optimized a proteomic approach (Fig. 1C) in brain samples. The whole range of Tau species was immunoprecipitated (IP) from protein extracts with the Tau-5 antibody, which recognizes amino acid residues 218–225. As shown by WB analysis (Fig. S1), Tau-5 IP allows the purification of full-length Tau (FL-Tau) as well as N- and C-terminally truncated Tau and aggregated species, which display lower and higher molecular weights, respectively. These new N-terminal sites were scattered across the Tau sequence (Fig. 1D), and except for Ala2, have not been described before.",
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     {
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         "Anatomy": {
           "cerebral cortex": true
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         "Method": {
           "Immunoprecipitation": true,
           "Liquid Chromatography": true,
@@ -6471,16 +7010,19 @@
       },
       "evidence": "In order to pinpoint new N-terminal truncation sites of Tau, we optimized a proteomic approach (Fig. 1C) in brain samples. The whole range of Tau species was immunoprecipitated (IP) from protein extracts with the Tau-5 antibody, which recognizes amino acid residues 218–225. As shown by WB analysis (Fig. S1), Tau-5 IP allows the purification of full-length Tau (FL-Tau) as well as N- and C-terminally truncated Tau and aggregated species, which display lower and higher molecular weights, respectively. These new N-terminal sites were scattered across the Tau sequence (Fig. 1D), and except for Ala2, have not been described before.",
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     {
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           "cerebral cortex": true
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         "Method": {
           "Immunoprecipitation": true,
           "Liquid Chromatography": true,
@@ -6520,16 +7062,19 @@
       },
       "evidence": "In order to pinpoint new N-terminal truncation sites of Tau, we optimized a proteomic approach (Fig. 1C) in brain samples. The whole range of Tau species was immunoprecipitated (IP) from protein extracts with the Tau-5 antibody, which recognizes amino acid residues 218–225. As shown by WB analysis (Fig. S1), Tau-5 IP allows the purification of full-length Tau (FL-Tau) as well as N- and C-terminally truncated Tau and aggregated species, which display lower and higher molecular weights, respectively. These new N-terminal sites were scattered across the Tau sequence (Fig. 1D), and except for Ala2, have not been described before.",
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@@ -6566,16 +7111,19 @@
       },
       "evidence": "Regarding the effect of N-terminally truncated Tau, the Met11-Tau fragment showed the same properties as FL-Tau while Gln124-Tau was associated with a markedly increased level of acetylated tubulin compared to FL-Tau.",
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@@ -6612,10 +7160,10 @@
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       "evidence": "In agreement with this possibility, the investigation of another posttranslational modification of tubulin, detyrosination, which is also representative of a stable population of microtubules, revealed that it was significantly increased with Gln124-Tau when compared to FL-Tau",
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@@ -6661,13 +7209,13 @@
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       "evidence": "In agreement with this possibility, the investigation of another posttranslational modification of tubulin, detyrosination, which is also representative of a stable population of microtubules, revealed that it was significantly increased with Gln124-Tau when compared to FL-Tau",
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@@ -6713,19 +7261,22 @@
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       "evidence": "In agreement with this possibility, the investigation of another posttranslational modification of tubulin, detyrosination, which is also representative of a stable population of microtubules, revealed that it was significantly increased with Gln124-Tau when compared to FL-Tau",
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@@ -6765,16 +7316,19 @@
       },
       "evidence": "In order to pinpoint new N-terminal truncation sites of Tau, we optimized a proteomic approach (Fig. 1C) in brain samples. The whole range of Tau species was immunoprecipitated (IP) from protein extracts with the Tau-5 antibody, which recognizes amino acid residues 218–225. As shown by WB analysis (Fig. S1), Tau-5 IP allows the purification of full-length Tau (FL-Tau) as well as N- and C-terminally truncated Tau and aggregated species, which display lower and higher molecular weights, respectively. These new N-terminal sites were scattered across the Tau sequence (Fig. 1D), and except for Ala2, have not been described before.",
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@@ -6814,16 +7368,19 @@
       },
       "evidence": "In order to pinpoint new N-terminal truncation sites of Tau, we optimized a proteomic approach (Fig. 1C) in brain samples. The whole range of Tau species was immunoprecipitated (IP) from protein extracts with the Tau-5 antibody, which recognizes amino acid residues 218–225. As shown by WB analysis (Fig. S1), Tau-5 IP allows the purification of full-length Tau (FL-Tau) as well as N- and C-terminally truncated Tau and aggregated species, which display lower and higher molecular weights, respectively. These new N-terminal sites were scattered across the Tau sequence (Fig. 1D), and except for Ala2, have not been described before.",
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     {
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@@ -6863,16 +7420,19 @@
       },
       "evidence": "In order to pinpoint new N-terminal truncation sites of Tau, we optimized a proteomic approach (Fig. 1C) in brain samples. The whole range of Tau species was immunoprecipitated (IP) from protein extracts with the Tau-5 antibody, which recognizes amino acid residues 218–225. As shown by WB analysis (Fig. S1), Tau-5 IP allows the purification of full-length Tau (FL-Tau) as well as N- and C-terminally truncated Tau and aggregated species, which display lower and higher molecular weights, respectively. These new N-terminal sites were scattered across the Tau sequence (Fig. 1D), and except for Ala2, have not been described before.",
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@@ -6912,16 +7472,19 @@
       },
       "evidence": "In order to pinpoint new N-terminal truncation sites of Tau, we optimized a proteomic approach (Fig. 1C) in brain samples. The whole range of Tau species was immunoprecipitated (IP) from protein extracts with the Tau-5 antibody, which recognizes amino acid residues 218–225. As shown by WB analysis (Fig. S1), Tau-5 IP allows the purification of full-length Tau (FL-Tau) as well as N- and C-terminally truncated Tau and aggregated species, which display lower and higher molecular weights, respectively. These new N-terminal sites were scattered across the Tau sequence (Fig. 1D), and except for Ala2, have not been described before.",
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@@ -6961,16 +7524,19 @@
       },
       "evidence": "In order to pinpoint new N-terminal truncation sites of Tau, we optimized a proteomic approach (Fig. 1C) in brain samples. The whole range of Tau species was immunoprecipitated (IP) from protein extracts with the Tau-5 antibody, which recognizes amino acid residues 218–225. As shown by WB analysis (Fig. S1), Tau-5 IP allows the purification of full-length Tau (FL-Tau) as well as N- and C-terminally truncated Tau and aggregated species, which display lower and higher molecular weights, respectively. These new N-terminal sites were scattered across the Tau sequence (Fig. 1D), and except for Ala2, have not been described before.",
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@@ -7010,16 +7576,19 @@
       },
       "evidence": "In order to pinpoint new N-terminal truncation sites of Tau, we optimized a proteomic approach (Fig. 1C) in brain samples. The whole range of Tau species was immunoprecipitated (IP) from protein extracts with the Tau-5 antibody, which recognizes amino acid residues 218–225. As shown by WB analysis (Fig. S1), Tau-5 IP allows the purification of full-length Tau (FL-Tau) as well as N- and C-terminally truncated Tau and aggregated species, which display lower and higher molecular weights, respectively. These new N-terminal sites were scattered across the Tau sequence (Fig. 1D), and except for Ala2, have not been described before.",
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@@ -7059,16 +7628,19 @@
       },
       "evidence": "In order to pinpoint new N-terminal truncation sites of Tau, we optimized a proteomic approach (Fig. 1C) in brain samples. The whole range of Tau species was immunoprecipitated (IP) from protein extracts with the Tau-5 antibody, which recognizes amino acid residues 218–225. As shown by WB analysis (Fig. S1), Tau-5 IP allows the purification of full-length Tau (FL-Tau) as well as N- and C-terminally truncated Tau and aggregated species, which display lower and higher molecular weights, respectively. These new N-terminal sites were scattered across the Tau sequence (Fig. 1D), and except for Ala2, have not been described before.",
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     {
       "annotations": {
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           "cerebral cortex": true
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@@ -7108,16 +7680,19 @@
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       "evidence": "In order to pinpoint new N-terminal truncation sites of Tau, we optimized a proteomic approach (Fig. 1C) in brain samples. The whole range of Tau species was immunoprecipitated (IP) from protein extracts with the Tau-5 antibody, which recognizes amino acid residues 218–225. As shown by WB analysis (Fig. S1), Tau-5 IP allows the purification of full-length Tau (FL-Tau) as well as N- and C-terminally truncated Tau and aggregated species, which display lower and higher molecular weights, respectively. These new N-terminal sites were scattered across the Tau sequence (Fig. 1D), and except for Ala2, have not been described before.",
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       "annotations": {
         "Anatomy": {
           "cerebral cortex": true
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         "volume": "5"
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       "evidence": "In order to pinpoint new N-terminal truncation sites of Tau, we optimized a proteomic approach (Fig. 1C) in brain samples. The whole range of Tau species was immunoprecipitated (IP) from protein extracts with the Tau-5 antibody, which recognizes amino acid residues 218–225. As shown by WB analysis (Fig. S1), Tau-5 IP allows the purification of full-length Tau (FL-Tau) as well as N- and C-terminally truncated Tau and aggregated species, which display lower and higher molecular weights, respectively. These new N-terminal sites were scattered across the Tau sequence (Fig. 1D), and except for Ala2, have not been described before.",
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     {
       "annotations": {
         "Anatomy": {
           "cerebral cortex": true
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@@ -7205,17 +7783,20 @@
         "volume": "5"
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       "evidence": "In order to pinpoint new N-terminal truncation sites of Tau, we optimized a proteomic approach (Fig. 1C) in brain samples. The whole range of Tau species was immunoprecipitated (IP) from protein extracts with the Tau-5 antibody, which recognizes amino acid residues 218–225. As shown by WB analysis (Fig. S1), Tau-5 IP allows the purification of full-length Tau (FL-Tau) as well as N- and C-terminally truncated Tau and aggregated species, which display lower and higher molecular weights, respectively. These new N-terminal sites were scattered across the Tau sequence (Fig. 1D), and except for Ala2, have not been described before.",
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     {
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         "Anatomy": {
           "cerebral cortex": true
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         "volume": "5"
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       "evidence": "In order to pinpoint new N-terminal truncation sites of Tau, we optimized a proteomic approach (Fig. 1C) in brain samples. The whole range of Tau species was immunoprecipitated (IP) from protein extracts with the Tau-5 antibody, which recognizes amino acid residues 218–225. As shown by WB analysis (Fig. S1), Tau-5 IP allows the purification of full-length Tau (FL-Tau) as well as N- and C-terminally truncated Tau and aggregated species, which display lower and higher molecular weights, respectively. These new N-terminal sites were scattered across the Tau sequence (Fig. 1D), and except for Ala2, have not been described before.",
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     {
       "annotations": {
         "Anatomy": {
           "cerebral cortex": true
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@@ -7303,17 +7887,20 @@
         "volume": "5"
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       "evidence": "In order to pinpoint new N-terminal truncation sites of Tau, we optimized a proteomic approach (Fig. 1C) in brain samples. The whole range of Tau species was immunoprecipitated (IP) from protein extracts with the Tau-5 antibody, which recognizes amino acid residues 218–225. As shown by WB analysis (Fig. S1), Tau-5 IP allows the purification of full-length Tau (FL-Tau) as well as N- and C-terminally truncated Tau and aggregated species, which display lower and higher molecular weights, respectively. These new N-terminal sites were scattered across the Tau sequence (Fig. 1D), and except for Ala2, have not been described before.",
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         "Anatomy": {
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@@ -7352,17 +7939,20 @@
         "volume": "5"
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       "evidence": "In order to pinpoint new N-terminal truncation sites of Tau, we optimized a proteomic approach (Fig. 1C) in brain samples. The whole range of Tau species was immunoprecipitated (IP) from protein extracts with the Tau-5 antibody, which recognizes amino acid residues 218–225. As shown by WB analysis (Fig. S1), Tau-5 IP allows the purification of full-length Tau (FL-Tau) as well as N- and C-terminally truncated Tau and aggregated species, which display lower and higher molecular weights, respectively. These new N-terminal sites were scattered across the Tau sequence (Fig. 1D), and except for Ala2, have not been described before.",
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       "annotations": {
         "Anatomy": {
           "cerebral cortex": true
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@@ -7401,26 +7991,28 @@
         "volume": "5"
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       "evidence": "In order to pinpoint new N-terminal truncation sites of Tau, we optimized a proteomic approach (Fig. 1C) in brain samples. The whole range of Tau species was immunoprecipitated (IP) from protein extracts with the Tau-5 antibody, which recognizes amino acid residues 218–225. As shown by WB analysis (Fig. S1), Tau-5 IP allows the purification of full-length Tau (FL-Tau) as well as N- and C-terminally truncated Tau and aggregated species, which display lower and higher molecular weights, respectively. These new N-terminal sites were scattered across the Tau sequence (Fig. 1D), and except for Ala2, have not been described before.",
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     {
       "annotations": {
         "Anatomy": {
           "cerebral cortex": true
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           "Mass Spectrometry": true,
           "Western Blot": true
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-        "Tau_Antibody": {
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+        "Tau_Structure": {
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         "volume": "5"
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       "evidence": "In order to pinpoint new N-terminal truncation sites of Tau, we optimized a proteomic approach (Fig. 1C) in brain samples. The whole range of Tau species was immunoprecipitated (IP) from protein extracts with the Tau-5 antibody, which recognizes amino acid residues 218–225. As shown by WB analysis (Fig. S1), Tau-5 IP allows the purification of full-length Tau (FL-Tau) as well as N- and C-terminally truncated Tau and aggregated species, which display lower and higher molecular weights, respectively. These new N-terminal sites were scattered across the Tau sequence (Fig. 1D), and except for Ala2, have not been described before.",
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     {
       "annotations": {
         "Anatomy": {
           "cerebral cortex": true
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+        "Confidence": {
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@@ -7501,58 +8096,11 @@
         "volume": "5"
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       "evidence": "In order to pinpoint new N-terminal truncation sites of Tau, we optimized a proteomic approach (Fig. 1C) in brain samples. The whole range of Tau species was immunoprecipitated (IP) from protein extracts with the Tau-5 antibody, which recognizes amino acid residues 218–225. As shown by WB analysis (Fig. S1), Tau-5 IP allows the purification of full-length Tau (FL-Tau) as well as N- and C-terminally truncated Tau and aggregated species, which display lower and higher molecular weights, respectively. These new N-terminal sites were scattered across the Tau sequence (Fig. 1D), and except for Ala2, have not been described before.",
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-        "authors": [
-          "Huang L",
-          "Liu C",
-          "Qin C",
-          "Sheng SL",
-          "Sui XL",
-          "Tao JJ",
-          "Wu J",
-          "Xu YF",
-          "Yao ZG",
-          "Zhang L",
-          "Zhu H"
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-        "date": "2014-01-01",
-        "first": "Zhang L",
-        "last": "Qin C",
-        "name": "Journal of Alzheimer's disease : JAD",
-        "pages": "1193-205",
-        "reference": "24844691",
-        "title": "Tubastatin A/ACY-1215 improves cognition in Alzheimer's disease transgenic mice.",
-        "type": "PubMed",
-        "volume": "41"
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-      "evidence": "In the present study, we tested the potential of two selective HDAC6 inhibitors, tubastatin A and ACY-1215, to rescue cognitive deficits in a mouse model of AD. We found that both tubastatin A and ACY-1215 alleviated behavioral deficits, altered amyloid-β (Aβ) load, and reduced tau hyperphosphorylation in AD mice without obvious adverse effects. Our data suggested that tubastatin A and ACY-1215 not only promoted tubulin acetylation, but also reduced production and facilitated autophagic clearance of Aβ and hyperphosphorylated tau.",
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@@ -7560,13 +8108,17 @@
           "cerebral cortex": true
         },
         "Confidence": {
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         },
         "Method": {
           "Immunoprecipitation": true,
           "Liquid Chromatography": true,
           "Mass Spectrometry": true,
           "Western Blot": true
+        },
+        "Tau_Antibody": {
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+          "Tau-13": true
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       "citation": {
@@ -7596,15 +8148,57 @@
         "type": "PubMed",
         "volume": "5"
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-      "evidence": "In agreement with this possibility, the investigation of another posttranslational modification of tubulin, detyrosination, which is also representative of a stable population of microtubules, revealed that it was significantly increased with Gln124-Tau when compared to FL-Tau",
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-      "relation": "positiveCorrelation",
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-      "subject": {
-        "modifier": "Activity"
+      "evidence": "In order to pinpoint new N-terminal truncation sites of Tau, we optimized a proteomic approach (Fig. 1C) in brain samples. The whole range of Tau species was immunoprecipitated (IP) from protein extracts with the Tau-5 antibody, which recognizes amino acid residues 218–225. As shown by WB analysis (Fig. S1), Tau-5 IP allows the purification of full-length Tau (FL-Tau) as well as N- and C-terminally truncated Tau and aggregated species, which display lower and higher molecular weights, respectively. These new N-terminal sites were scattered across the Tau sequence (Fig. 1D), and except for Ala2, have not been described before.",
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+    {
+      "annotations": {
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+        }
       },
-      "target": 606
+      "citation": {
+        "authors": [
+          "Cohen TJ",
+          "Friedmann D",
+          "Hwang AW",
+          "Lee VM",
+          "Marmorstein R",
+          "Trzeciakiewicz H",
+          "Yuan CX"
+        ],
+        "date": "2016-01-01",
+        "first": "Hwang AW",
+        "last": "Cohen TJ",
+        "name": "PloS one",
+        "pages": "e0168913",
+        "reference": "28002468",
+        "title": "Conserved Lysine Acetylation within the Microtubule-Binding Domain Regulates MAP2/Tau Family Members.",
+        "type": "PubMed",
+        "volume": "11"
+      },
+      "evidence": "Similar to tau, MAP2 acetylation can occur in a cysteine-dependent auto-regulatory manner in the presence of acetyl-CoA. Tubulin reduced MAP2 acetylation, suggesting tubulin binding dictates MAP acetylation status.",
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@@ -7649,14 +8243,14 @@
         "volume": "5"
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       "evidence": "In agreement with this possibility, the investigation of another posttranslational modification of tubulin, detyrosination, which is also representative of a stable population of microtubules, revealed that it was significantly increased with Gln124-Tau when compared to FL-Tau",
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@@ -7701,14 +8295,14 @@
         "volume": "5"
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       "evidence": "In agreement with this possibility, the investigation of another posttranslational modification of tubulin, detyrosination, which is also representative of a stable population of microtubules, revealed that it was significantly increased with Gln124-Tau when compared to FL-Tau",
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@@ -7753,20 +8347,28 @@
         "volume": "5"
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       "evidence": "In agreement with this possibility, the investigation of another posttranslational modification of tubulin, detyrosination, which is also representative of a stable population of microtubules, revealed that it was significantly increased with Gln124-Tau when compared to FL-Tau",
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     {
       "annotations": {
-        "Tau_Antibody": {
-          "Tau-12": true,
-          "Tau-13": true
+        "Anatomy": {
+          "cerebral cortex": true
+        },
+        "Confidence": {
+          "Medium": true
+        },
+        "Method": {
+          "Immunoprecipitation": true,
+          "Liquid Chromatography": true,
+          "Mass Spectrometry": true,
+          "Western Blot": true
         }
       },
       "citation": {
@@ -7796,22 +8398,21 @@
         "type": "PubMed",
         "volume": "5"
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-      "evidence": "Hyperphosphorylation with Prostate-derived sterile 20-like kinase 1 alpha/beta (PSK1/TAOK2), Prostate-derived sterile 20-like kinase 2 (PSK2/TAOK1), CK1.",
-      "key": "9d7443d5fa99fdf28a4943fd160be3f8d9b1860ec3613e18af0d8c8e131e45ef367bba542c8e6c8597c8595124abc63fc82a8b71c099aaa5212337d881ebd5c7",
+      "evidence": "In agreement with this possibility, the investigation of another posttranslational modification of tubulin, detyrosination, which is also representative of a stable population of microtubules, revealed that it was significantly increased with Gln124-Tau when compared to FL-Tau",
+      "key": "b8b8fb447289178d72f4999ec8f9c64280bfe71720ef51732c55cf531af81c988fd56a7dc54936b99ce7d0a47c6acd8672887230fc7371565094cbed609200fe",
       "line": 182,
-      "relation": "directlyIncreases",
-      "source": 719,
+      "relation": "increases",
+      "source": 837,
       "subject": {
-        "effect": {
-          "name": "kin",
-          "namespace": "bel"
-        },
         "modifier": "Activity"
       },
-      "target": 575
+      "target": 847
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "Tau_Antibody": {
           "Tau-12": true,
           "Tau-13": true
@@ -7845,14 +8446,221 @@
         "volume": "5"
       },
       "evidence": "Hyperphosphorylation with Prostate-derived sterile 20-like kinase 1 alpha/beta (PSK1/TAOK2), Prostate-derived sterile 20-like kinase 2 (PSK2/TAOK1), CK1.",
-      "key": "7fffd8e3c05d1021c0c6c5cf2e79aafa89a8b4efa419faed36a2c46ac76d6c980ccc5487af1bbab3fc610a694db2a69649d148ba2269e7fc07b259d92d5038b4",
-      "line": 185,
-      "relation": "isA",
-      "source": 575,
-      "target": 486
+      "key": "769f69d74dbda0c0efa103e6aa24bc6efcb9d9dba9ca59a3d25de421ab812faa99e9dc13ef423e35b2a3f4666dbdd5ea080670959b0a8937f8d14c12ca88bfa1",
+      "line": 191,
+      "relation": "directlyIncreases",
+      "source": 809,
+      "subject": {
+        "effect": {
+          "name": "kin",
+          "namespace": "bel"
+        },
+        "modifier": "Activity"
+      },
+      "target": 599
+    },
+    {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "Research_Model": {
+          "5xFAD mice": true
+        },
+        "Species": {
+          "10090": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Ando K",
+          "Brion JP",
+          "D'Amico E",
+          "Duyckaerts C",
+          "Erneux C",
+          "Jia Y",
+          "Leroy K",
+          "Luo HR",
+          "Pouillon V",
+          "Schurmans S",
+          "Stygelbout V"
+        ],
+        "date": "2014-02-01",
+        "first": "Stygelbout V",
+        "last": "Brion JP",
+        "name": "Brain : a journal of neurology",
+        "pages": "537-52",
+        "reference": "24401760",
+        "title": "Inositol trisphosphate 3-kinase B is increased in human Alzheimer brain and exacerbates mouse Alzheimer pathology.",
+        "type": "PubMed",
+        "volume": "137"
+      },
+      "evidence": "We show here that ITPKB protein level was increased 3-fold in the cerebral cortex of most patients with Alzheimer's disease compared with control subjects, and accumulated in dystrophic neurites associated to amyloid plaques. In mouse Neuro-2a neuroblastoma cells, Itpkb overexpression was associated with increased cell apoptosis and increased β-secretase 1 activity leading to overproduction of amyloid-β peptides. In this cellular model, an inhibitor of mitogen-activated kinase kinases 1/2 completely prevented overproduction of amyloid-β peptides. Transgenic overexpression of ITPKB in mouse forebrain neurons was not sufficient to induce amyloid plaque formation or tau hyperphosphorylation. However, in the 5X familial Alzheimer's disease mouse model, neuronal ITPKB overexpression significantly increased extracellular signal-regulated kinases 1/2 activation and β-secretase 1 activity, resulting in exacerbated Alzheimer's disease pathology as shown by increased astrogliosis, amyloid-β40 peptide production and tau hyperphosphorylation.",
+      "key": "bf12cd4b9d18e35a0123458aad8b00416f2d9365ed44b2c181b4d637214d34cfdf3441c5dc5208c0eae1d1ae76e6ba27357ecf1344946293e200c7531d22c60b",
+      "line": 3531,
+      "relation": "positiveCorrelation",
+      "source": 599,
+      "target": 1017
+    },
+    {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "Species": {
+          "7227": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Jin S",
+          "Wu J",
+          "Xiong Y",
+          "Xu Z",
+          "Zhang YQ",
+          "Zhao K"
+        ],
+        "date": "2013-03-19",
+        "first": "Xiong Y",
+        "last": "Zhang YQ",
+        "name": "Proceedings of the National Academy of Sciences of the United States of America",
+        "pages": "4604-9",
+        "reference": "23487739",
+        "title": "HDAC6 mutations rescue human tau-induced microtubule defects in Drosophila.",
+        "type": "PubMed",
+        "volume": "110"
+      },
+      "evidence": "Overexpressed tau was hyperphosphorylated and resulted in decreased MT density and greater fragmentation. Using genetic screen, a histone deacetylase 6 (HDAC6) null mutation rescued tau-induced MT defects in both muscles and neurons. Genetic and pharmacological inhibition of the tubulin-specific deacetylase activity of HDAC6 indicates that the rescue effect may be mediated by increased MT acetylation.",
+      "key": "d27b6e592bf75a98eb0e8116483015e0f7f4569fe17d9af643c3a756b839f8479cb9c645dc06547f7baf69b5bd7435db3eae55ed833c216c6f410c7d59b62206",
+      "line": 4034,
+      "relation": "decreases",
+      "source": 599,
+      "target": 99
+    },
+    {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Dehennaut V",
+          "Drougat L",
+          "Guinez C",
+          "Lefebvre T",
+          "Michalski JC",
+          "Mir AM",
+          "Mortuaire M",
+          "Olivier S",
+          "Vercoutter-Edouart AS"
+        ],
+        "date": "2010-02-01",
+        "first": "Lefebvre T",
+        "last": "Michalski JC",
+        "name": "Biochimica et biophysica acta",
+        "pages": "67-79",
+        "reference": "19732809",
+        "title": "Dysregulation of the nutrient/stress sensor O-GlcNAcylation is involved in the etiology of cardiovascular disorders, type-2 diabetes and Alzheimer's disease.",
+        "type": "PubMed",
+        "volume": "1800"
+      },
+      "evidence": "These results are in accord with our previous study showing that Tau hyperphosphorylation is associated with a decrease in its O-GlcNAcylation level. A recent observation argues for the hypothesis that O-GlcNAcylation occurs first and that its modification reflects on the phosphorylation status.",
+      "key": "e303bbb04098d1508e438882f77dfc61258cce8089a807f96f994401c57bff614648acbe06cb66102efacbce1eeba075922f7524dc37eb61b069e6d4b90f911b",
+      "line": 4258,
+      "relation": "negativeCorrelation",
+      "source": 599,
+      "target": 596
+    },
+    {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Cerebral Cortex": true
+        },
+        "MeSHDisease": {
+          "Alzheimer Disease": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Feng Y",
+          "Jiang J",
+          "Liu XH",
+          "Liu ZC",
+          "Luo HB",
+          "Shu XJ",
+          "Wang JZ",
+          "Wang XC",
+          "Xia YY",
+          "Xiong YS",
+          "Ye K",
+          "Yin G",
+          "Yu G",
+          "Zeng K"
+        ],
+        "date": "2014-11-18",
+        "first": "Luo HB",
+        "last": "Wang JZ",
+        "name": "Proceedings of the National Academy of Sciences of the United States of America",
+        "pages": "16586-91",
+        "reference": "25378699",
+        "title": "SUMOylation at K340 inhibits tau degradation through deregulating its phosphorylation and ubiquitination.",
+        "type": "PubMed",
+        "volume": "111"
+      },
+      "evidence": "Furthermore, the enhanced SUMO-immunoreactivity, costained with the hyperphosphorylated tau, is detected in cerebral cortex of the AD brains, and β-amyloid exposure of rat primary hippocampal neurons induces a dose-dependent SUMOylation of the hyperphosphorylated tau. Our findings suggest that tau SUMOylation reciprocally stimulates its phosphorylation and inhibits the ubiquitination-mediated tau degradation, which provides a new insight into the AD-like tau accumulation.",
+      "key": "7c5fce1eb0b39f76481f28599b537532b374c926d70487e9cc37ad3db178882a07e6d85a33cf5caccb18469aaec4cbd90c979f85140470be0ea1efe7ec05bc6f",
+      "line": 4322,
+      "relation": "positiveCorrelation",
+      "source": 599,
+      "target": 678
+    },
+    {
+      "annotations": {
+        "Cell": {
+          "cerebral cortex neuron": true
+        },
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHDisease": {
+          "Alzheimer Disease": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Braidy N",
+          "Brew BJ",
+          "Cullen KM",
+          "Guillemin GJ",
+          "Rahman A",
+          "Ting K"
+        ],
+        "date": "2009-07-22",
+        "first": "Rahman A",
+        "last": "Guillemin GJ",
+        "name": "PloS one",
+        "pages": "e6344",
+        "reference": "19623258",
+        "title": "The excitotoxin quinolinic acid induces tau phosphorylation in human neurons.",
+        "type": "PubMed",
+        "volume": "4"
+      },
+      "evidence": "Kynurenic pathway is overactive in AD. QA is co-localized with hyperphosphorylated tau within cortical neurons in AD brain. In primary cultures of human neurons, QA treatment increased tau phosphorylation at serine 199/202, threonine 231 and serine 396/404 in a dose dependent manner. This increase in tau phosphorylation was paralleled by a substantial decrease in the total protein phosphatase activity, mostly in PP2A expression and modest in PP1.",
+      "key": "81c0de5f9cdca5506e18c2c0e0760bb40aeb682724138851c013f3172d28ce8911cbc3b7fc8037851d9262cd9cff661193f65a1932cf248a99a2ef7510d12b7a",
+      "line": 4802,
+      "relation": "association",
+      "source": 599,
+      "target": 32
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "Tau_Antibody": {
           "Tau-12": true,
           "Tau-13": true
@@ -7886,10 +8694,10 @@
         "volume": "5"
       },
       "evidence": "Hyperphosphorylation with Prostate-derived sterile 20-like kinase 1 alpha/beta (PSK1/TAOK2), Prostate-derived sterile 20-like kinase 2 (PSK2/TAOK1), CK1.",
-      "key": "b1ea162f0b6267f62cfa008a44dc4cb9b8535b605c8970b65ef7a72fc8328655e8d0741da04ef76298f6af4dadd685c4b183e25f6e4199e307df210fcb798e39",
-      "line": 183,
+      "key": "550624dc06db2b4fe5d22d49104eb742a5a97cf216418ecbd5657a7f32b527ee6456c7efb24a5a8f2f0fb2c59552bdf447d77951654797b54fe14a12be889eec",
+      "line": 192,
       "relation": "directlyIncreases",
-      "source": 720,
+      "source": 810,
       "subject": {
         "effect": {
           "name": "kin",
@@ -7897,10 +8705,13 @@
         },
         "modifier": "Activity"
       },
-      "target": 575
+      "target": 599
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "Tau_Antibody": {
           "Tau-12": true,
           "Tau-13": true
@@ -7934,10 +8745,10 @@
         "volume": "5"
       },
       "evidence": "Hyperphosphorylation with Prostate-derived sterile 20-like kinase 1 alpha/beta (PSK1/TAOK2), Prostate-derived sterile 20-like kinase 2 (PSK2/TAOK1), CK1.",
-      "key": "382c4691e87773235c74ced0a6600a42fa5d90c522e8ab70fc5294c71bc48cc6e6776acbde20d0d163020ca629b79f2731fb90916d31c1f7a4abb145573998a9",
-      "line": 184,
+      "key": "ea4f7c475530b6a15d221d5ac644cba0d150c468077caaf4c96192a782bf86831c4f39bb48a9d349aaafe395544917cf509bb10423ec2f886e9250c2553b7796",
+      "line": 193,
       "relation": "directlyIncreases",
-      "source": 411,
+      "source": 490,
       "subject": {
         "effect": {
           "name": "kin",
@@ -7945,9 +8756,14 @@
         },
         "modifier": "Activity"
       },
-      "target": 575
+      "target": 599
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Alessi DR",
@@ -7975,12 +8791,17 @@
       },
       "evidence": "The CK1 group of eukaryotic protein kinases are composed of seven CK1 isoforms (CK1α, CK1α2, CK1δ, CK1ε, CK1γ1, CK1γ2, and CK1γ3), two Tau–tubulin kinase isoforms (TTBK1 and TTBK2), and three VRK isoforms (VRK1, VRK2, and VRK3)",
       "key": "697a7eb082f2a9c8e7da5b4635900c38ce01802f7dca7e3ca9663d97cdd582fe1426e8ad51f871f1590d32f04eac4d7eec337d68151bda596f4d9abea7d4da37",
-      "line": 1391,
+      "line": 1679,
       "relation": "isA",
-      "source": 411,
-      "target": 286
+      "source": 490,
+      "target": 356
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "Berkovitch SS",
@@ -8003,13 +8824,18 @@
         "volume": "10"
       },
       "evidence": "The N-terminus of β-catenin has phosphorylation, ubiquitination, and acetylation sites that regulate its stability and signaling. In the absence of a Wnt signal, Ser33, Ser37, and Thr41 are constitutively phosphorylated by glycogen synthase kinase 3β (GSK3β). β-Catenin phosphorylated at these sites is recognized by β-transducin repeat-containing protein (βTrCP), which results in ubiquitination and degradation by the ubiquitin-proteasome pathway. The N-terminal regulatory domain of β-catenin also includes Ser45, a phosphorylation site for Casein Kinase 1α (CK1α) and Lys49, which is acetylated by the acetyltransferase p300/CBP-associated factor (PCAF). The relevance of Lys49 acetylation and Ser45 phosphorylation to the function of β-catenin is an active area of investigation. We find that HDAC6 inhibitors increase Lys49 acetylation and Ser45 phosphorylation but do not affect Ser33, Ser37, and Thr41 phosphorylation. Lys49 acetylation results in decreased ubiquitination of β-catenin in the presence of proteasome inhibition. While increased Lys49 acetylation does not affect total levels of β-catenin, it results in increased membrane localization of β-catenin.",
-      "key": "4f99102af0b3763d567c5a700e4cebbd6b25c0d4d193fe52fb869a821210617ee45c06f8f0ffaa51360141b83688a642ff63b12eab2e5f89c582b3fb3b920fa8",
-      "line": 2995,
+      "key": "731add58b75a31e071b25739f804265a9ad4c194af6f18f7e9ca55294f6523ba5ac9f960c60ba39c1751dfd0fd05e7ffab88b773baa9a9f855f4dcc3ecda3ab2",
+      "line": 3689,
       "relation": "increases",
-      "source": 411,
-      "target": 423
+      "source": 490,
+      "target": 503
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Berry RW",
@@ -8029,12 +8855,17 @@
       },
       "evidence": "Previously, we showed that peroxynitrite (ONOO-) induces the oxidative 3,3¢- dityrosine (3,3¢-DT) cross-linking and site-selective nitration of tau monomers [Reynolds et al. (2005)",
       "key": "fbce9f7a8556b360405b1a6d06a0f4b35480951ded0b641d8ddfc0d862c9bee9a03f65528c841bb585ba09d9019b55bb53cfa0301f8e2b755be56b5bddb61cd3",
-      "line": 194,
+      "line": 202,
       "relation": "increases",
-      "source": 64,
-      "target": 517
+      "source": 76,
+      "target": 601
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "Binder LI",
@@ -8055,16 +8886,50 @@
       },
       "evidence": "PN-treated wild-type tau and 5XY→F tau consistently displayed lysine formylation throughout tau in a non-sequence specific distribution. Lysine formylation likely results from reactive free radical exposure caused by PN treatment.",
       "key": "c4fc6ac0631313a4424478885c9279ff670b45ad6b4d3c353732c0644f3658f782fb7da25aaffda52ddf65a2316d5b989f229e05ddc74f68668b70e676229005",
-      "line": 851,
+      "line": 1014,
       "relation": "increases",
-      "source": 64,
-      "target": 514
+      "source": 76,
+      "target": 597
+    },
+    {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Binder LI",
+          "Hakala K",
+          "Kanaan NM",
+          "Vana L",
+          "Weintraub ST"
+        ],
+        "date": "2011-02-22",
+        "first": "Vana L",
+        "last": "Binder LI",
+        "name": "Biochemistry",
+        "pages": "1203-12",
+        "reference": "21210655",
+        "title": "Peroxynitrite-induced nitrative and oxidative modifications alter tau filament formation.",
+        "type": "PubMed",
+        "volume": "50"
+      },
+      "evidence": "PN-treated wild-type tau and 5XY→F tau consistently displayed lysine formylation throughout tau in a non-sequence specific distribution. Lysine formylation likely results from reactive free radical exposure caused by PN treatment.",
+      "key": "e3da6251aeb6cea5f63780f0ef00db0468e1d2ced2614bf841bc5336c8cd582575ee52628bd0df23478476f2cbc2546a61febac6f22061850b624b6cba7b96d2",
+      "line": 1015,
+      "relation": "increases",
+      "source": 76,
+      "target": 207
     },
     {
       "annotations": {
         "Anatomy": {
           "hippocampal formation": true
         },
+        "Confidence": {
+          "Medium": true
+        },
         "ExpMethod": {
           "in vivo": true
         },
@@ -8093,17 +8958,20 @@
         "volume": "20"
       },
       "evidence": "In the present study we injected bilaterally 3-morpholino-sydnonimine (SIN-1), a recognized and widely used peroxynitrite donor (25–30), into rat hippocampus, and investigated whether or not peroxynitrite could induce simultaneously nitration and hyperphosphorylation of tau and the underlying mechanisms in vivo. The level of nitrated and hyperphosphorylated tau was markedly increased in rat hippocampus 24 h, and prevented by preinjection of uric acid, a natural scavenger of peroxynitrite. GSK-3beta and p38 MAPKs, including p38alpha, p38beta, and p38delta activity was increased, but no change in the activity of p38gamma, ERK, and c-Jun amino-terminal kinase (JNK). Both nitrated tau and hyperphosphorylated tau were aggregated in the hippocampus, with activity of 20S proteasome significantly arrested in SIN-1-injected rats. Hyperphosphorylated tau was degraded as efficiently as normal tau by 20S proteasome, but the nitrated tau with an unorderly secondary structure became more resistant to the proteolysis, providing evidence that peroxynitrite simultaneously induces tau hyperphosphorylation, nitration, and accumulation, and that activation of GSK-3beta, p38alpha, p38beta, p38delta isoforms and the inhibition of proteasome activity are respectively responsible for the peroxynitrite-induced tau hyperphosphorylation and accumulation.",
-      "key": "b5aa3e6883cd3e13a2fa368e5031d1c41dbc068b97419a44b396b29277d858b8d37ec7c5a8171fbf6d174fbc78ff4da4aaa1e79dd8aafc4a6dceee04a56e5e36",
-      "line": 881,
+      "key": "cf95eea987b21e15c61bf69432dbbc37094cfa50e9143aee584b510f5900f12092efc4ef72045bcc8c4c09664ae06066af6c03abfd4e02edc434cbc8ae106923",
+      "line": 1044,
       "relation": "increases",
-      "source": 64,
-      "target": 877
+      "source": 76,
+      "target": 968
     },
     {
       "annotations": {
         "Anatomy": {
           "hippocampal formation": true
         },
+        "Confidence": {
+          "Medium": true
+        },
         "ExpMethod": {
           "in vivo": true
         },
@@ -8133,16 +9001,19 @@
       },
       "evidence": "In the present study we injected bilaterally 3-morpholino-sydnonimine (SIN-1), a recognized and widely used peroxynitrite donor (25–30), into rat hippocampus, and investigated whether or not peroxynitrite could induce simultaneously nitration and hyperphosphorylation of tau and the underlying mechanisms in vivo. The level of nitrated and hyperphosphorylated tau was markedly increased in rat hippocampus 24 h, and prevented by preinjection of uric acid, a natural scavenger of peroxynitrite. GSK-3beta and p38 MAPKs, including p38alpha, p38beta, and p38delta activity was increased, but no change in the activity of p38gamma, ERK, and c-Jun amino-terminal kinase (JNK). Both nitrated tau and hyperphosphorylated tau were aggregated in the hippocampus, with activity of 20S proteasome significantly arrested in SIN-1-injected rats. Hyperphosphorylated tau was degraded as efficiently as normal tau by 20S proteasome, but the nitrated tau with an unorderly secondary structure became more resistant to the proteolysis, providing evidence that peroxynitrite simultaneously induces tau hyperphosphorylation, nitration, and accumulation, and that activation of GSK-3beta, p38alpha, p38beta, p38delta isoforms and the inhibition of proteasome activity are respectively responsible for the peroxynitrite-induced tau hyperphosphorylation and accumulation.",
       "key": "69db52113ef15ec8647b622ea327782a97bef7efa52020ffc8ebb1bd622660a92c642386d65ff3faa9ebb718324e5975a41375d6a3d034f6783e3c414e4bacbe",
-      "line": 882,
+      "line": 1045,
       "relation": "increases",
-      "source": 64,
-      "target": 876
+      "source": 76,
+      "target": 970
     },
     {
       "annotations": {
         "Anatomy": {
           "hippocampal formation": true
         },
+        "Confidence": {
+          "Medium": true
+        },
         "ExpMethod": {
           "in vivo": true
         },
@@ -8172,19 +9043,22 @@
       },
       "evidence": "In the present study we injected bilaterally 3-morpholino-sydnonimine (SIN-1), a recognized and widely used peroxynitrite donor (25–30), into rat hippocampus, and investigated whether or not peroxynitrite could induce simultaneously nitration and hyperphosphorylation of tau and the underlying mechanisms in vivo. The level of nitrated and hyperphosphorylated tau was markedly increased in rat hippocampus 24 h, and prevented by preinjection of uric acid, a natural scavenger of peroxynitrite. GSK-3beta and p38 MAPKs, including p38alpha, p38beta, and p38delta activity was increased, but no change in the activity of p38gamma, ERK, and c-Jun amino-terminal kinase (JNK). Both nitrated tau and hyperphosphorylated tau were aggregated in the hippocampus, with activity of 20S proteasome significantly arrested in SIN-1-injected rats. Hyperphosphorylated tau was degraded as efficiently as normal tau by 20S proteasome, but the nitrated tau with an unorderly secondary structure became more resistant to the proteolysis, providing evidence that peroxynitrite simultaneously induces tau hyperphosphorylation, nitration, and accumulation, and that activation of GSK-3beta, p38alpha, p38beta, p38delta isoforms and the inhibition of proteasome activity are respectively responsible for the peroxynitrite-induced tau hyperphosphorylation and accumulation.",
       "key": "903bf887211f6a97d8ce23ecd1deb6de8b6aae421d8c7b0b9e951f1a9ad53c4f5db5ed636153cfc4ffd0b110666f40eea8fbe45a68441f0167c04bdc7d5124e1",
-      "line": 883,
+      "line": 1049,
       "object": {
         "modifier": "Activity"
       },
       "relation": "increases",
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-      "target": 866
+      "source": 76,
+      "target": 958
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     {
       "annotations": {
         "Anatomy": {
           "hippocampal formation": true
         },
+        "Confidence": {
+          "Medium": true
+        },
         "ExpMethod": {
           "in vivo": true
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@@ -8214,19 +9088,22 @@
       },
       "evidence": "In the present study we injected bilaterally 3-morpholino-sydnonimine (SIN-1), a recognized and widely used peroxynitrite donor (25–30), into rat hippocampus, and investigated whether or not peroxynitrite could induce simultaneously nitration and hyperphosphorylation of tau and the underlying mechanisms in vivo. The level of nitrated and hyperphosphorylated tau was markedly increased in rat hippocampus 24 h, and prevented by preinjection of uric acid, a natural scavenger of peroxynitrite. GSK-3beta and p38 MAPKs, including p38alpha, p38beta, and p38delta activity was increased, but no change in the activity of p38gamma, ERK, and c-Jun amino-terminal kinase (JNK). Both nitrated tau and hyperphosphorylated tau were aggregated in the hippocampus, with activity of 20S proteasome significantly arrested in SIN-1-injected rats. Hyperphosphorylated tau was degraded as efficiently as normal tau by 20S proteasome, but the nitrated tau with an unorderly secondary structure became more resistant to the proteolysis, providing evidence that peroxynitrite simultaneously induces tau hyperphosphorylation, nitration, and accumulation, and that activation of GSK-3beta, p38alpha, p38beta, p38delta isoforms and the inhibition of proteasome activity are respectively responsible for the peroxynitrite-induced tau hyperphosphorylation and accumulation.",
       "key": "a9d31a28af2305b10496a769525ce8d77420dcefca75d4501542c3b4947af83c9e1db4cbb44cf1e06cdfb192adbf3e84445b61d59b5f0af4ec6e9d57c65ecc68",
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       "object": {
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       "relation": "increases",
-      "source": 64,
-      "target": 874
+      "source": 76,
+      "target": 966
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     {
       "annotations": {
         "Anatomy": {
           "hippocampal formation": true
         },
+        "Confidence": {
+          "Medium": true
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         "ExpMethod": {
           "in vivo": true
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@@ -8256,19 +9133,22 @@
       },
       "evidence": "In the present study we injected bilaterally 3-morpholino-sydnonimine (SIN-1), a recognized and widely used peroxynitrite donor (25–30), into rat hippocampus, and investigated whether or not peroxynitrite could induce simultaneously nitration and hyperphosphorylation of tau and the underlying mechanisms in vivo. The level of nitrated and hyperphosphorylated tau was markedly increased in rat hippocampus 24 h, and prevented by preinjection of uric acid, a natural scavenger of peroxynitrite. GSK-3beta and p38 MAPKs, including p38alpha, p38beta, and p38delta activity was increased, but no change in the activity of p38gamma, ERK, and c-Jun amino-terminal kinase (JNK). Both nitrated tau and hyperphosphorylated tau were aggregated in the hippocampus, with activity of 20S proteasome significantly arrested in SIN-1-injected rats. Hyperphosphorylated tau was degraded as efficiently as normal tau by 20S proteasome, but the nitrated tau with an unorderly secondary structure became more resistant to the proteolysis, providing evidence that peroxynitrite simultaneously induces tau hyperphosphorylation, nitration, and accumulation, and that activation of GSK-3beta, p38alpha, p38beta, p38delta isoforms and the inhibition of proteasome activity are respectively responsible for the peroxynitrite-induced tau hyperphosphorylation and accumulation.",
       "key": "2db7bfcd182a849da5a6425dbd84176a2ddf689eb711382216f9dfc6f26bcfe5170b03a61bee092d87930a3ea3426df7284ed330859f5b52ed1ef0d3620d9e7b",
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       "object": {
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       "relation": "increases",
-      "source": 64,
-      "target": 871
+      "source": 76,
+      "target": 963
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     {
       "annotations": {
         "Anatomy": {
           "hippocampal formation": true
         },
+        "Confidence": {
+          "Medium": true
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         "ExpMethod": {
           "in vivo": true
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@@ -8298,19 +9178,22 @@
       },
       "evidence": "In the present study we injected bilaterally 3-morpholino-sydnonimine (SIN-1), a recognized and widely used peroxynitrite donor (25–30), into rat hippocampus, and investigated whether or not peroxynitrite could induce simultaneously nitration and hyperphosphorylation of tau and the underlying mechanisms in vivo. The level of nitrated and hyperphosphorylated tau was markedly increased in rat hippocampus 24 h, and prevented by preinjection of uric acid, a natural scavenger of peroxynitrite. GSK-3beta and p38 MAPKs, including p38alpha, p38beta, and p38delta activity was increased, but no change in the activity of p38gamma, ERK, and c-Jun amino-terminal kinase (JNK). Both nitrated tau and hyperphosphorylated tau were aggregated in the hippocampus, with activity of 20S proteasome significantly arrested in SIN-1-injected rats. Hyperphosphorylated tau was degraded as efficiently as normal tau by 20S proteasome, but the nitrated tau with an unorderly secondary structure became more resistant to the proteolysis, providing evidence that peroxynitrite simultaneously induces tau hyperphosphorylation, nitration, and accumulation, and that activation of GSK-3beta, p38alpha, p38beta, p38delta isoforms and the inhibition of proteasome activity are respectively responsible for the peroxynitrite-induced tau hyperphosphorylation and accumulation.",
       "key": "7e8b14c243b392f2ec3765990ea058094f5ba49a4cc2f3820c0956c847d30803fd91bba31ce82c5cc2c577077cf0f79014df0ea0b7128702bc5440a0dea0a5f5",
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       "relation": "increases",
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-      "target": 873
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+      "target": 965
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     {
       "annotations": {
         "Anatomy": {
           "hippocampal formation": true
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+        "Confidence": {
+          "Medium": true
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         "ExpMethod": {
           "in vivo": true
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@@ -8340,19 +9223,22 @@
       },
       "evidence": "In the present study we injected bilaterally 3-morpholino-sydnonimine (SIN-1), a recognized and widely used peroxynitrite donor (25–30), into rat hippocampus, and investigated whether or not peroxynitrite could induce simultaneously nitration and hyperphosphorylation of tau and the underlying mechanisms in vivo. The level of nitrated and hyperphosphorylated tau was markedly increased in rat hippocampus 24 h, and prevented by preinjection of uric acid, a natural scavenger of peroxynitrite. GSK-3beta and p38 MAPKs, including p38alpha, p38beta, and p38delta activity was increased, but no change in the activity of p38gamma, ERK, and c-Jun amino-terminal kinase (JNK). Both nitrated tau and hyperphosphorylated tau were aggregated in the hippocampus, with activity of 20S proteasome significantly arrested in SIN-1-injected rats. Hyperphosphorylated tau was degraded as efficiently as normal tau by 20S proteasome, but the nitrated tau with an unorderly secondary structure became more resistant to the proteolysis, providing evidence that peroxynitrite simultaneously induces tau hyperphosphorylation, nitration, and accumulation, and that activation of GSK-3beta, p38alpha, p38beta, p38delta isoforms and the inhibition of proteasome activity are respectively responsible for the peroxynitrite-induced tau hyperphosphorylation and accumulation.",
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-      "source": 64,
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     {
       "annotations": {
         "Anatomy": {
           "hippocampal formation": true
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@@ -8382,19 +9268,22 @@
       },
       "evidence": "In the present study we injected bilaterally 3-morpholino-sydnonimine (SIN-1), a recognized and widely used peroxynitrite donor (25–30), into rat hippocampus, and investigated whether or not peroxynitrite could induce simultaneously nitration and hyperphosphorylation of tau and the underlying mechanisms in vivo. The level of nitrated and hyperphosphorylated tau was markedly increased in rat hippocampus 24 h, and prevented by preinjection of uric acid, a natural scavenger of peroxynitrite. GSK-3beta and p38 MAPKs, including p38alpha, p38beta, and p38delta activity was increased, but no change in the activity of p38gamma, ERK, and c-Jun amino-terminal kinase (JNK). Both nitrated tau and hyperphosphorylated tau were aggregated in the hippocampus, with activity of 20S proteasome significantly arrested in SIN-1-injected rats. Hyperphosphorylated tau was degraded as efficiently as normal tau by 20S proteasome, but the nitrated tau with an unorderly secondary structure became more resistant to the proteolysis, providing evidence that peroxynitrite simultaneously induces tau hyperphosphorylation, nitration, and accumulation, and that activation of GSK-3beta, p38alpha, p38beta, p38delta isoforms and the inhibition of proteasome activity are respectively responsible for the peroxynitrite-induced tau hyperphosphorylation and accumulation.",
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-      "target": 288
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     {
       "annotations": {
         "Anatomy": {
           "hippocampal formation": true
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@@ -8424,19 +9313,22 @@
       },
       "evidence": "In the present study we injected bilaterally 3-morpholino-sydnonimine (SIN-1), a recognized and widely used peroxynitrite donor (25–30), into rat hippocampus, and investigated whether or not peroxynitrite could induce simultaneously nitration and hyperphosphorylation of tau and the underlying mechanisms in vivo. The level of nitrated and hyperphosphorylated tau was markedly increased in rat hippocampus 24 h, and prevented by preinjection of uric acid, a natural scavenger of peroxynitrite. GSK-3beta and p38 MAPKs, including p38alpha, p38beta, and p38delta activity was increased, but no change in the activity of p38gamma, ERK, and c-Jun amino-terminal kinase (JNK). Both nitrated tau and hyperphosphorylated tau were aggregated in the hippocampus, with activity of 20S proteasome significantly arrested in SIN-1-injected rats. Hyperphosphorylated tau was degraded as efficiently as normal tau by 20S proteasome, but the nitrated tau with an unorderly secondary structure became more resistant to the proteolysis, providing evidence that peroxynitrite simultaneously induces tau hyperphosphorylation, nitration, and accumulation, and that activation of GSK-3beta, p38alpha, p38beta, p38delta isoforms and the inhibition of proteasome activity are respectively responsible for the peroxynitrite-induced tau hyperphosphorylation and accumulation.",
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     {
       "annotations": {
         "Anatomy": {
           "hippocampal formation": true
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@@ -8465,13 +9357,18 @@
         "volume": "20"
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       "evidence": "In the present study we injected bilaterally 3-morpholino-sydnonimine (SIN-1), a recognized and widely used peroxynitrite donor (25–30), into rat hippocampus, and investigated whether or not peroxynitrite could induce simultaneously nitration and hyperphosphorylation of tau and the underlying mechanisms in vivo. The level of nitrated and hyperphosphorylated tau was markedly increased in rat hippocampus 24 h, and prevented by preinjection of uric acid, a natural scavenger of peroxynitrite. GSK-3beta and p38 MAPKs, including p38alpha, p38beta, and p38delta activity was increased, but no change in the activity of p38gamma, ERK, and c-Jun amino-terminal kinase (JNK). Both nitrated tau and hyperphosphorylated tau were aggregated in the hippocampus, with activity of 20S proteasome significantly arrested in SIN-1-injected rats. Hyperphosphorylated tau was degraded as efficiently as normal tau by 20S proteasome, but the nitrated tau with an unorderly secondary structure became more resistant to the proteolysis, providing evidence that peroxynitrite simultaneously induces tau hyperphosphorylation, nitration, and accumulation, and that activation of GSK-3beta, p38alpha, p38beta, p38delta isoforms and the inhibition of proteasome activity are respectively responsible for the peroxynitrite-induced tau hyperphosphorylation and accumulation.",
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           "Berry RW",
@@ -8491,12 +9388,17 @@
       },
       "evidence": "Select nitration of residues Tyr18, Tyr29, Tyr197, and Tyr394, events known to stabilize the pathological Alz-50 conformation inhibits the ability of monomeric tau to promote tubulin assembly, effect specific for the 3-NT modification, as mutant tau proteins pseudophosphorylated at each Tyr residue are fully competent to stabilize MTs, suggesting that ONOO(-)-mediated modifications stabilize tau filaments via 3,3'-DT bonding and destabilize MTs by site-selective nitration of tau monomers.",
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-      "target": 518
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     {
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       "citation": {
         "authors": [
           "Berry RW",
@@ -8516,12 +9418,17 @@
       },
       "evidence": "Select nitration of residues Tyr18, Tyr29, Tyr197, and Tyr394, events known to stabilize the pathological Alz-50 conformation inhibits the ability of monomeric tau to promote tubulin assembly, effect specific for the 3-NT modification, as mutant tau proteins pseudophosphorylated at each Tyr residue are fully competent to stabilize MTs, suggesting that ONOO(-)-mediated modifications stabilize tau filaments via 3,3'-DT bonding and destabilize MTs by site-selective nitration of tau monomers.",
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     {
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       "citation": {
         "authors": [
           "Berry RW",
@@ -8541,12 +9448,17 @@
       },
       "evidence": "Select nitration of residues Tyr18, Tyr29, Tyr197, and Tyr394, events known to stabilize the pathological Alz-50 conformation inhibits the ability of monomeric tau to promote tubulin assembly, effect specific for the 3-NT modification, as mutant tau proteins pseudophosphorylated at each Tyr residue are fully competent to stabilize MTs, suggesting that ONOO(-)-mediated modifications stabilize tau filaments via 3,3'-DT bonding and destabilize MTs by site-selective nitration of tau monomers.",
       "key": "77b650d4399cecb6a899730ac18178fbeaf891cf0dbe65dd4be6ba3ccd4d67e533fbebc290fedbdecc7cd9b8ea0f46ced8c1694e1d02eb039ec7f6546b878e22",
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-      "target": 519
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+      "target": 603
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     {
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       "citation": {
         "authors": [
           "Berry RW",
@@ -8566,13 +9478,46 @@
       },
       "evidence": "Select nitration of residues Tyr18, Tyr29, Tyr197, and Tyr394, events known to stabilize the pathological Alz-50 conformation inhibits the ability of monomeric tau to promote tubulin assembly, effect specific for the 3-NT modification, as mutant tau proteins pseudophosphorylated at each Tyr residue are fully competent to stabilize MTs, suggesting that ONOO(-)-mediated modifications stabilize tau filaments via 3,3'-DT bonding and destabilize MTs by site-selective nitration of tau monomers.",
       "key": "4063eed223b51628a0048a7b8615b114f3f55154d5f1456feab40ae55a0aa49eb191c19b373f2ddfd299caf3465a7d505774404fd5563480fb1248262b2fd915",
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-      "target": 521
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+      "target": 605
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+    {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Berry RW",
+          "Binder LI",
+          "Lukas TJ",
+          "Reynolds MR"
+        ],
+        "date": "2006-04-04",
+        "first": "Reynolds MR",
+        "last": "Binder LI",
+        "name": "Biochemistry",
+        "pages": "4314-26",
+        "reference": "16566606",
+        "title": "Peroxynitrite-mediated tau modifications stabilize preformed filaments and destabilize microtubules through distinct mechanisms.",
+        "type": "PubMed",
+        "volume": "45"
+      },
+      "evidence": "Select nitration of residues Tyr18, Tyr29, Tyr197, and Tyr394, events known to stabilize the pathological Alz-50 conformation inhibits the ability of monomeric tau to promote tubulin assembly, effect specific for the 3-NT modification, as mutant tau proteins pseudophosphorylated at each Tyr residue are fully competent to stabilize MTs, suggesting that ONOO(-)-mediated modifications stabilize tau filaments via 3,3'-DT bonding and destabilize MTs by site-selective nitration of tau monomers.",
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+      "relation": "increases",
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+      "target": 102
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     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "Tau_Antibody": {
           "9G3": true,
           "Tau-12": true,
@@ -8599,12 +9544,53 @@
       },
       "evidence": "Further, select nitration of residues Tyr18, Tyr29, Tyr197, and Tyr394, events known to stabilize the pathological Alz-50 conformation [Reynolds et al. (2005) Biochemistry 44, 13997-14009], inhibits the ability of monomeric tau to promote tubulin assembly.",
       "key": "a0b8d65a4979863448591ce784d3774a93f5d10fa5b04b8372b78eef1ee5f830485c16609b85e992878452ad56ef2e273a017ff061d12094ea84cb0ad4abf1e7",
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       "relation": "decreases",
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-      "target": 194
+      "source": 602,
+      "target": 210
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+      "annotations": {
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+          "Medium": true
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+          "9G3": true,
+          "Tau-12": true,
+          "Tau-13": true,
+          "pY18": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Berry RW",
+          "Binder LI",
+          "Lukas TJ",
+          "Reynolds MR"
+        ],
+        "date": "2006-04-04",
+        "first": "Reynolds MR",
+        "last": "Binder LI",
+        "name": "Biochemistry",
+        "pages": "4314-26",
+        "reference": "16566606",
+        "title": "Peroxynitrite-mediated tau modifications stabilize preformed filaments and destabilize microtubules through distinct mechanisms.",
+        "type": "PubMed",
+        "volume": "45"
+      },
+      "evidence": "Further, select nitration of residues Tyr18, Tyr29, Tyr197, and Tyr394, events known to stabilize the pathological Alz-50 conformation [Reynolds et al. (2005) Biochemistry 44, 13997-14009], inhibits the ability of monomeric tau to promote tubulin assembly.",
+      "key": "5bb65fca360b07713b0cd39cc4685b9ee307e03d195bf1289fe35b2d07126ae1d34237ef205a0f632c4a1b30e279c6fa0f489ac0cff46fe65d03d4b812e0ecff",
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+      "relation": "association",
+      "source": 602,
+      "target": 600
     },
     {
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+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Binder LI",
@@ -8624,12 +9610,17 @@
       },
       "evidence": "Tau-nY18 did not label the classical pathological lesions of CBD or PSP but did label the neuronal lesions associated with PiD. Tau-nY29 revealed some, but not all classes of tau inclusions associated with both CBD and PSP but did label numerous Pick body inclusions in PiD. Tau-nY197 was restricted to the neuropil threads in both CBD and PSP; however, similar to Tau-nY29, extensive Pick body pathology was clearly labeled. Tau-nY394 did not detect any of the lesions associated with these disorders.",
       "key": "5a67f61f7d0b7fbc233c4d1bd094ae0e3ddc5ab7f2987c3f7d2853aa0c81f43d0fd5e57877df93dbb68f50198903c0a3f8c2c0d855fa9e6d39b5ea9d0014ccb7",
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       "relation": "positiveCorrelation",
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+      "target": 1026
     },
     {
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+        }
+      },
       "citation": {
         "authors": [
           "Berry R",
@@ -8652,15 +9643,20 @@
       },
       "evidence": "This antibody detects nitrated tau in soluble preparations from both severe AD brains (Braak stage V, VI) and age-matched controls, suggesting that nitration at Tyr 18 may be linked to astrocyte activation, an early event associated with amyloid plaque formation",
       "key": "549584e035b1f6941b60116bb72b06bd6f56bad886314f78ce16b7b3ce87d8f3ea1d4f53437dbdaf4f244c93f08d73634ecae778f445a2eedfea5a80375aacf5",
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       "object": {
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       "relation": "association",
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-      "target": 165
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+      "target": 149
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     {
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+        }
+      },
       "citation": {
         "authors": [
           "Berry R",
@@ -8683,13 +9679,16 @@
       },
       "evidence": "This antibody detects nitrated tau in soluble preparations from both severe AD brains (Braak stage V, VI) and age-matched controls, suggesting that nitration at Tyr 18 may be linked to astrocyte activation, an early event associated with amyloid plaque formation",
       "key": "1c5397f4d0b05de5b196547cd2389d4cba8c7873bfd238e127c0676d864c31cbb973c99c00accfe93c079c9806050283590794945c7e6556e9930252c1479186",
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       "relation": "positiveCorrelation",
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-      "target": 917
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+      "target": 1027
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "Disease": {
           "Alzheimer's disease": true
         }
@@ -8716,12 +9715,17 @@
       },
       "evidence": "Tau-nY29 detects soluble tau and paired helical filament tau from severely affected Alzheimer's brain but fails to recognize tau from normal aged brain. This observation suggests that nitration at Tyr29 is a disease-related event that may alter the intrinsic ability of tau to self-polymerize. In Alzheimer's brain, Tau-nY29 labels the fibrillar triad of tau lesions, including neurofibrillary tangles, neuritic plaques, and, to a lesser extent, neuropil threads. Intriguingly, although Tau-nY29 stains both the neuronal and glial tau pathology of Pick disease, it detects only the neuronal pathology in corticobasal degeneration and progressive supranuclear palsy without labeling the predominant glial pathology.",
       "key": "82c99dd51869786c5c411b621cff843b74ed417a5c9eaf62baab88228ff6be79e8f38b30adaa0b590520a0d818b5cc7691c0bf71d8176028ea14f980a9a57caa",
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+      "target": 601
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     {
+      "annotations": {
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+          "Medium": true
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       "citation": {
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@@ -8740,13 +9744,18 @@
         "volume": "45"
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       "evidence": "Select nitration of residues Tyr18, Tyr29, Tyr197, and Tyr394, events known to stabilize the pathological Alz-50 conformation inhibits the ability of monomeric tau to promote tubulin assembly, effect specific for the 3-NT modification, as mutant tau proteins pseudophosphorylated at each Tyr residue are fully competent to stabilize MTs, suggesting that ONOO(-)-mediated modifications stabilize tau filaments via 3,3'-DT bonding and destabilize MTs by site-selective nitration of tau monomers.",
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@@ -8765,22 +9774,16 @@
         "volume": "45"
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       "evidence": "Select nitration of residues Tyr18, Tyr29, Tyr197, and Tyr394, events known to stabilize the pathological Alz-50 conformation inhibits the ability of monomeric tau to promote tubulin assembly, effect specific for the 3-NT modification, as mutant tau proteins pseudophosphorylated at each Tyr residue are fully competent to stabilize MTs, suggesting that ONOO(-)-mediated modifications stabilize tau filaments via 3,3'-DT bonding and destabilize MTs by site-selective nitration of tau monomers.",
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@@ -8800,14 +9803,238 @@
         "type": "PubMed",
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+      "evidence": "Select nitration of residues Tyr18, Tyr29, Tyr197, and Tyr394, events known to stabilize the pathological Alz-50 conformation inhibits the ability of monomeric tau to promote tubulin assembly, effect specific for the 3-NT modification, as mutant tau proteins pseudophosphorylated at each Tyr residue are fully competent to stabilize MTs, suggesting that ONOO(-)-mediated modifications stabilize tau filaments via 3,3'-DT bonding and destabilize MTs by site-selective nitration of tau monomers.",
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+          "Binder LI",
+          "Lukas TJ",
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+        "first": "Reynolds MR",
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+      "evidence": "Further, select nitration of residues Tyr18, Tyr29, Tyr197, and Tyr394, events known to stabilize the pathological Alz-50 conformation [Reynolds et al. (2005) Biochemistry 44, 13997-14009], inhibits the ability of monomeric tau to promote tubulin assembly.",
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+      "evidence": "Further, select nitration of residues Tyr18, Tyr29, Tyr197, and Tyr394, events known to stabilize the pathological Alz-50 conformation [Reynolds et al. (2005) Biochemistry 44, 13997-14009], inhibits the ability of monomeric tau to promote tubulin assembly.",
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+          "Binder LI",
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+        "first": "Reynolds MR",
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+        "name": "Biochemistry",
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+        "title": "Peroxynitrite-mediated tau modifications stabilize preformed filaments and destabilize microtubules through distinct mechanisms.",
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+      "evidence": "Further, select nitration of residues Tyr18, Tyr29, Tyr197, and Tyr394, events known to stabilize the pathological Alz-50 conformation [Reynolds et al. (2005) Biochemistry 44, 13997-14009], inhibits the ability of monomeric tau to promote tubulin assembly.",
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+        "date": "2006-04-04",
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+        "name": "Biochemistry",
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+      "evidence": "Further, select nitration of residues Tyr18, Tyr29, Tyr197, and Tyr394, events known to stabilize the pathological Alz-50 conformation [Reynolds et al. (2005) Biochemistry 44, 13997-14009], inhibits the ability of monomeric tau to promote tubulin assembly.",
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+        "name": "Biochemistry",
+        "pages": "4314-26",
+        "reference": "16566606",
+        "title": "Peroxynitrite-mediated tau modifications stabilize preformed filaments and destabilize microtubules through distinct mechanisms.",
+        "type": "PubMed",
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+      "evidence": "Further, select nitration of residues Tyr18, Tyr29, Tyr197, and Tyr394, events known to stabilize the pathological Alz-50 conformation [Reynolds et al. (2005) Biochemistry 44, 13997-14009], inhibits the ability of monomeric tau to promote tubulin assembly.",
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+        "name": "Biochemistry",
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+        "title": "Peroxynitrite-mediated tau modifications stabilize preformed filaments and destabilize microtubules through distinct mechanisms.",
+        "type": "PubMed",
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+      "evidence": "Further, select nitration of residues Tyr18, Tyr29, Tyr197, and Tyr394, events known to stabilize the pathological Alz-50 conformation [Reynolds et al. (2005) Biochemistry 44, 13997-14009], inhibits the ability of monomeric tau to promote tubulin assembly.",
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     {
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       "citation": {
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@@ -8827,15 +10054,90 @@
       },
       "evidence": "Tau-nY18 did not label the classical pathological lesions of CBD or PSP but did label the neuronal lesions associated with PiD. Tau-nY29 revealed some, but not all classes of tau inclusions associated with both CBD and PSP but did label numerous Pick body inclusions in PiD. Tau-nY197 was restricted to the neuropil threads in both CBD and PSP; however, similar to Tau-nY29, extensive Pick body pathology was clearly labeled. Tau-nY394 did not detect any of the lesions associated with these disorders.",
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       "relation": "positiveCorrelation",
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+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "Disease": {
+          "Alzheimer's disease": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Berry RW",
+          "Bigio EH",
+          "Binder LI",
+          "Fu Y",
+          "Guillozet-Bongaarts AL",
+          "Reyes JF",
+          "Reynolds MR"
+        ],
+        "date": "2006-10-18",
+        "first": "Reynolds MR",
+        "last": "Binder LI",
+        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
+        "pages": "10636-45",
+        "reference": "17050703",
+        "title": "Tau nitration occurs at tyrosine 29 in the fibrillar lesions of Alzheimer's disease and other tauopathies.",
+        "type": "PubMed",
+        "volume": "26"
+      },
+      "evidence": "Tau-nY29 detects soluble tau and paired helical filament tau from severely affected Alzheimer's brain but fails to recognize tau from normal aged brain. This observation suggests that nitration at Tyr29 is a disease-related event that may alter the intrinsic ability of tau to self-polymerize. In Alzheimer's brain, Tau-nY29 labels the fibrillar triad of tau lesions, including neurofibrillary tangles, neuritic plaques, and, to a lesser extent, neuropil threads. Intriguingly, although Tau-nY29 stains both the neuronal and glial tau pathology of Pick disease, it detects only the neuronal pathology in corticobasal degeneration and progressive supranuclear palsy without labeling the predominant glial pathology.",
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+        "authors": [
+          "Berry RW",
+          "Binder LI",
+          "Lukas TJ",
+          "Reynolds MR"
+        ],
+        "date": "2006-04-04",
+        "first": "Reynolds MR",
+        "last": "Binder LI",
+        "name": "Biochemistry",
+        "pages": "4314-26",
+        "reference": "16566606",
+        "title": "Peroxynitrite-mediated tau modifications stabilize preformed filaments and destabilize microtubules through distinct mechanisms.",
+        "type": "PubMed",
+        "volume": "45"
+      },
+      "evidence": "Select nitration of residues Tyr18, Tyr29, Tyr197, and Tyr394, events known to stabilize the pathological Alz-50 conformation inhibits the ability of monomeric tau to promote tubulin assembly, effect specific for the 3-NT modification, as mutant tau proteins pseudophosphorylated at each Tyr residue are fully competent to stabilize MTs, suggesting that ONOO(-)-mediated modifications stabilize tau filaments via 3,3'-DT bonding and destabilize MTs by site-selective nitration of tau monomers.",
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+      "relation": "positiveCorrelation",
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+      "target": 127
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "Disease": {
           "Alzheimer's disease": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
         }
       },
       "citation": {
@@ -8860,15 +10162,21 @@
       },
       "evidence": "Tau-nY29 detects soluble tau and paired helical filament tau from severely affected Alzheimer's brain but fails to recognize tau from normal aged brain. This observation suggests that nitration at Tyr29 is a disease-related event that may alter the intrinsic ability of tau to self-polymerize. In Alzheimer's brain, Tau-nY29 labels the fibrillar triad of tau lesions, including neurofibrillary tangles, neuritic plaques, and, to a lesser extent, neuropil threads. Intriguingly, although Tau-nY29 stains both the neuronal and glial tau pathology of Pick disease, it detects only the neuronal pathology in corticobasal degeneration and progressive supranuclear palsy without labeling the predominant glial pathology.",
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     {
       "annotations": {
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+          "Medium": true
+        },
         "Disease": {
           "Alzheimer's disease": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
         }
       },
       "citation": {
@@ -8893,15 +10201,21 @@
       },
       "evidence": "Tau-nY29 detects soluble tau and paired helical filament tau from severely affected Alzheimer's brain but fails to recognize tau from normal aged brain. This observation suggests that nitration at Tyr29 is a disease-related event that may alter the intrinsic ability of tau to self-polymerize. In Alzheimer's brain, Tau-nY29 labels the fibrillar triad of tau lesions, including neurofibrillary tangles, neuritic plaques, and, to a lesser extent, neuropil threads. Intriguingly, although Tau-nY29 stains both the neuronal and glial tau pathology of Pick disease, it detects only the neuronal pathology in corticobasal degeneration and progressive supranuclear palsy without labeling the predominant glial pathology.",
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       "relation": "positiveCorrelation",
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     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "Disease": {
           "Alzheimer's disease": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
         }
       },
       "citation": {
@@ -8926,15 +10240,21 @@
       },
       "evidence": "Tau-nY29 detects soluble tau and paired helical filament tau from severely affected Alzheimer's brain but fails to recognize tau from normal aged brain. This observation suggests that nitration at Tyr29 is a disease-related event that may alter the intrinsic ability of tau to self-polymerize. In Alzheimer's brain, Tau-nY29 labels the fibrillar triad of tau lesions, including neurofibrillary tangles, neuritic plaques, and, to a lesser extent, neuropil threads. Intriguingly, although Tau-nY29 stains both the neuronal and glial tau pathology of Pick disease, it detects only the neuronal pathology in corticobasal degeneration and progressive supranuclear palsy without labeling the predominant glial pathology.",
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       "relation": "partOf",
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     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "Disease": {
           "Alzheimer's disease": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
         }
       },
       "citation": {
@@ -8959,15 +10279,60 @@
       },
       "evidence": "Tau-nY29 detects soluble tau and paired helical filament tau from severely affected Alzheimer's brain but fails to recognize tau from normal aged brain. This observation suggests that nitration at Tyr29 is a disease-related event that may alter the intrinsic ability of tau to self-polymerize. In Alzheimer's brain, Tau-nY29 labels the fibrillar triad of tau lesions, including neurofibrillary tangles, neuritic plaques, and, to a lesser extent, neuropil threads. Intriguingly, although Tau-nY29 stains both the neuronal and glial tau pathology of Pick disease, it detects only the neuronal pathology in corticobasal degeneration and progressive supranuclear palsy without labeling the predominant glial pathology.",
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       "relation": "partOf",
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+    {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "Disease": {
+          "Alzheimer's disease": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Berry RW",
+          "Bigio EH",
+          "Binder LI",
+          "Fu Y",
+          "Guillozet-Bongaarts AL",
+          "Reyes JF",
+          "Reynolds MR"
+        ],
+        "date": "2006-10-18",
+        "first": "Reynolds MR",
+        "last": "Binder LI",
+        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
+        "pages": "10636-45",
+        "reference": "17050703",
+        "title": "Tau nitration occurs at tyrosine 29 in the fibrillar lesions of Alzheimer's disease and other tauopathies.",
+        "type": "PubMed",
+        "volume": "26"
+      },
+      "evidence": "Tau-nY29 detects soluble tau and paired helical filament tau from severely affected Alzheimer's brain but fails to recognize tau from normal aged brain. This observation suggests that nitration at Tyr29 is a disease-related event that may alter the intrinsic ability of tau to self-polymerize. In Alzheimer's brain, Tau-nY29 labels the fibrillar triad of tau lesions, including neurofibrillary tangles, neuritic plaques, and, to a lesser extent, neuropil threads. Intriguingly, although Tau-nY29 stains both the neuronal and glial tau pathology of Pick disease, it detects only the neuronal pathology in corticobasal degeneration and progressive supranuclear palsy without labeling the predominant glial pathology.",
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         "Disease": {
           "Alzheimer's disease": true
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       "annotations": {
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         "Disease": {
           "Alzheimer's disease": true
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+        "MeSHAnatomy": {
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       "evidence": "Tau-nY29 detects soluble tau and paired helical filament tau from severely affected Alzheimer's brain but fails to recognize tau from normal aged brain. This observation suggests that nitration at Tyr29 is a disease-related event that may alter the intrinsic ability of tau to self-polymerize. In Alzheimer's brain, Tau-nY29 labels the fibrillar triad of tau lesions, including neurofibrillary tangles, neuritic plaques, and, to a lesser extent, neuropil threads. Intriguingly, although Tau-nY29 stains both the neuronal and glial tau pathology of Pick disease, it detects only the neuronal pathology in corticobasal degeneration and progressive supranuclear palsy without labeling the predominant glial pathology.",
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         "volume": "45"
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@@ -9108,16 +10492,19 @@
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@@ -9144,16 +10531,55 @@
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       "evidence": "Further, select nitration of residues Tyr18, Tyr29, Tyr197, and Tyr394, events known to stabilize the pathological Alz-50 conformation [Reynolds et al. (2005) Biochemistry 44, 13997-14009], inhibits the ability of monomeric tau to promote tubulin assembly.",
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+          "Binder LI",
+          "Lukas TJ",
+          "Reynolds MR"
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+        "date": "2006-04-04",
+        "first": "Reynolds MR",
+        "last": "Binder LI",
+        "name": "Biochemistry",
+        "pages": "4314-26",
+        "reference": "16566606",
+        "title": "Peroxynitrite-mediated tau modifications stabilize preformed filaments and destabilize microtubules through distinct mechanisms.",
+        "type": "PubMed",
+        "volume": "45"
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+      "evidence": "Further, select nitration of residues Tyr18, Tyr29, Tyr197, and Tyr394, events known to stabilize the pathological Alz-50 conformation [Reynolds et al. (2005) Biochemistry 44, 13997-14009], inhibits the ability of monomeric tau to promote tubulin assembly.",
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     {
       "annotations": {
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           "neuropil": true
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         "Disease": {
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@@ -9180,16 +10606,19 @@
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     {
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@@ -9252,13 +10684,16 @@
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@@ -9285,12 +10720,17 @@
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       "evidence": "Tau-nY29 detects soluble tau and paired helical filament tau from severely affected Alzheimer's brain but fails to recognize tau from normal aged brain. This observation suggests that nitration at Tyr29 is a disease-related event that may alter the intrinsic ability of tau to self-polymerize. In Alzheimer's brain, Tau-nY29 labels the fibrillar triad of tau lesions, including neurofibrillary tangles, neuritic plaques, and, to a lesser extent, neuropil threads. Intriguingly, although Tau-nY29 stains both the neuronal and glial tau pathology of Pick disease, it detects only the neuronal pathology in corticobasal degeneration and progressive supranuclear palsy without labeling the predominant glial pathology.",
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@@ -9309,13 +10749,18 @@
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@@ -9334,22 +10779,16 @@
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         "type": "PubMed",
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@@ -9394,14 +10847,55 @@
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+      "evidence": "Further, select nitration of residues Tyr18, Tyr29, Tyr197, and Tyr394, events known to stabilize the pathological Alz-50 conformation [Reynolds et al. (2005) Biochemistry 44, 13997-14009], inhibits the ability of monomeric tau to promote tubulin assembly.",
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@@ -9420,16 +10914,48 @@
         "volume": "45"
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+      "evidence": "Select nitration of residues Tyr18, Tyr29, Tyr197, and Tyr394, events known to stabilize the pathological Alz-50 conformation inhibits the ability of monomeric tau to promote tubulin assembly, effect specific for the 3-NT modification, as mutant tau proteins pseudophosphorylated at each Tyr residue are fully competent to stabilize MTs, suggesting that ONOO(-)-mediated modifications stabilize tau filaments via 3,3'-DT bonding and destabilize MTs by site-selective nitration of tau monomers.",
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@@ -9450,16 +10976,70 @@
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-      "target": 154
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+    {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
+        "MeSHDisease": {
+          "Chronic Traumatic Encephalopathy": true
+        },
+        "Method": {
+          "ELISA": true,
+          "Immunofluorescence": true,
+          "Immunohistochemistry": true
+        },
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+          "TN1": true,
+          "TOC1": true,
+          "TauC3": true
+        }
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+        "authors": [
+          "Alvarez VE",
+          "Cox K",
+          "Kanaan NM",
+          "McKee AC",
+          "Poncil S",
+          "Stein TD"
+        ],
+        "date": "2016-01-01",
+        "first": "Kanaan NM",
+        "last": "McKee AC",
+        "name": "Journal of neuropathology and experimental neurology",
+        "pages": "19-34",
+        "reference": "26671985",
+        "title": "Characterization of Early Pathological Tau Conformations and Phosphorylation in Chronic Traumatic Encephalopathy.",
+        "type": "PubMed",
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@@ -9481,18 +11061,40 @@
       },
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     {
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+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
+        "MeSHDisease": {
+          "Chronic Traumatic Encephalopathy": true
+        },
+        "Method": {
+          "ELISA": true,
+          "Immunofluorescence": true,
+          "Immunohistochemistry": true
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+          "TN1": true,
+          "TOC1": true,
+          "TauC3": true
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       "citation": {
         "authors": [
           "Alvarez VE",
@@ -9512,51 +11114,57 @@
         "type": "PubMed",
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       },
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     {
       "annotations": {
-        "MeSHDisease": {
-          "Alzheimer Disease": true
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+          "Medium": true
         }
       },
       "citation": {
         "authors": [
-          "Cornwell LB",
-          "Gylys KH",
-          "Henkins KM",
-          "Miller CA",
-          "Poon WW",
-          "Saing T",
-          "Sokolow S",
-          "Vinters HV"
+          "Babić Leko M",
+          "Bažadona D",
+          "Buée L",
+          "Delalle I",
+          "Di Giovanni G",
+          "Harrington C",
+          "Hof PR",
+          "Jovanov-Milošević N",
+          "Wischik C",
+          "Wray S",
+          "de Silva R",
+          "Šimić G"
         ],
-        "date": "2012-11-01",
-        "first": "Henkins KM",
-        "last": "Gylys KH",
-        "name": "Brain pathology (Zurich, Switzerland)",
-        "pages": "826-33",
-        "reference": "22486774",
-        "title": "Extensive p-tau pathology and SDS-stable p-tau oligomers in Alzheimer's cortical synapses.",
+        "date": "2016-01-06",
+        "first": "Šimić G",
+        "last": "Hof PR",
+        "name": "Biomolecules",
+        "pages": "6",
+        "reference": "26751493",
+        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
         "type": "PubMed",
-        "volume": "22"
+        "volume": "6"
       },
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-      "relation": "partOf",
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+      "evidence": "The most recent data obtained indicate that tau pathology indeed may be induced and propagated after the injection of tau oligomers or aggregates in either wild-type or mutated MAPT transgenic mice [164], and that tau aggregates can be transferred from cell to cell in vitro [164,165] and in vivo [166,167].",
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     {
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+      },
       "citation": {
         "authors": [
           "Barton Whittle T",
@@ -9582,13 +11190,18 @@
         "volume": "55"
       },
       "evidence": "Tau Oligomers co-localize with astrocytes, microglia, and HMGB1, a pro-inflammatory cytokine, are present in the retina and are associated with inflammatory cells.",
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       "citation": {
         "authors": [
           "Barton Whittle T",
@@ -9614,13 +11227,55 @@
         "volume": "55"
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       "evidence": "This work supports the hypothesis that tau oligomers are toxic species that can drive the spread of tau pathology and neurodegeneration.",
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+      "citation": {
+        "authors": [
+          "Barton Whittle T",
+          "Castillo-Carranza DL",
+          "English KC",
+          "Gerson JE",
+          "Gupta P",
+          "Kayed R",
+          "Nicolas Crain C",
+          "Nilson AN",
+          "Sengupta U",
+          "Xue J",
+          "Zhang W"
+        ],
+        "date": "2017-01-01",
+        "first": "Nilson AN",
+        "last": "Kayed R",
+        "name": "Journal of Alzheimer's disease : JAD",
+        "pages": "1083-1099",
+        "reference": "27716675",
+        "title": "Tau Oligomers Associate with Inflammation in the Brain and Retina of Tauopathy Mice and in Neurodegenerative Diseases.",
+        "type": "PubMed",
+        "volume": "55"
+      },
+      "evidence": "This work supports the hypothesis that tau oligomers are toxic species that can drive the spread of tau pathology and neurodegeneration.",
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       "citation": {
         "authors": [
           "Alvarez VE",
@@ -9641,16 +11296,119 @@
         "volume": "75"
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+      "target": 236
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+    {
+      "annotations": {
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+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
+        "MeSHDisease": {
+          "Chronic Traumatic Encephalopathy": true
+        },
+        "Method": {
+          "ELISA": true,
+          "Immunofluorescence": true,
+          "Immunohistochemistry": true
+        },
+        "Tau_Antibody": {
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+          "TN1": true,
+          "TOC1": true,
+          "TauC3": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Alvarez VE",
+          "Cox K",
+          "Kanaan NM",
+          "McKee AC",
+          "Poncil S",
+          "Stein TD"
+        ],
+        "date": "2016-01-01",
+        "first": "Kanaan NM",
+        "last": "McKee AC",
+        "name": "Journal of neuropathology and experimental neurology",
+        "pages": "19-34",
+        "reference": "26671985",
+        "title": "Characterization of Early Pathological Tau Conformations and Phosphorylation in Chronic Traumatic Encephalopathy.",
+        "type": "PubMed",
+        "volume": "75"
+      },
+      "evidence": "We performed immunohistochemistry and immunofluorescence on fixed brain sections and biochemical analysis of fresh brain extracts to characterize the presence of PAD-exposed tau (TNT1 antibody), tau oligomers (TOC1 antibody), tau phosphorylated at S422 (pS422 antibody), and tau truncated at D421 (TauC3 antibody) in the brains of 9-11 cases with CTE and cases of nondemented aged controls and AD (Braak VI) (n = 6, each). These 4 markers are particularly useful in understanding potential posttraumatic events in CTE because PAD exposure impairs axonal transport (24), oligomers confer toxicity (28, 38–40), pS422 correlates with cognitive decline (15), and D421 truncated tau may be related to cell toxicity (41, 42). All 3 early tau markers (ie, TNT1, TOC1, and pS422) were present in CTE and displayed extensive colocalization in perivascular tau lesions that are considered diagnostic for CTE.",
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+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
+        "MeSHDisease": {
+          "Chronic Traumatic Encephalopathy": true
+        },
+        "Method": {
+          "ELISA": true,
+          "Immunofluorescence": true,
+          "Immunohistochemistry": true
+        },
+        "Tau_Antibody": {
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+          "TN1": true,
+          "TOC1": true,
+          "TauC3": true
+        }
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+      "citation": {
+        "authors": [
+          "Alvarez VE",
+          "Cox K",
+          "Kanaan NM",
+          "McKee AC",
+          "Poncil S",
+          "Stein TD"
+        ],
+        "date": "2016-01-01",
+        "first": "Kanaan NM",
+        "last": "McKee AC",
+        "name": "Journal of neuropathology and experimental neurology",
+        "pages": "19-34",
+        "reference": "26671985",
+        "title": "Characterization of Early Pathological Tau Conformations and Phosphorylation in Chronic Traumatic Encephalopathy.",
+        "type": "PubMed",
+        "volume": "75"
+      },
+      "evidence": "We performed immunohistochemistry and immunofluorescence on fixed brain sections and biochemical analysis of fresh brain extracts to characterize the presence of PAD-exposed tau (TNT1 antibody), tau oligomers (TOC1 antibody), tau phosphorylated at S422 (pS422 antibody), and tau truncated at D421 (TauC3 antibody) in the brains of 9-11 cases with CTE and cases of nondemented aged controls and AD (Braak VI) (n = 6, each). These 4 markers are particularly useful in understanding potential posttraumatic events in CTE because PAD exposure impairs axonal transport (24), oligomers confer toxicity (28, 38–40), pS422 correlates with cognitive decline (15), and D421 truncated tau may be related to cell toxicity (41, 42). All 3 early tau markers (ie, TNT1, TOC1, and pS422) were present in CTE and displayed extensive colocalization in perivascular tau lesions that are considered diagnostic for CTE.",
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       "citation": {
         "authors": [
           "Alvarez VE",
@@ -9671,16 +11429,21 @@
         "volume": "75"
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       "evidence": "Several lines of evidence in other tauopathies suggest that tau oligomer formation induces neurotoxicity and that tau oligomer-mediated neurotoxicity involves induction of axonal dysfunction through exposure of an N-terminal motif in tau, the phosphatase-activating domain (PAD).",
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       "subject": {
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       "citation": {
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           "Alvarez VE",
@@ -9701,16 +11464,21 @@
         "volume": "75"
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       "evidence": "Several lines of evidence in other tauopathies suggest that tau oligomer formation induces neurotoxicity and that tau oligomer-mediated neurotoxicity involves induction of axonal dysfunction through exposure of an N-terminal motif in tau, the phosphatase-activating domain (PAD).",
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-      "relation": "positiveCorrelation",
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@@ -9732,12 +11500,17 @@
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       "evidence": "Several lines of evidence in other tauopathies suggest that tau oligomer formation induces neurotoxicity and that tau oligomer-mediated neurotoxicity involves induction of axonal dysfunction through exposure of an N-terminal motif in tau, the phosphatase-activating domain (PAD).",
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@@ -9758,17 +11531,23 @@
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       "evidence": "Several lines of evidence in other tauopathies suggest that tau oligomer formation induces neurotoxicity and that tau oligomer-mediated neurotoxicity involves induction of axonal dysfunction through exposure of an N-terminal motif in tau, the phosphatase-activating domain (PAD).",
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     },
     {
       "annotations": {
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+          "Medium": true
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+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "MeSHDisease": {
           "Chronic Traumatic Encephalopathy": true
         },
@@ -9805,13 +11584,19 @@
       },
       "evidence": "We performed immunohistochemistry and immunofluorescence on fixed brain sections and biochemical analysis of fresh brain extracts to characterize the presence of PAD-exposed tau (TNT1 antibody), tau oligomers (TOC1 antibody), tau phosphorylated at S422 (pS422 antibody), and tau truncated at D421 (TauC3 antibody) in the brains of 9-11 cases with CTE and cases of nondemented aged controls and AD (Braak VI) (n = 6, each). These 4 markers are particularly useful in understanding potential posttraumatic events in CTE because PAD exposure impairs axonal transport (24), oligomers confer toxicity (28, 38–40), pS422 correlates with cognitive decline (15), and D421 truncated tau may be related to cell toxicity (41, 42). All 3 early tau markers (ie, TNT1, TOC1, and pS422) were present in CTE and displayed extensive colocalization in perivascular tau lesions that are considered diagnostic for CTE.",
       "key": "0c0ed84d85bec8c3111bc9ce613eb4f69316e1509c847e5d8cf77d6f13e0351c29f761168181a3e8da41cd61ef3c7b62eb483a8b2835d2241021428489391d85",
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+      "line": 251,
       "relation": "biomarkerFor",
-      "source": 359,
-      "target": 910
+      "source": 439,
+      "target": 1019
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "MeSHDisease": {
           "Chronic Traumatic Encephalopathy": true
         },
@@ -9848,9 +11633,45 @@
       },
       "evidence": "We performed immunohistochemistry and immunofluorescence on fixed brain sections and biochemical analysis of fresh brain extracts to characterize the presence of PAD-exposed tau (TNT1 antibody), tau oligomers (TOC1 antibody), tau phosphorylated at S422 (pS422 antibody), and tau truncated at D421 (TauC3 antibody) in the brains of 9-11 cases with CTE and cases of nondemented aged controls and AD (Braak VI) (n = 6, each). These 4 markers are particularly useful in understanding potential posttraumatic events in CTE because PAD exposure impairs axonal transport (24), oligomers confer toxicity (28, 38–40), pS422 correlates with cognitive decline (15), and D421 truncated tau may be related to cell toxicity (41, 42). All 3 early tau markers (ie, TNT1, TOC1, and pS422) were present in CTE and displayed extensive colocalization in perivascular tau lesions that are considered diagnostic for CTE.",
       "key": "8ef167c9dd506ac601d2a373fd568142bbea30bcf62ce18eb19117c329b9228f1b248a5bf0bc6d7d4efdc847f2ccf3b855b5e961cf418d2cef7f82969c78e9b6",
-      "line": 234,
+      "line": 255,
       "relation": "decreases",
-      "source": 359,
+      "source": 439,
+      "target": 175
+    },
+    {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Andreadis A",
+          "Binder LI",
+          "Brady ST",
+          "Fu Y",
+          "Kanaan NM",
+          "LaPointe NE",
+          "Morfini GA",
+          "Patterson KR",
+          "Pigino GF",
+          "Song Y"
+        ],
+        "date": "2011-07-06",
+        "first": "Kanaan NM",
+        "last": "Binder LI",
+        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
+        "pages": "9858-68",
+        "reference": "21734277",
+        "title": "Pathogenic forms of tau inhibit kinesin-dependent axonal transport through a mechanism involving activation of axonal phosphotransferases.",
+        "type": "PubMed",
+        "volume": "31"
+      },
+      "evidence": "Filamentous, but not soluble, forms of wild-type tau inhibit anterograde, kinesin-based fast axonal transport (FAT) by activating axonal protein phosphatase 1 (PP1) and glycogen synthase kinase 3 (GSK3), independent of microtubule binding. Amino acids 2-18 of tau, comprising a phosphatase-activating domain (PAD), are necessary and sufficient for activation of this pathway. Various pathogenic forms of tau displaying increased exposure of PAD inhibited anterograde FAT in squid axoplasm. Immunohistochemical studies using a novel PAD-specific monoclonal antibody in human postmortem tissue indicated that increased PAD exposure represents an early pathogenic event in AD that closely associates in time with AT8 immunoreactivity. We propose a model of pathogenesis in which disease-associated changes in tau conformation lead to increased exposure of PAD, activation of PP1-GSK3, and inhibition of FAT",
+      "key": "87db91e1a2fd5b36f4fd45a2b7de736980268a72241e797a9102e9d1a695097fa39f54a858187f325508334f09ab8c1dd69eb9672a2d94fbc4210406d3fe0442",
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+      "relation": "negativeCorrelation",
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       "target": 175
     },
     {
@@ -9858,6 +11679,9 @@
         "Braak_Stage": {
           "Stage I": true,
           "Stage II": true
+        },
+        "Confidence": {
+          "High": true
         }
       },
       "citation": {
@@ -9878,16 +11702,19 @@
       },
       "evidence": "Previously, we have shown that TNT1 is a marker of PAD exposure and that this event occurs early in the progression of Alzheimer’s disease. Establishing whether this was true for all N-terminal antibodies was important for understanding more about PAD exposure in Alzheimer’s disease. We significantly extend these findings with TNT1 and show that TNT2 behaves similarly as a marker of PAD exposure. In contrast, other N-terminal antibodies, with slightly different epitopes, do not function as pathological, PAD exposure-specific markers and recognize all forms of tau similarly. Here, we found that TNT1 and TNT2 appear in Braak I–II stages and do not colocalize with ThR in the diffuse, granular pre-tangle pathology conclusively demonstrating that PAD exposure is an early event.",
       "key": "fa8e385996bba28925d97b60ea456a530dbe9c7180ea6818163aca0ecbfef9b6bfc6c1ca702df41d9be755367a37cbc33ae08e42347b8ef5aa333c42090b735f",
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       "relation": "association",
-      "source": 359,
-      "target": 328
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+      "target": 405
     },
     {
       "annotations": {
         "Braak_Stage": {
           "Stage I": true,
           "Stage II": true
+        },
+        "Confidence": {
+          "High": true
         }
       },
       "citation": {
@@ -9908,36 +11735,17 @@
       },
       "evidence": "Previously, we have shown that TNT1 is a marker of PAD exposure and that this event occurs early in the progression of Alzheimer’s disease. Establishing whether this was true for all N-terminal antibodies was important for understanding more about PAD exposure in Alzheimer’s disease. We significantly extend these findings with TNT1 and show that TNT2 behaves similarly as a marker of PAD exposure. In contrast, other N-terminal antibodies, with slightly different epitopes, do not function as pathological, PAD exposure-specific markers and recognize all forms of tau similarly. Here, we found that TNT1 and TNT2 appear in Braak I–II stages and do not colocalize with ThR in the diffuse, granular pre-tangle pathology conclusively demonstrating that PAD exposure is an early event.",
       "key": "bbe5955b93ae893783eb6d3f5de8aeb531d35a20f377c991051c4513f18c8be7c7af84494094f006bb1a7c6da79e54d46444f0d1c28328abac1be6dd601d8367",
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       "relation": "association",
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     },
     {
-      "citation": {
-        "authors": [
-          "Combs B",
-          "Hamel C",
-          "Kanaan NM"
-        ],
-        "date": "2016-10-01",
-        "first": "Combs B",
-        "last": "Kanaan NM",
-        "name": "Neurobiology of disease",
-        "pages": "18-31",
-        "reference": "27260838",
-        "title": "Pathological conformations involving the amino terminus of tau occur early in Alzheimer's disease and are differentially detected by monoclonal antibodies.",
-        "type": "PubMed",
-        "volume": "94"
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
       },
-      "evidence": "Apparent ThR-positive ghost tangles (i.e., without nuclei (Braak et al., 1994)) are no longer labeled by TNT1 or TNT2, which confirms that PAD exposure is lost in the latest stages of NFT evolution.",
-      "key": "136a819feb6e554df0f6bd5544fc81873c1f137c7f9e9be2f6992dc0854550641e13f69442906b4a3a5c9b1d272e8b82c47170de88c6114650e02601ed7c38de",
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       "citation": {
         "authors": [
           "Abdelmesih B",
@@ -9959,12 +11767,17 @@
       },
       "evidence": "Aggregation-induced increases in PAD exposure and oligomerization are common features among all tau isoforms. The extent of PAD exposure and oligomerization was larger for tau aggregates composed of 4-repeat isoforms compared with those made of 3-repeat isoforms.",
       "key": "03e7e9fe945fde72dc17d78a31d662a0d1a81b35b75a9e24d256ea59945d75d20e7095a9b0d10cacaa2d31e812f6680e42ac6f066d79175309abd8e6a00d58a5",
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       "relation": "positiveCorrelation",
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     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Brady ST",
@@ -9987,12 +11800,17 @@
       },
       "evidence": "Highlighting the relevance of these findings to human disease, pS422 tau was found to colocalize with tau oligomers and with a fraction of tau showing increased PAD exposure in the human AD brain. This study identifies novel effects of pS422 on tau biochemical properties, including prolonged nucleation and enhanced dimer formation, which correlate with a distinct inhibitory effect on FAT.",
       "key": "0365bac2d8b1bacec58891ffa7d1a4ce15f96b9b9d324fb4a8569b9472452737a693b9b233c0a7a62780f3d4271d072b43170f8cf83a2da89cf3281927da2cea",
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       "relation": "positiveCorrelation",
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+      "target": 654
     },
     {
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+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "Andreadis A",
@@ -10017,16 +11835,168 @@
         "volume": "31"
       },
       "evidence": "Filamentous, but not soluble, forms of wild-type tau inhibit anterograde, kinesin-based fast axonal transport (FAT) by activating axonal protein phosphatase 1 (PP1) and glycogen synthase kinase 3 (GSK3), independent of microtubule binding. Amino acids 2-18 of tau, comprising a phosphatase-activating domain (PAD), are necessary and sufficient for activation of this pathway. Various pathogenic forms of tau displaying increased exposure of PAD inhibited anterograde FAT in squid axoplasm. Immunohistochemical studies using a novel PAD-specific monoclonal antibody in human postmortem tissue indicated that increased PAD exposure represents an early pathogenic event in AD that closely associates in time with AT8 immunoreactivity. We propose a model of pathogenesis in which disease-associated changes in tau conformation lead to increased exposure of PAD, activation of PP1-GSK3, and inhibition of FAT",
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+          "Medium": true
+        }
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+      "citation": {
+        "authors": [
+          "Andreadis A",
+          "Binder LI",
+          "Brady ST",
+          "Fu Y",
+          "Kanaan NM",
+          "LaPointe NE",
+          "Morfini GA",
+          "Patterson KR",
+          "Pigino GF",
+          "Song Y"
+        ],
+        "date": "2011-07-06",
+        "first": "Kanaan NM",
+        "last": "Binder LI",
+        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
+        "pages": "9858-68",
+        "reference": "21734277",
+        "title": "Pathogenic forms of tau inhibit kinesin-dependent axonal transport through a mechanism involving activation of axonal phosphotransferases.",
+        "type": "PubMed",
+        "volume": "31"
+      },
+      "evidence": "Filamentous, but not soluble, forms of wild-type tau inhibit anterograde, kinesin-based fast axonal transport (FAT) by activating axonal protein phosphatase 1 (PP1) and glycogen synthase kinase 3 (GSK3), independent of microtubule binding. Amino acids 2-18 of tau, comprising a phosphatase-activating domain (PAD), are necessary and sufficient for activation of this pathway. Various pathogenic forms of tau displaying increased exposure of PAD inhibited anterograde FAT in squid axoplasm. Immunohistochemical studies using a novel PAD-specific monoclonal antibody in human postmortem tissue indicated that increased PAD exposure represents an early pathogenic event in AD that closely associates in time with AT8 immunoreactivity. We propose a model of pathogenesis in which disease-associated changes in tau conformation lead to increased exposure of PAD, activation of PP1-GSK3, and inhibition of FAT",
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+        }
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+        "authors": [
+          "Andreadis A",
+          "Binder LI",
+          "Brady ST",
+          "Fu Y",
+          "Kanaan NM",
+          "LaPointe NE",
+          "Morfini GA",
+          "Patterson KR",
+          "Pigino GF",
+          "Song Y"
+        ],
+        "date": "2011-07-06",
+        "first": "Kanaan NM",
+        "last": "Binder LI",
+        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
+        "pages": "9858-68",
+        "reference": "21734277",
+        "title": "Pathogenic forms of tau inhibit kinesin-dependent axonal transport through a mechanism involving activation of axonal phosphotransferases.",
+        "type": "PubMed",
+        "volume": "31"
+      },
+      "evidence": "Filamentous, but not soluble, forms of wild-type tau inhibit anterograde, kinesin-based fast axonal transport (FAT) by activating axonal protein phosphatase 1 (PP1) and glycogen synthase kinase 3 (GSK3), independent of microtubule binding. Amino acids 2-18 of tau, comprising a phosphatase-activating domain (PAD), are necessary and sufficient for activation of this pathway. Various pathogenic forms of tau displaying increased exposure of PAD inhibited anterograde FAT in squid axoplasm. Immunohistochemical studies using a novel PAD-specific monoclonal antibody in human postmortem tissue indicated that increased PAD exposure represents an early pathogenic event in AD that closely associates in time with AT8 immunoreactivity. We propose a model of pathogenesis in which disease-associated changes in tau conformation lead to increased exposure of PAD, activation of PP1-GSK3, and inhibition of FAT",
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+        }
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+        "authors": [
+          "Andreadis A",
+          "Binder LI",
+          "Brady ST",
+          "Fu Y",
+          "Kanaan NM",
+          "LaPointe NE",
+          "Morfini GA",
+          "Patterson KR",
+          "Pigino GF",
+          "Song Y"
+        ],
+        "date": "2011-07-06",
+        "first": "Kanaan NM",
+        "last": "Binder LI",
+        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
+        "pages": "9858-68",
+        "reference": "21734277",
+        "title": "Pathogenic forms of tau inhibit kinesin-dependent axonal transport through a mechanism involving activation of axonal phosphotransferases.",
+        "type": "PubMed",
+        "volume": "31"
+      },
+      "evidence": "Filamentous, but not soluble, forms of wild-type tau inhibit anterograde, kinesin-based fast axonal transport (FAT) by activating axonal protein phosphatase 1 (PP1) and glycogen synthase kinase 3 (GSK3), independent of microtubule binding. Amino acids 2-18 of tau, comprising a phosphatase-activating domain (PAD), are necessary and sufficient for activation of this pathway. Various pathogenic forms of tau displaying increased exposure of PAD inhibited anterograde FAT in squid axoplasm. Immunohistochemical studies using a novel PAD-specific monoclonal antibody in human postmortem tissue indicated that increased PAD exposure represents an early pathogenic event in AD that closely associates in time with AT8 immunoreactivity. We propose a model of pathogenesis in which disease-associated changes in tau conformation lead to increased exposure of PAD, activation of PP1-GSK3, and inhibition of FAT",
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-      "relation": "directlyIncreases",
-      "source": 359,
-      "target": 652
+      "relation": "increases",
+      "source": 439,
+      "target": 374
+    },
+    {
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+      "citation": {
+        "authors": [
+          "Andreadis A",
+          "Binder LI",
+          "Brady ST",
+          "Fu Y",
+          "Kanaan NM",
+          "LaPointe NE",
+          "Morfini GA",
+          "Patterson KR",
+          "Pigino GF",
+          "Song Y"
+        ],
+        "date": "2011-07-06",
+        "first": "Kanaan NM",
+        "last": "Binder LI",
+        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
+        "pages": "9858-68",
+        "reference": "21734277",
+        "title": "Pathogenic forms of tau inhibit kinesin-dependent axonal transport through a mechanism involving activation of axonal phosphotransferases.",
+        "type": "PubMed",
+        "volume": "31"
+      },
+      "evidence": "Filamentous, but not soluble, forms of wild-type tau inhibit anterograde, kinesin-based fast axonal transport (FAT) by activating axonal protein phosphatase 1 (PP1) and glycogen synthase kinase 3 (GSK3), independent of microtubule binding. Amino acids 2-18 of tau, comprising a phosphatase-activating domain (PAD), are necessary and sufficient for activation of this pathway. Various pathogenic forms of tau displaying increased exposure of PAD inhibited anterograde FAT in squid axoplasm. Immunohistochemical studies using a novel PAD-specific monoclonal antibody in human postmortem tissue indicated that increased PAD exposure represents an early pathogenic event in AD that closely associates in time with AT8 immunoreactivity. We propose a model of pathogenesis in which disease-associated changes in tau conformation lead to increased exposure of PAD, activation of PP1-GSK3, and inhibition of FAT",
+      "key": "983725118b5616a824ef83dd4295e3e10f7b93007b9359e4e2fa2a537034ca775782510d4d1dee02e9383a7ae4b0d9722406a2651530c3e243e3006ab57789b4",
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+      "object": {
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+      "relation": "increases",
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+      "target": 537
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "Alvarez VE",
@@ -10048,12 +12018,17 @@
       },
       "evidence": "Several lines of evidence in other tauopathies suggest that tau oligomer formation induces neurotoxicity and that tau oligomer-mediated neurotoxicity involves induction of axonal dysfunction through exposure of an N-terminal motif in tau, the phosphatase-activating domain (PAD).",
       "key": "81679d02f5de1cedc784788579b5e8e662384e62aa6355bea6cf8304b26bb99c6d16959a1a367b7b5c12a949817cce55a02f8d04b6983ee330140f4376e4013d",
-      "line": 215,
+      "line": 232,
       "relation": "equivalentTo",
-      "source": 489,
-      "target": 359
+      "source": 570,
+      "target": 439
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "Alvarez VE",
@@ -10075,13 +12050,16 @@
       },
       "evidence": "Several lines of evidence in other tauopathies suggest that tau oligomer formation induces neurotoxicity and that tau oligomer-mediated neurotoxicity involves induction of axonal dysfunction through exposure of an N-terminal motif in tau, the phosphatase-activating domain (PAD).",
       "key": "8bf7c0fcba0bf0d875c5cd22982ebb5c6bed7c3fef60757a06265a2a24d31b119d4737f63633fc1de4536adad427250f42609a84eaa937b909690867883825b7",
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+      "line": 233,
       "relation": "partOf",
-      "source": 489,
-      "target": 487
+      "source": 570,
+      "target": 568
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "MeSHDisease": {
           "Chronic Traumatic Encephalopathy": true
         }
@@ -10108,13 +12086,19 @@
       },
       "evidence": "We also tested for ac-tau 280 in early stage Alzheimer's disease (Braak stage 1). Histopathological examination using the ac tau 280 antibody was performed in three Alzheimer's cases and three CTE patients. Presence of ac-tau 280 was confirmed in all cases at early sites of disease manifestation. These findings suggest that tau acetylation may precede tau phosphorylation and could be the first ",
       "key": "417305002abf02f3c879b95f8713f39a10cdbfacdeb114f3b43cc79152b6f6ebda000fb4ab190eefb88b74224d08d87114d6bc978b0cb4f1ec667a928865dc8d",
-      "line": 3069,
+      "line": 3784,
       "relation": "positiveCorrelation",
-      "source": 910,
-      "target": 498
+      "source": 1019,
+      "target": 580
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "MeSHDisease": {
           "Chronic Traumatic Encephalopathy": true
         },
@@ -10151,13 +12135,19 @@
       },
       "evidence": "We performed immunohistochemistry and immunofluorescence on fixed brain sections and biochemical analysis of fresh brain extracts to characterize the presence of PAD-exposed tau (TNT1 antibody), tau oligomers (TOC1 antibody), tau phosphorylated at S422 (pS422 antibody), and tau truncated at D421 (TauC3 antibody) in the brains of 9-11 cases with CTE and cases of nondemented aged controls and AD (Braak VI) (n = 6, each). These 4 markers are particularly useful in understanding potential posttraumatic events in CTE because PAD exposure impairs axonal transport (24), oligomers confer toxicity (28, 38–40), pS422 correlates with cognitive decline (15), and D421 truncated tau may be related to cell toxicity (41, 42). All 3 early tau markers (ie, TNT1, TOC1, and pS422) were present in CTE and displayed extensive colocalization in perivascular tau lesions that are considered diagnostic for CTE.",
       "key": "fd415d691e6b00151cdda7d2c3b8d006ddcdd2469c1a335de0dfa7c946d6d783cbbfc59b15ad03572caf361bcc81ceb578a16bf1d3b7b0d654bd04271ba79e18",
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       "relation": "biomarkerFor",
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-      "target": 910
+      "source": 654,
+      "target": 1019
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "MeSHDisease": {
           "Chronic Traumatic Encephalopathy": true
         },
@@ -10194,12 +12184,17 @@
       },
       "evidence": "We performed immunohistochemistry and immunofluorescence on fixed brain sections and biochemical analysis of fresh brain extracts to characterize the presence of PAD-exposed tau (TNT1 antibody), tau oligomers (TOC1 antibody), tau phosphorylated at S422 (pS422 antibody), and tau truncated at D421 (TauC3 antibody) in the brains of 9-11 cases with CTE and cases of nondemented aged controls and AD (Braak VI) (n = 6, each). These 4 markers are particularly useful in understanding potential posttraumatic events in CTE because PAD exposure impairs axonal transport (24), oligomers confer toxicity (28, 38–40), pS422 correlates with cognitive decline (15), and D421 truncated tau may be related to cell toxicity (41, 42). All 3 early tau markers (ie, TNT1, TOC1, and pS422) were present in CTE and displayed extensive colocalization in perivascular tau lesions that are considered diagnostic for CTE.",
       "key": "a5f271ae33ec1b913b5c391e632963d829b45ce5bb5624952dceb4d236699efce1abf0b44de658a95db19aae6b26c2f4d72a867eb905ceae3d22866c01dbcc7b",
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       "relation": "increases",
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       "citation": {
         "authors": [
           "El-Akkad E",
@@ -10223,109 +12218,264 @@
       },
       "evidence": "Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396.",
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     {
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       "citation": {
         "authors": [
-          "Kawakami F",
-          "Ohtsuki K",
-          "Suzuki K"
+          "Cowburn RF",
+          "Dahllund L",
+          "Gustafsson E",
+          "Lund H",
+          "Malinowsky D",
+          "Strömberg K",
+          "Sunnemark D",
+          "Svensson A"
         ],
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-        "reference": "18239272",
-        "title": "A novel consensus phosphorylation motif in sulfatide- and cholesterol-3-sulfate-binding protein substrates for CK1 in vitro.",
+        "date": "2013-07-01",
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+        "last": "Sunnemark D",
+        "name": "Brain pathology (Zurich, Switzerland)",
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         "type": "PubMed",
-        "volume": "31"
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+          "Bažadona D",
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+          "Delalle I",
+          "Di Giovanni G",
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+          "Hof PR",
+          "Jovanov-Milošević N",
+          "Wischik C",
+          "Wray S",
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+          "Šimić G"
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       },
       "evidence": "The pSer422 antibody displayed an almost identical pattern to that of AT8, in that it stained NFTs (Figure 5A–D), neuropil threads and neuritic plaques (Figure 5E–H)",
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+      "evidence": "These data suggest a role for TTBK1 in pre-tangle formation prior to the formation of fibrillar tau and strengthen the idea that tau is phosphorylated at Ser422 at an early intermediate stage in NFT formation.",
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       "citation": {
         "authors": [
-          "Kawakami F",
-          "Ohtsuki K",
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-        "title": "A novel consensus phosphorylation motif in sulfatide- and cholesterol-3-sulfate-binding protein substrates for CK1 in vitro.",
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         "type": "PubMed",
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       "evidence": "The pSer422 antibody displayed an almost identical pattern to that of AT8, in that it stained NFTs (Figure 5A–D), neuropil threads and neuritic plaques (Figure 5E–H)",
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-        "title": "A novel consensus phosphorylation motif in sulfatide- and cholesterol-3-sulfate-binding protein substrates for CK1 in vitro.",
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         "type": "PubMed",
-        "volume": "31"
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       "evidence": "The pSer422 antibody displayed an almost identical pattern to that of AT8, in that it stained NFTs (Figure 5A–D), neuropil threads and neuritic plaques (Figure 5E–H)",
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-        "reference": "18239272",
-        "title": "A novel consensus phosphorylation motif in sulfatide- and cholesterol-3-sulfate-binding protein substrates for CK1 in vitro.",
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         "type": "PubMed",
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       "evidence": "These data suggest a role for TTBK1 in pre-tangle formation prior to the formation of fibrillar tau and strengthen the idea that tau is phosphorylated at Ser422 at an early intermediate stage in NFT formation.",
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       "annotations": {
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         "Enzyme_Acitvity": {
           "1 U/ml": true
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@@ -10345,52 +12495,19 @@
         "type": "PubMed",
         "volume": "515"
       },
-      "evidence": "Finally, phosphorylation of S422 in tau, as recognisedby antibody AP422, was generated most e¤ciently by SAPK3/p38gamma, SAPK4/p38delta and SAPK2b/p38beta",
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+      "evidence": "Finally, phosphorylation of S422 in tau, as recognisedby antibody AP422, was generated most effciently by SAPK3/p38gamma, SAPK4/p38delta and SAPK2b/p38beta",
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       "annotations": {
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-          "Babić Leko M",
-          "Bažadona D",
-          "Buée L",
-          "Delalle I",
-          "Di Giovanni G",
-          "Harrington C",
-          "Hof PR",
-          "Jovanov-Milošević N",
-          "Wischik C",
-          "Wray S",
-          "de Silva R",
-          "Šimić G"
-        ],
-        "date": "2016-01-06",
-        "first": "Šimić G",
-        "last": "Hof PR",
-        "name": "Biomolecules",
-        "pages": "6",
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-        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
-        "type": "PubMed",
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-      "evidence": "3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain.",
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           "Babić Leko M",
@@ -10418,54 +12535,16 @@
       },
       "evidence": "A quite different strategy is to target tau clearance—e.g., by rapamycin that induces macroautophagy [175], inhibitors of Hsp90 chaperone protein that binds to misfolded proteins or by immunotherapeutic approaches [176].",
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-          "Ai J",
-          "Ban T",
-          "Bao YN",
-          "Chen QX",
-          "Hu XL",
-          "Jiang XM",
-          "Liu CD",
-          "Pei SC",
-          "Su XL",
-          "Sun LH",
-          "Sun LL",
-          "Wang X",
-          "Yan ML",
-          "Zhao LJ",
-          "Zong DK"
-        ],
-        "date": "2015-09-01",
-        "first": "Sun LH",
-        "last": "Ai J",
-        "name": "Journal of neurochemistry",
-        "pages": "1139-51",
-        "reference": "26118667",
-        "title": "Activation of Cdk5/p25 and tau phosphorylation following chronic brain hypoperfusion in rats involves microRNA-195 down-regulation.",
-        "type": "PubMed",
-        "volume": "134"
-      },
-      "evidence": "Endogenous miR-195 was knocked down using over-expression of its antisense molecule (pre-AMO-miR-195) via a lentivirus (lenti-pre-AMO-miR-195); this knockdown increased the tau phosphorylation at Ser202/Thr205, Ser262, Thr231, Ser422, and the Cdk5/p25 activation, but over-expression of miR-195 using lenti-pre-miR-195 decreased the tau phosphorylation and Cdk5/p25 activation.",
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         "Research_Model": {
           "pR5 mice": true
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@@ -10491,12 +12570,17 @@
       },
       "evidence": "We studied underlying pathomechanisms in tauopathies using pR5 mice that express the P301L tau mutation found in familial forms of frontotemporal dementia. In a longitudinal study we investigated the functional status of glycogen synthase kinase-3 and correlated it with the appearance of distinct tau phospho-epitopes. Neurons displaying increases in activating phosphorylation of glycogen synthase kinase-3α/β at tyrosine 279/216 also showed an intense rather than moderate AT8 (phospho-Ser202/Thr205 tau) immunoreactivity, and immunoreactivity for AT100 (phospho-Ser212/Thr214 tau) and phosphorylated Ser422, phospho-epitopes associated with fibrillar tau pathology.",
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           "Brady ST",
@@ -10519,12 +12603,17 @@
       },
       "evidence": "Highlighting the relevance of these findings to human disease, pS422 tau was found to colocalize with tau oligomers and with a fraction of tau showing increased PAD exposure in the human AD brain. This study identifies novel effects of pS422 on tau biochemical properties, including prolonged nucleation and enhanced dimer formation, which correlate with a distinct inhibitory effect on FAT.",
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@@ -10547,15 +12636,20 @@
       },
       "evidence": "Highlighting the relevance of these findings to human disease, pS422 tau was found to colocalize with tau oligomers and with a fraction of tau showing increased PAD exposure in the human AD brain. This study identifies novel effects of pS422 on tau biochemical properties, including prolonged nucleation and enhanced dimer formation, which correlate with a distinct inhibitory effect on FAT.",
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     {
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+        "authors": [
+          "Brady ST",
           "Combs B",
           "Counts SE",
           "Cox K",
@@ -10575,12 +12669,17 @@
       },
       "evidence": "Highlighting the relevance of these findings to human disease, pS422 tau was found to colocalize with tau oligomers and with a fraction of tau showing increased PAD exposure in the human AD brain. This study identifies novel effects of pS422 on tau biochemical properties, including prolonged nucleation and enhanced dimer formation, which correlate with a distinct inhibitory effect on FAT.",
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       "citation": {
         "authors": [
           "Andreadis A",
@@ -10605,60 +12704,17 @@
         "volume": "31"
       },
       "evidence": "Filamentous, but not soluble, forms of wild-type tau inhibit anterograde, kinesin-based fast axonal transport (FAT) by activating axonal protein phosphatase 1 (PP1) and glycogen synthase kinase 3 (GSK3), independent of microtubule binding. Amino acids 2-18 of tau, comprising a phosphatase-activating domain (PAD), are necessary and sufficient for activation of this pathway. Various pathogenic forms of tau displaying increased exposure of PAD inhibited anterograde FAT in squid axoplasm. Immunohistochemical studies using a novel PAD-specific monoclonal antibody in human postmortem tissue indicated that increased PAD exposure represents an early pathogenic event in AD that closely associates in time with AT8 immunoreactivity. We propose a model of pathogenesis in which disease-associated changes in tau conformation lead to increased exposure of PAD, activation of PP1-GSK3, and inhibition of FAT",
-      "key": "01c8d2e0bf23b3155145823ee21661efea3324d834093d9daad351be278ad78208ff148121a51d487b91de1caec76620a4d6beecf4246650f08e12de8159a51c",
-      "line": 3844,
-      "object": {
-        "modifier": "Activity"
-      },
+      "key": "adcce0b69830ea61e9e9e15cce0696912347f0103280d5263b85b436381d126dfa3255ac435615b189b206032ad5a0a0cf7dbb6d93cc03cbd724056da87ce356",
+      "line": 4769,
       "relation": "negativeCorrelation",
       "source": 175,
-      "target": 652
+      "target": 439
     },
     {
       "annotations": {
-        "MeSHDisease": {
-          "Chronic Traumatic Encephalopathy": true
-        },
-        "Method": {
-          "ELISA": true,
-          "Immunofluorescence": true,
-          "Immunohistochemistry": true
+        "Confidence": {
+          "High": true
         },
-        "Tau_Antibody": {
-          "Anti-pS422": true,
-          "TN1": true,
-          "TOC1": true,
-          "TauC3": true
-        }
-      },
-      "citation": {
-        "authors": [
-          "Alvarez VE",
-          "Cox K",
-          "Kanaan NM",
-          "McKee AC",
-          "Poncil S",
-          "Stein TD"
-        ],
-        "date": "2016-01-01",
-        "first": "Kanaan NM",
-        "last": "McKee AC",
-        "name": "Journal of neuropathology and experimental neurology",
-        "pages": "19-34",
-        "reference": "26671985",
-        "title": "Characterization of Early Pathological Tau Conformations and Phosphorylation in Chronic Traumatic Encephalopathy.",
-        "type": "PubMed",
-        "volume": "75"
-      },
-      "evidence": "We performed immunohistochemistry and immunofluorescence on fixed brain sections and biochemical analysis of fresh brain extracts to characterize the presence of PAD-exposed tau (TNT1 antibody), tau oligomers (TOC1 antibody), tau phosphorylated at S422 (pS422 antibody), and tau truncated at D421 (TauC3 antibody) in the brains of 9-11 cases with CTE and cases of nondemented aged controls and AD (Braak VI) (n = 6, each). These 4 markers are particularly useful in understanding potential posttraumatic events in CTE because PAD exposure impairs axonal transport (24), oligomers confer toxicity (28, 38–40), pS422 correlates with cognitive decline (15), and D421 truncated tau may be related to cell toxicity (41, 42). All 3 early tau markers (ie, TNT1, TOC1, and pS422) were present in CTE and displayed extensive colocalization in perivascular tau lesions that are considered diagnostic for CTE.",
-      "key": "e940f0e08506ca75eddfc00fb5854f57dbeec24c986438f7cdad8a75d966793fb4ae9d6ee99c3af527274d69aeab195c438194db9af98e528259e97b3bda93a0",
-      "line": 235,
-      "relation": "positiveCorrelation",
-      "source": 368,
-      "target": 604
-    },
-    {
-      "annotations": {
         "Gender": {
           "Female": true
         },
@@ -10687,13 +12743,16 @@
       },
       "evidence": "The genotype distribution of a polymorphism in intron 7 (rs761059) differed between AD cases and controls, with an adjusted odds ratio (OR) of 1.45 (p=0.046, 95% CI: 1.01-2.08). One haplotype (ht2 CAGAG) was found in 14.0% of the AD patients and in 11.1% of the controls (p=0.04, OR=1.43. 95% CI; 1.01-2.01). Stratification by the ApoE gave no significant difference between the groups but when stratified by gender, two SNPs (rs8052688, rs8063) were significantly associated with the risk of MCI among women.",
       "key": "a4f2a337655cc08daee0f8042c2ad3345fd082cb247819decd44de53d654e9562675451da9f46e8ff150eb74be75d81a9fdcb9b8ed6cc57583ac4f771722a5c5",
-      "line": 3624,
+      "line": 4496,
       "relation": "positiveCorrelation",
-      "source": 911,
-      "target": 256
+      "source": 1020,
+      "target": 323
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Gender": {
           "Female": true
         },
@@ -10722,25 +12781,25 @@
       },
       "evidence": "The genotype distribution of a polymorphism in intron 7 (rs761059) differed between AD cases and controls, with an adjusted odds ratio (OR) of 1.45 (p=0.046, 95% CI: 1.01-2.08). One haplotype (ht2 CAGAG) was found in 14.0% of the AD patients and in 11.1% of the controls (p=0.04, OR=1.43. 95% CI; 1.01-2.01). Stratification by the ApoE gave no significant difference between the groups but when stratified by gender, two SNPs (rs8052688, rs8063) were significantly associated with the risk of MCI among women.",
       "key": "ab179eb095a2038a190f79e029ede6d4537a1bef2898fdbf457a89ee388f0e2e8b4b0a3afc5f32e31f8a4a0ead96b7f8db7d807be63648747384e3d535f2b938",
-      "line": 3625,
+      "line": 4497,
       "relation": "positiveCorrelation",
-      "source": 911,
-      "target": 257
+      "source": 1020,
+      "target": 324
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "Method": {
           "CD Spectroscopy": true,
           "Liquid Chromatography": true,
           "Mass Spectrometry": true,
           "Tau aggregation assay": true,
           "Tubulin polymerization assay, light scattering method": true
-        },
-        "Tau_Motif": {
-          "PHF6": true
-        },
-        "Tau_Structure": {
-          "microtubule-binding region": true
         }
       },
       "citation": {
@@ -10765,14 +12824,20 @@
         "volume": "462"
       },
       "evidence": "An example of a spectrum identifying K311 as a site of dimethylation at 2.2 ppm mass accuracy is shown in Fig. 2B. This residue was reported as a possible methylation site in AD-brain derived tau protein on the basis of Edman degradation years ago [36]. It resides within the “PHF6” motif of the MTBR, which has been reported to mediate the aggregation propensity of recombinant monomeric tau in vitro [6, 37]. Other methylation sites within the MTBR include K259, K290, and K353, each of which lies in a KXGS motif associated with AMP-activated protein kinase mediated regulation of microtubule binding [38]. Within the N-terminal projection domain, Lys methylation was detected at K24, K44, K67, and K190 (Fig. 1).",
-      "key": "0744be66d29fb2dea1851ea249b05b8bbb0d7437c947b4dd9898e83b1df49ae9ed5481587cb02005f1d535c9b857c3e31ce4ee60f97eac5146381cf8ce15e52c",
-      "line": 250,
+      "key": "44e8e996daba856cc832b7ef838d6a8adb55155d09e820d84a3ce65752fd20b79c9e4276023bbe071e07c42754e49aa605f241084c00874a2f110cb90098ddcf",
+      "line": 274,
       "relation": "association",
-      "source": 536,
-      "target": 486
+      "source": 617,
+      "target": 1017
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "Method": {
           "CD Spectroscopy": true,
           "Liquid Chromatography": true,
@@ -10781,7 +12846,7 @@
           "Tubulin polymerization assay, light scattering method": true
         },
         "Tau_Motif": {
-          "KXGS": true
+          "PHF6": true
         },
         "Tau_Structure": {
           "microtubule-binding region": true
@@ -10809,20 +12874,32 @@
         "volume": "462"
       },
       "evidence": "An example of a spectrum identifying K311 as a site of dimethylation at 2.2 ppm mass accuracy is shown in Fig. 2B. This residue was reported as a possible methylation site in AD-brain derived tau protein on the basis of Edman degradation years ago [36]. It resides within the “PHF6” motif of the MTBR, which has been reported to mediate the aggregation propensity of recombinant monomeric tau in vitro [6, 37]. Other methylation sites within the MTBR include K259, K290, and K353, each of which lies in a KXGS motif associated with AMP-activated protein kinase mediated regulation of microtubule binding [38]. Within the N-terminal projection domain, Lys methylation was detected at K24, K44, K67, and K190 (Fig. 1).",
-      "key": "9f6ca7cc2e5fee6f92477341bd432e4ad7f1b976fc9473cf6122bda9255a6901bb449d59ff54e02cb39ed21e21b52252ed06b47b84e0193f77651f644fb47c14",
-      "line": 253,
+      "key": "cbe81337ffec09cd5f72a362ee87f672d98c7863a0ed4ddb5bf588a5472f0961d7e18b68c57d0469f70dec176886420382ed3cbb0babd07edcb2382e249916d0",
+      "line": 278,
       "relation": "association",
-      "source": 530,
-      "target": 486
+      "source": 617,
+      "target": 402
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "Method": {
           "CD Spectroscopy": true,
           "Liquid Chromatography": true,
           "Mass Spectrometry": true,
           "Tau aggregation assay": true,
           "Tubulin polymerization assay, light scattering method": true
+        },
+        "Tau_Motif": {
+          "PHF6": true
+        },
+        "Tau_Structure": {
+          "microtubule-binding region": true
         }
       },
       "citation": {
@@ -10847,276 +12924,290 @@
         "volume": "462"
       },
       "evidence": "An example of a spectrum identifying K311 as a site of dimethylation at 2.2 ppm mass accuracy is shown in Fig. 2B. This residue was reported as a possible methylation site in AD-brain derived tau protein on the basis of Edman degradation years ago [36]. It resides within the “PHF6” motif of the MTBR, which has been reported to mediate the aggregation propensity of recombinant monomeric tau in vitro [6, 37]. Other methylation sites within the MTBR include K259, K290, and K353, each of which lies in a KXGS motif associated with AMP-activated protein kinase mediated regulation of microtubule binding [38]. Within the N-terminal projection domain, Lys methylation was detected at K24, K44, K67, and K190 (Fig. 1).",
-      "key": "bbb5afac27d421c43d1ce5a5b8bbff13907aed2c7dc3fddfa87c5514d052742f5d564d74342dd313b9d8d311820987fbb1361b237db0a2bb7059a6c5dc1a5e14",
-      "line": 268,
-      "relation": "isA",
-      "source": 530,
-      "target": 523
+      "key": "2eb7abc7b2dbc4018349d389099386191112aa4e93f216e37020fed40eb04b869d503e69ded49a1f3928a0abdf7e223be0ef0de51f4fae368b8292899d5d8fa0",
+      "line": 278,
+      "relation": "association",
+      "source": 402,
+      "target": 617
     },
     {
       "annotations": {
-        "Method": {
-          "CD Spectroscopy": true,
-          "Liquid Chromatography": true,
-          "Mass Spectrometry": true,
-          "Tau aggregation assay": true,
-          "Tubulin polymerization assay, light scattering method": true
+        "Cell_Line": {
+          "SH-SY5Y": true
         },
-        "Tau_Motif": {
-          "KXGS": true
+        "Confidence": {
+          "High": true
         },
-        "Tau_Structure": {
-          "microtubule-binding region": true
+        "Method": {
+          "Atomic Force Microscopy": true,
+          "Cell Viability Assay, MTT": true,
+          "Flow Cytometry": true,
+          "Fluorescence Spectrophotometry": true,
+          "NBT colorimetric fructosamine assay": true
         }
       },
       "citation": {
         "authors": [
-          "Clark DJ",
-          "Cooper GL",
-          "Funk KE",
-          "Kuret J",
-          "Liao Z",
-          "Schafer KN",
-          "Thomas SN",
-          "Yang AJ"
+          "Chen L",
+          "He R",
+          "Wang X",
+          "Wei Y"
         ],
-        "date": "2014-08-15",
-        "first": "Funk KE",
-        "last": "Kuret J",
-        "name": "The Biochemical journal",
-        "pages": "77-88",
-        "reference": "24869773",
-        "title": "Lysine methylation is an endogenous post-translational modification of tau protein in human brain and a modulator of aggregation propensity.",
+        "date": "2009-08-01",
+        "first": "Chen L",
+        "last": "He R",
+        "name": "Cellular and molecular life sciences : CMLS",
+        "pages": "2559-71",
+        "reference": "19517062",
+        "title": "D-Ribosylated Tau forms globular aggregates with high cytotoxicity.",
         "type": "PubMed",
-        "volume": "462"
+        "volume": "66"
       },
-      "evidence": "An example of a spectrum identifying K311 as a site of dimethylation at 2.2 ppm mass accuracy is shown in Fig. 2B. This residue was reported as a possible methylation site in AD-brain derived tau protein on the basis of Edman degradation years ago [36]. It resides within the “PHF6” motif of the MTBR, which has been reported to mediate the aggregation propensity of recombinant monomeric tau in vitro [6, 37]. Other methylation sites within the MTBR include K259, K290, and K353, each of which lies in a KXGS motif associated with AMP-activated protein kinase mediated regulation of microtubule binding [38]. Within the N-terminal projection domain, Lys methylation was detected at K24, K44, K67, and K190 (Fig. 1).",
-      "key": "f8b8bf408536a8f817d42137a9f06aaa23c87965b3d8337f4e7ef6b47e459454e9c658f08634fd0fb1ee9aa1350b1b12a629b0c1af3eef02728275c1d2bc76d8",
-      "line": 254,
-      "relation": "association",
-      "source": 532,
-      "target": 486
+      "evidence": "D-ribosylated Tau aggregates were highly toxic to SHSY5Y cells and resulted in both apoptosis and necrosis",
+      "key": "4c73aa81daff7e83152ce1328e8d06976c39067d288020979559b57de3311c847de8a3f4e503493c0b143d440df5a1997e83a16c63f0b4973df7481ad82d5faa",
+      "line": 697,
+      "relation": "increases",
+      "source": 402,
+      "target": 173
     },
     {
       "annotations": {
-        "Anatomy": {
-          "hippocampal formation": true
+        "Cell_Line": {
+          "SH-SY5Y": true
         },
-        "Disease": {
-          "Alzheimer's disease": true
+        "Confidence": {
+          "High": true
         },
         "Method": {
-          "Chromatography, Immunoaffinity": true,
-          "Fluorescence Microscopy, Confocal": true,
-          "Immunohistochemistry": true,
-          "Liquid Chromatography": true,
-          "Mass Spectrometry": true
-        },
-        "Tau_State": {
-          "Paired Helical Filament": true
-        },
-        "Tau_Structure": {
-          "microtubule-binding region": true
+          "Atomic Force Microscopy": true,
+          "Cell Viability Assay, MTT": true,
+          "Flow Cytometry": true,
+          "Fluorescence Spectrophotometry": true,
+          "NBT colorimetric fructosamine assay": true
         }
       },
       "citation": {
         "authors": [
-          "Davies P",
-          "Funk KE",
-          "Kuret J",
-          "Liao Z",
-          "Thomas SN",
-          "Wan Y",
-          "Yang AJ"
+          "Chen L",
+          "He R",
+          "Wang X",
+          "Wei Y"
         ],
-        "date": "2012-01-01",
-        "first": "Thomas SN",
-        "last": "Yang AJ",
-        "name": "Acta neuropathologica",
-        "pages": "105-17",
-        "reference": "22033876",
-        "title": "Dual modification of Alzheimer's disease PHF-tau protein by lysine methylation and ubiquitylation: a mass spectrometry approach.",
+        "date": "2009-08-01",
+        "first": "Chen L",
+        "last": "He R",
+        "name": "Cellular and molecular life sciences : CMLS",
+        "pages": "2559-71",
+        "reference": "19517062",
+        "title": "D-Ribosylated Tau forms globular aggregates with high cytotoxicity.",
         "type": "PubMed",
-        "volume": "123"
+        "volume": "66"
       },
-      "evidence": "However, robust monomethylation was identified at seven sites distributed throughout the tau sequence (Table 1). Three of the sites (K163, K174, and K180) reside within the proline-rich region of the tau N-terminal projection domain, which mediates interactions with microtubule-associated proteins such as actin [27] and the Src homology three domain of plasma membrane-associated proteins including Src family kinases [37] and phospholipase Cc [54]. In contrast, K254, K267, and K290 are part of the first and second repeats of the microtubule binding domain. Although no Lys acetylation was detected at these sites in our datasets, it was possible to quantify relative methylation and ubiquitylation of K254.",
-      "key": "c679d9a2643eeb2dfbce6f7c2b617b5a3bbd4eff8dfa0b27526546b0150bec938056bf13f5e0b75039a34a5315bbb01d74d50f8a1aa8ac7d3f891036712d142b",
-      "line": 301,
-      "relation": "association",
-      "source": 532,
-      "target": 486
+      "evidence": "D-ribosylated Tau aggregates were highly toxic to SHSY5Y cells and resulted in both apoptosis and necrosis",
+      "key": "b2201b26505421a9ac547fe24501fe3a87f8427db2cc61031c71fc6d1d7045e254abe1b6b5e7ea364adbe64910416996f5eedb78407de23d6474f96ed4b9a156",
+      "line": 698,
+      "relation": "increases",
+      "source": 402,
+      "target": 195
     },
     {
       "annotations": {
-        "Method": {
-          "CD Spectroscopy": true,
-          "Liquid Chromatography": true,
-          "Mass Spectrometry": true,
-          "Tau aggregation assay": true,
-          "Tubulin polymerization assay, light scattering method": true
+        "Confidence": {
+          "Medium": true
         }
       },
       "citation": {
         "authors": [
-          "Clark DJ",
-          "Cooper GL",
-          "Funk KE",
-          "Kuret J",
-          "Liao Z",
-          "Schafer KN",
-          "Thomas SN",
-          "Yang AJ"
+          "Babić Leko M",
+          "Bažadona D",
+          "Buée L",
+          "Delalle I",
+          "Di Giovanni G",
+          "Harrington C",
+          "Hof PR",
+          "Jovanov-Milošević N",
+          "Wischik C",
+          "Wray S",
+          "de Silva R",
+          "Šimić G"
         ],
-        "date": "2014-08-15",
-        "first": "Funk KE",
-        "last": "Kuret J",
-        "name": "The Biochemical journal",
-        "pages": "77-88",
-        "reference": "24869773",
-        "title": "Lysine methylation is an endogenous post-translational modification of tau protein in human brain and a modulator of aggregation propensity.",
+        "date": "2016-01-06",
+        "first": "Šimić G",
+        "last": "Hof PR",
+        "name": "Biomolecules",
+        "pages": "6",
+        "reference": "26751493",
+        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
         "type": "PubMed",
-        "volume": "462"
+        "volume": "6"
       },
-      "evidence": "An example of a spectrum identifying K311 as a site of dimethylation at 2.2 ppm mass accuracy is shown in Fig. 2B. This residue was reported as a possible methylation site in AD-brain derived tau protein on the basis of Edman degradation years ago [36]. It resides within the “PHF6” motif of the MTBR, which has been reported to mediate the aggregation propensity of recombinant monomeric tau in vitro [6, 37]. Other methylation sites within the MTBR include K259, K290, and K353, each of which lies in a KXGS motif associated with AMP-activated protein kinase mediated regulation of microtubule binding [38]. Within the N-terminal projection domain, Lys methylation was detected at K24, K44, K67, and K190 (Fig. 1).",
-      "key": "a82397f973a6dc3cc57e37c68a25184d22185cfd2b51dfcbe93af56006b01843bfaccb5eaa2d98d811bee539ed9ba0f86a2404775079edf4b640256f2e9f9746",
-      "line": 269,
-      "relation": "isA",
-      "source": 532,
-      "target": 523
+      "evidence": "In the case of soluble monomeric or small oligomeric tau protein, the endocytosis appears to be clathrin-dependent (reviewed in [169]). In contrast, larger aggregates of tau could bind heparin in the extracellular matrix and be internalized through macropinocytosis [170]. As a result of exocytosis and endocytosis, the spreading of tau can occur in various neurodegenerative diseases (tauopathies) including AD. Three plausible mechanisms of tau spreading are shown schematically in Figure 6. Additionally, it appears that microglial cells may facilitate tau propagation by phagocytosis and exocytosis of tau protein [171].",
+      "key": "6998b66bea5047c085f3ce91d876fc8bbfe27fc29b27e727fa68f603afeba1357eb3a32f647acb443634f2175ef25e24efcc2e9491bb2d34c6a89abd8c56a96e",
+      "line": 2055,
+      "relation": "partOf",
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+      "target": 243
     },
     {
       "annotations": {
-        "Anatomy": {
-          "hippocampal formation": true
-        },
-        "Disease": {
-          "Alzheimer's disease": true
-        },
-        "Method": {
-          "Chromatography, Immunoaffinity": true,
-          "Fluorescence Microscopy, Confocal": true,
-          "Immunohistochemistry": true,
-          "Liquid Chromatography": true,
-          "Mass Spectrometry": true
-        },
-        "Tau_State": {
-          "Paired Helical Filament": true
+        "Confidence": {
+          "Medium": true
         },
-        "Tau_Structure": {
-          "microtubule-binding region": true
+        "MeSHDisease": {
+          "Tauopathies": true
         }
       },
       "citation": {
         "authors": [
-          "Davies P",
-          "Funk KE",
-          "Kuret J",
-          "Liao Z",
-          "Thomas SN",
-          "Wan Y",
-          "Yang AJ"
+          "Babić Leko M",
+          "Bažadona D",
+          "Buée L",
+          "Delalle I",
+          "Di Giovanni G",
+          "Harrington C",
+          "Hof PR",
+          "Jovanov-Milošević N",
+          "Wischik C",
+          "Wray S",
+          "de Silva R",
+          "Šimić G"
         ],
-        "date": "2012-01-01",
-        "first": "Thomas SN",
-        "last": "Yang AJ",
-        "name": "Acta neuropathologica",
-        "pages": "105-17",
-        "reference": "22033876",
-        "title": "Dual modification of Alzheimer's disease PHF-tau protein by lysine methylation and ubiquitylation: a mass spectrometry approach.",
+        "date": "2016-01-06",
+        "first": "Šimić G",
+        "last": "Hof PR",
+        "name": "Biomolecules",
+        "pages": "6",
+        "reference": "26751493",
+        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
         "type": "PubMed",
-        "volume": "123"
+        "volume": "6"
       },
-      "evidence": "However, robust monomethylation was identified at seven sites distributed throughout the tau sequence (Table 1). Three of the sites (K163, K174, and K180) reside within the proline-rich region of the tau N-terminal projection domain, which mediates interactions with microtubule-associated proteins such as actin [27] and the Src homology three domain of plasma membrane-associated proteins including Src family kinases [37] and phospholipase Cc [54]. In contrast, K254, K267, and K290 are part of the first and second repeats of the microtubule binding domain. Although no Lys acetylation was detected at these sites in our datasets, it was possible to quantify relative methylation and ubiquitylation of K254.",
-      "key": "9c7fb6cd8d3f52ae2e34eb7e1d868fd269dfb5a33130f7353433639c22b44a6374a8664201aa8de7769d0325a83f1716214a1fedf573805f519c76368bbf0262",
-      "line": 304,
-      "relation": "partOf",
-      "source": 532,
-      "target": 363
+      "evidence": "Recently, it has been proposed that tau protein acetylation may be responsible for tau aggregation in AD. Grinberg and collaborators detected tau acetylation at Lys274 in all tauopathies (both primary and secondary), except in AgD",
+      "key": "cbcd85a7f7322c600d736f64343f92b5c352ea380ac781aeba3fd25c981157d243acd5c28371488bba04e53782aa6bbc7e7a11f14edfbf697e700bba5333e6e3",
+      "line": 2097,
+      "relation": "positiveCorrelation",
+      "source": 402,
+      "target": 579
     },
     {
       "annotations": {
-        "Method": {
-          "CD Spectroscopy": true,
-          "Liquid Chromatography": true,
-          "Mass Spectrometry": true,
-          "Tau aggregation assay": true,
-          "Tubulin polymerization assay, light scattering method": true
-        },
-        "Tau_Motif": {
-          "KXGS": true
-        },
-        "Tau_Structure": {
-          "microtubule-binding region": true
+        "Confidence": {
+          "Medium": true
         }
       },
       "citation": {
         "authors": [
-          "Clark DJ",
-          "Cooper GL",
-          "Funk KE",
-          "Kuret J",
-          "Liao Z",
-          "Schafer KN",
-          "Thomas SN",
-          "Yang AJ"
+          "Acevedo-Aquino MC",
+          "Luna-Muñoz J",
+          "Mondragón-Rodríguez S",
+          "Perry G",
+          "Williams S"
         ],
-        "date": "2014-08-15",
-        "first": "Funk KE",
-        "last": "Kuret J",
-        "name": "The Biochemical journal",
-        "pages": "77-88",
-        "reference": "24869773",
-        "title": "Lysine methylation is an endogenous post-translational modification of tau protein in human brain and a modulator of aggregation propensity.",
+        "date": "2014-02-01",
+        "first": "Mondragón-Rodríguez S",
+        "last": "Williams S",
+        "name": "Neuropathology and applied neurobiology",
+        "pages": "121-35",
+        "reference": "24033439",
+        "title": "Phosphorylation of tau protein at sites Ser(396-404) is one of the earliest events in Alzheimer's disease and Down syndrome.",
         "type": "PubMed",
-        "volume": "462"
+        "volume": "40"
       },
-      "evidence": "An example of a spectrum identifying K311 as a site of dimethylation at 2.2 ppm mass accuracy is shown in Fig. 2B. This residue was reported as a possible methylation site in AD-brain derived tau protein on the basis of Edman degradation years ago [36]. It resides within the “PHF6” motif of the MTBR, which has been reported to mediate the aggregation propensity of recombinant monomeric tau in vitro [6, 37]. Other methylation sites within the MTBR include K259, K290, and K353, each of which lies in a KXGS motif associated with AMP-activated protein kinase mediated regulation of microtubule binding [38]. Within the N-terminal projection domain, Lys methylation was detected at K24, K44, K67, and K190 (Fig. 1).",
-      "key": "d57be1f74b4154622f028c793eac8729cc60a1a3ae023756c27a0b5e8ace4da86f805a67b9ce9ac7f371a6c0b0997efe57815c02134ebcf8379c309117337831",
-      "line": 255,
-      "relation": "association",
-      "source": 533,
-      "target": 486
+      "evidence": "Finally, these data validate PHF-1 as an efficient marker for AD cytopathology following the progression of tau aggregation into NFT.",
+      "key": "29443c5b6fbb614a659d3594a945a04f63720b96d6da3c6c8fe35e584adf99909f7eb1a1c6764ab0b1ad3fb1d8c28e01529341b9bbb23f57ce68729b6f1a2fb9",
+      "line": 3212,
+      "relation": "increases",
+      "source": 402,
+      "target": 94
     },
     {
       "annotations": {
-        "Method": {
-          "CD Spectroscopy": true,
-          "Liquid Chromatography": true,
-          "Mass Spectrometry": true,
-          "Tau aggregation assay": true,
-          "Tubulin polymerization assay, light scattering method": true
+        "Confidence": {
+          "Medium": true
         }
       },
       "citation": {
         "authors": [
-          "Clark DJ",
-          "Cooper GL",
-          "Funk KE",
-          "Kuret J",
-          "Liao Z",
-          "Schafer KN",
-          "Thomas SN",
-          "Yang AJ"
+          "Carlomagno Y",
+          "Castanedes-Casey M",
+          "Chung DC",
+          "Cook C",
+          "DeTure M",
+          "Dickson DW",
+          "Dunmore J",
+          "Madden BJ",
+          "Petrucelli L",
+          "Tong J",
+          "Yue M"
         ],
-        "date": "2014-08-15",
-        "first": "Funk KE",
-        "last": "Kuret J",
-        "name": "The Biochemical journal",
-        "pages": "77-88",
-        "reference": "24869773",
-        "title": "Lysine methylation is an endogenous post-translational modification of tau protein in human brain and a modulator of aggregation propensity.",
+        "date": "2017-09-15",
+        "first": "Carlomagno Y",
+        "last": "Cook C",
+        "name": "The Journal of biological chemistry",
+        "pages": "15277-15286",
+        "reference": "28760828",
+        "title": "An acetylation-phosphorylation switch that regulates tau aggregation propensity and function.",
         "type": "PubMed",
-        "volume": "462"
+        "volume": "292"
       },
-      "evidence": "An example of a spectrum identifying K311 as a site of dimethylation at 2.2 ppm mass accuracy is shown in Fig. 2B. This residue was reported as a possible methylation site in AD-brain derived tau protein on the basis of Edman degradation years ago [36]. It resides within the “PHF6” motif of the MTBR, which has been reported to mediate the aggregation propensity of recombinant monomeric tau in vitro [6, 37]. Other methylation sites within the MTBR include K259, K290, and K353, each of which lies in a KXGS motif associated with AMP-activated protein kinase mediated regulation of microtubule binding [38]. Within the N-terminal projection domain, Lys methylation was detected at K24, K44, K67, and K190 (Fig. 1).",
-      "key": "4af6618c38d6a3b6ff7d4455f7c40a1d8350d8a0ebe88d6698d03296676054f8045611453511589ac855beca76cd77cd3d031e3874b91746dd44411b25778253",
-      "line": 270,
-      "relation": "isA",
-      "source": 533,
-      "target": 523
+      "evidence": "Our findings indicate that several acetylation sites in tau are responsive to HDAC6 and that acetylation on Lys-321 (within a KCGS motif) is both essential for acetylation-mediated inhibition of tau aggregation in vitro and a molecular tactic for preventing phosphorylation on the downstream Ser-324 residue. Tau phosphorylation of Ser-324 (pSer-324) has not previously been evaluated in the context of tauopathy, and here we observed increased deposition of pSer-324-positive tau both in mouse models of tauopathy and in patients with Alzheimer's disease. These findings uncover a novel acetylation-phosphorylation switch at Lys-321/Ser-324 that coordinately regulates tau polymerization and function.",
+      "key": "64dc368457911aa66449d9dc2b348d57d8602d88c1835c5b6117908e2eac0eb2c0631a041db1f670726bdd695225ef53a3f90b2fa8fc46deb511dca0c1c4eda7",
+      "line": 4159,
+      "relation": "positiveCorrelation",
+      "source": 402,
+      "target": 646
+    },
+    {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        },
+        "Research_Model": {
+          "APP/PS1 x rTg4510 mice": true
+        },
+        "Species": {
+          "10090": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Bennett RE",
+          "Carlson GA",
+          "Corjuc B",
+          "DeVos SL",
+          "Dujardin S",
+          "Frosch MP",
+          "Gonzalez J",
+          "Gor R",
+          "Hyman BT",
+          "Pitstick R",
+          "Roe AD"
+        ],
+        "date": "2017-07-01",
+        "first": "Bennett RE",
+        "last": "Hyman BT",
+        "name": "The American journal of pathology",
+        "pages": "1601-1612",
+        "reference": "28500862",
+        "title": "Enhanced Tau Aggregation in the Presence of Amyloid β.",
+        "type": "PubMed",
+        "volume": "187"
+      },
+      "evidence": "In the HEK cell biosensor assay, tau from AD cases with plaques enhanced tau aggregates compared to tau from cases without plaques. In APP/PS1 cross with rTg4510 mice (P301L mutant human tau), tau seeding activity was threefold increased over the rTg4510 strain, without change in tau production or extracellular release.",
+      "key": "c50de00beec1a93108eb986d04695138b52aeed4ef3fabbfd3dc73295a2e08497bc5201506a5d2fd05eeb80b68f50b427bcb8b69f4b1793d8bf5491c94cd53ec",
+      "line": 4448,
+      "relation": "positiveCorrelation",
+      "source": 402,
+      "target": 12
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "Method": {
           "CD Spectroscopy": true,
           "Liquid Chromatography": true,
@@ -11124,8 +13215,11 @@
           "Tau aggregation assay": true,
           "Tubulin polymerization assay, light scattering method": true
         },
+        "Tau_Motif": {
+          "KXGS": true
+        },
         "Tau_Structure": {
-          "projection domain": true
+          "microtubule-binding region": true
         }
       },
       "citation": {
@@ -11150,14 +13244,17 @@
         "volume": "462"
       },
       "evidence": "An example of a spectrum identifying K311 as a site of dimethylation at 2.2 ppm mass accuracy is shown in Fig. 2B. This residue was reported as a possible methylation site in AD-brain derived tau protein on the basis of Edman degradation years ago [36]. It resides within the “PHF6” motif of the MTBR, which has been reported to mediate the aggregation propensity of recombinant monomeric tau in vitro [6, 37]. Other methylation sites within the MTBR include K259, K290, and K353, each of which lies in a KXGS motif associated with AMP-activated protein kinase mediated regulation of microtubule binding [38]. Within the N-terminal projection domain, Lys methylation was detected at K24, K44, K67, and K190 (Fig. 1).",
-      "key": "d151d1ccaaedbdc0734943986d40425c2e1f791063f8d70a461d345b2c9106523906e83f90def8c30e6dc93015e319ddb4cdf9c08e23875cbe6e80b59d846397",
-      "line": 258,
-      "relation": "association",
-      "source": 528,
-      "target": 486
+      "key": "3b27669db9b47b72a8b3c19c3d358eb0f1682cc81d8e000a2a1de8f64140847cbce43702af5e4017912912a2691980bf1fb0bc19d836055fce6bbc5460877d84",
+      "line": 281,
+      "relation": "regulates",
+      "source": 614,
+      "target": 246
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "Method": {
           "CD Spectroscopy": true,
           "Liquid Chromatography": true,
@@ -11188,14 +13285,152 @@
         "volume": "462"
       },
       "evidence": "An example of a spectrum identifying K311 as a site of dimethylation at 2.2 ppm mass accuracy is shown in Fig. 2B. This residue was reported as a possible methylation site in AD-brain derived tau protein on the basis of Edman degradation years ago [36]. It resides within the “PHF6” motif of the MTBR, which has been reported to mediate the aggregation propensity of recombinant monomeric tau in vitro [6, 37]. Other methylation sites within the MTBR include K259, K290, and K353, each of which lies in a KXGS motif associated with AMP-activated protein kinase mediated regulation of microtubule binding [38]. Within the N-terminal projection domain, Lys methylation was detected at K24, K44, K67, and K190 (Fig. 1).",
-      "key": "17d86157feb54fab6cd71a52513a2379da65c8598f22f1743d0e0a6585c048e1a852b463c2b422120a1682f621731eb383e203f87edf090a733e9cb442967813",
-      "line": 264,
+      "key": "bbb5afac27d421c43d1ce5a5b8bbff13907aed2c7dc3fddfa87c5514d052742f5d564d74342dd313b9d8d311820987fbb1361b237db0a2bb7059a6c5dc1a5e14",
+      "line": 298,
       "relation": "isA",
-      "source": 528,
-      "target": 523
+      "source": 614,
+      "target": 607
+    },
+    {
+      "key": "e30a63cb8051908bbf600613a93906b15c4705e7f7abe5a0ad62a2698f3a5262b6abcc9e9e0cf196429bd9a44486e8fc09c678ea23c20264267b728a4b6bb242",
+      "relation": "hasComponent",
+      "source": 246,
+      "target": 99
+    },
+    {
+      "key": "634e58096a5532932706dd2067ec8bba3b4f9fe5e640db2c3acaccb3b0e9efdaefea7e274911a0cf58de18a8e4b1fdc7e767f1b94021cfbd7dc9940098efdf19",
+      "relation": "hasComponent",
+      "source": 246,
+      "target": 567
+    },
+    {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Berry RW",
+          "Binder LI",
+          "Lukas TJ",
+          "Reynolds MR"
+        ],
+        "date": "2006-04-04",
+        "first": "Reynolds MR",
+        "last": "Binder LI",
+        "name": "Biochemistry",
+        "pages": "4314-26",
+        "reference": "16566606",
+        "title": "Peroxynitrite-mediated tau modifications stabilize preformed filaments and destabilize microtubules through distinct mechanisms.",
+        "type": "PubMed",
+        "volume": "45"
+      },
+      "evidence": "Select nitration of residues Tyr18, Tyr29, Tyr197, and Tyr394, events known to stabilize the pathological Alz-50 conformation inhibits the ability of monomeric tau to promote tubulin assembly, effect specific for the 3-NT modification, as mutant tau proteins pseudophosphorylated at each Tyr residue are fully competent to stabilize MTs, suggesting that ONOO(-)-mediated modifications stabilize tau filaments via 3,3'-DT bonding and destabilize MTs by site-selective nitration of tau monomers.",
+      "key": "5b3d95305d13753181be2d24615d306d69754cbd3e75872f0214a2d5d1d71b07c0f187ebc9bcc78a474ceda2b325871fde8fecc39d567235c95bf3d649557cb0",
+      "line": 1104,
+      "relation": "positiveCorrelation",
+      "source": 99,
+      "target": 673
+    },
+    {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Berry RW",
+          "Binder LI",
+          "Lukas TJ",
+          "Reynolds MR"
+        ],
+        "date": "2006-04-04",
+        "first": "Reynolds MR",
+        "last": "Binder LI",
+        "name": "Biochemistry",
+        "pages": "4314-26",
+        "reference": "16566606",
+        "title": "Peroxynitrite-mediated tau modifications stabilize preformed filaments and destabilize microtubules through distinct mechanisms.",
+        "type": "PubMed",
+        "volume": "45"
+      },
+      "evidence": "Select nitration of residues Tyr18, Tyr29, Tyr197, and Tyr394, events known to stabilize the pathological Alz-50 conformation inhibits the ability of monomeric tau to promote tubulin assembly, effect specific for the 3-NT modification, as mutant tau proteins pseudophosphorylated at each Tyr residue are fully competent to stabilize MTs, suggesting that ONOO(-)-mediated modifications stabilize tau filaments via 3,3'-DT bonding and destabilize MTs by site-selective nitration of tau monomers.",
+      "key": "c84fbc0eb822b0ea6859951fb259210ac8c56a35a8b98f8ea07561d15d1c14e74837beff03d87e419824d9db34cb8151cafbb5d9365441951e2e1245971def7a",
+      "line": 1105,
+      "relation": "positiveCorrelation",
+      "source": 99,
+      "target": 675
+    },
+    {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Berry RW",
+          "Binder LI",
+          "Lukas TJ",
+          "Reynolds MR"
+        ],
+        "date": "2006-04-04",
+        "first": "Reynolds MR",
+        "last": "Binder LI",
+        "name": "Biochemistry",
+        "pages": "4314-26",
+        "reference": "16566606",
+        "title": "Peroxynitrite-mediated tau modifications stabilize preformed filaments and destabilize microtubules through distinct mechanisms.",
+        "type": "PubMed",
+        "volume": "45"
+      },
+      "evidence": "Select nitration of residues Tyr18, Tyr29, Tyr197, and Tyr394, events known to stabilize the pathological Alz-50 conformation inhibits the ability of monomeric tau to promote tubulin assembly, effect specific for the 3-NT modification, as mutant tau proteins pseudophosphorylated at each Tyr residue are fully competent to stabilize MTs, suggesting that ONOO(-)-mediated modifications stabilize tau filaments via 3,3'-DT bonding and destabilize MTs by site-selective nitration of tau monomers.",
+      "key": "0fd5731d30a661178824bfcf74503a866b9fff2e797ed1c023c808380b4f7d2bdad126786bd0dd0de23fbc90237916391ad7f4afd749134bae82ca4449ddfa3e",
+      "line": 1106,
+      "relation": "positiveCorrelation",
+      "source": 99,
+      "target": 674
+    },
+    {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Berry RW",
+          "Binder LI",
+          "Lukas TJ",
+          "Reynolds MR"
+        ],
+        "date": "2006-04-04",
+        "first": "Reynolds MR",
+        "last": "Binder LI",
+        "name": "Biochemistry",
+        "pages": "4314-26",
+        "reference": "16566606",
+        "title": "Peroxynitrite-mediated tau modifications stabilize preformed filaments and destabilize microtubules through distinct mechanisms.",
+        "type": "PubMed",
+        "volume": "45"
+      },
+      "evidence": "Select nitration of residues Tyr18, Tyr29, Tyr197, and Tyr394, events known to stabilize the pathological Alz-50 conformation inhibits the ability of monomeric tau to promote tubulin assembly, effect specific for the 3-NT modification, as mutant tau proteins pseudophosphorylated at each Tyr residue are fully competent to stabilize MTs, suggesting that ONOO(-)-mediated modifications stabilize tau filaments via 3,3'-DT bonding and destabilize MTs by site-selective nitration of tau monomers.",
+      "key": "27536865cb3b54a1918e3668623a5aa22f136885c9cbcf701ef7f5d59389a2cae54310c348bcc51b1c717c1c0c955b9e4d69d36503c1413b2b9a0079054a52c6",
+      "line": 1107,
+      "relation": "positiveCorrelation",
+      "source": 99,
+      "target": 677
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "Method": {
           "CD Spectroscopy": true,
           "Liquid Chromatography": true,
@@ -11203,8 +13438,11 @@
           "Tau aggregation assay": true,
           "Tubulin polymerization assay, light scattering method": true
         },
+        "Tau_Motif": {
+          "KXGS": true
+        },
         "Tau_Structure": {
-          "projection domain": true
+          "microtubule-binding region": true
         }
       },
       "citation": {
@@ -11229,14 +13467,17 @@
         "volume": "462"
       },
       "evidence": "An example of a spectrum identifying K311 as a site of dimethylation at 2.2 ppm mass accuracy is shown in Fig. 2B. This residue was reported as a possible methylation site in AD-brain derived tau protein on the basis of Edman degradation years ago [36]. It resides within the “PHF6” motif of the MTBR, which has been reported to mediate the aggregation propensity of recombinant monomeric tau in vitro [6, 37]. Other methylation sites within the MTBR include K259, K290, and K353, each of which lies in a KXGS motif associated with AMP-activated protein kinase mediated regulation of microtubule binding [38]. Within the N-terminal projection domain, Lys methylation was detected at K24, K44, K67, and K190 (Fig. 1).",
-      "key": "8f2c63ace914a50400bfb1da4b3d5061fa9b5960d7cd63b9b1ed396ea3e251fb6ea5bc1e292fb07aa2c83d8931ead0d2cf0032179c1d1f502cae57224a4c8987",
-      "line": 259,
-      "relation": "association",
-      "source": 534,
-      "target": 486
+      "key": "21c13a94069f0ed7b58633047fa425afcae7423ead669d7f18883367cb523252486f855483a685c4b0900204fdd647bc67a7ea52c3773d5602507ce31917f1be",
+      "line": 282,
+      "relation": "regulates",
+      "source": 616,
+      "target": 246
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "Method": {
           "CD Spectroscopy": true,
           "Liquid Chromatography": true,
@@ -11267,14 +13508,72 @@
         "volume": "462"
       },
       "evidence": "An example of a spectrum identifying K311 as a site of dimethylation at 2.2 ppm mass accuracy is shown in Fig. 2B. This residue was reported as a possible methylation site in AD-brain derived tau protein on the basis of Edman degradation years ago [36]. It resides within the “PHF6” motif of the MTBR, which has been reported to mediate the aggregation propensity of recombinant monomeric tau in vitro [6, 37]. Other methylation sites within the MTBR include K259, K290, and K353, each of which lies in a KXGS motif associated with AMP-activated protein kinase mediated regulation of microtubule binding [38]. Within the N-terminal projection domain, Lys methylation was detected at K24, K44, K67, and K190 (Fig. 1).",
-      "key": "b954d82f14b78370a53f760407d1d03c0218c4d04fc3bd62eedc9e4575b8c3ddae77b1f267a63999b8834dff4d8e8326823145689badb9f61bc9458e25c4c102",
-      "line": 265,
+      "key": "a82397f973a6dc3cc57e37c68a25184d22185cfd2b51dfcbe93af56006b01843bfaccb5eaa2d98d811bee539ed9ba0f86a2404775079edf4b640256f2e9f9746",
+      "line": 299,
       "relation": "isA",
-      "source": 534,
-      "target": 523
+      "source": 616,
+      "target": 607
+    },
+    {
+      "annotations": {
+        "Anatomy": {
+          "hippocampal formation": true
+        },
+        "Confidence": {
+          "Medium": true
+        },
+        "Disease": {
+          "Alzheimer's disease": true
+        },
+        "Method": {
+          "Chromatography, Immunoaffinity": true,
+          "Fluorescence Microscopy, Confocal": true,
+          "Immunohistochemistry": true,
+          "Liquid Chromatography": true,
+          "Mass Spectrometry": true
+        },
+        "Tau_State": {
+          "Paired Helical Filament": true
+        },
+        "Tau_Structure": {
+          "microtubule-binding region": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Davies P",
+          "Funk KE",
+          "Kuret J",
+          "Liao Z",
+          "Thomas SN",
+          "Wan Y",
+          "Yang AJ"
+        ],
+        "date": "2012-01-01",
+        "first": "Thomas SN",
+        "last": "Yang AJ",
+        "name": "Acta neuropathologica",
+        "pages": "105-17",
+        "reference": "22033876",
+        "title": "Dual modification of Alzheimer's disease PHF-tau protein by lysine methylation and ubiquitylation: a mass spectrometry approach.",
+        "type": "PubMed",
+        "volume": "123"
+      },
+      "evidence": "However, robust monomethylation was identified at seven sites distributed throughout the tau sequence (Table 1). Three of the sites (K163, K174, and K180) reside within the proline-rich region of the tau N-terminal projection domain, which mediates interactions with microtubule-associated proteins such as actin [27] and the Src homology three domain of plasma membrane-associated proteins including Src family kinases [37] and  phospholipase Cγ [54]. In contrast, K254, K267, and K290 are part of the first and second repeats of the microtubule binding domain. Although no Lys acetylation was detected at these sites in our datasets, it was possible to quantify relative methylation and ubiquitylation of K254.",
+      "key": "408d7e529cae149fa1440f8b32d827bdb4d682aeed7492c1fe4239e8b98e40e56904fb8c8dfb71d9f05f843fbd82743a54d204c2593a9d1efe78457631c76107",
+      "line": 337,
+      "relation": "partOf",
+      "source": 616,
+      "target": 445
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "Method": {
           "CD Spectroscopy": true,
           "Liquid Chromatography": true,
@@ -11282,8 +13581,11 @@
           "Tau aggregation assay": true,
           "Tubulin polymerization assay, light scattering method": true
         },
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         "Tau_Structure": {
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+          "microtubule-binding region": true
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       "citation": {
@@ -11308,14 +13610,17 @@
         "volume": "462"
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       "evidence": "An example of a spectrum identifying K311 as a site of dimethylation at 2.2 ppm mass accuracy is shown in Fig. 2B. This residue was reported as a possible methylation site in AD-brain derived tau protein on the basis of Edman degradation years ago [36]. It resides within the “PHF6” motif of the MTBR, which has been reported to mediate the aggregation propensity of recombinant monomeric tau in vitro [6, 37]. Other methylation sites within the MTBR include K259, K290, and K353, each of which lies in a KXGS motif associated with AMP-activated protein kinase mediated regulation of microtubule binding [38]. Within the N-terminal projection domain, Lys methylation was detected at K24, K44, K67, and K190 (Fig. 1).",
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-      "relation": "association",
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+      "line": 283,
+      "relation": "regulates",
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+      "target": 246
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     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
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         "Method": {
           "CD Spectroscopy": true,
           "Liquid Chromatography": true,
@@ -11346,14 +13651,20 @@
         "volume": "462"
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       "evidence": "An example of a spectrum identifying K311 as a site of dimethylation at 2.2 ppm mass accuracy is shown in Fig. 2B. This residue was reported as a possible methylation site in AD-brain derived tau protein on the basis of Edman degradation years ago [36]. It resides within the “PHF6” motif of the MTBR, which has been reported to mediate the aggregation propensity of recombinant monomeric tau in vitro [6, 37]. Other methylation sites within the MTBR include K259, K290, and K353, each of which lies in a KXGS motif associated with AMP-activated protein kinase mediated regulation of microtubule binding [38]. Within the N-terminal projection domain, Lys methylation was detected at K24, K44, K67, and K190 (Fig. 1).",
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       "relation": "isA",
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-      "target": 523
+      "source": 618,
+      "target": 607
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "Method": {
           "CD Spectroscopy": true,
           "Liquid Chromatography": true,
@@ -11361,8 +13672,11 @@
           "Tau aggregation assay": true,
           "Tubulin polymerization assay, light scattering method": true
         },
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+        },
         "Tau_Structure": {
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+          "microtubule-binding region": true
         }
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       "citation": {
@@ -11387,20 +13701,29 @@
         "volume": "462"
       },
       "evidence": "An example of a spectrum identifying K311 as a site of dimethylation at 2.2 ppm mass accuracy is shown in Fig. 2B. This residue was reported as a possible methylation site in AD-brain derived tau protein on the basis of Edman degradation years ago [36]. It resides within the “PHF6” motif of the MTBR, which has been reported to mediate the aggregation propensity of recombinant monomeric tau in vitro [6, 37]. Other methylation sites within the MTBR include K259, K290, and K353, each of which lies in a KXGS motif associated with AMP-activated protein kinase mediated regulation of microtubule binding [38]. Within the N-terminal projection domain, Lys methylation was detected at K24, K44, K67, and K190 (Fig. 1).",
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-      "relation": "association",
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+      "target": 246
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "Method": {
           "CD Spectroscopy": true,
           "Liquid Chromatography": true,
           "Mass Spectrometry": true,
           "Tau aggregation assay": true,
           "Tubulin polymerization assay, light scattering method": true
+        },
+        "Tau_Structure": {
+          "projection domain": true
         }
       },
       "citation": {
@@ -11425,14 +13748,17 @@
         "volume": "462"
       },
       "evidence": "An example of a spectrum identifying K311 as a site of dimethylation at 2.2 ppm mass accuracy is shown in Fig. 2B. This residue was reported as a possible methylation site in AD-brain derived tau protein on the basis of Edman degradation years ago [36]. It resides within the “PHF6” motif of the MTBR, which has been reported to mediate the aggregation propensity of recombinant monomeric tau in vitro [6, 37]. Other methylation sites within the MTBR include K259, K290, and K353, each of which lies in a KXGS motif associated with AMP-activated protein kinase mediated regulation of microtubule binding [38]. Within the N-terminal projection domain, Lys methylation was detected at K24, K44, K67, and K190 (Fig. 1).",
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+      "relation": "association",
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+      "target": 567
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     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
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         "Method": {
           "CD Spectroscopy": true,
           "Liquid Chromatography": true,
@@ -11462,159 +13788,27 @@
         "type": "PubMed",
         "volume": "462"
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-          "Bažadona D",
-          "Buée L",
-          "Delalle I",
-          "Di Giovanni G",
-          "Harrington C",
-          "Hof PR",
-          "Jovanov-Milošević N",
-          "Wischik C",
-          "Wray S",
-          "de Silva R",
-          "Šimić G"
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-        "date": "2016-01-06",
-        "first": "Šimić G",
-        "last": "Hof PR",
-        "name": "Biomolecules",
-        "pages": "6",
-        "reference": "26751493",
-        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
-        "type": "PubMed",
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-      "evidence": "The most recent data obtained indicate that tau pathology indeed may be induced and propagated after the injection of tau oligomers or aggregates in either wild-type or mutated MAPT transgenic mice [164], and that tau aggregates can be transferred from cell to cell in vitro [164,165] and in vivo [166,167].",
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-            "name": "Neurons",
-            "namespace": "MESH"
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-        },
-        "modifier": "Translocation"
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-    {
-      "citation": {
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-          "Bažadona D",
-          "Buée L",
-          "Delalle I",
-          "Di Giovanni G",
-          "Harrington C",
-          "Hof PR",
-          "Jovanov-Milošević N",
-          "Wischik C",
-          "Wray S",
-          "de Silva R",
-          "Šimić G"
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-        "date": "2016-01-06",
-        "first": "Šimić G",
-        "last": "Hof PR",
-        "name": "Biomolecules",
-        "pages": "6",
-        "reference": "26751493",
-        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
-        "type": "PubMed",
-        "volume": "6"
-      },
-      "evidence": "The most recent data obtained indicate that tau pathology indeed may be induced and propagated after the injection of tau oligomers or aggregates in either wild-type or mutated MAPT transgenic mice [164], and that tau aggregates can be transferred from cell to cell in vitro [164,165] and in vivo [166,167].",
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-          },
-          "toLoc": {
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-        "Species": {
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-          "Campbell SN",
-          "Masliah E",
-          "Monte L",
-          "Rice KC",
-          "Rissman RA",
-          "Roe AD",
-          "Taché Y",
-          "Zhang C"
-        ],
-        "date": "2015-01-01",
-        "first": "Campbell SN",
-        "last": "Rissman RA",
-        "name": "Journal of Alzheimer's disease : JAD",
-        "pages": "967-76",
-        "reference": "25125464",
-        "title": "Increased tau phosphorylation and aggregation in the hippocampus of mice overexpressing corticotropin-releasing factor.",
-        "type": "PubMed",
-        "volume": "43"
-      },
-      "evidence": "CRF-OE mice had significantly elevated tau-P compared to wild type (WT) mice at the AT8 (S202/T204), PHF-1 (S396/404), S262, and S422 sites. Treating CRF-OE mice with R121919 blocked phosphorylation at the AT8 (S202/T204) and PHF-1 (S396/404) sites, but not at the S262 and S422 sites and reduced phosphorylation of c-Jun N Terminal Kinase (JNK).",
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-      "line": 2421,
-      "relation": "positiveCorrelation",
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+      "evidence": "An example of a spectrum identifying K311 as a site of dimethylation at 2.2 ppm mass accuracy is shown in Fig. 2B. This residue was reported as a possible methylation site in AD-brain derived tau protein on the basis of Edman degradation years ago [36]. It resides within the “PHF6” motif of the MTBR, which has been reported to mediate the aggregation propensity of recombinant monomeric tau in vitro [6, 37]. Other methylation sites within the MTBR include K259, K290, and K353, each of which lies in a KXGS motif associated with AMP-activated protein kinase mediated regulation of microtubule binding [38]. Within the N-terminal projection domain, Lys methylation was detected at K24, K44, K67, and K190 (Fig. 1).",
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     {
       "annotations": {
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-          "hippocampal formation": true
+        "Confidence": {
+          "Medium": true
         },
-        "Disease": {
-          "Alzheimer's disease": true
+        "MeSHAnatomy": {
+          "Brain": true
         },
         "Method": {
-          "Chromatography, Immunoaffinity": true,
-          "Fluorescence Microscopy, Confocal": true,
-          "Immunohistochemistry": true,
+          "CD Spectroscopy": true,
           "Liquid Chromatography": true,
-          "Mass Spectrometry": true
-        },
-        "Tau_State": {
-          "Paired Helical Filament": true
+          "Mass Spectrometry": true,
+          "Tau aggregation assay": true,
+          "Tubulin polymerization assay, light scattering method": true
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         "Tau_Structure": {
           "projection domain": true
@@ -11622,97 +13816,87 @@
       },
       "citation": {
         "authors": [
-          "Davies P",
+          "Clark DJ",
+          "Cooper GL",
           "Funk KE",
           "Kuret J",
           "Liao Z",
+          "Schafer KN",
           "Thomas SN",
-          "Wan Y",
           "Yang AJ"
         ],
-        "date": "2012-01-01",
-        "first": "Thomas SN",
-        "last": "Yang AJ",
-        "name": "Acta neuropathologica",
-        "pages": "105-17",
-        "reference": "22033876",
-        "title": "Dual modification of Alzheimer's disease PHF-tau protein by lysine methylation and ubiquitylation: a mass spectrometry approach.",
+        "date": "2014-08-15",
+        "first": "Funk KE",
+        "last": "Kuret J",
+        "name": "The Biochemical journal",
+        "pages": "77-88",
+        "reference": "24869773",
+        "title": "Lysine methylation is an endogenous post-translational modification of tau protein in human brain and a modulator of aggregation propensity.",
         "type": "PubMed",
-        "volume": "123"
+        "volume": "462"
       },
-      "evidence": "However, robust monomethylation was identified at seven sites distributed throughout the tau sequence (Table 1). Three of the sites (K163, K174, and K180) reside within the proline-rich region of the tau N-terminal projection domain, which mediates interactions with microtubule-associated proteins such as actin [27] and the Src homology three domain of plasma membrane-associated proteins including Src family kinases [37] and phospholipase Cc [54]. In contrast, K254, K267, and K290 are part of the first and second repeats of the microtubule binding domain. Although no Lys acetylation was detected at these sites in our datasets, it was possible to quantify relative methylation and ubiquitylation of K254.",
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-      "line": 289,
+      "evidence": "An example of a spectrum identifying K311 as a site of dimethylation at 2.2 ppm mass accuracy is shown in Fig. 2B. This residue was reported as a possible methylation site in AD-brain derived tau protein on the basis of Edman degradation years ago [36]. It resides within the “PHF6” motif of the MTBR, which has been reported to mediate the aggregation propensity of recombinant monomeric tau in vitro [6, 37]. Other methylation sites within the MTBR include K259, K290, and K353, each of which lies in a KXGS motif associated with AMP-activated protein kinase mediated regulation of microtubule binding [38]. Within the N-terminal projection domain, Lys methylation was detected at K24, K44, K67, and K190 (Fig. 1).",
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       "relation": "association",
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     {
       "annotations": {
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-          "hippocampal formation": true
-        },
-        "Disease": {
-          "Alzheimer's disease": true
+        "Confidence": {
+          "Medium": true
         },
         "Method": {
-          "Chromatography, Immunoaffinity": true,
-          "Fluorescence Microscopy, Confocal": true,
-          "Immunohistochemistry": true,
+          "CD Spectroscopy": true,
           "Liquid Chromatography": true,
-          "Mass Spectrometry": true
-        },
-        "Tau_State": {
-          "Paired Helical Filament": true
-        },
-        "Tau_Structure": {
-          "projection domain": true
+          "Mass Spectrometry": true,
+          "Tau aggregation assay": true,
+          "Tubulin polymerization assay, light scattering method": true
         }
       },
       "citation": {
         "authors": [
-          "Davies P",
+          "Clark DJ",
+          "Cooper GL",
           "Funk KE",
           "Kuret J",
           "Liao Z",
+          "Schafer KN",
           "Thomas SN",
-          "Wan Y",
           "Yang AJ"
         ],
-        "date": "2012-01-01",
-        "first": "Thomas SN",
-        "last": "Yang AJ",
-        "name": "Acta neuropathologica",
-        "pages": "105-17",
-        "reference": "22033876",
-        "title": "Dual modification of Alzheimer's disease PHF-tau protein by lysine methylation and ubiquitylation: a mass spectrometry approach.",
+        "date": "2014-08-15",
+        "first": "Funk KE",
+        "last": "Kuret J",
+        "name": "The Biochemical journal",
+        "pages": "77-88",
+        "reference": "24869773",
+        "title": "Lysine methylation is an endogenous post-translational modification of tau protein in human brain and a modulator of aggregation propensity.",
         "type": "PubMed",
-        "volume": "123"
+        "volume": "462"
       },
-      "evidence": "However, robust monomethylation was identified at seven sites distributed throughout the tau sequence (Table 1). Three of the sites (K163, K174, and K180) reside within the proline-rich region of the tau N-terminal projection domain, which mediates interactions with microtubule-associated proteins such as actin [27] and the Src homology three domain of plasma membrane-associated proteins including Src family kinases [37] and phospholipase Cc [54]. In contrast, K254, K267, and K290 are part of the first and second repeats of the microtubule binding domain. Although no Lys acetylation was detected at these sites in our datasets, it was possible to quantify relative methylation and ubiquitylation of K254.",
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-      "relation": "partOf",
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+      "evidence": "An example of a spectrum identifying K311 as a site of dimethylation at 2.2 ppm mass accuracy is shown in Fig. 2B. This residue was reported as a possible methylation site in AD-brain derived tau protein on the basis of Edman degradation years ago [36]. It resides within the “PHF6” motif of the MTBR, which has been reported to mediate the aggregation propensity of recombinant monomeric tau in vitro [6, 37]. Other methylation sites within the MTBR include K259, K290, and K353, each of which lies in a KXGS motif associated with AMP-activated protein kinase mediated regulation of microtubule binding [38]. Within the N-terminal projection domain, Lys methylation was detected at K24, K44, K67, and K190 (Fig. 1).",
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     {
       "annotations": {
-        "Anatomy": {
-          "hippocampal formation": true
+        "Confidence": {
+          "Medium": true
         },
-        "Disease": {
-          "Alzheimer's disease": true
+        "MeSHAnatomy": {
+          "Brain": true
         },
         "Method": {
-          "Chromatography, Immunoaffinity": true,
-          "Fluorescence Microscopy, Confocal": true,
-          "Immunohistochemistry": true,
+          "CD Spectroscopy": true,
           "Liquid Chromatography": true,
-          "Mass Spectrometry": true
-        },
-        "Tau_State": {
-          "Paired Helical Filament": true
+          "Mass Spectrometry": true,
+          "Tau aggregation assay": true,
+          "Tubulin polymerization assay, light scattering method": true
         },
         "Tau_Structure": {
           "projection domain": true
@@ -11720,100 +13904,87 @@
       },
       "citation": {
         "authors": [
-          "Davies P",
+          "Clark DJ",
+          "Cooper GL",
           "Funk KE",
           "Kuret J",
           "Liao Z",
+          "Schafer KN",
           "Thomas SN",
-          "Wan Y",
           "Yang AJ"
         ],
-        "date": "2012-01-01",
-        "first": "Thomas SN",
-        "last": "Yang AJ",
-        "name": "Acta neuropathologica",
-        "pages": "105-17",
-        "reference": "22033876",
-        "title": "Dual modification of Alzheimer's disease PHF-tau protein by lysine methylation and ubiquitylation: a mass spectrometry approach.",
+        "date": "2014-08-15",
+        "first": "Funk KE",
+        "last": "Kuret J",
+        "name": "The Biochemical journal",
+        "pages": "77-88",
+        "reference": "24869773",
+        "title": "Lysine methylation is an endogenous post-translational modification of tau protein in human brain and a modulator of aggregation propensity.",
         "type": "PubMed",
-        "volume": "123"
-      },
-      "evidence": "However, robust monomethylation was identified at seven sites distributed throughout the tau sequence (Table 1). Three of the sites (K163, K174, and K180) reside within the proline-rich region of the tau N-terminal projection domain, which mediates interactions with microtubule-associated proteins such as actin [27] and the Src homology three domain of plasma membrane-associated proteins including Src family kinases [37] and phospholipase Cc [54]. In contrast, K254, K267, and K290 are part of the first and second repeats of the microtubule binding domain. Although no Lys acetylation was detected at these sites in our datasets, it was possible to quantify relative methylation and ubiquitylation of K254.",
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-      "line": 295,
-      "object": {
-        "modifier": "Activity"
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+      "evidence": "First, we verified the colocalization of p-WAVE1 and pCRMP2 with aggregated hyperphosphorylated tau in the hippocampus at 23 months of age. Biochemical analysis revealed the inclusion of p-WAVE1, p-CRMP2, and tau in the sarkosyl-insoluble fractions of hippocampal homogenates",
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     {
       "annotations": {
-        "Anatomy": {
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-        },
-        "Disease": {
-          "Alzheimer's disease": true
-        },
-        "Method": {
-          "Chromatography, Immunoaffinity": true,
-          "Fluorescence Microscopy, Confocal": true,
-          "Immunohistochemistry": true,
-          "Liquid Chromatography": true,
-          "Mass Spectrometry": true
-        },
-        "Tau_State": {
-          "Paired Helical Filament": true
-        },
-        "Tau_Structure": {
-          "microtubule-binding region": true
+        "Confidence": {
+          "Medium": true
         }
       },
       "citation": {
         "authors": [
-          "Davies P",
-          "Funk KE",
-          "Kuret J",
-          "Liao Z",
-          "Thomas SN",
-          "Wan Y",
-          "Yang AJ"
+          "Babić Leko M",
+          "Bažadona D",
+          "Buée L",
+          "Delalle I",
+          "Di Giovanni G",
+          "Harrington C",
+          "Hof PR",
+          "Jovanov-Milošević N",
+          "Wischik C",
+          "Wray S",
+          "de Silva R",
+          "Šimić G"
         ],
-        "date": "2012-01-01",
-        "first": "Thomas SN",
-        "last": "Yang AJ",
-        "name": "Acta neuropathologica",
-        "pages": "105-17",
-        "reference": "22033876",
-        "title": "Dual modification of Alzheimer's disease PHF-tau protein by lysine methylation and ubiquitylation: a mass spectrometry approach.",
+        "date": "2016-01-06",
+        "first": "Šimić G",
+        "last": "Hof PR",
+        "name": "Biomolecules",
+        "pages": "6",
+        "reference": "26751493",
+        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
         "type": "PubMed",
-        "volume": "123"
+        "volume": "6"
       },
-      "evidence": "However, robust monomethylation was identified at seven sites distributed throughout the tau sequence (Table 1). Three of the sites (K163, K174, and K180) reside within the proline-rich region of the tau N-terminal projection domain, which mediates interactions with microtubule-associated proteins such as actin [27] and the Src homology three domain of plasma membrane-associated proteins including Src family kinases [37] and phospholipase Cc [54]. In contrast, K254, K267, and K290 are part of the first and second repeats of the microtubule binding domain. Although no Lys acetylation was detected at these sites in our datasets, it was possible to quantify relative methylation and ubiquitylation of K254.",
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-      "line": 298,
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+      "evidence": "The most recent data obtained indicate that tau pathology indeed may be induced and propagated after the injection of tau oligomers or aggregates in either wild-type or mutated MAPT transgenic mice [164], and that tau aggregates can be transferred from cell to cell in vitro [164,165] and in vivo [166,167].",
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+            "name": "Neurons",
+            "namespace": "MESH"
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+          "toLoc": {
+            "name": "Neurons",
+            "namespace": "MESH"
+          }
+        },
+        "modifier": "Translocation"
+      },
+      "relation": "positiveCorrelation",
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     {
       "annotations": {
-        "Anatomy": {
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-          "Alzheimer's disease": true
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-          "Chromatography, Immunoaffinity": true,
-          "Fluorescence Microscopy, Confocal": true,
-          "Immunohistochemistry": true,
-          "Liquid Chromatography": true,
-          "Mass Spectrometry": true
-        },
-        "Tau_State": {
-          "Paired Helical Filament": true
-        },
-        "Tau_Structure": {
-          "microtubule-binding region": true
+        "Confidence": {
+          "Medium": true
         }
       },
       "citation": {
         "authors": [
-          "Davies P",
-          "Funk KE",
-          "Kuret J",
-          "Liao Z",
-          "Thomas SN",
-          "Wan Y",
-          "Yang AJ"
+          "Babić Leko M",
+          "Bažadona D",
+          "Buée L",
+          "Delalle I",
+          "Di Giovanni G",
+          "Harrington C",
+          "Hof PR",
+          "Jovanov-Milošević N",
+          "Wischik C",
+          "Wray S",
+          "de Silva R",
+          "Šimić G"
         ],
-        "date": "2012-01-01",
-        "first": "Thomas SN",
-        "last": "Yang AJ",
-        "name": "Acta neuropathologica",
-        "pages": "105-17",
-        "reference": "22033876",
-        "title": "Dual modification of Alzheimer's disease PHF-tau protein by lysine methylation and ubiquitylation: a mass spectrometry approach.",
+        "date": "2016-01-06",
+        "first": "Šimić G",
+        "last": "Hof PR",
+        "name": "Biomolecules",
+        "pages": "6",
+        "reference": "26751493",
+        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
         "type": "PubMed",
-        "volume": "123"
+        "volume": "6"
       },
-      "evidence": "However, robust monomethylation was identified at seven sites distributed throughout the tau sequence (Table 1). Three of the sites (K163, K174, and K180) reside within the proline-rich region of the tau N-terminal projection domain, which mediates interactions with microtubule-associated proteins such as actin [27] and the Src homology three domain of plasma membrane-associated proteins including Src family kinases [37] and phospholipase Cc [54]. In contrast, K254, K267, and K290 are part of the first and second repeats of the microtubule binding domain. Although no Lys acetylation was detected at these sites in our datasets, it was possible to quantify relative methylation and ubiquitylation of K254.",
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-      "line": 302,
-      "relation": "partOf",
-      "source": 529,
-      "target": 362
-    },
-    {
-      "annotations": {
+      "evidence": "The most recent data obtained indicate that tau pathology indeed may be induced and propagated after the injection of tau oligomers or aggregates in either wild-type or mutated MAPT transgenic mice [164], and that tau aggregates can be transferred from cell to cell in vitro [164,165] and in vivo [166,167].",
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+        "effect": {
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+            "name": "Neurons",
+            "namespace": "MESH"
+          },
+          "toLoc": {
+            "name": "Neurons",
+            "namespace": "MESH"
+          }
+        },
+        "modifier": "Translocation"
+      },
+      "target": 116
+    },
+    {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Ait-Ghezala G",
+          "Beaulieu-Abdelahad D",
+          "Crawford F",
+          "Mouzon B",
+          "Mullan M",
+          "Paris D",
+          "Schweig JE",
+          "Yao H"
+        ],
+        "date": "2017-09-06",
+        "first": "Schweig JE",
+        "last": "Paris D",
+        "name": "Acta neuropathologica communications",
+        "pages": "69",
+        "reference": "28877763",
+        "title": "Alzheimer's disease pathological lesions activate the spleen tyrosine kinase.",
+        "type": "PubMed",
+        "volume": "5"
+      },
+      "evidence": "Additionally, we show that Syk overexpression leads to increased tau accumulation and promotes tau hyperphosphorylation at multiple epitopes in human neuron-like SH-SY5Y cells, further supporting a role of Syk in the formation of tau pathogenic species. Collectively, our data show that Syk activation occurs following Aβ deposition and the formation of tau pathological species.",
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+      "relation": "increases",
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+      "target": 795
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+    {
+      "annotations": {
+        "Cell_Line": {
+          "N2a": true,
+          "SH-SY5Y": true
+        },
+        "Confidence": {
+          "Medium": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Fan SJ",
+          "Huang FI",
+          "Liou JP",
+          "Yang CR"
+        ],
+        "date": "2018-05-29",
+        "first": "Fan SJ",
+        "last": "Yang CR",
+        "name": "Cell death &amp; disease",
+        "pages": "655",
+        "reference": "29844403",
+        "title": "The novel histone de acetylase 6 inhibitor, MPT0G211, ameliorates tau phosphorylation and cognitive deficits in an Alzheimer's disease model.",
+        "type": "PubMed",
+        "volume": "9"
+      },
+      "evidence": "This study aimed to investigate the protective effects and mechanism of the novel HDAC6 inhibitor, MPT0G211, using an AD model. Our results indicated that MPT0G211 significantly reduced tau phosphorylation and aggregation, the processes highly correlated with the formation of NFTs. This HDAC6 inhibitory activity resulted in an increase in acetylated Hsp90, which decreased Hsp90 and HDAC6 binding, causing ubiquitination of phosphorylated tau proteins. In addition, a significant increase of phospho-glycogen synthase kinase-3β (phospho-GSK3β) on Ser9 (the inactive form) through Akt phosphorylation was associated with the inhibition of phospho-tau Ser396 in response to MPT0G211 treatment.",
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+      "line": 4203,
+      "relation": "positiveCorrelation",
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+      "target": 94
+    },
+    {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "Method": {
+          "CD Spectroscopy": true,
+          "Liquid Chromatography": true,
+          "Mass Spectrometry": true,
+          "Tau aggregation assay": true,
+          "Tubulin polymerization assay, light scattering method": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Clark DJ",
+          "Cooper GL",
+          "Funk KE",
+          "Kuret J",
+          "Liao Z",
+          "Schafer KN",
+          "Thomas SN",
+          "Yang AJ"
+        ],
+        "date": "2014-08-15",
+        "first": "Funk KE",
+        "last": "Kuret J",
+        "name": "The Biochemical journal",
+        "pages": "77-88",
+        "reference": "24869773",
+        "title": "Lysine methylation is an endogenous post-translational modification of tau protein in human brain and a modulator of aggregation propensity.",
+        "type": "PubMed",
+        "volume": "462"
+      },
+      "evidence": "These data indicate that Lys methylation depressed the intrinsic aggregation propensity of tau, and did so in part by increasing the concentration of tau needed to support fibril formation.",
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+      "line": 308,
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+        "Confidence": {
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+        }
+      },
+      "citation": {
+        "authors": [
+          "Cowburn RF",
+          "Dahllund L",
+          "Gustafsson E",
+          "Lund H",
+          "Malinowsky D",
+          "Strömberg K",
+          "Sunnemark D",
+          "Svensson A"
+        ],
+        "date": "2013-07-01",
+        "first": "Lund H",
+        "last": "Sunnemark D",
+        "name": "Brain pathology (Zurich, Switzerland)",
+        "pages": "378-89",
+        "reference": "23088643",
+        "title": "Tau-tubulin kinase 1 expression, phosphorylation and co-localization with phospho-Ser422 tau in the Alzheimer's disease brain.",
+        "type": "PubMed",
+        "volume": "23"
+      },
+      "evidence": "These data suggest a role for TTBK1 in pre-tangle formation prior to the formation of fibrillar tau and strengthen the idea that tau is phosphorylated at Ser422 at an early intermediate stage in NFT formation.",
+      "key": "a72cc199e7c8ac6ec9bfc68ee0c69c8e423a616796e286ea37860a9edb3d0e70374c11b633d9f51952ae4bc0b8f07b680ab06aa2edea5981027600fd9de84087",
+      "line": 1569,
+      "relation": "association",
+      "source": 117,
+      "target": 824
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+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Cowburn RF",
+          "Dahllund L",
+          "Gustafsson E",
+          "Lund H",
+          "Malinowsky D",
+          "Strömberg K",
+          "Sunnemark D",
+          "Svensson A"
+        ],
+        "date": "2013-07-01",
+        "first": "Lund H",
+        "last": "Sunnemark D",
+        "name": "Brain pathology (Zurich, Switzerland)",
+        "pages": "378-89",
+        "reference": "23088643",
+        "title": "Tau-tubulin kinase 1 expression, phosphorylation and co-localization with phospho-Ser422 tau in the Alzheimer's disease brain.",
+        "type": "PubMed",
+        "volume": "23"
+      },
+      "evidence": "These data suggest a role for TTBK1 in pre-tangle formation prior to the formation of fibrillar tau and strengthen the idea that tau is phosphorylated at Ser422 at an early intermediate stage in NFT formation.",
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+      "line": 1570,
+      "relation": "increases",
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+    {
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         "Anatomy": {
           "hippocampal formation": true
         },
+        "Confidence": {
+          "Medium": true
+        },
         "Disease": {
           "Alzheimer's disease": true
         },
@@ -12211,7 +14519,7 @@
           "Paired Helical Filament": true
         },
         "Tau_Structure": {
-          "microtubule-binding region": true
+          "projection domain": true
         }
       },
       "citation": {
@@ -12234,45 +14542,73 @@
         "type": "PubMed",
         "volume": "123"
       },
-      "evidence": "However, robust monomethylation was identified at seven sites distributed throughout the tau sequence (Table 1). Three of the sites (K163, K174, and K180) reside within the proline-rich region of the tau N-terminal projection domain, which mediates interactions with microtubule-associated proteins such as actin [27] and the Src homology three domain of plasma membrane-associated proteins including Src family kinases [37] and phospholipase Cc [54]. In contrast, K254, K267, and K290 are part of the first and second repeats of the microtubule binding domain. Although no Lys acetylation was detected at these sites in our datasets, it was possible to quantify relative methylation and ubiquitylation of K254.",
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-      "line": 299,
-      "relation": "association",
-      "source": 595,
-      "target": 486
+      "evidence": "However, robust monomethylation was identified at seven sites distributed throughout the tau sequence (Table 1). Three of the sites (K163, K174, and K180) reside within the proline-rich region of the tau N-terminal projection domain, which mediates interactions with microtubule-associated proteins such as actin [27] and the Src homology three domain of plasma membrane-associated proteins including Src family kinases [37] and  phospholipase Cγ [54]. In contrast, K254, K267, and K290 are part of the first and second repeats of the microtubule binding domain. Although no Lys acetylation was detected at these sites in our datasets, it was possible to quantify relative methylation and ubiquitylation of K254.",
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+      "line": 326,
+      "relation": "partOf",
+      "source": 608,
+      "target": 441
     },
     {
+      "annotations": {
+        "Anatomy": {
+          "hippocampal formation": true
+        },
+        "Confidence": {
+          "Medium": true
+        },
+        "Disease": {
+          "Alzheimer's disease": true
+        },
+        "Method": {
+          "Chromatography, Immunoaffinity": true,
+          "Fluorescence Microscopy, Confocal": true,
+          "Immunohistochemistry": true,
+          "Liquid Chromatography": true,
+          "Mass Spectrometry": true
+        },
+        "Tau_State": {
+          "Paired Helical Filament": true
+        },
+        "Tau_Structure": {
+          "projection domain": true
+        }
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       "citation": {
         "authors": [
-          "Hasegawa M",
-          "Ihara Y",
-          "Morishima-Kawashima M",
-          "Suzuki M",
-          "Takio K",
-          "Titani K"
+          "Davies P",
+          "Funk KE",
+          "Kuret J",
+          "Liao Z",
+          "Thomas SN",
+          "Wan Y",
+          "Yang AJ"
         ],
-        "date": "1993-06-01",
-        "first": "Morishima-Kawashima M",
-        "last": "Ihara Y",
-        "name": "Neuron",
-        "pages": "1151-60",
-        "reference": "8391280",
-        "title": "Ubiquitin is conjugated with amino-terminally processed tau in paired helical filaments.",
+        "date": "2012-01-01",
+        "first": "Thomas SN",
+        "last": "Yang AJ",
+        "name": "Acta neuropathologica",
+        "pages": "105-17",
+        "reference": "22033876",
+        "title": "Dual modification of Alzheimer's disease PHF-tau protein by lysine methylation and ubiquitylation: a mass spectrometry approach.",
         "type": "PubMed",
-        "volume": "10"
+        "volume": "123"
       },
-      "evidence": "Ubiquitination occurs at lysines (K254, K257 K311) in repeat domain; participates in triage process",
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-      "line": 3510,
-      "relation": "positiveCorrelation",
-      "source": 595,
-      "target": 131
+      "evidence": "However, robust monomethylation was identified at seven sites distributed throughout the tau sequence (Table 1). Three of the sites (K163, K174, and K180) reside within the proline-rich region of the tau N-terminal projection domain, which mediates interactions with microtubule-associated proteins such as actin [27] and the Src homology three domain of plasma membrane-associated proteins including Src family kinases [37] and  phospholipase Cγ [54]. In contrast, K254, K267, and K290 are part of the first and second repeats of the microtubule binding domain. Although no Lys acetylation was detected at these sites in our datasets, it was possible to quantify relative methylation and ubiquitylation of K254.",
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+      "relation": "regulates",
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+      "target": 252
     },
     {
       "annotations": {
         "Anatomy": {
           "hippocampal formation": true
         },
+        "Confidence": {
+          "Medium": true
+        },
         "Disease": {
           "Alzheimer's disease": true
         },
@@ -12287,7 +14623,7 @@
           "Paired Helical Filament": true
         },
         "Tau_Structure": {
-          "microtubule-binding region": true
+          "projection domain": true
         }
       },
       "citation": {
@@ -12310,18 +14646,277 @@
         "type": "PubMed",
         "volume": "123"
       },
-      "evidence": "However, robust monomethylation was identified at seven sites distributed throughout the tau sequence (Table 1). Three of the sites (K163, K174, and K180) reside within the proline-rich region of the tau N-terminal projection domain, which mediates interactions with microtubule-associated proteins such as actin [27] and the Src homology three domain of plasma membrane-associated proteins including Src family kinases [37] and phospholipase Cc [54]. In contrast, K254, K267, and K290 are part of the first and second repeats of the microtubule binding domain. Although no Lys acetylation was detected at these sites in our datasets, it was possible to quantify relative methylation and ubiquitylation of K254.",
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-      "relation": "association",
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-      "target": 486
+      "evidence": "However, robust monomethylation was identified at seven sites distributed throughout the tau sequence (Table 1). Three of the sites (K163, K174, and K180) reside within the proline-rich region of the tau N-terminal projection domain, which mediates interactions with microtubule-associated proteins such as actin [27] and the Src homology three domain of plasma membrane-associated proteins including Src family kinases [37] and  phospholipase Cγ [54]. In contrast, K254, K267, and K290 are part of the first and second repeats of the microtubule binding domain. Although no Lys acetylation was detected at these sites in our datasets, it was possible to quantify relative methylation and ubiquitylation of K254.",
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+      "relation": "regulates",
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+    },
+    {
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+          "hippocampal formation": true
+        },
+        "Confidence": {
+          "Medium": true
+        },
+        "Disease": {
+          "Alzheimer's disease": true
+        },
+        "Method": {
+          "Chromatography, Immunoaffinity": true,
+          "Fluorescence Microscopy, Confocal": true,
+          "Immunohistochemistry": true,
+          "Liquid Chromatography": true,
+          "Mass Spectrometry": true
+        },
+        "Tau_State": {
+          "Paired Helical Filament": true
+        },
+        "Tau_Structure": {
+          "projection domain": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Davies P",
+          "Funk KE",
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       "evidence": "Western blot analyses showed a decrease of methyl-PP2A and an increase of demethyl-PP2A with a concomitant reduction in the methyl/demethyl PP2A ratio in both PSP (74%) and AD (76%) brains, associated with an LCMT-1 decrease and a demethylating enzyme increase, protein phosphatase methylesterase (PME-1), in both diseases.",
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@@ -12532,29 +15204,34 @@
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-          "Posey K",
-          "Schneider R",
-          "Schweiger S",
-          "Weber S"
-        ],
-        "date": "2017-10-23",
-        "first": "Schweiger S",
-        "last": "Krauß S",
-        "name": "Scientific reports",
-        "pages": "13753",
-        "reference": "29062069",
-        "title": "Resveratrol induces dephosphorylation of Tau by interfering with the MID1-PP2A complex.",
-        "type": "PubMed",
-        "volume": "7"
-      },
-      "evidence": "Here we show that resveratrol treatment directly interferes with the MID1-α4-PP2A degradation complex by reducing MID1 protein expression in vitro and in vivo. This leads to an increase of microtubule-associated PP2A activity and a time- and dose-dependent dephosphorylation of Tau. Interestingly, we further show that MID1 expression is elevated in AD tissue.",
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     {
-      "citation": {
-        "authors": [
-          "Asada A",
-          "Hasegawa M",
-          "Hisanaga S",
-          "Ishiguro K",
-          "Kimura T",
-          "Oikawa T",
-          "Saito T",
-          "Uchida C",
-          "Uchida T",
-          "Yotsumoto K"
-        ],
-        "date": "2009-06-19",
-        "first": "Yotsumoto K",
-        "last": "Hisanaga S",
-        "name": "The Journal of biological chemistry",
-        "pages": "16840-7",
-        "reference": "19401603",
-        "title": "Effect of Pin1 or microtubule binding on dephosphorylation of FTDP-17 mutant Tau.",
-        "type": "PubMed",
-        "volume": "284"
-      },
-      "evidence": "Pin1 is indicated to facilitate Tau dephosphorylation via PP2A by binding to the phospho-Thr-231-Pro or phospho-Thr-212-Pro site",
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-      "relation": "positiveCorrelation",
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       },
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-    {
       "citation": {
         "authors": [
           "Asada A",
@@ -12685,15 +15296,20 @@
       },
       "evidence": "Pin1 is indicated to facilitate Tau dephosphorylation via PP2A by binding to the phospho-Thr-231-Pro or phospho-Thr-212-Pro site",
       "key": "e89e56af73894bcc51cae512775388697aa640ee7d1342856cb3e68aa7a58aed4070f2dcf45174bababd6f2b4b8a32095d9aa9f3dfcf2c405b694528ab80708f",
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       "subject": {
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       },
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     {
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       "citation": {
         "authors": [
           "Asada A",
@@ -12719,22 +15335,28 @@
       },
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     {
       "annotations": {
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           "N2a": true
         },
+        "Confidence": {
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+        },
         "Disease": {
           "Alzheimer's disease": true
         },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "Method": {
           "Western Blot": true
         }
@@ -12755,17 +15377,22 @@
         "type": "PubMed",
         "volume": "288"
       },
-      "evidence": "Notably, methylation of PP2A catalytic C subunit on the Leu- 309 residue by leucine carboxyl methyltransferase 1 (LCMT1) promotes the biogenesis and stabilization of PP2A/B\u0001 enzymes (20). We have shown that decreased LCMT1 activity and/or expression levels correlate with down-regulation of PP2A methylation and PP2A/B\u0001 expression levels and with concomitant accumulation of phospho-Tau in AD-affected brain regions (21), in cultured N2a neuroblastoma cells and in vivo",
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+      "evidence": "Notably, methylation of PP2A catalytic C subunit on the Leu- 309 residue by leucine carboxyl methyltransferase 1 (LCMT1) promotes the biogenesis and stabilization of PP2A/B  enzymes (20). We have shown that decreased LCMT1 activity and/or expression levels correlate with down-regulation of PP2A methylation and PP2A/Bα expression levels and with concomitant accumulation of phospho-Tau in AD-affected brain regions (21), in cultured N2a neuroblastoma cells and in vivo",
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     {
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+      },
       "citation": {
         "authors": [
           "Hashimoto Y",
@@ -12785,20 +15412,25 @@
         "volume": "291"
       },
       "evidence": "Overexpression of UNC5B induces neuronal death by activating death-associated protein kinase (DAPK1) (19) via protein phosphatase 2A-mediated dephosphorylation of DAPK1 (20).",
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           "namespace": "bel"
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       },
-      "target": 740
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     {
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+        }
+      },
       "citation": {
         "authors": [
           "Hashimoto Y",
@@ -12818,36 +15450,48 @@
         "volume": "291"
       },
       "evidence": "Overexpression of UNC5B induces neuronal death by activating death-associated protein kinase (DAPK1) (19) via protein phosphatase 2A-mediated dephosphorylation of DAPK1 (20).",
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           "N2a": true
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+        },
         "Disease": {
           "Alzheimer's disease": true
         },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "Method": {
           "Western Blot": true
         }
@@ -12868,30 +15512,36 @@
         "type": "PubMed",
         "volume": "288"
       },
-      "evidence": "Notably, methylation of PP2A catalytic C subunit on the Leu- 309 residue by leucine carboxyl methyltransferase 1 (LCMT1) promotes the biogenesis and stabilization of PP2A/B\u0001 enzymes (20). We have shown that decreased LCMT1 activity and/or expression levels correlate with down-regulation of PP2A methylation and PP2A/B\u0001 expression levels and with concomitant accumulation of phospho-Tau in AD-affected brain regions (21), in cultured N2a neuroblastoma cells and in vivo",
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     {
       "annotations": {
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         },
+        "Confidence": {
+          "Medium": true
+        },
         "Disease": {
           "Alzheimer's disease": true
         },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "Method": {
           "Western Blot": true
         }
@@ -12912,21 +15562,27 @@
         "type": "PubMed",
         "volume": "288"
       },
-      "evidence": "Notably, methylation of PP2A catalytic C subunit on the Leu- 309 residue by leucine carboxyl methyltransferase 1 (LCMT1) promotes the biogenesis and stabilization of PP2A/B\u0001 enzymes (20). We have shown that decreased LCMT1 activity and/or expression levels correlate with down-regulation of PP2A methylation and PP2A/B\u0001 expression levels and with concomitant accumulation of phospho-Tau in AD-affected brain regions (21), in cultured N2a neuroblastoma cells and in vivo",
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+      "evidence": "Notably, methylation of PP2A catalytic C subunit on the Leu- 309 residue by leucine carboxyl methyltransferase 1 (LCMT1) promotes the biogenesis and stabilization of PP2A/B  enzymes (20). We have shown that decreased LCMT1 activity and/or expression levels correlate with down-regulation of PP2A methylation and PP2A/Bα expression levels and with concomitant accumulation of phospho-Tau in AD-affected brain regions (21), in cultured N2a neuroblastoma cells and in vivo",
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       "annotations": {
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           "N2a": true
         },
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+          "Medium": true
+        },
         "Disease": {
           "Alzheimer's disease": true
         },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "Method": {
           "Western Blot": true
         }
@@ -12947,14 +15603,22 @@
         "type": "PubMed",
         "volume": "288"
       },
-      "evidence": "Notably, methylation of PP2A catalytic C subunit on the Leu- 309 residue by leucine carboxyl methyltransferase 1 (LCMT1) promotes the biogenesis and stabilization of PP2A/B\u0001 enzymes (20). We have shown that decreased LCMT1 activity and/or expression levels correlate with down-regulation of PP2A methylation and PP2A/B\u0001 expression levels and with concomitant accumulation of phospho-Tau in AD-affected brain regions (21), in cultured N2a neuroblastoma cells and in vivo",
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+      "evidence": "Notably, methylation of PP2A catalytic C subunit on the Leu- 309 residue by leucine carboxyl methyltransferase 1 (LCMT1) promotes the biogenesis and stabilization of PP2A/B  enzymes (20). We have shown that decreased LCMT1 activity and/or expression levels correlate with down-regulation of PP2A methylation and PP2A/Bα expression levels and with concomitant accumulation of phospho-Tau in AD-affected brain regions (21), in cultured N2a neuroblastoma cells and in vivo",
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     {
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+        },
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+          "Brain": true
+        }
+      },
       "citation": {
         "authors": [
           "Gong CX",
@@ -12974,81 +15638,57 @@
       },
       "evidence": "We recently discovered that the human brain tau is also modified by O-GlcNAcylation in addition to phosphorylation and that O-GlcNAcylation modulates phosphorylation of tau inversely (Liu et al.,2004a). We found that fasting induced a time-dependent decrease in tau O-GlcNAcylation and concurrent hyperphosphorylation of tau at most of the phosphorylation sites studied.",
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       "relation": "negativeCorrelation",
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     },
     {
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       "citation": {
         "authors": [
-          "Feng Y",
-          "Jiang J",
-          "Liu XH",
-          "Liu ZC",
-          "Luo HB",
-          "Shu XJ",
-          "Wang JZ",
-          "Wang XC",
-          "Xia YY",
-          "Xiong YS",
-          "Ye K",
-          "Yin G",
-          "Yu G",
-          "Zeng K"
+          "Cho SH",
+          "Cole PA",
+          "Gan L",
+          "Haroutunian V",
+          "Huang EJ",
+          "Masliah E",
+          "Meyers D",
+          "Min SW",
+          "Mukherjee C",
+          "Ott M",
+          "Schroeder S",
+          "Seeley WW",
+          "Shen Y",
+          "Zhou Y"
         ],
-        "date": "2014-11-18",
-        "first": "Luo HB",
-        "last": "Wang JZ",
-        "name": "Proceedings of the National Academy of Sciences of the United States of America",
-        "pages": "16586-91",
-        "reference": "25378699",
-        "title": "SUMOylation at K340 inhibits tau degradation through deregulating its phosphorylation and ubiquitination.",
+        "date": "2010-09-23",
+        "first": "Min SW",
+        "last": "Gan L",
+        "name": "Neuron",
+        "pages": "953-66",
+        "reference": "20869593",
+        "title": "Acetylation of tau inhibits its degradation and contributes to tauopathy.",
         "type": "PubMed",
-        "volume": "111"
+        "volume": "67"
       },
-      "evidence": "Furthermore, the enhanced SUMO-immunoreactivity, costained with the hyperphosphorylated tau, is detected in cerebral cortex of the AD brains, and β-amyloid exposure of rat primary hippocampal neurons induces a dose-dependent SUMOylation of the hyperphosphorylated tau. Our findings suggest that tau SUMOylation reciprocally stimulates its phosphorylation and inhibits the ubiquitination-mediated tau degradation, which provides a new insight into the AD-like tau accumulation.",
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+      "evidence": "Thus, the increase in ac-tau induced by SIRT1 deficiency is accompanied by accumulation of pathogenic p-tau in primary neurons. In mouse brains, deleting SIRT1, which elevated ac-tau, also increased AT8-positive p-tau.",
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-          "Hettich MM",
-          "Kickstein E",
-          "Krauß S",
-          "Matthes F",
-          "Pfurtscheller S",
-          "Posey K",
-          "Schneider R",
-          "Schweiger S",
-          "Weber S"
-        ],
-        "date": "2017-10-23",
-        "first": "Schweiger S",
-        "last": "Krauß S",
-        "name": "Scientific reports",
-        "pages": "13753",
-        "reference": "29062069",
-        "title": "Resveratrol induces dephosphorylation of Tau by interfering with the MID1-PP2A complex.",
-        "type": "PubMed",
-        "volume": "7"
-      },
-      "evidence": "Here we show that resveratrol treatment directly interferes with the MID1-α4-PP2A degradation complex by reducing MID1 protein expression in vitro and in vivo. This leads to an increase of microtubule-associated PP2A activity and a time- and dose-dependent dephosphorylation of Tau. Interestingly, we further show that MID1 expression is elevated in AD tissue.",
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-      "object": {
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       },
-      "relation": "negativeCorrelation",
-      "source": 538,
-      "target": 657
-    },
-    {
       "citation": {
         "authors": [
           "Asada A",
@@ -13073,17 +15713,20 @@
         "volume": "284"
       },
       "evidence": "Taken together, these results indicate that the binding of P-Tau to microtubules suppresses its dephosphorylation.",
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       "relation": "positiveCorrelation",
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     },
     {
       "annotations": {
         "Cell_Line": {
           "SH-SY5Y": true
         },
+        "Confidence": {
+          "High": true
+        },
         "Method": {
           "Confocal Microscopy": true,
           "Western Blot": true
@@ -13110,19 +15753,22 @@
       },
       "evidence": "Incubation of human SH-SY5Y neuroblastoma cells for 2 h with L-dopa induced a dose-dependent decrease in both soluble and insoluble methylated PP2A C subunit levels, and concomitant accumulation of demethylated PP2A enzymes",
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       "subject": {
         "modifier": "Activity"
       },
-      "target": 658
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     },
     {
       "annotations": {
         "Anatomy": {
           "dopaminergic cell groups": true
         },
+        "Confidence": {
+          "Medium": true
+        },
         "Method": {
           "Confocal Microscopy": true,
           "Western Blot": true
@@ -13149,19 +15795,22 @@
       },
       "evidence": "Significantly, we found similar effects in human dopaminergic neurons (Fig. 2F). Treatment of neurons with L-Dopa induced a 40–49% decrease in methylated PP2A and concomitant 168–179% increase in endogenous p-Tau (PHF-1) levels (Fig. 2G).",
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@@ -13186,21 +15835,24 @@
         "type": "PubMed",
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-      "evidence": "Significantly, we found similar effects in human dopaminergic neurons (Fig. 2F). Treatment of neurons with L-Dopa induced a 40–49% decrease in methylated PP2A and concomitant 168–179% increase in endogenous p-Tau (PHF-1) levels (Fig. 2G).",
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+      "evidence": "Folate starvation in the presence of L-dopa resulted in a 200–210% increase in demethylated PP2A levels, and 235–250% increase in p-Tau levels in the dopaminergic neurons, relative to untreated controls maintained in NF medium.",
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@@ -13225,27 +15877,27 @@
         "type": "PubMed",
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+      "evidence": "Significantly, we found similar effects in human dopaminergic neurons (Fig. 2F). Treatment of neurons with L-Dopa induced a 40–49% decrease in methylated PP2A and concomitant 168–179% increase in endogenous p-Tau (PHF-1) levels (Fig. 2G).",
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@@ -13267,21 +15919,66 @@
         "type": "PubMed",
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-      "evidence": "Here, we found that administration of L-dopa led to a significant 5-fold increase in plasma tHcy concentrations, when compared to saline treated mice (Table 1). This L-dopa induced increase in plasma tHcy was significantly greater in mice that had been reared on either low folate (LF) or FD diets (Table 1).",
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+      "evidence": "Significantly, we found similar effects in human dopaminergic neurons (Fig. 2F). Treatment of neurons with L-Dopa induced a 40–49% decrease in methylated PP2A and concomitant 168–179% increase in endogenous p-Tau (PHF-1) levels (Fig. 2G).",
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+        "Method": {
+          "Confocal Microscopy": true,
+          "Western Blot": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Arning E",
+          "Bottiglieri T",
+          "Nunbhakdi-Craig V",
+          "Sontag E",
+          "Sontag JM",
+          "Wasek B"
+        ],
+        "date": "2012-07-04",
+        "first": "Bottiglieri T",
+        "last": "Sontag E",
+        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
+        "pages": "9173-81",
+        "reference": "22764226",
+        "title": "Acute administration of L-DOPA induces changes in methylation metabolites, reduced protein phosphatase 2A methylation, and hyperphosphorylation of Tau protein in mouse brain.",
+        "type": "PubMed",
+        "volume": "32"
+      },
+      "evidence": "Folate starvation in the presence of L-dopa resulted in a 200–210% increase in demethylated PP2A levels, and 235–250% increase in p-Tau levels in the dopaminergic neurons, relative to untreated controls maintained in NF medium.",
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     {
       "annotations": {
         "Anatomy": {
           "blood plasma": true
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         "Method": {
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@@ -13311,18 +16008,21 @@
       },
       "evidence": "Here, we found that administration of L-dopa led to a significant 5-fold increase in plasma tHcy concentrations, when compared to saline treated mice (Table 1). This L-dopa induced increase in plasma tHcy was significantly greater in mice that had been reared on either low folate (LF) or FD diets (Table 1).",
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     {
       "annotations": {
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+        "Confidence": {
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+          "Brain": true
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         "Method": {
           "Confocal Microscopy": true,
@@ -13353,15 +16053,20 @@
       },
       "evidence": "Reductions in PP2A methylation were associated with a concomitant increase in each brain region of p-Tau at the PHF-1 epitope (Fig. 6A,B).",
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       "citation": {
         "authors": [
           "Fan Y",
@@ -13386,19 +16091,58 @@
         "volume": "162"
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       "evidence": "These findings suggest a scenario in which MC-LR-mediated demethylation of PP2Ac is associated with GSK-3β phosphorylation at Ser9 and contributes to dissociation of Bα from PP2Ac, which would result in Bα degradation and disruption of PP2A/Bα-tau interactions, thus promoting tau hyperphosphorylation and paired helical filaments-tau accumulation and, consequently, axonal degeneration and cell death.",
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+      "citation": {
+        "authors": [
+          "Fan Y",
+          "Feng Y",
+          "Li Y",
+          "Qian W",
+          "Wang E",
+          "Wang Y",
+          "Yin H",
+          "Yuan T",
+          "Zhang J",
+          "Zhang Y"
+        ],
+        "date": "2018-04-01",
+        "first": "Zhang Y",
+        "last": "Yuan T",
+        "name": "Toxicological sciences : an official journal of the Society of Toxicology",
+        "pages": "475-487",
+        "reference": "29228318",
+        "title": "Microcystin-Leucine-Arginine Induces Tau Pathology Through Bα Degradation via Protein Phosphatase 2A Demethylation and Associated Glycogen Synthase Kinase-3β Phosphorylation.",
+        "type": "PubMed",
+        "volume": "162"
+      },
+      "evidence": "These findings suggest a scenario in which MC-LR-mediated demethylation of PP2Ac is associated with GSK-3β phosphorylation at Ser9 and contributes to dissociation of Bα from PP2Ac, which would result in Bα degradation and disruption of PP2A/Bα-tau interactions, thus promoting tau hyperphosphorylation and paired helical filaments-tau accumulation and, consequently, axonal degeneration and cell death.",
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     {
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         },
         "Method": {
           "Confocal Microscopy": true,
@@ -13428,40 +16172,52 @@
         "volume": "32"
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       "evidence": "Reductions in PP2A methylation were associated with a concomitant increase in each brain region of p-Tau at the PHF-1 epitope (Fig. 6A,B).",
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       "citation": {
         "authors": [
-          "Lu B",
-          "Malenka R",
-          "Polepalli J",
-          "Rajadas J",
-          "Wagh D",
-          "Yu W"
+          "El-Akkad E",
+          "Gong CX",
+          "Grundke-Iqbal I",
+          "Iqbal K",
+          "Liang Z",
+          "Liu F",
+          "Shi J",
+          "Yin D"
         ],
-        "date": "2012-03-15",
-        "first": "Yu W",
-        "last": "Lu B",
-        "name": "Human molecular genetics",
-        "pages": "1384-90",
-        "reference": "22156579",
-        "title": "A critical role for the PAR-1/MARK-tau axis in mediating the toxic effects of Aβ on synapses and dendritic spines.",
+        "date": "2006-11-13",
+        "first": "Liu F",
+        "last": "Gong CX",
+        "name": "FEBS letters",
+        "pages": "6269-74",
+        "reference": "17078951",
+        "title": "PKA modulates GSK-3beta- and cdk5-catalyzed phosphorylation of tau in site- and kinase-specific manners.",
         "type": "PubMed",
-        "volume": "21"
+        "volume": "580"
       },
-      "evidence": "We first confirmed that expression of an MKI-GFP fusion protein in rat hippocampal neurons effectively attenuated MARK4-mediated phosphorylation of both endogenous tau (Fig. 3A) and transfected human tau at the 12E8 sites (Fig. 3B). Phosphorylation of tau at the PHF-1 site was also reduced by MKI (Fig. 3A). It is possible that the PHF-1 site is also targeted by PAR-1/MARKs in vivo, or that the phosphorylation of tau at the 12E8 sites is a prerequisite for PHF-1 site phosphorylation, as the 12E8 sites were previously shown to be required for tau phosphorylation at other sites",
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+      "evidence": "Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396.",
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       "citation": {
         "authors": [
           "Lu B",
@@ -13482,77 +16238,127 @@
         "volume": "21"
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       "evidence": "We first confirmed that expression of an MKI-GFP fusion protein in rat hippocampal neurons effectively attenuated MARK4-mediated phosphorylation of both endogenous tau (Fig. 3A) and transfected human tau at the 12E8 sites (Fig. 3B). Phosphorylation of tau at the PHF-1 site was also reduced by MKI (Fig. 3A). It is possible that the PHF-1 site is also targeted by PAR-1/MARKs in vivo, or that the phosphorylation of tau at the 12E8 sites is a prerequisite for PHF-1 site phosphorylation, as the 12E8 sites were previously shown to be required for tau phosphorylation at other sites",
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     {
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       "citation": {
         "authors": [
-          "Lu B",
-          "Malenka R",
-          "Polepalli J",
-          "Rajadas J",
-          "Wagh D",
-          "Yu W"
+          "Ait-Ghezala G",
+          "Bachmeier C",
+          "Beaulieu-Abdelahad D",
+          "Crawford F",
+          "Jin C",
+          "Laco G",
+          "Lin Y",
+          "Mullan M",
+          "Paris D"
         ],
-        "date": "2012-03-15",
-        "first": "Yu W",
-        "last": "Lu B",
-        "name": "Human molecular genetics",
-        "pages": "1384-90",
-        "reference": "22156579",
-        "title": "A critical role for the PAR-1/MARK-tau axis in mediating the toxic effects of Aβ on synapses and dendritic spines.",
+        "date": "2014-12-05",
+        "first": "Paris D",
+        "last": "Mullan M",
+        "name": "The Journal of biological chemistry",
+        "pages": "33927-44",
+        "reference": "25331948",
+        "title": "The spleen tyrosine kinase (Syk) regulates Alzheimer amyloid-β production and Tau hyperphosphorylation.",
         "type": "PubMed",
-        "volume": "21"
+        "volume": "289"
       },
-      "evidence": "We first confirmed that expression of an MKI-GFP fusion protein in rat hippocampal neurons effectively attenuated MARK4-mediated phosphorylation of both endogenous tau (Fig. 3A) and transfected human tau at the 12E8 sites (Fig. 3B). Phosphorylation of tau at the PHF-1 site was also reduced by MKI (Fig. 3A). It is possible that the PHF-1 site is also targeted by PAR-1/MARKs in vivo, or that the phosphorylation of tau at the 12E8 sites is a prerequisite for PHF-1 site phosphorylation, as the 12E8 sites were previously shown to be required for tau phosphorylation at other sites",
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-      "relation": "positiveCorrelation",
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+      "evidence": "Western blot analyses of brain homogenates show that (−)-nilvadipine significantly reduces Tau phosphorylation in AT8 (phosphorylated Ser-199/Ser-202/Thr-205) and PHF-1 (phosphorylated Ser-396/Ser-404) epitopes",
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     {
       "annotations": {
         "Anatomy": {
           "hippocampal formation": true
         },
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         "Species": {
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       },
       "citation": {
         "authors": [
-          "Campbell SN",
-          "Masliah E",
-          "Monte L",
-          "Rice KC",
-          "Rissman RA",
-          "Roe AD",
-          "Taché Y",
-          "Zhang C"
+          "Boehm J",
+          "Bourgeois C",
+          "Dudilot A",
+          "Lauzon M",
+          "Leclerc N",
+          "Mondragón-Rodríguez S",
+          "Trillaud-Doppia E"
         ],
-        "date": "2015-01-01",
-        "first": "Campbell SN",
-        "last": "Rissman RA",
+        "date": "2012-09-14",
+        "first": "Mondragón-Rodríguez S",
+        "last": "Boehm J",
+        "name": "The Journal of biological chemistry",
+        "pages": "32040-53",
+        "reference": "22833681",
+        "title": "Interaction of endogenous tau protein with synaptic proteins is regulated by N-methyl-D-aspartate receptor-dependent tau phosphorylation.",
+        "type": "PubMed",
+        "volume": "287"
+      },
+      "evidence": "Hence, LTD-inducing NMDA receptor activation leads to an increase in tau phosphorylation at sites PHF-1, AT180, as well as AT8 and to a reduction at AT100.",
+      "key": "97f6549b80d847e36757d79c25a18dbdc7bb9729388ab4b35df527d6660335cfa8725b30c6fa3a12a927b8b11041ae4934f6a1eb24081fac7f1954c977d4655f",
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+    {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Chai GS",
+          "Chen NN",
+          "Cheng XS",
+          "Duan DX",
+          "Hu Y",
+          "Liu GP",
+          "Luo Y",
+          "Ni ZF",
+          "Wang JZ"
+        ],
+        "date": "2013-01-01",
+        "first": "Duan DX",
+        "last": "Liu GP",
         "name": "Journal of Alzheimer's disease : JAD",
-        "pages": "967-76",
-        "reference": "25125464",
-        "title": "Increased tau phosphorylation and aggregation in the hippocampus of mice overexpressing corticotropin-releasing factor.",
+        "pages": "795-808",
+        "reference": "23948915",
+        "title": "Phosphorylation of tau by death-associated protein kinase 1 antagonizes the kinase-induced cell apoptosis.",
         "type": "PubMed",
-        "volume": "43"
+        "volume": "37"
       },
-      "evidence": "CRF-OE mice had significantly elevated tau-P compared to wild type (WT) mice at the AT8 (S202/T204), PHF-1 (S396/404), S262, and S422 sites. Treating CRF-OE mice with R121919 blocked phosphorylation at the AT8 (S202/T204) and PHF-1 (S396/404) sites, but not at the S262 and S422 sites and reduced phosphorylation of c-Jun N Terminal Kinase (JNK).",
-      "key": "5cc1b45614633d4a0283231ba87aec7b5ac7bb023fa38003dbe00eb15f8bb3b749ca99639ae89ced245c322ecdf629ac420a7dee4b898eb8e382663f839ef718",
-      "line": 2417,
-      "relation": "positiveCorrelation",
-      "source": 116,
-      "target": 780
+      "evidence": "These data suggest that tau hyperphosphorylation at Thr231, Ser262, and Ser396 by DAPK1 renders the cells more resistant to the kinase-induced apoptotic cell death, providing new insights into the tau-involved apoptotic abortion in the course of chronic neurodegeneration.",
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     {
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       "citation": {
         "authors": [
           "Gamblin TC",
@@ -13569,16 +16375,54 @@
         "volume": "48"
       },
       "evidence": "Because S199/S202/T205E, S396/S404E, 6-Phos and 7-Phos all demonstrated an AD-like shift in mobility as a result of phosphorylation-like changes, we conclude that they have the characteristics of hyperphosphorylated tau. These mutants will therefore be referred to as pseudo-hyperphosphorylated tau throughout the manuscript. On the basis of the observations that pseudohyperphosphorylated tau has decreased affinity for microtubules and reduced inducer-initiated rates of nucleation and polymerization, we propose that this combination could be the cause of the increased cytotoxicity of hyperphosphorylated tau in Alzheimer's disease and also explain the potentially beneficial role of tau polymerization and NFT formation.",
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       "relation": "decreases",
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+        "Research_Model": {
+          "rTg4510 mice": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Boehm J",
+          "Bourgeois C",
+          "Dudilot A",
+          "Lauzon M",
+          "Leclerc N",
+          "Mondragón-Rodríguez S",
+          "Trillaud-Doppia E"
+        ],
+        "date": "2012-09-14",
+        "first": "Mondragón-Rodríguez S",
+        "last": "Boehm J",
+        "name": "The Journal of biological chemistry",
+        "pages": "32040-53",
+        "reference": "22833681",
+        "title": "Interaction of endogenous tau protein with synaptic proteins is regulated by N-methyl-D-aspartate receptor-dependent tau phosphorylation.",
+        "type": "PubMed",
+        "volume": "287"
+      },
+      "evidence": "Acute treatment of rTg4510 mice with an O-GlcNAcase inhibitor transiently reduced tau phosphorylation at epitopes implicated in tau pathology. More importantly, long-term inhibitor treatment strongly increased tau O-GlcNAcylation, reduced the number of dystrophic neurons, and protected against the formation of pathological tau species without altering the phosphorylation of non-pathological tau.",
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     {
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+      },
       "citation": {
         "authors": [
           "Carlomagno Y",
@@ -13598,58 +16442,26 @@
         "volume": "6"
       },
       "evidence": "In particular, previous studies have demonstrated that the tau ubiquitin ligase, CHIP, is unable to bind and ubiquitinate tau species phosphorylated by Par-1/MARK2 on the 12E8 epitope (S262/356) [33], a p-tau species that is also resistant to degradation upon treatment with Hsp90 inhibitors [32,33]. Tau phosphorylated at the PHF1 epitope (S396/404) is still susceptible to degradation following Hsp90 inhibition and actually exhibits an enhanced interaction with Hsp90",
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-      "relation": "positiveCorrelation",
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     {
       "annotations": {
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-        }
-      },
-      "citation": {
-        "authors": [
-          "Lu B",
-          "Malenka R",
-          "Polepalli J",
-          "Rajadas J",
-          "Wagh D",
-          "Yu W"
-        ],
-        "date": "2012-03-15",
-        "first": "Yu W",
-        "last": "Lu B",
-        "name": "Human molecular genetics",
-        "pages": "1384-90",
-        "reference": "22156579",
-        "title": "A critical role for the PAR-1/MARK-tau axis in mediating the toxic effects of Aβ on synapses and dendritic spines.",
-        "type": "PubMed",
-        "volume": "21"
-      },
-      "evidence": "Consistent with previous reports (11,34), treatment of rat hippocampal neurons with synthetic Aβ, prepared using a well-characterized procedure that enriches for Aβ oligomers (37), resulted in increased tau phosphorylation at the 12E8 sites (Fig. 2A), suggesting that Aβ treatment had activated MARK kinases. Increased phosphorylation of tau at a site recognized by the PHF-1 phospho-tau antibody was also observed (data not shown).",
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-    {
-      "annotations": {
-        "Anatomy": {
-          "dopaminergic cell groups": true
+        "MeSHAnatomy": {
+          "Brain": true
         },
         "Method": {
           "Confocal Microscopy": true,
           "Western Blot": true
+        },
+        "Species": {
+          "10090": true
         }
       },
       "citation": {
@@ -13671,123 +16483,314 @@
         "type": "PubMed",
         "volume": "32"
       },
-      "evidence": "Folate starvation in the presence of L-dopa resulted in a 200–210% increase in demethylated PP2A levels, and 235–250% increase in p-Tau levels in the dopaminergic neurons, relative to untreated controls maintained in NF medium.",
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-      "line": 345,
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+      "evidence": "Reductions in PP2A methylation were associated with a concomitant increase in each brain region of p-Tau at the PHF-1 epitope (Fig. 6A,B).",
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       "relation": "negativeCorrelation",
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     {
       "annotations": {
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-          "blood plasma": true
-        },
-        "Method": {
-          "Confocal Microscopy": true,
-          "Western Blot": true
-        },
-        "Species": {
-          "10090": true
+        "Confidence": {
+          "Medium": true
         }
       },
       "citation": {
         "authors": [
-          "Arning E",
-          "Bottiglieri T",
-          "Nunbhakdi-Craig V",
-          "Sontag E",
-          "Sontag JM",
-          "Wasek B"
+          "El-Akkad E",
+          "Gong CX",
+          "Grundke-Iqbal I",
+          "Iqbal K",
+          "Liang Z",
+          "Liu F",
+          "Shi J",
+          "Yin D"
         ],
-        "date": "2012-07-04",
-        "first": "Bottiglieri T",
-        "last": "Sontag E",
-        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
-        "pages": "9173-81",
-        "reference": "22764226",
-        "title": "Acute administration of L-DOPA induces changes in methylation metabolites, reduced protein phosphatase 2A methylation, and hyperphosphorylation of Tau protein in mouse brain.",
+        "date": "2006-11-13",
+        "first": "Liu F",
+        "last": "Gong CX",
+        "name": "FEBS letters",
+        "pages": "6269-74",
+        "reference": "17078951",
+        "title": "PKA modulates GSK-3beta- and cdk5-catalyzed phosphorylation of tau in site- and kinase-specific manners.",
         "type": "PubMed",
-        "volume": "32"
-      },
-      "evidence": "Here, we found that administration of L-dopa led to a significant 5-fold increase in plasma tHcy concentrations, when compared to saline treated mice (Table 1). This L-dopa induced increase in plasma tHcy was significantly greater in mice that had been reared on either low folate (LF) or FD diets (Table 1).",
-      "key": "d42208f5668ff03eb225bab48666575daddd846846edec1a0d4984fe9e2771ef60695ce0f38d25d4f120791e74c03798a71cbc781b6f19b33f1e5154f40ced1e",
-      "line": 353,
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+      "evidence": "Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396.",
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     {
       "annotations": {
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-          "blood plasma": true
+        "Confidence": {
+          "High": true
         },
-        "MeSHDisease": {
-          "Alzheimer Disease": true
+        "Enzyme_Acitvity": {
+          "1 U/ml": true
         }
       },
       "citation": {
         "authors": [
-          "Alexopoulos P",
-          "Arbones M",
-          "Badel A",
-          "Camproux AC",
-          "Delabar JM",
-          "Dubois B",
-          "Feraudet-Tarisse C",
-          "Janel N",
-          "Lagarde J",
-          "Lamari F",
-          "Lamourette P",
-          "Paul JL",
-          "Potier MC",
-          "Sarazin M",
-          "Simon S"
+          "Buée-Scherrer V",
+          "Goedert M"
         ],
-        "date": "2017-06-20",
-        "first": "Janel N",
-        "last": "Delabar JM",
-        "name": "Translational psychiatry",
-        "pages": "e1154",
-        "reference": "28632203",
-        "title": "Combined assessment of DYRK1A, BDNF and homocysteine levels as diagnostic marker for Alzheimer's disease.",
+        "date": "2002-03-27",
+        "first": "Buée-Scherrer V",
+        "last": "Goedert M",
+        "name": "FEBS letters",
+        "pages": "151-4",
+        "reference": "11943212",
+        "title": "Phosphorylation of microtubule-associated protein tau by stress-activated protein kinases in intact cells.",
         "type": "PubMed",
-        "volume": "7"
+        "volume": "515"
       },
-      "evidence": "Receiver-operating characteristic curves and logistic regression analyses showed that combined assessment of DYRK1A, BDNF and homocysteine has a sensitivity of 0.952, a specificity of 0.889 and an accuracy of 0.933 in testing for AD. The blood levels of these markers provide a diagnosis assessment profile. Combined assessment of these three markers outperforms most of the previous markers and could become a useful substitute to the current panel of AD biomarkers.",
-      "key": "75a37907739ff948e7e0b40878cc1901c4bd97a15ea0aa1c728651c4fc1801d762538c7783f2289c1cb19b35afe013784364d3727494efcf8a26d98a0f05aaea",
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+      "evidence": "The AD2 epitope, which corresponds to phosphorylated S396 and S404 in tau, was generated most effectively by SAPK3/p38gamma and SAPK4/p38delta",
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       "annotations": {
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-        "Method": {
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-          "Western Blot": true
-        },
-        "Species": {
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         }
       },
       "citation": {
         "authors": [
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-          "Bottiglieri T",
-          "Nunbhakdi-Craig V",
-          "Sontag E",
-          "Sontag JM",
-          "Wasek B"
+          "Lu B",
+          "Malenka R",
+          "Polepalli J",
+          "Rajadas J",
+          "Wagh D",
+          "Yu W"
+        ],
+        "date": "2012-03-15",
+        "first": "Yu W",
+        "last": "Lu B",
+        "name": "Human molecular genetics",
+        "pages": "1384-90",
+        "reference": "22156579",
+        "title": "A critical role for the PAR-1/MARK-tau axis in mediating the toxic effects of Aβ on synapses and dendritic spines.",
+        "type": "PubMed",
+        "volume": "21"
+      },
+      "evidence": "We first confirmed that expression of an MKI-GFP fusion protein in rat hippocampal neurons effectively attenuated MARK4-mediated phosphorylation of both endogenous tau (Fig. 3A) and transfected human tau at the 12E8 sites (Fig. 3B). Phosphorylation of tau at the PHF-1 site was also reduced by MKI (Fig. 3A). It is possible that the PHF-1 site is also targeted by PAR-1/MARKs in vivo, or that the phosphorylation of tau at the 12E8 sites is a prerequisite for PHF-1 site phosphorylation, as the 12E8 sites were previously shown to be required for tau phosphorylation at other sites",
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+      "citation": {
+        "authors": [
+          "Ait-Ghezala G",
+          "Bachmeier C",
+          "Beaulieu-Abdelahad D",
+          "Crawford F",
+          "Jin C",
+          "Laco G",
+          "Lin Y",
+          "Mullan M",
+          "Paris D"
+        ],
+        "date": "2014-12-05",
+        "first": "Paris D",
+        "last": "Mullan M",
+        "name": "The Journal of biological chemistry",
+        "pages": "33927-44",
+        "reference": "25331948",
+        "title": "The spleen tyrosine kinase (Syk) regulates Alzheimer amyloid-β production and Tau hyperphosphorylation.",
+        "type": "PubMed",
+        "volume": "289"
+      },
+      "evidence": "Western blot analyses of brain homogenates show that (−)-nilvadipine significantly reduces Tau phosphorylation in AT8 (phosphorylated Ser-199/Ser-202/Thr-205) and PHF-1 (phosphorylated Ser-396/Ser-404) epitopes",
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+        }
+      },
+      "citation": {
+        "authors": [
+          "Boehm J",
+          "Bourgeois C",
+          "Dudilot A",
+          "Lauzon M",
+          "Leclerc N",
+          "Mondragón-Rodríguez S",
+          "Trillaud-Doppia E"
+        ],
+        "date": "2012-09-14",
+        "first": "Mondragón-Rodríguez S",
+        "last": "Boehm J",
+        "name": "The Journal of biological chemistry",
+        "pages": "32040-53",
+        "reference": "22833681",
+        "title": "Interaction of endogenous tau protein with synaptic proteins is regulated by N-methyl-D-aspartate receptor-dependent tau phosphorylation.",
+        "type": "PubMed",
+        "volume": "287"
+      },
+      "evidence": "Hence, LTD-inducing NMDA receptor activation leads to an increase in tau phosphorylation at sites PHF-1, AT180, as well as AT8 and to a reduction at AT100.",
+      "key": "cdf0c67cc70de6838030d05494f1ec21262f8069e4e3a376d9b7bb30276609795ba9ea1cd537d2d6b27e2b523225fe20348960b1cf2f4f418f6cf764620ea188",
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+      },
+      "citation": {
+        "authors": [
+          "Gamblin TC",
+          "Sun Q"
+        ],
+        "date": "2009-06-30",
+        "first": "Sun Q",
+        "last": "Gamblin TC",
+        "name": "Biochemistry",
+        "pages": "6002-11",
+        "reference": "19459590",
+        "title": "Pseudohyperphosphorylation causing AD-like changes in tau has significant effects on its polymerization.",
+        "type": "PubMed",
+        "volume": "48"
+      },
+      "evidence": "Because S199/S202/T205E, S396/S404E, 6-Phos and 7-Phos all demonstrated an AD-like shift in mobility as a result of phosphorylation-like changes, we conclude that they have the characteristics of hyperphosphorylated tau. These mutants will therefore be referred to as pseudo-hyperphosphorylated tau throughout the manuscript. On the basis of the observations that pseudohyperphosphorylated tau has decreased affinity for microtubules and reduced inducer-initiated rates of nucleation and polymerization, we propose that this combination could be the cause of the increased cytotoxicity of hyperphosphorylated tau in Alzheimer's disease and also explain the potentially beneficial role of tau polymerization and NFT formation.",
+      "key": "471219441c9ff260b12d41b28af56dcf35519c1fc5822aea013f81e93a758f05160f2174e7a50a86fb29f4d5e3697468a2c634bb40619ccb840df2739e315d47",
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+      "relation": "decreases",
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+    {
+      "annotations": {
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+          "Medium": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Carlomagno Y",
+          "Cook C",
+          "Petrucelli L",
+          "Stankowski JN",
+          "Stetler C"
+        ],
+        "date": "2014-01-01",
+        "first": "Cook C",
+        "last": "Petrucelli L",
+        "name": "Alzheimer's research &amp; therapy",
+        "pages": "29",
+        "reference": "25031639",
+        "title": "Acetylation: a new key to unlock tau's role in neurodegeneration.",
+        "type": "PubMed",
+        "volume": "6"
+      },
+      "evidence": "In particular, previous studies have demonstrated that the tau ubiquitin ligase, CHIP, is unable to bind and ubiquitinate tau species phosphorylated by Par-1/MARK2 on the 12E8 epitope (S262/356) [33], a p-tau species that is also resistant to degradation upon treatment with Hsp90 inhibitors [32,33]. Tau phosphorylated at the PHF1 epitope (S396/404) is still susceptible to degradation following Hsp90 inhibition and actually exhibits an enhanced interaction with Hsp90",
+      "key": "8df9f6e3f31262285a9a448c2d6e45363495e29c28ff22b339f956c25a07f77ace3b9cd2f4f8724e897b47b11a110ce5fdd15edff432136c154dcb71bdac7d21",
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+    {
+      "annotations": {
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+        },
+        "Confidence": {
+          "High": true
+        },
+        "MeSHDisease": {
+          "Alzheimer Disease": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Alexopoulos P",
+          "Arbones M",
+          "Badel A",
+          "Camproux AC",
+          "Delabar JM",
+          "Dubois B",
+          "Feraudet-Tarisse C",
+          "Janel N",
+          "Lagarde J",
+          "Lamari F",
+          "Lamourette P",
+          "Paul JL",
+          "Potier MC",
+          "Sarazin M",
+          "Simon S"
+        ],
+        "date": "2017-06-20",
+        "first": "Janel N",
+        "last": "Delabar JM",
+        "name": "Translational psychiatry",
+        "pages": "e1154",
+        "reference": "28632203",
+        "title": "Combined assessment of DYRK1A, BDNF and homocysteine levels as diagnostic marker for Alzheimer's disease.",
+        "type": "PubMed",
+        "volume": "7"
+      },
+      "evidence": "Receiver-operating characteristic curves and logistic regression analyses showed that combined assessment of DYRK1A, BDNF and homocysteine has a sensitivity of 0.952, a specificity of 0.889 and an accuracy of 0.933 in testing for AD. The blood levels of these markers provide a diagnosis assessment profile. Combined assessment of these three markers outperforms most of the previous markers and could become a useful substitute to the current panel of AD biomarkers.",
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+      "relation": "biomarkerFor",
+      "source": 64,
+      "target": 1017
+    },
+    {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
+        "Method": {
+          "Confocal Microscopy": true,
+          "Western Blot": true
+        },
+        "Species": {
+          "10090": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Arning E",
+          "Bottiglieri T",
+          "Nunbhakdi-Craig V",
+          "Sontag E",
+          "Sontag JM",
+          "Wasek B"
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         "volume": "14"
       },
-      "evidence": "Taken together, our results show that DMF reduces GSK-3 activity in vivo as determined by a significant and subtle reduction in the phosphorylation levels of its two substrates TAU and CRMP2 respectively.",
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-        },
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+      "evidence": "The second mechanism is related to GSK-3, which phosphorylates NRF2 creating a recognition site for β-Transducin Repeat Containing E3 Ubiquitin Protein Ligase (β-TrCP). β-TrCP leads to Cullin-1/Rbx1-mediated NRF2 ubiquitination and its subsequent degradation [8]. Since GSK-3β is inhibited by phosphorylation at Ser9 by Ser/Thr protein kinases such as AKT, it has been suggested that NRF2 might be up-regulated through activation of AKT and permanent inactivation of GSK-3 [9], [10].",
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     },
     {
       "annotations": {
-        "Ki": {
-          "4-80 nM": true
+        "Confidence": {
+          "Medium": true
         }
       },
-      "citation": {
-        "authors": [
-          "Bibb JA",
-          "Biernat J",
-          "Greengard P",
-          "Gussio R",
-          "Kunick C",
-          "Leost M",
-          "Link A",
-          "Mandelkow EM",
-          "Meijer L",
-          "Sausville EA",
-          "Schultz C",
-          "Senderowicz AM",
-          "Snyder GL",
-          "Wu YZ",
-          "Zaharevitz DW"
-        ],
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-        "first": "Leost M",
-        "last": "Meijer L",
-        "name": "European journal of biochemistry",
-        "pages": "5983-94",
-        "reference": "10998059",
-        "title": "Paullones are potent inhibitors of glycogen synthase kinase-3beta and cyclin-dependent kinase 5/p25.",
-        "type": "PubMed",
-        "volume": "267"
-      },
-      "evidence": "Alsterpaullone, the most active paullone, was demonstrated to act by competing with ATP for binding to GSK-3beta. Alsterpaullone inhibits the phosphorylation of tau in vivo at sites which are typically phosphorylated by GSK-3beta in Alzheimer's disease. Alsterpaullone also inhibits the CDK5/p25-dependent phosphorylation of DARPP-32 in mouse striatum slices in vitro. ",
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       "citation": {
         "authors": [
           "Cuadrado A",
@@ -14610,38 +18038,20 @@
         "volume": "14"
       },
       "evidence": "The second mechanism is related to GSK-3, which phosphorylates NRF2 creating a recognition site for β-Transducin Repeat Containing E3 Ubiquitin Protein Ligase (β-TrCP). β-TrCP leads to Cullin-1/Rbx1-mediated NRF2 ubiquitination and its subsequent degradation [8]. Since GSK-3β is inhibited by phosphorylation at Ser9 by Ser/Thr protein kinases such as AKT, it has been suggested that NRF2 might be up-regulated through activation of AKT and permanent inactivation of GSK-3 [9], [10].",
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-          "Kügler S",
-          "Lastres-Becker I"
-        ],
-        "date": "2018-04-01",
-        "first": "Cuadrado A",
-        "last": "Lastres-Becker I",
-        "name": "Redox biology",
-        "pages": "522-534",
-        "reference": "29121589",
-        "title": "Pharmacological targeting of GSK-3 and NRF2 provides neuroprotection in a preclinical model of tauopathy.",
-        "type": "PubMed",
-        "volume": "14"
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-      "evidence": "The second mechanism is related to GSK-3, which phosphorylates NRF2 creating a recognition site for β-Transducin Repeat Containing E3 Ubiquitin Protein Ligase (β-TrCP). β-TrCP leads to Cullin-1/Rbx1-mediated NRF2 ubiquitination and its subsequent degradation [8]. Since GSK-3β is inhibited by phosphorylation at Ser9 by Ser/Thr protein kinases such as AKT, it has been suggested that NRF2 might be up-regulated through activation of AKT and permanent inactivation of GSK-3 [9], [10].",
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     {
       "annotations": {
+        "Confidence": {
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         "Research_Model": {
           "SAMP8 mice": true
         },
@@ -14674,49 +18084,16 @@
       },
       "evidence": "Nuclear factor erythroid-2-related factor 2 (Nrf2) is a transcription factor known to increase the level of many antioxidants, including glutathione-S transferase (GST), and is negatively regulated by the activity of GSK-3β. Our results indicated the increased nuclear localization of Nrf2 and level of GST, suggesting the increased activity of the transcription factor as a result of GSK-3β suppression, consistent with the decreased oxidative stress observed. Consistent with the improved learning and memory, and consistent with GSK-3b being a tau kinase, we observed decreased tau phosphorylation in brain of GAO-treated SAMP8 mice compared to that of RAO-treated SAMP8 mice.",
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-          "Kügler S",
-          "Lastres-Becker I"
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-        "name": "Redox biology",
-        "pages": "522-534",
-        "reference": "29121589",
-        "title": "Pharmacological targeting of GSK-3 and NRF2 provides neuroprotection in a preclinical model of tauopathy.",
-        "type": "PubMed",
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-      "evidence": "Taken together, our results show that DMF reduces GSK-3 activity in vivo as determined by a significant and subtle reduction in the phosphorylation levels of its two substrates TAU and CRMP2 respectively.",
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-      "annotations": {
         "Km": {
           "200 μM": true
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@@ -14743,9 +18120,9 @@
       },
       "evidence": "Vm (nM/min/mg) is 2400, 80, 106, 650, and 140; Km is 200, 59, 114, 16 (all uM) and 5mg/ml for phospho-CREB peptide, myelin basic protein, k-casein, phosphatase Inhibitor-2 and phosvitin",
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@@ -14753,10 +18130,13 @@
         },
         "modifier": "Activity"
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-      "target": 285
+      "target": 355
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     {
       "annotations": {
+        "Confidence": {
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         "Km": {
           "59 μM": true
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@@ -14783,9 +18163,9 @@
       },
       "evidence": "Vm (nM/min/mg) is 2400, 80, 106, 650, and 140; Km is 200, 59, 114, 16 (all uM) and 5mg/ml for phospho-CREB peptide, myelin basic protein, k-casein, phosphatase Inhibitor-2 and phosvitin",
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@@ -14793,10 +18173,13 @@
         },
         "modifier": "Activity"
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+      "target": 725
     },
     {
       "annotations": {
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+        },
         "Km": {
           "114 μM": true
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@@ -14823,9 +18206,9 @@
       },
       "evidence": "Vm (nM/min/mg) is 2400, 80, 106, 650, and 140; Km is 200, 59, 114, 16 (all uM) and 5mg/ml for phospho-CREB peptide, myelin basic protein, k-casein, phosphatase Inhibitor-2 and phosvitin",
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@@ -14833,10 +18216,13 @@
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     {
       "annotations": {
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         "Km": {
           "5 μM": true
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@@ -14863,9 +18249,9 @@
       },
       "evidence": "Vm (nM/min/mg) is 2400, 80, 106, 650, and 140; Km is 200, 59, 114, 16 (all uM) and 5mg/ml for phospho-CREB peptide, myelin basic protein, k-casein, phosphatase Inhibitor-2 and phosvitin",
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@@ -14873,10 +18259,13 @@
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     {
       "annotations": {
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         "Km": {
           "16 μM": true
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@@ -14903,9 +18292,9 @@
       },
       "evidence": "Vm (nM/min/mg) is 2400, 80, 106, 650, and 140; Km is 200, 59, 114, 16 (all uM) and 5mg/ml for phospho-CREB peptide, myelin basic protein, k-casein, phosphatase Inhibitor-2 and phosvitin",
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@@ -14913,9 +18302,14 @@
         },
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+      "target": 498
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     {
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+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "El-Akkad E",
@@ -14939,9 +18333,9 @@
       },
       "evidence": "Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396.",
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@@ -14949,9 +18343,14 @@
         },
         "modifier": "Activity"
       },
-      "target": 577
+      "target": 661
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "El-Akkad E",
@@ -14975,9 +18374,9 @@
       },
       "evidence": "Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396.",
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@@ -14985,9 +18384,14 @@
         },
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       },
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+      "target": 628
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     {
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+        }
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       "citation": {
         "authors": [
           "Gamblin TC",
@@ -15005,9 +18409,9 @@
       },
       "evidence": "Because S199/S202/T205E, S396/S404E, 6-Phos and 7-Phos all demonstrated an AD-like shift in mobility as a result of phosphorylation-like changes, we conclude that they have the characteristics of hyperphosphorylated tau. These mutants will therefore be referred to as pseudo-hyperphosphorylated tau throughout the manuscript. On the basis of the observations that pseudohyperphosphorylated tau has decreased affinity for microtubules and reduced inducer-initiated rates of nucleation and polymerization, we propose that this combination could be the cause of the increased cytotoxicity of hyperphosphorylated tau in Alzheimer's disease and also explain the potentially beneficial role of tau polymerization and NFT formation.",
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           "name": "kin",
@@ -15015,43 +18419,14 @@
         },
         "modifier": "Activity"
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-      "citation": {
-        "authors": [
-          "Andreadis A",
-          "Binder LI",
-          "Brady ST",
-          "Fu Y",
-          "Kanaan NM",
-          "LaPointe NE",
-          "Morfini GA",
-          "Patterson KR",
-          "Pigino GF",
-          "Song Y"
-        ],
-        "date": "2011-07-06",
-        "first": "Kanaan NM",
-        "last": "Binder LI",
-        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
-        "pages": "9858-68",
-        "reference": "21734277",
-        "title": "Pathogenic forms of tau inhibit kinesin-dependent axonal transport through a mechanism involving activation of axonal phosphotransferases.",
-        "type": "PubMed",
-        "volume": "31"
-      },
-      "evidence": "Filamentous, but not soluble, forms of wild-type tau inhibit anterograde, kinesin-based fast axonal transport (FAT) by activating axonal protein phosphatase 1 (PP1) and glycogen synthase kinase 3 (GSK3), independent of microtubule binding. Amino acids 2-18 of tau, comprising a phosphatase-activating domain (PAD), are necessary and sufficient for activation of this pathway. Various pathogenic forms of tau displaying increased exposure of PAD inhibited anterograde FAT in squid axoplasm. Immunohistochemical studies using a novel PAD-specific monoclonal antibody in human postmortem tissue indicated that increased PAD exposure represents an early pathogenic event in AD that closely associates in time with AT8 immunoreactivity. We propose a model of pathogenesis in which disease-associated changes in tau conformation lead to increased exposure of PAD, activation of PP1-GSK3, and inhibition of FAT",
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-      "subject": {
-        "modifier": "Activity"
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+        }
       },
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-    {
       "citation": {
         "authors": [
           "El-Akkad E",
@@ -15075,9 +18450,9 @@
       },
       "evidence": "Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396.",
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         "effect": {
           "name": "kin",
@@ -15085,43 +18460,49 @@
         },
         "modifier": "Activity"
       },
-      "target": 544
+      "target": 629
     },
     {
+      "annotations": {
+        "Confidence": {
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+        }
+      },
       "citation": {
         "authors": [
-          "Andreadis A",
-          "Binder LI",
-          "Brady ST",
-          "Fu Y",
-          "Kanaan NM",
-          "LaPointe NE",
-          "Morfini GA",
-          "Patterson KR",
-          "Pigino GF",
-          "Song Y"
+          "Gamblin TC",
+          "Sun Q"
         ],
-        "date": "2011-07-06",
-        "first": "Kanaan NM",
-        "last": "Binder LI",
-        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
-        "pages": "9858-68",
-        "reference": "21734277",
-        "title": "Pathogenic forms of tau inhibit kinesin-dependent axonal transport through a mechanism involving activation of axonal phosphotransferases.",
+        "date": "2009-06-30",
+        "first": "Sun Q",
+        "last": "Gamblin TC",
+        "name": "Biochemistry",
+        "pages": "6002-11",
+        "reference": "19459590",
+        "title": "Pseudohyperphosphorylation causing AD-like changes in tau has significant effects on its polymerization.",
         "type": "PubMed",
-        "volume": "31"
+        "volume": "48"
       },
-      "evidence": "Filamentous, but not soluble, forms of wild-type tau inhibit anterograde, kinesin-based fast axonal transport (FAT) by activating axonal protein phosphatase 1 (PP1) and glycogen synthase kinase 3 (GSK3), independent of microtubule binding. Amino acids 2-18 of tau, comprising a phosphatase-activating domain (PAD), are necessary and sufficient for activation of this pathway. Various pathogenic forms of tau displaying increased exposure of PAD inhibited anterograde FAT in squid axoplasm. Immunohistochemical studies using a novel PAD-specific monoclonal antibody in human postmortem tissue indicated that increased PAD exposure represents an early pathogenic event in AD that closely associates in time with AT8 immunoreactivity. We propose a model of pathogenesis in which disease-associated changes in tau conformation lead to increased exposure of PAD, activation of PP1-GSK3, and inhibition of FAT",
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-      "line": 3842,
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+      "evidence": "Because S199/S202/T205E, S396/S404E, 6-Phos and 7-Phos all demonstrated an AD-like shift in mobility as a result of phosphorylation-like changes, we conclude that they have the characteristics of hyperphosphorylated tau. These mutants will therefore be referred to as pseudo-hyperphosphorylated tau throughout the manuscript. On the basis of the observations that pseudohyperphosphorylated tau has decreased affinity for microtubules and reduced inducer-initiated rates of nucleation and polymerization, we propose that this combination could be the cause of the increased cytotoxicity of hyperphosphorylated tau in Alzheimer's disease and also explain the potentially beneficial role of tau polymerization and NFT formation.",
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         "modifier": "Activity"
       },
-      "target": 544
+      "target": 629
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "El-Akkad E",
@@ -15145,9 +18526,9 @@
       },
       "evidence": "Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396.",
       "key": "15d89e9d216b2c064343fe7416b9e5722b38aec3fdb1628ce3f7e49f71e497075a6e82a437336f4a22cdaf324d10bc568a3e18b82e3c3de2f352fd0472b060ed",
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       "relation": "increases",
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       "subject": {
         "effect": {
           "name": "kin",
@@ -15155,43 +18536,49 @@
         },
         "modifier": "Activity"
       },
-      "target": 579
+      "target": 663
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
-          "Andreadis A",
-          "Binder LI",
-          "Brady ST",
-          "Fu Y",
-          "Kanaan NM",
-          "LaPointe NE",
-          "Morfini GA",
-          "Patterson KR",
-          "Pigino GF",
-          "Song Y"
+          "Gamblin TC",
+          "Sun Q"
         ],
-        "date": "2011-07-06",
-        "first": "Kanaan NM",
-        "last": "Binder LI",
-        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
-        "pages": "9858-68",
-        "reference": "21734277",
-        "title": "Pathogenic forms of tau inhibit kinesin-dependent axonal transport through a mechanism involving activation of axonal phosphotransferases.",
+        "date": "2009-06-30",
+        "first": "Sun Q",
+        "last": "Gamblin TC",
+        "name": "Biochemistry",
+        "pages": "6002-11",
+        "reference": "19459590",
+        "title": "Pseudohyperphosphorylation causing AD-like changes in tau has significant effects on its polymerization.",
         "type": "PubMed",
-        "volume": "31"
+        "volume": "48"
       },
-      "evidence": "Filamentous, but not soluble, forms of wild-type tau inhibit anterograde, kinesin-based fast axonal transport (FAT) by activating axonal protein phosphatase 1 (PP1) and glycogen synthase kinase 3 (GSK3), independent of microtubule binding. Amino acids 2-18 of tau, comprising a phosphatase-activating domain (PAD), are necessary and sufficient for activation of this pathway. Various pathogenic forms of tau displaying increased exposure of PAD inhibited anterograde FAT in squid axoplasm. Immunohistochemical studies using a novel PAD-specific monoclonal antibody in human postmortem tissue indicated that increased PAD exposure represents an early pathogenic event in AD that closely associates in time with AT8 immunoreactivity. We propose a model of pathogenesis in which disease-associated changes in tau conformation lead to increased exposure of PAD, activation of PP1-GSK3, and inhibition of FAT",
-      "key": "964f4bc0a5d9b8237c50b221bdc0fce870d0cd90f44f2ecad0bb6cdfd5bc145983e742e95e253696bc4eab6d5f96c26d54f4737a8bc341956a09b217a868bc1e",
-      "line": 3843,
-      "relation": "directlyIncreases",
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+      "evidence": "Because S199/S202/T205E, S396/S404E, 6-Phos and 7-Phos all demonstrated an AD-like shift in mobility as a result of phosphorylation-like changes, we conclude that they have the characteristics of hyperphosphorylated tau. These mutants will therefore be referred to as pseudo-hyperphosphorylated tau throughout the manuscript. On the basis of the observations that pseudohyperphosphorylated tau has decreased affinity for microtubules and reduced inducer-initiated rates of nucleation and polymerization, we propose that this combination could be the cause of the increased cytotoxicity of hyperphosphorylated tau in Alzheimer's disease and also explain the potentially beneficial role of tau polymerization and NFT formation.",
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+      "relation": "increases",
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       "subject": {
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+          "namespace": "bel"
+        },
         "modifier": "Activity"
       },
-      "target": 579
+      "target": 663
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "El-Akkad E",
@@ -15215,9 +18602,9 @@
       },
       "evidence": "Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396.",
       "key": "be21fff161dc246831b972c48b24298350595cbc76f78641f157d926b74b23fc260b63fc554cb6452694afa84fefa63b094664c0133cd3892410130b2985bfa2",
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       "relation": "increases",
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         "effect": {
           "name": "kin",
@@ -15225,9 +18612,14 @@
         },
         "modifier": "Activity"
       },
-      "target": 582
+      "target": 666
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "El-Akkad E",
@@ -15251,9 +18643,9 @@
       },
       "evidence": "Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396.",
       "key": "02bcb3da558fe2c42e7d7ec6c3d0941ad68d76bbfea5d4ee4efd299d97777228c03a9bc94265d5ee64ba9ba8d2ba83fc63a94c973dd286e6feef6764e9e94521",
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           "name": "kin",
@@ -15261,9 +18653,14 @@
         },
         "modifier": "Activity"
       },
-      "target": 583
+      "target": 667
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     {
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+        }
+      },
       "citation": {
         "authors": [
           "El-Akkad E",
@@ -15287,9 +18684,9 @@
       },
       "evidence": "Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396.",
       "key": "f078e4939b4bcb1e7f51c80ea951b942f71e44c6eb4a5ac6ec4a5aa05d9e13f25cc443f2d5633379c1715985cce8dd84f0686a6d31ca897299e6f0a27b7057a4",
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       "subject": {
         "effect": {
           "name": "kin",
@@ -15297,9 +18694,14 @@
         },
         "modifier": "Activity"
       },
-      "target": 564
+      "target": 649
     },
     {
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+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "Gamblin TC",
@@ -15317,9 +18719,9 @@
       },
       "evidence": "Because S199/S202/T205E, S396/S404E, 6-Phos and 7-Phos all demonstrated an AD-like shift in mobility as a result of phosphorylation-like changes, we conclude that they have the characteristics of hyperphosphorylated tau. These mutants will therefore be referred to as pseudo-hyperphosphorylated tau throughout the manuscript. On the basis of the observations that pseudohyperphosphorylated tau has decreased affinity for microtubules and reduced inducer-initiated rates of nucleation and polymerization, we propose that this combination could be the cause of the increased cytotoxicity of hyperphosphorylated tau in Alzheimer's disease and also explain the potentially beneficial role of tau polymerization and NFT formation.",
       "key": "e3691709488e492d76563df6e4cf63d6b294d745ac0102574a5c9553f2e90ebcf04b695bb5dcc6f52cd0659db64da4e168e87d5de277b3a3db274840aa5e8b82",
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         "effect": {
           "name": "kin",
@@ -15327,13 +18729,16 @@
         },
         "modifier": "Activity"
       },
-      "target": 564
+      "target": 649
     },
     {
       "annotations": {
         "Cell_Line": {
           "N2a": true,
           "SH-SY5Y": true
+        },
+        "Confidence": {
+          "Medium": true
         }
       },
       "citation": {
@@ -15354,16 +18759,21 @@
         "volume": "9"
       },
       "evidence": "This study aimed to investigate the protective effects and mechanism of the novel HDAC6 inhibitor, MPT0G211, using an AD model. Our results indicated that MPT0G211 significantly reduced tau phosphorylation and aggregation, the processes highly correlated with the formation of NFTs. This HDAC6 inhibitory activity resulted in an increase in acetylated Hsp90, which decreased Hsp90 and HDAC6 binding, causing ubiquitination of phosphorylated tau proteins. In addition, a significant increase of phospho-glycogen synthase kinase-3β (phospho-GSK3β) on Ser9 (the inactive form) through Akt phosphorylation was associated with the inhibition of phospho-tau Ser396 in response to MPT0G211 treatment.",
-      "key": "a16c8438b51435b58c848ea16883464c6675d4fd2781deaae0aa755bdb253e34753280c6b72758c0ff80c96cc40ce855ae410f182bb2aca91e12fc2a5ff39e80",
-      "line": 3387,
-      "relation": "positiveCorrelation",
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+      "line": 4210,
+      "relation": "decreases",
+      "source": 537,
       "subject": {
         "modifier": "Activity"
       },
-      "target": 564
+      "target": 649
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "El-Akkad E",
@@ -15387,9 +18797,9 @@
       },
       "evidence": "Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396.",
       "key": "888d0aebffa9b7dc4149a76244af3256c845c20e9aa363a1f82568f987118edf58c79b141dc674f7b36f4f1f7eeff14adefcb084b0654df9357014ce7667027e",
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       "relation": "increases",
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       "subject": {
         "effect": {
           "name": "kin",
@@ -15397,9 +18807,14 @@
         },
         "modifier": "Activity"
       },
-      "target": 569
+      "target": 654
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "El-Akkad E",
@@ -15423,9 +18838,9 @@
       },
       "evidence": "Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396.",
       "key": "2f465eb423870aba37881de25c775d2dba1c77837652d7d174e142af1060ea328724d95b0ac2453ebc7fa45b5b54bed857dc35d2ac12d5c2733d3997e5e6ef90",
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       "subject": {
         "effect": {
           "name": "kin",
@@ -15433,9 +18848,14 @@
         },
         "modifier": "Activity"
       },
-      "target": 565
+      "target": 650
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "Gamblin TC",
@@ -15453,9 +18873,9 @@
       },
       "evidence": "Because S199/S202/T205E, S396/S404E, 6-Phos and 7-Phos all demonstrated an AD-like shift in mobility as a result of phosphorylation-like changes, we conclude that they have the characteristics of hyperphosphorylated tau. These mutants will therefore be referred to as pseudo-hyperphosphorylated tau throughout the manuscript. On the basis of the observations that pseudohyperphosphorylated tau has decreased affinity for microtubules and reduced inducer-initiated rates of nucleation and polymerization, we propose that this combination could be the cause of the increased cytotoxicity of hyperphosphorylated tau in Alzheimer's disease and also explain the potentially beneficial role of tau polymerization and NFT formation.",
       "key": "98bb32e796e7a576216063e6b35ba9f51257239b186c33960c7c5de9b64627a7447fb14e207660ee75fe2dc9702e04dd61a0cb3ed2d4d4bdc901fe7e2d82d2f4",
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       "relation": "increases",
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       "subject": {
         "effect": {
           "name": "kin",
@@ -15463,9 +18883,14 @@
         },
         "modifier": "Activity"
       },
-      "target": 565
+      "target": 650
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "El-Akkad E",
@@ -15489,9 +18914,9 @@
       },
       "evidence": "Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396.",
       "key": "c30aefaf492a5cb2db875628e15abc1b98ee4fa6bf9605b9db6a92ec31af4cb0258df2740fd6183fd330c5d6af63aad856ddd0221f730808d9dc76fd3311a3f9",
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       "relation": "increases",
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       "subject": {
         "effect": {
           "name": "kin",
@@ -15499,9 +18924,14 @@
         },
         "modifier": "Activity"
       },
-      "target": 580
+      "target": 664
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "Imahori K",
@@ -15519,9 +18949,9 @@
       },
       "evidence": "By using a yeast two hybrid system, TPKI was found to interact with pyruvate dehydrogenase (PDH), which is a key enzyme in the glycolytic pathway. PDH was phosphorylated in vitro by TPKI to reduce the activity converting pyruvate into acetyl-CoA, which is required for acetylcholine synthesis.",
       "key": "77f6654764a811f58407bb54c7193a86be1b27023d9829b1e09c4ae7ba70261c3395f7f9062b6acc2c2fd581ca3f9cde4dd0ffa63b70c97b997a45981c1772fb",
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       "relation": "increases",
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       "subject": {
         "effect": {
           "name": "kin",
@@ -15529,9 +18959,14 @@
         },
         "modifier": "Activity"
       },
-      "target": 298
+      "target": 371
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "Imahori K",
@@ -15549,12 +18984,68 @@
       },
       "evidence": "By using a yeast two hybrid system, TPKI was found to interact with pyruvate dehydrogenase (PDH), which is a key enzyme in the glycolytic pathway. PDH was phosphorylated in vitro by TPKI to reduce the activity converting pyruvate into acetyl-CoA, which is required for acetylcholine synthesis.",
       "key": "8e2bd56d369e595d349444e447e0528aa29e3b79064ebc7d24280910856552a36aaef2593e3b4323048db4b0351d1c038fc9211b6529b02711e27f0560e52d5e",
-      "line": 1159,
+      "line": 1384,
       "relation": "isA",
-      "source": 456,
-      "target": 270
+      "source": 537,
+      "target": 340
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "Ki": {
+          "4-80 nM": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Bibb JA",
+          "Biernat J",
+          "Greengard P",
+          "Gussio R",
+          "Kunick C",
+          "Leost M",
+          "Link A",
+          "Mandelkow EM",
+          "Meijer L",
+          "Sausville EA",
+          "Schultz C",
+          "Senderowicz AM",
+          "Snyder GL",
+          "Wu YZ",
+          "Zaharevitz DW"
+        ],
+        "date": "2000-10-01",
+        "first": "Leost M",
+        "last": "Meijer L",
+        "name": "European journal of biochemistry",
+        "pages": "5983-94",
+        "reference": "10998059",
+        "title": "Paullones are potent inhibitors of glycogen synthase kinase-3beta and cyclin-dependent kinase 5/p25.",
+        "type": "PubMed",
+        "volume": "267"
+      },
+      "evidence": "Alsterpaullone, the most active paullone, was demonstrated to act by competing with ATP for binding to GSK-3beta. Alsterpaullone inhibits the phosphorylation of tau in vivo at sites which are typically phosphorylated by GSK-3beta in Alzheimer's disease. Alsterpaullone also inhibits the CDK5/p25-dependent phosphorylation of DARPP-32 in mouse striatum slices in vitro. ",
+      "key": "7e8cd51a1f72b05594bdc95c42e311bbda6be3d2dc628de4c1183a6568c6d4f1273f0ff0c7a3336c5ffabac9fcc12ff891091b9c69012eeb0cce98b3c797b0e9",
+      "line": 1432,
+      "relation": "increases",
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+      "subject": {
+        "effect": {
+          "name": "kin",
+          "namespace": "bel"
+        },
+        "modifier": "Activity"
+      },
+      "target": 622
+    },
+    {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "Hosomi N",
@@ -15578,13 +19069,16 @@
       },
       "evidence": "Pretangles contained either paired helical filaments (PHFs) or PtdIns(4,5)P2-immunopositive small vesicles (approximately 1 µm in diameter) with nearly identical topology to granulovacuolar degeneration (GVD) bodies. Various combinations of these vesicles and GVD bodies, the latter of which are pathological hallmarks observed within the neurons of AD patients, were found concurrently in neurons.These vesicles and GVD bodies were both immunopositive not only for PtdIns(4,5)P2, but also for several tau kinases such as glycogen synthase kinase-3ß and spleen tyrosine kinase.",
       "key": "7b99cd63e3a2cb1ac681484bf2b32a5d275f4d80e0598573fd94b921afb918a97996bfb167d949c2444765d08aab3047f47db8e1cd199d774becd754f584e007",
-      "line": 2224,
+      "line": 2735,
       "relation": "partOf",
-      "source": 456,
-      "target": 101
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+      "target": 110
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "Species": {
           "10090": true
         }
@@ -15612,10 +19106,10 @@
         "volume": "289"
       },
       "evidence": "We further validated Syk as a target-regulating Aβ by showing that pharmacological inhibition of Syk or down-regulation of Syk expression reduces Aβ production and increases the clearance of Aβ across the BBB mimicking (-)-nilvadipine effects. Moreover, treatment of transgenic mice overexpressing Aβ and transgenic Tau P301S mice with a selective Syk inhibitor respectively decreased brain Aβ accumulation and Tau hyperphosphorylation at multiple AD relevant epitopes.",
-      "key": "63c4803e671fb5000574af188e2dab04411434eb52fcd283bf5d88ffbe71fb834f7f86e5ec168ea3fcae11a8502cb5fbaef2bcbe9d89bd4b7ada3a4da0a2085f",
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+      "key": "239c7a5939d90058834c82ff201ebb12b43670a13eab8a760a507b08e7ccbaa23381740d11cc17491d7fb6fec4200f997a95f2b32b354d7ac8f59e43a00b7864",
+      "line": 2777,
       "relation": "increases",
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       "subject": {
         "effect": {
           "name": "kin",
@@ -15623,55 +19117,16 @@
         },
         "modifier": "Activity"
       },
-      "target": 116
+      "target": 417
     },
     {
       "annotations": {
-        "Cell_Line": {
-          "SH-SY5Y": true
-        }
-      },
-      "citation": {
-        "authors": [
-          "Ait-Ghezala G",
-          "Bachmeier C",
-          "Beaulieu-Abdelahad D",
-          "Crawford F",
-          "Jin C",
-          "Laco G",
-          "Lin Y",
-          "Mullan M",
-          "Paris D"
-        ],
-        "date": "2014-12-05",
-        "first": "Paris D",
-        "last": "Mullan M",
-        "name": "The Journal of biological chemistry",
-        "pages": "33927-44",
-        "reference": "25331948",
-        "title": "The spleen tyrosine kinase (Syk) regulates Alzheimer amyloid-β production and Tau hyperphosphorylation.",
-        "type": "PubMed",
-        "volume": "289"
-      },
-      "evidence": "We observed that pharmacological inhibition of Syk with BAY61-3606 stimulates Ser-9 phosphorylation of GSK3β in SH-SY5Y cells (Fig. 9, A and B) suggesting that blocking Syk activity results in GSK3β inhibition.",
-      "key": "0606e3e25741081b101e1fc280248a186aefe07ddf5713aa4c911b512b1b235c0a385576d84fd87460171e9b0450a4ec3d8a4a748c598007505d386403c06ac3",
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-      },
-      "relation": "positiveCorrelation",
-      "source": 456,
-      "subject": {
-        "effect": {
-          "name": "kin",
-          "namespace": "bel"
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Cerebral Cortex": true
         },
-        "modifier": "Activity"
-      },
-      "target": 705
-    },
-    {
-      "annotations": {
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -15697,9 +19152,9 @@
       },
       "evidence": "We found that GSK3β mRNA was overexpressed only in patients with initial AD, with no effect on the levels of the protein. On the other hand, we unexpectedly observed the decrease of the inactive GSK3β in cortex from AD patients at Braak stages I-II, whereas considerable increase was observed in AD patients at stages V-VI compared to the control subjects.",
       "key": "cf442862d8518e96f21c3fc84a7b857526082a87f61f16dba92730eb8e48ced0f0bd9d935d07c42bd106198477b709e1f31be67cf12428d1ce4f1a50498d7d25",
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+      "line": 2801,
       "relation": "positiveCorrelation",
-      "source": 456,
+      "source": 537,
       "subject": {
         "effect": {
           "name": "kin",
@@ -15707,10 +19162,16 @@
         },
         "modifier": "Activity"
       },
-      "target": 94
+      "target": 105
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Cerebral Cortex": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -15736,9 +19197,9 @@
       },
       "evidence": "We found that GSK3β mRNA was overexpressed only in patients with initial AD, with no effect on the levels of the protein. On the other hand, we unexpectedly observed the decrease of the inactive GSK3β in cortex from AD patients at Braak stages I-II, whereas considerable increase was observed in AD patients at stages V-VI compared to the control subjects.",
       "key": "2933fb9eb116d81726d4d67a6adb252297654e417ccaca73ed9d00e05ef7aa88d7722f668a9b661df8dcddb62c029db94ebd82ad068eaf7f06a1fc39f9b74dd6",
-      "line": 2272,
+      "line": 2802,
       "relation": "positiveCorrelation",
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+      "source": 537,
       "subject": {
         "effect": {
           "name": "kin",
@@ -15746,10 +19207,16 @@
         },
         "modifier": "Activity"
       },
-      "target": 95
+      "target": 106
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Cerebral Cortex": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -15775,39 +19242,9 @@
       },
       "evidence": "We found that GSK3β mRNA was overexpressed only in patients with initial AD, with no effect on the levels of the protein. On the other hand, we unexpectedly observed the decrease of the inactive GSK3β in cortex from AD patients at Braak stages I-II, whereas considerable increase was observed in AD patients at stages V-VI compared to the control subjects.",
       "key": "a12c34fb18f1bf92b9877fc94fd6d1d12479a1897602a0af5eb862f985cfcd6cbde65e87d8f156e16cbb76e416af175cf69558301167e4e6eee84f2256a63070",
-      "line": 2274,
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       "relation": "negativeCorrelation",
-      "source": 456,
-      "subject": {
-        "effect": {
-          "name": "kin",
-          "namespace": "bel"
-        },
-        "modifier": "Activity"
-      },
-      "target": 96
-    },
-    {
-      "citation": {
-        "authors": [
-          "Gamblin TC",
-          "Sun Q"
-        ],
-        "date": "2009-06-30",
-        "first": "Sun Q",
-        "last": "Gamblin TC",
-        "name": "Biochemistry",
-        "pages": "6002-11",
-        "reference": "19459590",
-        "title": "Pseudohyperphosphorylation causing AD-like changes in tau has significant effects on its polymerization.",
-        "type": "PubMed",
-        "volume": "48"
-      },
-      "evidence": "Because S199/S202/T205E, S396/S404E, 6-Phos and 7-Phos all demonstrated an AD-like shift in mobility as a result of phosphorylation-like changes, we conclude that they have the characteristics of hyperphosphorylated tau. These mutants will therefore be referred to as pseudo-hyperphosphorylated tau throughout the manuscript. On the basis of the observations that pseudohyperphosphorylated tau has decreased affinity for microtubules and reduced inducer-initiated rates of nucleation and polymerization, we propose that this combination could be the cause of the increased cytotoxicity of hyperphosphorylated tau in Alzheimer's disease and also explain the potentially beneficial role of tau polymerization and NFT formation.",
-      "key": "b5453fb8ab91baffdf91a753158d49279efbf7682d71cf52ed2b601af77a84c9fc11273fc4afa69ecc21e8df2d0079ff8bf100a08046724c0544337c30de1e30",
-      "line": 2455,
-      "relation": "increases",
-      "source": 456,
+      "source": 537,
       "subject": {
         "effect": {
           "name": "kin",
@@ -15815,10 +19252,13 @@
         },
         "modifier": "Activity"
       },
-      "target": 336
+      "target": 107
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Research_Model": {
           "SAMP8 mice": true
         },
@@ -15851,13 +19291,16 @@
       },
       "evidence": "Nuclear factor erythroid-2-related factor 2 (Nrf2) is a transcription factor known to increase the level of many antioxidants, including glutathione-S transferase (GST), and is negatively regulated by the activity of GSK-3β. Our results indicated the increased nuclear localization of Nrf2 and level of GST, suggesting the increased activity of the transcription factor as a result of GSK-3β suppression, consistent with the decreased oxidative stress observed. Consistent with the improved learning and memory, and consistent with GSK-3b being a tau kinase, we observed decreased tau phosphorylation in brain of GAO-treated SAMP8 mice compared to that of RAO-treated SAMP8 mice.",
       "key": "31a4f1ca81aa0ee846d5e86e04b14799245e10cb650cae9a1fe18bbe8ec2bd1328b18dbecf8e737b9e21d7f7d35019c21bc151aa05e819dc7f0a19c5e2466bf8",
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       "relation": "positiveCorrelation",
-      "source": 456,
-      "target": 205
+      "source": 537,
+      "target": 226
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Research_Model": {
           "SAMP8 mice": true
         },
@@ -15890,13 +19333,16 @@
       },
       "evidence": "Nuclear factor erythroid-2-related factor 2 (Nrf2) is a transcription factor known to increase the level of many antioxidants, including glutathione-S transferase (GST), and is negatively regulated by the activity of GSK-3β. Our results indicated the increased nuclear localization of Nrf2 and level of GST, suggesting the increased activity of the transcription factor as a result of GSK-3β suppression, consistent with the decreased oxidative stress observed. Consistent with the improved learning and memory, and consistent with GSK-3b being a tau kinase, we observed decreased tau phosphorylation in brain of GAO-treated SAMP8 mice compared to that of RAO-treated SAMP8 mice.",
       "key": "e511cbaa1a92fd510784b4fb1fd05a7305c89595abd3d2aef432e8fefd386d90ae5487ab9a5e458de70b59b070669c34d0b5caf245423a7b766b83735353a010",
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       "relation": "negativeCorrelation",
-      "source": 456,
-      "target": 197
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+      "target": 215
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Research_Model": {
           "SAMP8 mice": true
         },
@@ -15929,13 +19375,16 @@
       },
       "evidence": "Nuclear factor erythroid-2-related factor 2 (Nrf2) is a transcription factor known to increase the level of many antioxidants, including glutathione-S transferase (GST), and is negatively regulated by the activity of GSK-3β. Our results indicated the increased nuclear localization of Nrf2 and level of GST, suggesting the increased activity of the transcription factor as a result of GSK-3β suppression, consistent with the decreased oxidative stress observed. Consistent with the improved learning and memory, and consistent with GSK-3b being a tau kinase, we observed decreased tau phosphorylation in brain of GAO-treated SAMP8 mice compared to that of RAO-treated SAMP8 mice.",
       "key": "5933ba81101d746373291c3cfc310809a849fd85aba792ec78084c6314ad975c00805d2908d8751cb844cf42731b03fa1d541e9f8e6ef101ecbb7f0da58a4c8f",
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       "relation": "negativeCorrelation",
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-      "target": 200
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+      "target": 219
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Research_Model": {
           "SAMP8 mice": true
         },
@@ -15968,9 +19417,9 @@
       },
       "evidence": "Nuclear factor erythroid-2-related factor 2 (Nrf2) is a transcription factor known to increase the level of many antioxidants, including glutathione-S transferase (GST), and is negatively regulated by the activity of GSK-3β. Our results indicated the increased nuclear localization of Nrf2 and level of GST, suggesting the increased activity of the transcription factor as a result of GSK-3β suppression, consistent with the decreased oxidative stress observed. Consistent with the improved learning and memory, and consistent with GSK-3b being a tau kinase, we observed decreased tau phosphorylation in brain of GAO-treated SAMP8 mice compared to that of RAO-treated SAMP8 mice.",
       "key": "b7439c5e720206c9646a0a5b1e7697f0cfa8dc556f7edf9ae90d26e2aa050d95182c029aafa113c903eea44af3f7384f41f12a33753f3a640d96891dbbd0faaf",
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       "subject": {
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@@ -15978,10 +19427,13 @@
         },
         "modifier": "Activity"
       },
-      "target": 834
+      "target": 923
     },
     {
       "annotations": {
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+          "High": true
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         "Research_Model": {
           "SAMP8 mice": true
         },
@@ -16014,9 +19466,9 @@
       },
       "evidence": "Nuclear factor erythroid-2-related factor 2 (Nrf2) is a transcription factor known to increase the level of many antioxidants, including glutathione-S transferase (GST), and is negatively regulated by the activity of GSK-3β. Our results indicated the increased nuclear localization of Nrf2 and level of GST, suggesting the increased activity of the transcription factor as a result of GSK-3β suppression, consistent with the decreased oxidative stress observed. Consistent with the improved learning and memory, and consistent with GSK-3b being a tau kinase, we observed decreased tau phosphorylation in brain of GAO-treated SAMP8 mice compared to that of RAO-treated SAMP8 mice.",
       "key": "aab40d2adc72e76ced69a631b6997076d55313e63e12db5556e7e9b633c46af9f6040ddca219c33c1b3d878d6e29b6ebbb0cb7a7dc225976c002ff351006b4e5",
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       "relation": "directlyIncreases",
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       "subject": {
         "effect": {
           "name": "kin",
@@ -16024,9 +19476,14 @@
         },
         "modifier": "Activity"
       },
-      "target": 819
+      "target": 908
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "Berkovitch SS",
@@ -16050,9 +19507,9 @@
       },
       "evidence": "The N-terminus of β-catenin has phosphorylation, ubiquitination, and acetylation sites that regulate its stability and signaling. In the absence of a Wnt signal, Ser33, Ser37, and Thr41 are constitutively phosphorylated by glycogen synthase kinase 3β (GSK3β). β-Catenin phosphorylated at these sites is recognized by β-transducin repeat-containing protein (βTrCP), which results in ubiquitination and degradation by the ubiquitin-proteasome pathway. The N-terminal regulatory domain of β-catenin also includes Ser45, a phosphorylation site for Casein Kinase 1α (CK1α) and Lys49, which is acetylated by the acetyltransferase p300/CBP-associated factor (PCAF). The relevance of Lys49 acetylation and Ser45 phosphorylation to the function of β-catenin is an active area of investigation. We find that HDAC6 inhibitors increase Lys49 acetylation and Ser45 phosphorylation but do not affect Ser33, Ser37, and Thr41 phosphorylation. Lys49 acetylation results in decreased ubiquitination of β-catenin in the presence of proteasome inhibition. While increased Lys49 acetylation does not affect total levels of β-catenin, it results in increased membrane localization of β-catenin.",
       "key": "6afabcfed57d75f038e357697b060314e72e53d8a29d2f3c827ae1cc11d6f8437f94eb2fb8f063af148017bf4ffcf27b171548dfafee4e53e66b486e90a78a77",
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       "relation": "directlyIncreases",
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       "subject": {
         "effect": {
           "name": "kin",
@@ -16060,9 +19517,14 @@
         },
         "modifier": "Activity"
       },
-      "target": 422
+      "target": 501
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "Berkovitch SS",
@@ -16086,9 +19548,9 @@
       },
       "evidence": "The N-terminus of β-catenin has phosphorylation, ubiquitination, and acetylation sites that regulate its stability and signaling. In the absence of a Wnt signal, Ser33, Ser37, and Thr41 are constitutively phosphorylated by glycogen synthase kinase 3β (GSK3β). β-Catenin phosphorylated at these sites is recognized by β-transducin repeat-containing protein (βTrCP), which results in ubiquitination and degradation by the ubiquitin-proteasome pathway. The N-terminal regulatory domain of β-catenin also includes Ser45, a phosphorylation site for Casein Kinase 1α (CK1α) and Lys49, which is acetylated by the acetyltransferase p300/CBP-associated factor (PCAF). The relevance of Lys49 acetylation and Ser45 phosphorylation to the function of β-catenin is an active area of investigation. We find that HDAC6 inhibitors increase Lys49 acetylation and Ser45 phosphorylation but do not affect Ser33, Ser37, and Thr41 phosphorylation. Lys49 acetylation results in decreased ubiquitination of β-catenin in the presence of proteasome inhibition. While increased Lys49 acetylation does not affect total levels of β-catenin, it results in increased membrane localization of β-catenin.",
       "key": "459392357c6333f63402315327bb081e5b4b5bb62236224ee1e19b696624d8bd5fe51e8877edb39a19a2832de5ac36fa3ee002560e4890efbca9e3b68b4dfe41",
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       "relation": "directlyIncreases",
-      "source": 456,
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       "subject": {
         "effect": {
           "name": "kin",
@@ -16096,9 +19558,14 @@
         },
         "modifier": "Activity"
       },
-      "target": 424
+      "target": 502
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "Berkovitch SS",
@@ -16122,9 +19589,9 @@
       },
       "evidence": "The N-terminus of β-catenin has phosphorylation, ubiquitination, and acetylation sites that regulate its stability and signaling. In the absence of a Wnt signal, Ser33, Ser37, and Thr41 are constitutively phosphorylated by glycogen synthase kinase 3β (GSK3β). β-Catenin phosphorylated at these sites is recognized by β-transducin repeat-containing protein (βTrCP), which results in ubiquitination and degradation by the ubiquitin-proteasome pathway. The N-terminal regulatory domain of β-catenin also includes Ser45, a phosphorylation site for Casein Kinase 1α (CK1α) and Lys49, which is acetylated by the acetyltransferase p300/CBP-associated factor (PCAF). The relevance of Lys49 acetylation and Ser45 phosphorylation to the function of β-catenin is an active area of investigation. We find that HDAC6 inhibitors increase Lys49 acetylation and Ser45 phosphorylation but do not affect Ser33, Ser37, and Thr41 phosphorylation. Lys49 acetylation results in decreased ubiquitination of β-catenin in the presence of proteasome inhibition. While increased Lys49 acetylation does not affect total levels of β-catenin, it results in increased membrane localization of β-catenin.",
       "key": "5628a1d52e4e83894e1afc7b4887da9884f9e29c4b918e86c395f8a9f808c81bfe40b2911c323e598b4a4c787c64d594e8e3fc3992ae00bfec8183e878c7aacd",
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       "relation": "directlyIncreases",
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       "subject": {
         "effect": {
           "name": "kin",
@@ -16132,13 +19599,67 @@
         },
         "modifier": "Activity"
       },
-      "target": 425
+      "target": 504
+    },
+    {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Andreadis A",
+          "Binder LI",
+          "Brady ST",
+          "Fu Y",
+          "Kanaan NM",
+          "LaPointe NE",
+          "Morfini GA",
+          "Patterson KR",
+          "Pigino GF",
+          "Song Y"
+        ],
+        "date": "2011-07-06",
+        "first": "Kanaan NM",
+        "last": "Binder LI",
+        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
+        "pages": "9858-68",
+        "reference": "21734277",
+        "title": "Pathogenic forms of tau inhibit kinesin-dependent axonal transport through a mechanism involving activation of axonal phosphotransferases.",
+        "type": "PubMed",
+        "volume": "31"
+      },
+      "evidence": "Filamentous, but not soluble, forms of wild-type tau inhibit anterograde, kinesin-based fast axonal transport (FAT) by activating axonal protein phosphatase 1 (PP1) and glycogen synthase kinase 3 (GSK3), independent of microtubule binding. Amino acids 2-18 of tau, comprising a phosphatase-activating domain (PAD), are necessary and sufficient for activation of this pathway. Various pathogenic forms of tau displaying increased exposure of PAD inhibited anterograde FAT in squid axoplasm. Immunohistochemical studies using a novel PAD-specific monoclonal antibody in human postmortem tissue indicated that increased PAD exposure represents an early pathogenic event in AD that closely associates in time with AT8 immunoreactivity. We propose a model of pathogenesis in which disease-associated changes in tau conformation lead to increased exposure of PAD, activation of PP1-GSK3, and inhibition of FAT",
+      "key": "09709d78b358c24f79640e7b59bd89d665ecd7b2633e8d09fbedab46a5e91a3fb0ea5949b445e604f7cf8d55c09df553ec002d6834219a685c3cb4743d1f7efd",
+      "line": 4768,
+      "relation": "decreases",
+      "source": 537,
+      "subject": {
+        "modifier": "Activity"
+      },
+      "target": 175
+    },
+    {
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+      "relation": "hasComponent",
+      "source": 314,
+      "target": 58
+    },
+    {
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+      "relation": "hasComponent",
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+      "target": 159
     },
     {
       "annotations": {
         "Anatomy": {
           "hippocampal formation": true
         },
+        "Confidence": {
+          "Medium": true
+        },
         "Method": {
           "Cell Viability Assay, MTT": true,
           "Confocal Laser Microscopy": true,
@@ -16166,17 +19687,20 @@
         "volume": "256"
       },
       "evidence": "Primary hippocampal neuron cells at different concentrations (0, 50, 100, 200 lg/ml) of glucose–BSA were incubated together for 24 h, and then thr205- phosphorylated tau was estimated by the western immunoblotting method. Western blot analysis of each experimental group showed that glucose–BSA promoted tau thr205-phosphorylation in a concentration-dependent manner (Fig. 3(a)). In the present study, it was also shown that 100 nM GLP-1 or Ex-4 treatment reduced tau hyperphosphorylation induced by glucose–BSA (Fig. 3(b, c)).",
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       "relation": "increases",
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-      "target": 579
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+      "target": 663
     },
     {
       "annotations": {
         "Anatomy": {
           "hippocampal formation": true
         },
+        "Confidence": {
+          "Medium": true
+        },
         "Method": {
           "Cell Viability Assay, MTT": true,
           "Confocal Laser Microscopy": true,
@@ -16204,47 +19728,18 @@
         "volume": "256"
       },
       "evidence": "Western blot analysis of different experimental groups, primary hippocampal neuron cells concurrent treatment with different concentrations (0, 50, 100, 200 lg/ml) of glucose–BSA for 24 h, also showed that glucose–BSA inhibited the phosphorylation of GSK-3b in a concentration-dependent manner (Fig. 4(a)). And 100 nM GLP-1 or Ex-4 can up-regulate phosphorylation of GSK-3b at Ser9, which was decreased by treatment with glucose–BSA (Fig. 4(b, c)).",
-      "key": "853813a5a8a9aa53fb53e72ab4a3225a0083c810c121eeb5a382aa22b846bc9c250c4bcb25ed9b0a155217874e3a0864dcf1fc387c031a8d2d7f1319ec0010e5",
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+      "line": 458,
       "relation": "decreases",
-      "source": 49,
-      "target": 457
+      "source": 314,
+      "target": 538
     },
     {
       "annotations": {
-        "Method": {
-          "Immunohistochemistry": true,
-          "Western Blot": true
-        },
-        "Species": {
-          "10090": true
+        "Confidence": {
+          "Medium": true
         }
       },
-      "citation": {
-        "authors": [
-          "Gong CX",
-          "Li X",
-          "Lu F",
-          "Wang JZ"
-        ],
-        "date": "2006-04-01",
-        "first": "Li X",
-        "last": "Gong CX",
-        "name": "The European journal of neuroscience",
-        "pages": "2078-86",
-        "reference": "16630055",
-        "title": "Concurrent alterations of O-GlcNAcylation and phosphorylation of tau in mouse brains during fasting.",
-        "type": "PubMed",
-        "volume": "23"
-      },
-      "evidence": "We recently discovered that the human brain tau is also modified by O-GlcNAcylation in addition to phosphorylation and that O-GlcNAcylation modulates phosphorylation of tau inversely (Liu et al.,2004a). We found that fasting induced a time-dependent decrease in tau O-GlcNAcylation and concurrent hyperphosphorylation of tau at most of the phosphorylation sites studied.",
-      "key": "2fef4c78d9e04bd58a2fd425f90ffbbb52e1e1d855c4b0c8b32ec65ccd0a407b763c19ecade8185374c8591e385744ef810120823cdd2a8e7005004efe617946",
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-      "relation": "negativeCorrelation",
-      "source": 49,
-      "target": 921
-    },
-    {
       "citation": {
         "authors": [
           "El-Akkad E",
@@ -16268,37 +19763,132 @@
       },
       "evidence": "Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396.",
       "key": "e0743fe9706d8f6353d08e0e5712599e5626d402f85b9f41cd4f167b9a4b69fb3a048c0fe2055ec5c1a9a43a3306f9a901a7b261c084faf8edaaf364242e533f",
-      "line": 1116,
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       "relation": "positiveCorrelation",
-      "source": 579,
-      "target": 299
+      "source": 663,
+      "target": 372
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "Method": {
+          "Electron Microscopy, Transmission": true,
+          "NMR Spectroscopy": true,
+          "Thioflavin T Assay": true
+        }
+      },
       "citation": {
         "authors": [
-          "Kawakami F",
-          "Ohtsuki K",
-          "Suzuki K"
+          "Baulieu EE",
+          "Byrne C",
+          "Cantrelle FX",
+          "Chambraud B",
+          "Despres C",
+          "Huvent I",
+          "Jacquot Y",
+          "Landrieu I",
+          "Lippens G",
+          "Qi H",
+          "Smet-Nocca C"
         ],
-        "date": "2008-02-01",
-        "first": "Kawakami F",
-        "last": "Ohtsuki K",
-        "name": "Biological &amp; pharmaceutical bulletin",
-        "pages": "193-200",
-        "reference": "18239272",
-        "title": "A novel consensus phosphorylation motif in sulfatide- and cholesterol-3-sulfate-binding protein substrates for CK1 in vitro.",
+        "date": "2017-08-22",
+        "first": "Despres C",
+        "last": "Smet-Nocca C",
+        "name": "Proceedings of the National Academy of Sciences of the United States of America",
+        "pages": "9080-9085",
+        "reference": "28784767",
+        "title": "Identification of the Tau phosphorylation pattern that drives its aggregation.",
         "type": "PubMed",
-        "volume": "31"
+        "volume": "114"
       },
-      "evidence": "Epitopes S198, S199, S202, T205, S422 (Lund 2013)",
-      "key": "da9ede1f3f483b4c032f1f194cbaaa93e4445a44aaf84bed6b503af83b3285e85d397851f726b5a75c2b6c41e11600bc16551f5a7ed947645ce25f49f712a3ef",
-      "line": 1287,
+      "evidence": "When combined with ERK2 catalyzed phosphorylation, the turn-like disrupting G207V mutation in TauF8 hence leads to fast aggregation that already occurs during the phosphorylation reaction.",
+      "key": "0c83d70bf47e9e3595fead70044117c5e45686cee8a349e68fd457be9cadb043d207eece9c0ec187643959a2c1bce6b065dbbf5fc8efd3977e83a51b200f2657",
+      "line": 1857,
       "relation": "partOf",
-      "source": 579,
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+      "target": 415
+    },
+    {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Ait-Ghezala G",
+          "Bachmeier C",
+          "Beaulieu-Abdelahad D",
+          "Crawford F",
+          "Jin C",
+          "Laco G",
+          "Lin Y",
+          "Mullan M",
+          "Paris D"
+        ],
+        "date": "2014-12-05",
+        "first": "Paris D",
+        "last": "Mullan M",
+        "name": "The Journal of biological chemistry",
+        "pages": "33927-44",
+        "reference": "25331948",
+        "title": "The spleen tyrosine kinase (Syk) regulates Alzheimer amyloid-β production and Tau hyperphosphorylation.",
+        "type": "PubMed",
+        "volume": "289"
+      },
+      "evidence": "Western blot analyses of brain homogenates show that (−)-nilvadipine significantly reduces Tau phosphorylation in AT8 (phosphorylated Ser-199/Ser-202/Thr-205) and PHF-1 (phosphorylated Ser-396/Ser-404) epitopes",
+      "key": "8ed9c770257c88b3c71a85604456b2ab128d2454701afc09d1b5bcfcc67f9d1441696e2ba58a2c6963e80ef9cea971c6bdd6a169c1bbc69c3a70fd07edf3f232",
+      "line": 2760,
+      "relation": "partOf",
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+    },
+    {
+      "annotations": {
+        "Anatomy": {
+          "hippocampal formation": true
+        },
+        "Confidence": {
+          "Medium": true
+        },
+        "Species": {
+          "10116": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Boehm J",
+          "Bourgeois C",
+          "Dudilot A",
+          "Lauzon M",
+          "Leclerc N",
+          "Mondragón-Rodríguez S",
+          "Trillaud-Doppia E"
+        ],
+        "date": "2012-09-14",
+        "first": "Mondragón-Rodríguez S",
+        "last": "Boehm J",
+        "name": "The Journal of biological chemistry",
+        "pages": "32040-53",
+        "reference": "22833681",
+        "title": "Interaction of endogenous tau protein with synaptic proteins is regulated by N-methyl-D-aspartate receptor-dependent tau phosphorylation.",
+        "type": "PubMed",
+        "volume": "287"
+      },
+      "evidence": "Hence, LTD-inducing NMDA receptor activation leads to an increase in tau phosphorylation at sites PHF-1, AT180, as well as AT8 and to a reduction at AT100.",
+      "key": "2761bca4b214eaa02eaa9e3249efb2e943edd5f9cdb0687acd87c756c5fb27c81c0b12fe6a38ea0861036d9871ad1f8c65772254dd6108840fb1ce7cee093777",
+      "line": 3049,
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+      "target": 415
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "Method": {
           "Electron Microscopy, Transmission": true,
           "NMR Spectroscopy": true,
@@ -16330,55 +19920,84 @@
         "volume": "114"
       },
       "evidence": "When combined with ERK2 catalyzed phosphorylation, the turn-like disrupting G207V mutation in TauF8 hence leads to fast aggregation that already occurs during the phosphorylation reaction.",
-      "key": "0c83d70bf47e9e3595fead70044117c5e45686cee8a349e68fd457be9cadb043d207eece9c0ec187643959a2c1bce6b065dbbf5fc8efd3977e83a51b200f2657",
-      "line": 1536,
-      "relation": "partOf",
-      "source": 579,
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+      "key": "fbae35b18fbce9126bf8be041d7da735255ff3cea1dbfe89d956d9c1c07bff2e8cd4b412ac9b8dabb26dd7509df7aa628ca153ff6c2b2704e834db2fae4bc77e",
+      "line": 1862,
+      "relation": "increases",
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+      "target": 402
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+    {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Gamblin TC",
+          "Sun Q"
+        ],
+        "date": "2009-06-30",
+        "first": "Sun Q",
+        "last": "Gamblin TC",
+        "name": "Biochemistry",
+        "pages": "6002-11",
+        "reference": "19459590",
+        "title": "Pseudohyperphosphorylation causing AD-like changes in tau has significant effects on its polymerization.",
+        "type": "PubMed",
+        "volume": "48"
+      },
+      "evidence": "Because S199/S202/T205E, S396/S404E, 6-Phos and 7-Phos all demonstrated an AD-like shift in mobility as a result of phosphorylation-like changes, we conclude that they have the characteristics of hyperphosphorylated tau. These mutants will therefore be referred to as pseudo-hyperphosphorylated tau throughout the manuscript. On the basis of the observations that pseudohyperphosphorylated tau has decreased affinity for microtubules and reduced inducer-initiated rates of nucleation and polymerization, we propose that this combination could be the cause of the increased cytotoxicity of hyperphosphorylated tau in Alzheimer's disease and also explain the potentially beneficial role of tau polymerization and NFT formation.",
+      "key": "7c87c8c6cc2ec80314367ef9f3d3b51388f9704a217a4cf8703207d0998332d3e07e5e8cabbc359493d6a560a0dbbed90aa1506b80342da0fa907f7d55d25df3",
+      "line": 3035,
+      "relation": "decreases",
+      "source": 663,
+      "target": 247
     },
     {
       "annotations": {
+        "Anatomy": {
+          "hippocampal formation": true
+        },
+        "Confidence": {
+          "Medium": true
+        },
         "Species": {
           "10116": true
         }
       },
       "citation": {
         "authors": [
-          "Ai J",
-          "Ban T",
-          "Bao YN",
-          "Chen QX",
-          "Hu XL",
-          "Jiang XM",
-          "Liu CD",
-          "Pei SC",
-          "Su XL",
-          "Sun LH",
-          "Sun LL",
-          "Wang X",
-          "Yan ML",
-          "Zhao LJ",
-          "Zong DK"
+          "Boehm J",
+          "Bourgeois C",
+          "Dudilot A",
+          "Lauzon M",
+          "Leclerc N",
+          "Mondragón-Rodríguez S",
+          "Trillaud-Doppia E"
         ],
-        "date": "2015-09-01",
-        "first": "Sun LH",
-        "last": "Ai J",
-        "name": "Journal of neurochemistry",
-        "pages": "1139-51",
-        "reference": "26118667",
-        "title": "Activation of Cdk5/p25 and tau phosphorylation following chronic brain hypoperfusion in rats involves microRNA-195 down-regulation.",
+        "date": "2012-09-14",
+        "first": "Mondragón-Rodríguez S",
+        "last": "Boehm J",
+        "name": "The Journal of biological chemistry",
+        "pages": "32040-53",
+        "reference": "22833681",
+        "title": "Interaction of endogenous tau protein with synaptic proteins is regulated by N-methyl-D-aspartate receptor-dependent tau phosphorylation.",
         "type": "PubMed",
-        "volume": "134"
+        "volume": "287"
       },
-      "evidence": "Endogenous miR-195 was knocked down using over-expression of its antisense molecule (pre-AMO-miR-195) via a lentivirus (lenti-pre-AMO-miR-195); this knockdown increased the tau phosphorylation at Ser202/Thr205, Ser262, Thr231, Ser422, and the Cdk5/p25 activation, but over-expression of miR-195 using lenti-pre-miR-195 decreased the tau phosphorylation and Cdk5/p25 activation.",
-      "key": "28ed2f012fd38c4d64f9e1b5a58444f4b769c1abc99c5a1eb8ba70a708a5332f56ccd55d21d71da20681792b9e9cffdec7a0daff48c48fefb8dea5151c346b56",
-      "line": 2324,
-      "relation": "negativeCorrelation",
-      "source": 579,
-      "target": 264
+      "evidence": "This result is supported by recent studies showing that the interaction between Fyn and tau is regulated through tau phosphorylation at the AT8 site, increasing tau-Fyn interaction by 42-fold after tau is phosphorylated or bearing a phosphomimetic mutation at the AT8 site (63). In our experiments, tau phosphorylation at AT8 is strongly up-regulated through the activation of NMDA receptors (Fig. 3), suggesting that NMDA receptor activation could massively enhance the interaction between tau and Fyn.",
+      "key": "8dce122f8abe060dd35e71a23076c97de59ac5b6e92173640a9e7ffc8f0e990a769a64329e6de65f7720e4f88593db8dea27a8774b77822e13aeb8556f7f9038",
+      "line": 3071,
+      "relation": "increases",
+      "source": 663,
+      "target": 279
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "Research_Model": {
           "rTg4510 mice": true
         }
@@ -16405,13 +20024,19 @@
       },
       "evidence": "Acute treatment of rTg4510 mice with an O-GlcNAcase inhibitor transiently reduced tau phosphorylation at epitopes implicated in tau pathology. More importantly, long-term inhibitor treatment strongly increased tau O-GlcNAcylation, reduced the number of dystrophic neurons, and protected against the formation of pathological tau species without altering the phosphorylation of non-pathological tau.",
       "key": "72ccf29ee9c3cc799684ea8327d4a6bd0eb8fc2cefc231da60372fb4a396602b8edd56ab5cfb239df577d2b3508a4fabfb4dde3e8562581a8386c5499518374d",
-      "line": 2499,
+      "line": 3090,
       "relation": "positiveCorrelation",
-      "source": 579,
-      "target": 513
+      "source": 663,
+      "target": 596
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Hippocampus": true
+        },
         "Research_Model": {
           "TPR50 mice": true
         },
@@ -16442,13 +20067,16 @@
       },
       "evidence": "We developed a transgenic mouse, named TPR50, harboring human P301S tau. Tau phosphorylation in the hippocampus of TPR50 mice increased with age, particularly at S202/T205. Therefore, cognitive dysfunction in TPR50 mice may result from early MT dysfunction and impaired axonal transport rather than accumulation of insoluble tau and neurodegeneration.",
       "key": "8c2c2cd46b7a9db97539888ede19e19bfc6902e15a00ca8c825320dab915b9e5a361cbb959b99808ebe3829eb0db5791cbd1fb65e7b3fa5e29688a4016a93e26",
-      "line": 2516,
+      "line": 3111,
       "relation": "positiveCorrelation",
-      "source": 579,
-      "target": 626
+      "source": 663,
+      "target": 712
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "Research_Model": {
           "pR5 mice": true
         },
@@ -16474,13 +20102,16 @@
       },
       "evidence": "We studied underlying pathomechanisms in tauopathies using pR5 mice that express the P301L tau mutation found in familial forms of frontotemporal dementia. In a longitudinal study we investigated the functional status of glycogen synthase kinase-3 and correlated it with the appearance of distinct tau phospho-epitopes. Neurons displaying increases in activating phosphorylation of glycogen synthase kinase-3α/β at tyrosine 279/216 also showed an intense rather than moderate AT8 (phospho-Ser202/Thr205 tau) immunoreactivity, and immunoreactivity for AT100 (phospho-Ser212/Thr214 tau) and phosphorylated Ser422, phospho-epitopes associated with fibrillar tau pathology.",
       "key": "70b72ae48c0bebbe333f00dbc56158176696f6f3be8d9719b3d99d8098ae68dba4424ac101eb98ed85b7b3c7e94891da2b031b8ef2bbb3446136446b6628ad9d",
-      "line": 2535,
+      "line": 3135,
       "relation": "positiveCorrelation",
-      "source": 579,
-      "target": 625
+      "source": 663,
+      "target": 711
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Disease_Progression": {
           "Late Stage": true
         },
@@ -16510,13 +20141,19 @@
       },
       "evidence": "Phosphorylation at the epitope Ser202/Thr205 is regarded as a good marker for late-stage NFTs (5, 72). Hyman and colleagues (5) demonstrated that AT8 immunoreactivity is present primarily in eNFTs and in certain cases in iNFTs. These investigators also found that AT8 revealed dense neuropil thread staining.",
       "key": "bceba1f946ae45359442accdc9326e92a831ddf1c228fea3605d1ba39320032d707c0cb869f996ad4fc5cb53327d68d7db8c8df595b4f3b2a12a3e5c7b1ff51d",
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       "relation": "partOf",
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-      "target": 80
+      "source": 663,
+      "target": 94
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Synapses": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -16544,16 +20181,55 @@
       },
       "evidence": "Oligomers positive for pS202/pT205 accumulate at synapses in AD",
       "key": "8b221d2ec935d3e90753d4c572a368642d568f80d7fcb3bac2a79a37eb69094e252532d4848de377a42898561a9f4d5a60cb68828c99ea94e02e2a9e670d27c7",
-      "line": 2623,
+      "line": 3245,
       "relation": "partOf",
-      "source": 579,
-      "target": 117
+      "source": 663,
+      "target": 118
+    },
+    {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Andreadis A",
+          "Binder LI",
+          "Brady ST",
+          "Fu Y",
+          "Kanaan NM",
+          "LaPointe NE",
+          "Morfini GA",
+          "Patterson KR",
+          "Pigino GF",
+          "Song Y"
+        ],
+        "date": "2011-07-06",
+        "first": "Kanaan NM",
+        "last": "Binder LI",
+        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
+        "pages": "9858-68",
+        "reference": "21734277",
+        "title": "Pathogenic forms of tau inhibit kinesin-dependent axonal transport through a mechanism involving activation of axonal phosphotransferases.",
+        "type": "PubMed",
+        "volume": "31"
+      },
+      "evidence": "Filamentous, but not soluble, forms of wild-type tau inhibit anterograde, kinesin-based fast axonal transport (FAT) by activating axonal protein phosphatase 1 (PP1) and glycogen synthase kinase 3 (GSK3), independent of microtubule binding. Amino acids 2-18 of tau, comprising a phosphatase-activating domain (PAD), are necessary and sufficient for activation of this pathway. Various pathogenic forms of tau displaying increased exposure of PAD inhibited anterograde FAT in squid axoplasm. Immunohistochemical studies using a novel PAD-specific monoclonal antibody in human postmortem tissue indicated that increased PAD exposure represents an early pathogenic event in AD that closely associates in time with AT8 immunoreactivity. We propose a model of pathogenesis in which disease-associated changes in tau conformation lead to increased exposure of PAD, activation of PP1-GSK3, and inhibition of FAT",
+      "key": "51d505468ec4f5961cfd6dfc19ab0f75bda9b257b816659812e8e94c78878dd497fb082be35fcca3bf148e05f37284081b7d9329db4c072e30a5cc23551e5378",
+      "line": 4772,
+      "relation": "positiveCorrelation",
+      "source": 663,
+      "target": 439
     },
     {
       "annotations": {
         "Anatomy": {
           "hippocampal formation": true
         },
+        "Confidence": {
+          "Medium": true
+        },
         "Method": {
           "Cell Viability Assay, MTT": true,
           "Confocal Laser Microscopy": true,
@@ -16582,16 +20258,19 @@
       },
       "evidence": "Primary hippocampal neuron cells at different concentrations (0, 50, 100, 200 lg/ml) of glucose–BSA were incubated together for 24 h, and then thr205- phosphorylated tau was estimated by the western immunoblotting method. Western blot analysis of each experimental group showed that glucose–BSA promoted tau thr205-phosphorylation in a concentration-dependent manner (Fig. 3(a)). In the present study, it was also shown that 100 nM GLP-1 or Ex-4 treatment reduced tau hyperphosphorylation induced by glucose–BSA (Fig. 3(b, c)).",
       "key": "1a583d10191f79b3519cc88092362d5d8f68a0b1f874d0b1de045930432bf39f42affa19c21ab132c0937ca19cd955af0270cdf7043bf881141785a3c15fee5e",
-      "line": 392,
+      "line": 449,
       "relation": "decreases",
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-      "target": 579
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+      "target": 663
     },
     {
       "annotations": {
         "Anatomy": {
           "hippocampal formation": true
         },
+        "Confidence": {
+          "Medium": true
+        },
         "Method": {
           "Cell Viability Assay, MTT": true,
           "Confocal Laser Microscopy": true,
@@ -16620,15 +20299,18 @@
       },
       "evidence": "Western blot analysis of different experimental groups, primary hippocampal neuron cells concurrent treatment with different concentrations (0, 50, 100, 200 lg/ml) of glucose–BSA for 24 h, also showed that glucose–BSA inhibited the phosphorylation of GSK-3b in a concentration-dependent manner (Fig. 4(a)). And 100 nM GLP-1 or Ex-4 can up-regulate phosphorylation of GSK-3b at Ser9, which was decreased by treatment with glucose–BSA (Fig. 4(b, c)).",
       "key": "915cbec30bd07892299da2cbe43bc459680b54d95c8adf68499a04ec6dc0f98affd57c94e80a9f65005eb858b298478ae2c549e76cc7b3380026412b0fa7e424",
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       "relation": "increases",
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-      "target": 457
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+      "target": 538
     },
     {
       "annotations": {
         "Cell_Line": {
           "PC12": true
+        },
+        "Confidence": {
+          "Medium": true
         }
       },
       "citation": {
@@ -16653,19 +20335,19 @@
         "volume": "300"
       },
       "evidence": "In this study, we demonstrated that GLP-1RA could inhibit oxidative stress and repair mitochondrial damage in addition to decreasing tau hyperphosphorylation in PC12 cells treated with AGEs. Importantly, we first observed AGEs in the circulatory system could induce tau hyperphosphorylation after we injected AGEs (1μg/kg bodyweight) into the mice tail vein. We found GLP-1RA could promote mitochondrial biogenesis and antioxidant system via regulating peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) signaling pathway in vivo besides down-regulating the activity of glycogen synthase kinase 3β (GSK-3β) to reverse tau hyperphosphorylation directly.",
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       "relation": "decreases",
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-      "subject": {
-        "modifier": "Activity"
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-      "target": 205
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+      "target": 226
     },
     {
       "annotations": {
         "Cell_Line": {
           "PC12": true
+        },
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+          "Medium": true
         }
       },
       "citation": {
@@ -16690,23 +20372,60 @@
         "volume": "300"
       },
       "evidence": "In this study, we demonstrated that GLP-1RA could inhibit oxidative stress and repair mitochondrial damage in addition to decreasing tau hyperphosphorylation in PC12 cells treated with AGEs. Importantly, we first observed AGEs in the circulatory system could induce tau hyperphosphorylation after we injected AGEs (1μg/kg bodyweight) into the mice tail vein. We found GLP-1RA could promote mitochondrial biogenesis and antioxidant system via regulating peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) signaling pathway in vivo besides down-regulating the activity of glycogen synthase kinase 3β (GSK-3β) to reverse tau hyperphosphorylation directly.",
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       "object": {
         "modifier": "Activity"
       },
       "relation": "increases",
-      "source": 451,
-      "subject": {
-        "modifier": "Activity"
+      "source": 534,
+      "target": 100
+    },
+    {
+      "annotations": {
+        "Cell_Line": {
+          "PC12": true
+        },
+        "Confidence": {
+          "Medium": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "An FM",
+          "Chen S",
+          "Gao XD",
+          "Liu AR",
+          "Wang Y",
+          "Xu Z",
+          "Yao WB",
+          "Yin L"
+        ],
+        "date": "2015-08-06",
+        "first": "An FM",
+        "last": "Gao XD",
+        "name": "Neuroscience",
+        "pages": "75-84",
+        "reference": "25987199",
+        "title": "Glucagon-like peptide-1 regulates mitochondrial biogenesis and tau phosphorylation against advanced glycation end product-induced neuronal insult: Studies in vivo and in vitro.",
+        "type": "PubMed",
+        "volume": "300"
       },
-      "target": 87
+      "evidence": "In this study, we demonstrated that GLP-1RA could inhibit oxidative stress and repair mitochondrial damage in addition to decreasing tau hyperphosphorylation in PC12 cells treated with AGEs. Importantly, we first observed AGEs in the circulatory system could induce tau hyperphosphorylation after we injected AGEs (1μg/kg bodyweight) into the mice tail vein. We found GLP-1RA could promote mitochondrial biogenesis and antioxidant system via regulating peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) signaling pathway in vivo besides down-regulating the activity of glycogen synthase kinase 3β (GSK-3β) to reverse tau hyperphosphorylation directly.",
+      "key": "30aa167bc55f9acade389a7c206ef0e3c58835b2bde21e07b808d35ac359615a5060fc87edb87ed8b0350c3e09cd9320fb04819c792aab4485d03f90307a71c7",
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+      "relation": "decreases",
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       "annotations": {
         "Anatomy": {
           "hippocampal formation": true
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         "type": "PubMed",
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-          "Cuadrado A",
-          "Kügler S",
-          "Lastres-Becker I"
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-        "name": "Redox biology",
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-        "title": "Pharmacological targeting of GSK-3 and NRF2 provides neuroprotection in a preclinical model of tauopathy.",
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-      "evidence": "The second mechanism is related to GSK-3, which phosphorylates NRF2 creating a recognition site for β-Transducin Repeat Containing E3 Ubiquitin Protein Ligase (β-TrCP). β-TrCP leads to Cullin-1/Rbx1-mediated NRF2 ubiquitination and its subsequent degradation [8]. Since GSK-3β is inhibited by phosphorylation at Ser9 by Ser/Thr protein kinases such as AKT, it has been suggested that NRF2 might be up-regulated through activation of AKT and permanent inactivation of GSK-3 [9], [10].",
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+      "evidence": "Primary hippocampal neuron cells at different concentrations (0, 50, 100, 200 lg/ml) of glucose–BSA were incubated together for 24 h, and then thr205- phosphorylated tau was estimated by the western immunoblotting method. Western blot analysis of each experimental group showed that glucose–BSA promoted tau thr205-phosphorylation in a concentration-dependent manner (Fig. 3(a)). In the present study, it was also shown that 100 nM GLP-1 or Ex-4 treatment reduced tau hyperphosphorylation induced by glucose–BSA (Fig. 3(b, c)).",
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       },
       "citation": {
         "authors": [
-          "Fan SJ",
-          "Huang FI",
-          "Liou JP",
-          "Yang CR"
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-        "first": "Fan SJ",
-        "last": "Yang CR",
-        "name": "Cell death &amp; disease",
-        "pages": "655",
-        "reference": "29844403",
-        "title": "The novel histone de acetylase 6 inhibitor, MPT0G211, ameliorates tau phosphorylation and cognitive deficits in an Alzheimer's disease model.",
+          "An FM",
+          "Chen S",
+          "Gao XD",
+          "Liu AR",
+          "Yao WB",
+          "Yin DK",
+          "Yin L"
+        ],
+        "date": "2014-01-03",
+        "first": "Chen S",
+        "last": "Gao XD",
+        "name": "Neuroscience",
+        "pages": "137-46",
+        "reference": "24183963",
+        "title": "Glucagon-like peptide-1 protects hippocampal neurons against advanced glycation end product-induced tau hyperphosphorylation.",
         "type": "PubMed",
-        "volume": "9"
-      },
-      "evidence": "This study aimed to investigate the protective effects and mechanism of the novel HDAC6 inhibitor, MPT0G211, using an AD model. Our results indicated that MPT0G211 significantly reduced tau phosphorylation and aggregation, the processes highly correlated with the formation of NFTs. This HDAC6 inhibitory activity resulted in an increase in acetylated Hsp90, which decreased Hsp90 and HDAC6 binding, causing ubiquitination of phosphorylated tau proteins. In addition, a significant increase of phospho-glycogen synthase kinase-3β (phospho-GSK3β) on Ser9 (the inactive form) through Akt phosphorylation was associated with the inhibition of phospho-tau Ser396 in response to MPT0G211 treatment.",
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+      "evidence": "Western blot analysis of different experimental groups, primary hippocampal neuron cells concurrent treatment with different concentrations (0, 50, 100, 200 lg/ml) of glucose–BSA for 24 h, also showed that glucose–BSA inhibited the phosphorylation of GSK-3b in a concentration-dependent manner (Fig. 4(a)). And 100 nM GLP-1 or Ex-4 can up-regulate phosphorylation of GSK-3b at Ser9, which was decreased by treatment with glucose–BSA (Fig. 4(b, c)).",
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     {
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+        "Method": {
+          "Cell Viability Assay, MTT": true,
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       "citation": {
         "authors": [
-          "Andreadis A",
-          "Binder LI",
-          "Brady ST",
-          "Fu Y",
-          "Kanaan NM",
-          "LaPointe NE",
-          "Morfini GA",
-          "Patterson KR",
-          "Pigino GF",
-          "Song Y"
+          "An FM",
+          "Chen S",
+          "Gao XD",
+          "Liu AR",
+          "Yao WB",
+          "Yin DK",
+          "Yin L"
         ],
-        "date": "2011-07-06",
-        "first": "Kanaan NM",
-        "last": "Binder LI",
-        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
-        "pages": "9858-68",
-        "reference": "21734277",
-        "title": "Pathogenic forms of tau inhibit kinesin-dependent axonal transport through a mechanism involving activation of axonal phosphotransferases.",
+        "date": "2014-01-03",
+        "first": "Chen S",
+        "last": "Gao XD",
+        "name": "Neuroscience",
+        "pages": "137-46",
+        "reference": "24183963",
+        "title": "Glucagon-like peptide-1 protects hippocampal neurons against advanced glycation end product-induced tau hyperphosphorylation.",
         "type": "PubMed",
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+        "volume": "256"
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-      "evidence": "Filamentous, but not soluble, forms of wild-type tau inhibit anterograde, kinesin-based fast axonal transport (FAT) by activating axonal protein phosphatase 1 (PP1) and glycogen synthase kinase 3 (GSK3), independent of microtubule binding. Amino acids 2-18 of tau, comprising a phosphatase-activating domain (PAD), are necessary and sufficient for activation of this pathway. Various pathogenic forms of tau displaying increased exposure of PAD inhibited anterograde FAT in squid axoplasm. Immunohistochemical studies using a novel PAD-specific monoclonal antibody in human postmortem tissue indicated that increased PAD exposure represents an early pathogenic event in AD that closely associates in time with AT8 immunoreactivity. We propose a model of pathogenesis in which disease-associated changes in tau conformation lead to increased exposure of PAD, activation of PP1-GSK3, and inhibition of FAT",
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       "annotations": {
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         "authors": [
-          "Ait-Ghezala G",
-          "Bachmeier C",
-          "Beaulieu-Abdelahad D",
-          "Crawford F",
-          "Jin C",
-          "Laco G",
-          "Lin Y",
-          "Mullan M",
-          "Paris D"
+          "Cuadrado A",
+          "Kügler S",
+          "Lastres-Becker I"
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-        "date": "2014-12-05",
-        "first": "Paris D",
-        "last": "Mullan M",
-        "name": "The Journal of biological chemistry",
-        "pages": "33927-44",
-        "reference": "25331948",
-        "title": "The spleen tyrosine kinase (Syk) regulates Alzheimer amyloid-β production and Tau hyperphosphorylation.",
+        "date": "2018-04-01",
+        "first": "Cuadrado A",
+        "last": "Lastres-Becker I",
+        "name": "Redox biology",
+        "pages": "522-534",
+        "reference": "29121589",
+        "title": "Pharmacological targeting of GSK-3 and NRF2 provides neuroprotection in a preclinical model of tauopathy.",
         "type": "PubMed",
-        "volume": "289"
+        "volume": "14"
       },
-      "evidence": "We observed that pharmacological inhibition of Syk with BAY61-3606 stimulates Ser-9 phosphorylation of GSK3β in SH-SY5Y cells (Fig. 9, A and B) suggesting that blocking Syk activity results in GSK3β inhibition.",
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+      "evidence": "The second mechanism is related to GSK-3, which phosphorylates NRF2 creating a recognition site for β-Transducin Repeat Containing E3 Ubiquitin Protein Ligase (β-TrCP). β-TrCP leads to Cullin-1/Rbx1-mediated NRF2 ubiquitination and its subsequent degradation [8]. Since GSK-3β is inhibited by phosphorylation at Ser9 by Ser/Thr protein kinases such as AKT, it has been suggested that NRF2 might be up-regulated through activation of AKT and permanent inactivation of GSK-3 [9], [10].",
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       "citation": {
         "authors": [
-          "George RC",
-          "Graves DJ",
-          "Lew J"
+          "Fan SJ",
+          "Huang FI",
+          "Liou JP",
+          "Yang CR"
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-        "date": "2013-01-01",
-        "first": "George RC",
-        "last": "Graves DJ",
-        "name": "Journal of Alzheimer's disease : JAD",
-        "pages": "21-40",
-        "reference": "23531502",
-        "title": "Interaction of cinnamaldehyde and epicatechin with tau: implications of beneficial effects in modulating Alzheimer's disease pathogenesis.",
+        "date": "2018-05-29",
+        "first": "Fan SJ",
+        "last": "Yang CR",
+        "name": "Cell death &amp; disease",
+        "pages": "655",
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+        "title": "The novel histone de acetylase 6 inhibitor, MPT0G211, ameliorates tau phosphorylation and cognitive deficits in an Alzheimer's disease model.",
         "type": "PubMed",
-        "volume": "36"
+        "volume": "9"
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-      "evidence": "CA and the oxidized form of EC (ECox) inhibited tau aggregation in vitro due to their interaction with the two cysteine residues in tau. A synthetic peptide, SKCGS, representing the actual tau sequence, identified the thiol as reacting with CA and ECox which necessitates of cysteine for aggregation inhibition by CA.",
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@@ -16944,47 +20663,17 @@
         "volume": "36"
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       "evidence": "CA and the oxidized form of EC (ECox) inhibited tau aggregation in vitro due to their interaction with the two cysteine residues in tau. A synthetic peptide, SKCGS, representing the actual tau sequence, identified the thiol as reacting with CA and ECox which necessitates of cysteine for aggregation inhibition by CA.",
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-          "Electron Microscopy, Transmission": true,
-          "Mass Spectrometry": true
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-      "citation": {
-        "authors": [
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-          "Graves DJ",
-          "Lew J"
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-      "evidence": "The data (Fig. 8B) shows that no significant difference in the extent of tubulin assembly could be observed with normal tau or tau incubated with CA. These results also indicate that once assembled, the microtubules remained stable to the same extent in the presence or in the absence of CA.",
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@@ -17010,17 +20699,20 @@
         "volume": "36"
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       "evidence": "We found that CA (lane 4) and EC (lane 6) substantially prevented the H2O2 induced formation of the high molecular weight species.",
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@@ -17045,41 +20737,30 @@
         "type": "PubMed",
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-      "evidence": "CA and the oxidized form of EC (ECox) inhibited tau aggregation in vitro due to their interaction with the two cysteine residues in tau. A synthetic peptide, SKCGS, representing the actual tau sequence, identified the thiol as reacting with CA and ECox which necessitates of cysteine for aggregation inhibition by CA.",
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+      "evidence": "We found that CA (lane 4) and EC (lane 6) substantially prevented the H2O2 induced formation of the high molecular weight species.",
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-          "Carlomagno Y",
-          "Cook C",
-          "Petrucelli L",
-          "Stankowski JN",
-          "Stetler C"
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-        "date": "2014-01-01",
-        "first": "Cook C",
-        "last": "Petrucelli L",
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-        "title": "Acetylation: a new key to unlock tau's role in neurodegeneration.",
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-      "evidence": "We demonstrate that elevated HDAC6 activity increases phosphorylation of tau at the 12E8 epitope (pS262/356), a phospho-epitope present within the KXGS motifs of tau’s microtubule-binding domain. The phosphorylation of KXGS motifs within tau by the kinase Par-1/MARK2 is required for tau proteotoxicity in Drosophila [29], observed at very early stages of NFT formation in AD brain [30], and appears to prime tau for subsequent phosphorylation events",
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@@ -17105,14 +20786,17 @@
         "volume": "36"
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-          "Hwang AW",
-          "Lee VM",
-          "Marmorstein R",
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-          "Yuan CX"
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-        "first": "Hwang AW",
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-        "title": "Conserved Lysine Acetylation within the Microtubule-Binding Domain Regulates MAP2/Tau Family Members.",
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-      "evidence": "All three MAPs possess highly lysine-rich MTBRs that mediate MAP-MT electrostatic interactions, indicating the potential for conserved acetylation within their repeats. Notably, tau/MAP4 alignments showed conservation of critical tau residues K280/K281 within the 2nd repeat motif 275VQIINK/K281, and the combined tau/MAP2c/MAP4 alignment showed conservation of the 3rd repeat motif harboring tau lysine K311, 306VQIVYK311",
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-        "first": "von Bergen M",
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-        "name": "The Journal of biological chemistry",
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-        "title": "Mutations of tau protein in frontotemporal dementia promote aggregation of paired helical filaments by enhancing local beta-structure.",
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-      "evidence": "We also show that two of the tau mutations found in hereditary frontotemporal dementias, DeltaK280 and P301L, have a much stronger tendency for PHF aggregation which correlates with their high propensity for beta-structure around the hexapeptide motifs.",
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-        "name": "The Journal of biological chemistry",
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-      "evidence": "We also show that two of the tau mutations found in hereditary frontotemporal dementias, DeltaK280 and P301L, have a much stronger tendency for PHF aggregation which correlates with their high propensity for beta-structure around the hexapeptide motifs.",
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-          "Huvent I",
-          "Jacquot Y",
-          "Kamah A",
-          "Landrieu I",
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         "type": "PubMed",
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         "type": "PubMed",
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+      "evidence": "The data (Fig. 8B) shows that no significant difference in the extent of tubulin assembly could be observed with normal tau or tau incubated with CA. These results also indicate that once assembled, the microtubules remained stable to the same extent in the presence or in the absence of CA.",
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-          "Mass Spectrometry": true
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-          "George RC",
-          "Graves DJ",
-          "Lew J"
+          "Marani L",
+          "Marino S",
+          "Selvatici R",
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-        "first": "George RC",
-        "last": "Graves DJ",
-        "name": "Journal of Alzheimer's disease : JAD",
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-        "reference": "23531502",
-        "title": "Interaction of cinnamaldehyde and epicatechin with tau: implications of beneficial effects in modulating Alzheimer's disease pathogenesis.",
+        "date": "2013-08-01",
+        "first": "Selvatici R",
+        "last": "Siniscalchi A",
+        "name": "Neurochemistry international",
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-      "evidence": "We were prompted to carry out this study because Acr is mainly localized in the neurons [54], is found in association with NFTs and dystrophic neurites surrounding senile plaques [55], is highly toxic to neurons, is found elevated 2–5 fold in affected regions of AD brain. EC can sequester highly reactive and toxic byproducts of oxidation such as acrolein.",
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+        "name": "Neurochemistry international",
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+      "evidence": "Primary cortical neurons exposed to the mitochondrial toxin NaN3 (0.1-3 mM) were submitted to oxidative stress with H2O2 (30-150 μM), to mimic conditions observed in neurodegenerative disorders. The effects of such treatment on a series of parameters useful in characterizing neuronal damage were investigated: (i) the basal release of glutamate, evaluated as (3)H-d-Aspartate efflux, was sharply, concentration-dependently, increased; (ii) the phosphorylation status of intracellular markers known to be involved in the neurodegenerative processes, in particular in Alzheimer disease: tau and GSK3β were increased, as well as the protein level of β-secretase (BACE1) and p35/25 evaluated by Western blotting, while (iii) the cell metabolic activity, measured with the MTT method, was reduced, in a concentration- and time-dependent manner. The latter effect, as well as tau hyperphosphorylation, was prevented both by a mixture of antioxidant drugs (100 μM ascorbic acid, 10 μM trolox, 100 μM glutathione) and by the anti-Alzheimer drug, memantine, 20 μM.",
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@@ -17486,38 +21084,59 @@
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     {
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+          "SDS-PAGE": true,
+          "Thioflavin T Assay": true,
+          "Western Blot": true
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+      },
       "citation": {
         "authors": [
-          "Ikura T",
-          "Ito N"
+          "Arendt T",
+          "Flach K",
+          "Haase C",
+          "Kuhla B",
+          "Lüth HJ",
+          "Münch G"
         ],
-        "date": "2013-09-01",
-        "first": "Ikura T",
-        "last": "Ito N",
-        "name": "Protein engineering, design &amp; selection : PEDS",
-        "pages": "539-46",
-        "reference": "23832849",
-        "title": "Peptidyl-prolyl isomerase activity of FK506 binding protein 12 prevents tau peptide from aggregating.",
+        "date": "2007-03-09",
+        "first": "Kuhla B",
+        "last": "Münch G",
+        "name": "The Journal of biological chemistry",
+        "pages": "6984-91",
+        "reference": "17082178",
+        "title": "Effect of pseudophosphorylation and cross-linking by lipid peroxidation and advanced glycation end product precursors on tau aggregation and filament formation.",
         "type": "PubMed",
-        "volume": "26"
+        "volume": "282"
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-      "evidence": "We then investigated the function of FK506-binding protein (FKBP) 12, which is known to accumulate in neurofibrillary tangles in vivo, on aggregation of the R3 peptide and found that FKBP12 completely prevented the peptide from aggregating at a concentration ratio of 1 : 4 (peptide:FKBP12). FKBP12 also restored the oligomer of the peptide to its monomeric status. Mutational studies on the catalytic center of FKBP12 indicated that peptidyl-prolyl isomerase activity of FKBP12 was essential for prevention of aggregation. Assuming that the propensity of aggregation of the peptide is different in each cis-/trans-isomer, we propose that the aggregation behavior of the R3 peptide can be theoretically described with a simple kinetic scheme, in which only the cis-isomer can aggregate and FKBP12 catalyzes isomerization of the peptide in both the monomeric and aggregative states.",
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+      "evidence": "Acrolein and methylglyoxal were the most reactive compounds followed by glyoxal and malondialdehyde in terms of formation of Tau dimers and higher molecular weight oligomers. Analysis of the Tau aggregates by electron microscopy study showed that formation of fibrils using wild-type Tau and several Tau mutants could be observed with acrolein and methylglyoxal but not with glyoxal and malondialdehyde.",
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@@ -17542,142 +21161,21 @@
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         "volume": "36"
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-      "evidence": "CA and the oxidized form of EC (ECox) inhibited tau aggregation in vitro due to their interaction with the two cysteine residues in tau. A synthetic peptide, SKCGS, representing the actual tau sequence, identified the thiol as reacting with CA and ECox which necessitates of cysteine for aggregation inhibition by CA.",
-      "key": "f028d41761a8001cfc5bfb4dd9d86a47618d79b766aa48162b586afb905e7c3f70630fd0b6cc65c68bce0301152ac84eddd91a010de40daa9ab048bf790ae52f",
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-          "Johnson GV",
-          "Kuret J",
-          "Tucholski J"
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-        "first": "Tucholski J",
-        "last": "Johnson GV",
-        "name": "Journal of neurochemistry",
-        "pages": "1871-80",
-        "reference": "10537045",
-        "title": "Tau is modified by tissue transglutaminase in situ: possible functional and metabolic effects of polyamination.",
-        "type": "PubMed",
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-      "evidence": "For these studies, SH-SY5Y cells stably overexpressing tTG were used. tTG coimmunoprecipitated with tau, and elevating intracellular calcium levels with maitotoxin resulted in a 52 +/- 4% increase in the amount of tTG that coimmunoprecipitated with tau. The increase in association of tTG with tau after treatment with maitotoxin corresponded to a coimmunolocalization of tTG, tTG activity, and tau in the cells. Further, tau was modified by tTG in situ in response to maitotoxin treatment. In vitro polyaminated tau was significantly less susceptible to micro-calpain proteolysis; however, tTG-mediated polyamination of tau did not significantly alter the microtubule-binding capacity of tau.",
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-          "Babić Leko M",
-          "Bažadona D",
-          "Buée L",
-          "Delalle I",
-          "Di Giovanni G",
-          "Harrington C",
-          "Hof PR",
-          "Jovanov-Milošević N",
-          "Wischik C",
-          "Wray S",
-          "de Silva R",
-          "Šimić G"
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-        "date": "2016-01-06",
-        "first": "Šimić G",
-        "last": "Hof PR",
-        "name": "Biomolecules",
-        "pages": "6",
-        "reference": "26751493",
-        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
-        "type": "PubMed",
-        "volume": "6"
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-      "evidence": "Apart from binding to MT, the repeat domains of tau also bind to tubulin deacetylase, histone deacetylase 6 (HDAC6) [68] and apolipoprotein E (apoE) more with the ",
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-          "Johnson GV",
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-        "first": "Tucholski J",
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-        "name": "Journal of neurochemistry",
-        "pages": "1871-80",
-        "reference": "10537045",
-        "title": "Tau is modified by tissue transglutaminase in situ: possible functional and metabolic effects of polyamination.",
-        "type": "PubMed",
-        "volume": "73"
-      },
-      "evidence": "For these studies, SH-SY5Y cells stably overexpressing tTG were used. tTG coimmunoprecipitated with tau, and elevating intracellular calcium levels with maitotoxin resulted in a 52 +/- 4% increase in the amount of tTG that coimmunoprecipitated with tau. The increase in association of tTG with tau after treatment with maitotoxin corresponded to a coimmunolocalization of tTG, tTG activity, and tau in the cells. Further, tau was modified by tTG in situ in response to maitotoxin treatment. In vitro polyaminated tau was significantly less susceptible to micro-calpain proteolysis; however, tTG-mediated polyamination of tau did not significantly alter the microtubule-binding capacity of tau.",
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+      "evidence": "We were prompted to carry out this study because Acr is mainly localized in the neurons [54], is found in association with NFTs and dystrophic neurites surrounding senile plaques [55], is highly toxic to neurons, is found elevated 2–5 fold in affected regions of AD brain [33], and has been shown to increase tau phosphorylation at pathological sites, attributed to activation of both GSK3beta and the stress activated kinase p38 [56], which possibly promotes tau aggregation [57].",
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-          "Harrington C",
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-          "Wischik C",
-          "Wray S",
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-        "first": "Šimić G",
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-        "name": "Biomolecules",
-        "pages": "6",
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-        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
-        "type": "PubMed",
-        "volume": "6"
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-      "evidence": "Apart from binding to MT, the repeat domains of tau also bind to tubulin deacetylase, histone deacetylase 6 (HDAC6) [68] and apolipoprotein E (apoE) more with the ",
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       "annotations": {
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         "ExpMethod": {
           "in vitro": true
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@@ -17702,155 +21200,60 @@
         "type": "PubMed",
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-      "evidence": "We found that CA (lane 4) and EC (lane 6) substantially prevented the H2O2 induced formation of the high molecular weight species.",
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-      "relation": "positiveCorrelation",
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-    {
-      "annotations": {
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-        "Disease": {
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-      "citation": {
-        "authors": [
-          "Deng Y",
-          "Iqbal J",
-          "Li L",
-          "Liu K",
-          "Liu Y",
-          "Qin P",
-          "Qing H"
-        ],
-        "date": "2016-02-01",
-        "first": "Liu K",
-        "last": "Qing H",
-        "name": "Biochimica et biophysica acta",
-        "pages": "192-201",
-        "reference": "26655600",
-        "title": "Glycation alter the process of Tau phosphorylation to change Tau isoforms aggregation property.",
-        "type": "PubMed",
-        "volume": "1862"
-      },
-      "evidence": "However, granule cells of the dentate gyrus mainly express 3R isoforms, which resist Tau aggregation in AD, but accumulate 3R aggregates in Pick's disease [14]. 3R Tau is a major Tau isoform in laser microdissected Pick bodies [15].",
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-          "Berry RW",
-          "Bigio EH",
-          "Binder LI",
-          "Fu Y",
-          "Guillozet-Bongaarts AL",
-          "Reyes JF",
-          "Reynolds MR"
-        ],
-        "date": "2006-10-18",
-        "first": "Reynolds MR",
-        "last": "Binder LI",
-        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
-        "pages": "10636-45",
-        "reference": "17050703",
-        "title": "Tau nitration occurs at tyrosine 29 in the fibrillar lesions of Alzheimer's disease and other tauopathies.",
-        "type": "PubMed",
-        "volume": "26"
-      },
-      "evidence": "Tau-nY29 detects soluble tau and paired helical filament tau from severely affected Alzheimer's brain but fails to recognize tau from normal aged brain. This observation suggests that nitration at Tyr29 is a disease-related event that may alter the intrinsic ability of tau to self-polymerize. In Alzheimer's brain, Tau-nY29 labels the fibrillar triad of tau lesions, including neurofibrillary tangles, neuritic plaques, and, to a lesser extent, neuropil threads. Intriguingly, although Tau-nY29 stains both the neuronal and glial tau pathology of Pick disease, it detects only the neuronal pathology in corticobasal degeneration and progressive supranuclear palsy without labeling the predominant glial pathology.",
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-      "line": 837,
-      "relation": "positiveCorrelation",
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-      "target": 520
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     {
       "annotations": {
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-          "hippocampal formation": true
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+          "Medium": true
         },
         "ExpMethod": {
-          "in vivo": true
+          "in vitro": true
         },
-        "Species": {
-          "10116": true
+        "Method": {
+          "Electron Microscopy, Transmission": true,
+          "Mass Spectrometry": true
         }
       },
       "citation": {
         "authors": [
-          "Li HL",
-          "Liu YH",
-          "Wang JZ",
-          "Wang Q",
-          "Xu YF",
-          "Yin J",
-          "Zhang YJ"
-        ],
-        "date": "2006-07-01",
-        "first": "Zhang YJ",
-        "last": "Wang JZ",
-        "name": "FASEB journal : official publication of the Federation of American Societies for Experimental Biology",
-        "pages": "1431-42",
-        "reference": "16816118",
-        "title": "Peroxynitrite induces Alzheimer-like tau modifications and accumulation in rat brain and its underlying mechanisms.",
-        "type": "PubMed",
-        "volume": "20"
-      },
-      "evidence": "In the present study we injected bilaterally 3-morpholino-sydnonimine (SIN-1), a recognized and widely used peroxynitrite donor (25–30), into rat hippocampus, and investigated whether or not peroxynitrite could induce simultaneously nitration and hyperphosphorylation of tau and the underlying mechanisms in vivo. The level of nitrated and hyperphosphorylated tau was markedly increased in rat hippocampus 24 h, and prevented by preinjection of uric acid, a natural scavenger of peroxynitrite. GSK-3beta and p38 MAPKs, including p38alpha, p38beta, and p38delta activity was increased, but no change in the activity of p38gamma, ERK, and c-Jun amino-terminal kinase (JNK). Both nitrated tau and hyperphosphorylated tau were aggregated in the hippocampus, with activity of 20S proteasome significantly arrested in SIN-1-injected rats. Hyperphosphorylated tau was degraded as efficiently as normal tau by 20S proteasome, but the nitrated tau with an unorderly secondary structure became more resistant to the proteolysis, providing evidence that peroxynitrite simultaneously induces tau hyperphosphorylation, nitration, and accumulation, and that activation of GSK-3beta, p38alpha, p38beta, p38delta isoforms and the inhibition of proteasome activity are respectively responsible for the peroxynitrite-induced tau hyperphosphorylation and accumulation.",
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-    {
-      "citation": {
-        "authors": [
-          "Gamblin TC",
-          "Sun Q"
+          "George RC",
+          "Graves DJ",
+          "Lew J"
         ],
-        "date": "2009-06-30",
-        "first": "Sun Q",
-        "last": "Gamblin TC",
-        "name": "Biochemistry",
-        "pages": "6002-11",
-        "reference": "19459590",
-        "title": "Pseudohyperphosphorylation causing AD-like changes in tau has significant effects on its polymerization.",
+        "date": "2013-01-01",
+        "first": "George RC",
+        "last": "Graves DJ",
+        "name": "Journal of Alzheimer's disease : JAD",
+        "pages": "21-40",
+        "reference": "23531502",
+        "title": "Interaction of cinnamaldehyde and epicatechin with tau: implications of beneficial effects in modulating Alzheimer's disease pathogenesis.",
         "type": "PubMed",
-        "volume": "48"
+        "volume": "36"
       },
-      "evidence": "Because S199/S202/T205E, S396/S404E, 6-Phos and 7-Phos all demonstrated an AD-like shift in mobility as a result of phosphorylation-like changes, we conclude that they have the characteristics of hyperphosphorylated tau. These mutants will therefore be referred to as pseudo-hyperphosphorylated tau throughout the manuscript. On the basis of the observations that pseudohyperphosphorylated tau has decreased affinity for microtubules and reduced inducer-initiated rates of nucleation and polymerization, we propose that this combination could be the cause of the increased cytotoxicity of hyperphosphorylated tau in Alzheimer's disease and also explain the potentially beneficial role of tau polymerization and NFT formation.",
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     {
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           "in vitro": true
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@@ -17875,96 +21278,21 @@
         "type": "PubMed",
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+      "evidence": "We were prompted to carry out this study because Acr is mainly localized in the neurons [54], is found in association with NFTs and dystrophic neurites surrounding senile plaques [55], is highly toxic to neurons, is found elevated 2–5 fold in affected regions of AD brain [33], and has been shown to increase tau phosphorylation at pathological sites, attributed to activation of both GSK3beta and the stress activated kinase p38 [56], which possibly promotes tau aggregation [57].",
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-          "Marani L",
-          "Marino S",
-          "Selvatici R",
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-        "first": "Selvatici R",
-        "last": "Siniscalchi A",
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-        "title": "In vitro mitochondrial failure and oxidative stress mimic biochemical features of Alzheimer disease.",
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-      "evidence": "Primary cortical neurons exposed to the mitochondrial toxin NaN3 (0.1-3 mM) were submitted to oxidative stress with H2O2 (30-150 μM), to mimic conditions observed in neurodegenerative disorders. The effects of such treatment on a series of parameters useful in characterizing neuronal damage were investigated: (i) the basal release of glutamate, evaluated as (3)H-d-Aspartate efflux, was sharply, concentration-dependently, increased; (ii) the phosphorylation status of intracellular markers known to be involved in the neurodegenerative processes, in particular in Alzheimer disease: tau and GSK3β were increased, as well as the protein level of β-secretase (BACE1) and p35/25 evaluated by Western blotting, while (iii) the cell metabolic activity, measured with the MTT method, was reduced, in a concentration- and time-dependent manner. The latter effect, as well as tau hyperphosphorylation, was prevented both by a mixture of antioxidant drugs (100 μM ascorbic acid, 10 μM trolox, 100 μM glutathione) and by the anti-Alzheimer drug, memantine, 20 μM.",
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-        "type": "PubMed",
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-      "evidence": "Primary cortical neurons exposed to the mitochondrial toxin NaN3 (0.1-3 mM) were submitted to oxidative stress with H2O2 (30-150 μM), to mimic conditions observed in neurodegenerative disorders. The effects of such treatment on a series of parameters useful in characterizing neuronal damage were investigated: (i) the basal release of glutamate, evaluated as (3)H-d-Aspartate efflux, was sharply, concentration-dependently, increased; (ii) the phosphorylation status of intracellular markers known to be involved in the neurodegenerative processes, in particular in Alzheimer disease: tau and GSK3β were increased, as well as the protein level of β-secretase (BACE1) and p35/25 evaluated by Western blotting, while (iii) the cell metabolic activity, measured with the MTT method, was reduced, in a concentration- and time-dependent manner. The latter effect, as well as tau hyperphosphorylation, was prevented both by a mixture of antioxidant drugs (100 μM ascorbic acid, 10 μM trolox, 100 μM glutathione) and by the anti-Alzheimer drug, memantine, 20 μM.",
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@@ -17989,18 +21317,24 @@
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@@ -18096,90 +21404,97 @@
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-          "Kawakami F",
-          "Ohtsuki K",
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+          "Cowburn RF",
+          "Dahllund L",
+          "Gustafsson E",
+          "Lund H",
+          "Malinowsky D",
+          "Strömberg K",
+          "Sunnemark D",
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-        "reference": "18239272",
-        "title": "A novel consensus phosphorylation motif in sulfatide- and cholesterol-3-sulfate-binding protein substrates for CK1 in vitro.",
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+        "name": "Brain pathology (Zurich, Switzerland)",
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+        "title": "Tau-tubulin kinase 1 expression, phosphorylation and co-localization with phospho-Ser422 tau in the Alzheimer's disease brain.",
         "type": "PubMed",
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+          "Ando K",
+          "Brion JP",
+          "D'Amico E",
+          "Duyckaerts C",
+          "Erneux C",
+          "Jia Y",
+          "Leroy K",
+          "Luo HR",
+          "Pouillon V",
+          "Schurmans S",
+          "Stygelbout V"
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+        "first": "Stygelbout V",
+        "last": "Brion JP",
+        "name": "Brain : a journal of neurology",
+        "pages": "537-52",
+        "reference": "24401760",
+        "title": "Inositol trisphosphate 3-kinase B is increased in human Alzheimer brain and exacerbates mouse Alzheimer pathology.",
+        "type": "PubMed",
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+      "evidence": "We show here that ITPKB protein level was increased 3-fold in the cerebral cortex of most patients with Alzheimer's disease compared with control subjects, and accumulated in dystrophic neurites associated to amyloid plaques. In mouse Neuro-2a neuroblastoma cells, Itpkb overexpression was associated with increased cell apoptosis and increased β-secretase 1 activity leading to overproduction of amyloid-β peptides. In this cellular model, an inhibitor of mitogen-activated kinase kinases 1/2 completely prevented overproduction of amyloid-β peptides. Transgenic overexpression of ITPKB in mouse forebrain neurons was not sufficient to induce amyloid plaque formation or tau hyperphosphorylation. However, in the 5X familial Alzheimer's disease mouse model, neuronal ITPKB overexpression significantly increased extracellular signal-regulated kinases 1/2 activation and β-secretase 1 activity, resulting in exacerbated Alzheimer's disease pathology as shown by increased astrogliosis, amyloid-β40 peptide production and tau hyperphosphorylation.",
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       "citation": {
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           "Ait-Ghezala G",
@@ -18361,16 +21781,19 @@
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       "evidence": "We found an increase in Syk activation in DNs surrounding Aβ deposits as well as in neurons displaying an accumulation of phosphorylated Tau at Y18 and elevated levels of MC1 pathogenic tau conformers in AD brain sections whereas only weak immunoreactivity for pSyk was observed in brain sections from a non-demented control",
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         "MeSHDisease": {
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@@ -18401,16 +21824,98 @@
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+      },
+      "citation": {
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+          "George RC",
+          "Graves DJ",
+          "Lew J"
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+        "first": "George RC",
+        "last": "Graves DJ",
+        "name": "Journal of Alzheimer's disease : JAD",
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+        "reference": "23531502",
+        "title": "Interaction of cinnamaldehyde and epicatechin with tau: implications of beneficial effects in modulating Alzheimer's disease pathogenesis.",
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+      "evidence": "We were prompted to carry out this study because Acr is mainly localized in the neurons [54], is found in association with NFTs and dystrophic neurites surrounding senile plaques [55], is highly toxic to neurons, is found elevated 2–5 fold in affected regions of AD brain [33], and has been shown to increase tau phosphorylation at pathological sites, attributed to activation of both GSK3beta and the stress activated kinase p38 [56], which possibly promotes tau aggregation [57].",
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+        "MeSHAnatomy": {
+          "Brain": true
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+        "Research_Model": {
+          "APPPS1 mice": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Ait-Ghezala G",
+          "Beaulieu-Abdelahad D",
+          "Crawford F",
+          "Mouzon B",
+          "Mullan M",
+          "Paris D",
+          "Schweig JE",
+          "Yao H"
+        ],
+        "date": "2017-09-06",
+        "first": "Schweig JE",
+        "last": "Paris D",
+        "name": "Acta neuropathologica communications",
+        "pages": "69",
+        "reference": "28877763",
+        "title": "Alzheimer's disease pathological lesions activate the spleen tyrosine kinase.",
+        "type": "PubMed",
+        "volume": "5"
+      },
+      "evidence": "The upregulation of Syk activation observed in the brains of Tg APPsw and Tg PS1/APPsw is mainly attributable to pSyk accumulations in dystrophic neurites that are associated with Aβ plaques and increase with age and Aβ burden.",
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     {
       "annotations": {
         "Anatomy": {
           "cerebral cortex": true
         },
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         "MeSHDisease": {
           "Alzheimer Disease": true
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         "volume": "137"
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       "evidence": "We show here that ITPKB protein level was increased 3-fold in the cerebral cortex of most patients with Alzheimer's disease compared with control subjects, and accumulated in dystrophic neurites associated to amyloid plaques. In mouse Neuro-2a neuroblastoma cells, Itpkb overexpression was associated with increased cell apoptosis and increased β-secretase 1 activity leading to overproduction of amyloid-β peptides. In this cellular model, an inhibitor of mitogen-activated kinase kinases 1/2 completely prevented overproduction of amyloid-β peptides. Transgenic overexpression of ITPKB in mouse forebrain neurons was not sufficient to induce amyloid plaque formation or tau hyperphosphorylation. However, in the 5X familial Alzheimer's disease mouse model, neuronal ITPKB overexpression significantly increased extracellular signal-regulated kinases 1/2 activation and β-secretase 1 activity, resulting in exacerbated Alzheimer's disease pathology as shown by increased astrogliosis, amyloid-β40 peptide production and tau hyperphosphorylation.",
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     {
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       "citation": {
         "authors": [
-          "Ip NY",
-          "Lai KO",
-          "Liang Z",
-          "Plattner F",
-          "Shen Y",
-          "Wong CC",
-          "Yates JR 3rd",
-          "Zhan Y"
+          "Ando K",
+          "Brion JP",
+          "D'Amico E",
+          "Duyckaerts C",
+          "Erneux C",
+          "Jia Y",
+          "Leroy K",
+          "Luo HR",
+          "Pouillon V",
+          "Schurmans S",
+          "Stygelbout V"
         ],
-        "date": "2016-10-31",
-        "first": "Liang Z",
-        "last": "Ip NY",
-        "name": "Nature communications",
-        "pages": "13282",
-        "reference": "27796283",
-        "title": "The pseudokinase CaMKv is required for the activity-dependent maintenance of dendritic spines.",
+        "date": "2014-02-01",
+        "first": "Stygelbout V",
+        "last": "Brion JP",
+        "name": "Brain : a journal of neurology",
+        "pages": "537-52",
+        "reference": "24401760",
+        "title": "Inositol trisphosphate 3-kinase B is increased in human Alzheimer brain and exacerbates mouse Alzheimer pathology.",
         "type": "PubMed",
-        "volume": "7"
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-      "evidence": "These observations suggest that CaMKv blocks RhoA activity by preventing its interaction with Lfc. These results demonstrate that CaMKv regulates spine maintenance through RhoA inhibition. The suppression of the Lfc/RhoA pathway by AMPA receptors is implicated in dendritic spine maintenance10. Given that CaMKv expression is upregulated by synaptic activity, CaMKv may be a key signalling protein that transduces the signals from AMPA receptors to suppress RhoA during activity-dependent spine maintenance. Corroborating this, the AMPA receptor blocker NBQX attenuated CaMKv expression in neurons (Fig. 3i,j). Importantly, CaMKv overexpression completely rescued NBQX-induced spine loss (Fig. 3k,l). These findings collectively reveal that activity-dependent CaMKv expression and the subsequent inhibition of Lfc/RhoA are required to mediate AMPA receptor function in spine maintenance.",
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+      "evidence": "We show here that ITPKB protein level was increased 3-fold in the cerebral cortex of most patients with Alzheimer's disease compared with control subjects, and accumulated in dystrophic neurites associated to amyloid plaques. In mouse Neuro-2a neuroblastoma cells, Itpkb overexpression was associated with increased cell apoptosis and increased β-secretase 1 activity leading to overproduction of amyloid-β peptides. In this cellular model, an inhibitor of mitogen-activated kinase kinases 1/2 completely prevented overproduction of amyloid-β peptides. Transgenic overexpression of ITPKB in mouse forebrain neurons was not sufficient to induce amyloid plaque formation or tau hyperphosphorylation. However, in the 5X familial Alzheimer's disease mouse model, neuronal ITPKB overexpression significantly increased extracellular signal-regulated kinases 1/2 activation and β-secretase 1 activity, resulting in exacerbated Alzheimer's disease pathology as shown by increased astrogliosis, amyloid-β40 peptide production and tau hyperphosphorylation.",
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       "annotations": {
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       "citation": {
         "authors": [
-          "Chen X",
-          "Collins N",
-          "Dai X",
-          "Huang T",
-          "LaDu MJ",
-          "Lin L",
-          "Shen H",
-          "Wei Z",
-          "Wu X",
-          "Xiao N",
-          "York J",
-          "Zhang J",
-          "Zhou M",
-          "Zhu Y"
+          "George RC",
+          "Graves DJ",
+          "Lew J"
         ],
-        "date": "2016-01-01",
-        "first": "Zhou M",
-        "last": "Chen X",
-        "name": "Current Alzheimer research",
-        "pages": "1048-55",
-        "reference": "27087442",
-        "title": "APOE4 Induces Site-Specific Tau Phosphorylation Through Calpain-CDK5 Signaling Pathway in EFAD-Tg Mice.",
+        "date": "2013-01-01",
+        "first": "George RC",
+        "last": "Graves DJ",
+        "name": "Journal of Alzheimer's disease : JAD",
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+        "title": "Interaction of cinnamaldehyde and epicatechin with tau: implications of beneficial effects in modulating Alzheimer's disease pathogenesis.",
         "type": "PubMed",
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       },
-      "evidence": "Our data showed that CDK5 knock down induced an increase in p35 protein levels and Rac activity in triple transgenic Alzheimer's mice, which correlated with the recovery of cognitive function; these findings confirm that increased p35 and active Rac are involved in neuroprotection. In summary, our data suggest that p35 acts as a mediator of Rho GTPase activity and contributes to the neuroprotection induced by CDK5 RNAi.",
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+      "evidence": "We were prompted to carry out this study because Acr is mainly localized in the neurons [54], is found in association with NFTs and dystrophic neurites surrounding senile plaques [55], is highly toxic to neurons, is found elevated 2–5 fold in affected regions of AD brain [33], and has been shown to increase tau phosphorylation at pathological sites, attributed to activation of both GSK3beta and the stress activated kinase p38 [56], which possibly promotes tau aggregation [57].",
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       "annotations": {
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+          "1 U/ml": true
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       },
       "citation": {
         "authors": [
-          "Chen X",
-          "Collins N",
-          "Dai X",
-          "Huang T",
-          "LaDu MJ",
-          "Lin L",
-          "Shen H",
-          "Wei Z",
-          "Wu X",
-          "Xiao N",
-          "York J",
-          "Zhang J",
-          "Zhou M",
-          "Zhu Y"
+          "Buée-Scherrer V",
+          "Goedert M"
         ],
-        "date": "2016-01-01",
-        "first": "Zhou M",
-        "last": "Chen X",
-        "name": "Current Alzheimer research",
-        "pages": "1048-55",
-        "reference": "27087442",
-        "title": "APOE4 Induces Site-Specific Tau Phosphorylation Through Calpain-CDK5 Signaling Pathway in EFAD-Tg Mice.",
+        "date": "2002-03-27",
+        "first": "Buée-Scherrer V",
+        "last": "Goedert M",
+        "name": "FEBS letters",
+        "pages": "151-4",
+        "reference": "11943212",
+        "title": "Phosphorylation of microtubule-associated protein tau by stress-activated protein kinases in intact cells.",
         "type": "PubMed",
-        "volume": "13"
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-      "evidence": "Our data showed that CDK5 knock down induced an increase in p35 protein levels and Rac activity in triple transgenic Alzheimer's mice, which correlated with the recovery of cognitive function; these findings confirm that increased p35 and active Rac are involved in neuroprotection. In summary, our data suggest that p35 acts as a mediator of Rho GTPase activity and contributes to the neuroprotection induced by CDK5 RNAi.",
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-          "LaDu MJ",
-          "Lin L",
-          "Shen H",
-          "Wei Z",
-          "Wu X",
-          "Xiao N",
-          "York J",
-          "Zhang J",
-          "Zhou M",
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-        "name": "Current Alzheimer research",
-        "pages": "1048-55",
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-        "title": "APOE4 Induces Site-Specific Tau Phosphorylation Through Calpain-CDK5 Signaling Pathway in EFAD-Tg Mice.",
-        "type": "PubMed",
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-      "evidence": "Our data showed that CDK5 knock down induced an increase in p35 protein levels and Rac activity in triple transgenic Alzheimer's mice, which correlated with the recovery of cognitive function; these findings confirm that increased p35 and active Rac are involved in neuroprotection. In summary, our data suggest that p35 acts as a mediator of Rho GTPase activity and contributes to the neuroprotection induced by CDK5 RNAi.",
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+      "evidence": "All five SAP kinases generated the AT270 epitope, indicative of phosphorylation of T181 in tau.",
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           "dentate gyrus granule cell layer": true
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         "Disease": {
           "Alzheimer's disease": true
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@@ -18640,17 +22097,20 @@
         "volume": "1862"
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       "evidence": "However, granule cells of the dentate gyrus mainly express 3R isoforms, which resist Tau aggregation in AD, but accumulate 3R aggregates in Pick's disease [14]. 3R Tau is a major Tau isoform in laser microdissected Pick bodies [15].",
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@@ -18676,13 +22136,24 @@
         "volume": "1862"
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       "evidence": "However, granule cells of the dentate gyrus mainly express 3R isoforms, which resist Tau aggregation in AD, but accumulate 3R aggregates in Pick's disease [14]. 3R Tau is a major Tau isoform in laser microdissected Pick bodies [15].",
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       "citation": {
         "authors": [
           "Babić Leko M",
@@ -18710,13 +22181,16 @@
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       "evidence": "On the other side, sarkosyl extracts from the filaments of PSP [129], corticobasal degeneration (CBD; [130]), argyrophilic grain disease (AgD; [131]), and some cases of FTDP-17, contain tau protein that separates as doublets of 64 and 69 kDa and are predominantly composed of tau isoforms with 4R (class II tauopathies), whereas sarkosyl extracts from filaments of Pick’s disease are characterized by the presence of pathological tau doublets of 60 and 64 kDa and contain mainly 3R tau isoforms (class III tauopathy).",
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         "MeSHDisease": {
           "Alzheimer Disease": true,
           "Down Syndrome": true
@@ -18747,53 +22221,19 @@
       },
       "evidence": "Inhibition of Dyrk1A enhanced tau exon 10 inclusion, leading to an increase in 4R-tau/3R-tau ratio in differentiated-human neuronal progenitors and in the neonatal rat brains. Accompanied with overexpression of Dyrk1A, 3R-tau was increased and 4R-tau was decreased in the neonatal brains of Ts65Dn mice, a model of Down syndrome.",
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-          "Sun X",
-          "Wang L",
-          "Wang P"
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-        "date": "2017-08-03",
-        "first": "Wang P",
-        "last": "Sun X",
-        "name": "Scientific reports",
-        "pages": "7240",
-        "reference": "28775333",
-        "title": "Dual-specificity tyrosine-phosphorylation regulated kinase 1A Gene Transcription is regulated by Myocyte Enhancer Factor 2D.",
-        "type": "PubMed",
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-      "evidence": "Treatment with Dyrk1A inhibitor, green tea flavonol epigallocatechin-gallate (EGCG), from gestation to adulthood suppressed 3R-tau expression and rescued anxiety and memory deficits in Ts65Dn mouse brains.",
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     {
       "annotations": {
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           "dentate gyrus granule cell layer": true
         },
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           "Pick's disease": true
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@@ -18819,14 +22259,122 @@
         "volume": "1862"
       },
       "evidence": "However, granule cells of the dentate gyrus mainly express 3R isoforms, which resist Tau aggregation in AD, but accumulate 3R aggregates in Pick's disease [14]. 3R Tau is a major Tau isoform in laser microdissected Pick bodies [15].",
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       "relation": "positiveCorrelation",
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+      "citation": {
+        "authors": [
+          "Binder LI",
+          "Geula C",
+          "Reyes JF",
+          "Vana L"
+        ],
+        "date": "2012-01-01",
+        "first": "Reyes JF",
+        "last": "Binder LI",
+        "name": "Acta neuropathologica",
+        "pages": "119-32",
+        "reference": "22057784",
+        "title": "Selective tau tyrosine nitration in non-AD tauopathies.",
+        "type": "PubMed",
+        "volume": "123"
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+      "evidence": "Tau-nY18 did not label the classical pathological lesions of CBD or PSP but did label the neuronal lesions associated with PiD. Tau-nY29 revealed some, but not all classes of tau inclusions associated with both CBD and PSP but did label numerous Pick body inclusions in PiD. Tau-nY197 was restricted to the neuropil threads in both CBD and PSP; however, similar to Tau-nY29, extensive Pick body pathology was clearly labeled. Tau-nY394 did not detect any of the lesions associated with these disorders.",
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+        ],
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+        "pages": "119-32",
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+        "Disease": {
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+        "HBP_Disease": {
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+        },
+        "MeSHDisease": {
+          "Pick Disease of the Brain": true
+        }
+      },
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+          "Binder LI",
+          "Geula C",
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+        "name": "Acta neuropathologica",
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@@ -18936,20 +22490,23 @@
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@@ -19301,17 +22876,20 @@
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@@ -20428,16 +23702,19 @@
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@@ -20714,54 +24062,64 @@
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       "evidence": "The treatment of 10 mM D-ribose for 24 h resulted in a significant increase in active form of CaMKII (p-Thr286/287), yet simultaneously in a decrease in inactive form of CaMKII (p-Thr305/306) phosphorylation (Fig. 4e). The enzyme activity assay supported this result.",
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-          "Fluorescence Spectrophotometry": true,
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+          "Han C",
           "He R",
-          "Wang X",
-          "Wei Y"
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+          "Su T",
+          "Wang Y",
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-        "title": "D-Ribosylated Tau forms globular aggregates with high cytotoxicity.",
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@@ -20789,12 +24147,17 @@
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@@ -21033,48 +24273,39 @@
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-          "Bi L",
-          "Guo Y",
-          "Jin H",
-          "Li H",
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-          "Pang P",
-          "Pei L",
-          "Shang Y",
-          "Shu S",
-          "Tian Q",
-          "Tian T",
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-          "Wei N",
-          "Wu J",
-          "Xu M",
-          "Yan H",
-          "Yang X",
-          "Yao C",
-          "Zhu LQ"
+          "Ciborowski P",
+          "Ikezu T",
+          "Jacobsen MT",
+          "Martinez LB",
+          "Okuyama S",
+          "Sato S",
+          "Schlautman JD",
+          "Swan RJ",
+          "Walsh SM",
+          "Xu J"
         ],
-        "date": "2015-11-01",
-        "first": "Pei L",
-        "last": "Lu Y",
-        "name": "Cerebral cortex (New York, N.Y. : 1991)",
-        "pages": "4559-71",
-        "reference": "25995053",
-        "title": "A Novel Mechanism of Spine Damages in Stroke via DAPK1 and Tau.",
+        "date": "2008-12-31",
+        "first": "Sato S",
+        "last": "Ikezu T",
+        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
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+        "reference": "19118186",
+        "title": "Spatial learning impairment, enhanced CDK5/p35 activity, and downregulation of NMDA receptor expression in transgenic mice expressing tau-tubulin kinase 1.",
         "type": "PubMed",
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-      "evidence": "Direct interaction of DAPK1 with Tau causes spine loss and subsequently neuronal death. DAPK1 phosphorylates Tau protein at Ser262 (pS(262)) in cortical neurons of stroke mice.",
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+      "evidence": "TTBK1-Tg mice show significant age-dependent memory impairment as determined by radial arm water maze test, which is associated with enhancement of tau and neurofilament phosphorylation, increased levels of p25 and p35, both activators of cyclin-dependent protein kinase 5 (CDK5), enhanced calpain I activity, and reduced levels of hippocampal NMDA receptor types 2B (NR2B) and D. Enhanced CDK5/p35 complex formation is strongly correlated with dissociation of F-actin from p35, suggesting the inhibitory mechanism of CDK5/p35 complex formation by F-actin.",
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@@ -21083,6 +24314,9 @@
           "cerebral cortex": true,
           "hippocampal formation": true
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           "Alzheimer Disease": true,
           "Down Syndrome": true
@@ -21117,34 +24351,25 @@
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-          "Crawford F",
-          "Mouzon B",
-          "Mullan M",
-          "Paris D",
-          "Schweig JE",
-          "Yao H"
+          "Ait-Ghezala G",
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+          "Crawford F",
+          "Mouzon B",
+          "Mullan M",
+          "Paris D",
+          "Schweig JE",
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       },
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@@ -21388,20 +24578,18 @@
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@@ -21409,33 +24597,169 @@
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-          "He R",
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-          "Su T",
-          "Wang Y",
-          "Wei Y",
-          "Wu B"
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+          "Ohshima T",
+          "Toba J",
+          "Watamura N",
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+          "Obriot H",
+          "Outeiro TF",
+          "Sergeant N"
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       "annotations": {
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         "MeSHDisease": {
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@@ -21467,39 +24791,17 @@
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       "evidence": "3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain.",
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-          "Ciraci V",
-          "Ferrer I",
-          "Fuso A",
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-        "first": "Nicolia V",
-        "last": "Fuso A",
-        "name": "Current Alzheimer research",
-        "pages": "753-759",
-        "reference": "28176663",
-        "title": "GSK3β 5'-flanking DNA Methylation and Expression in Alzheimer's Disease Patients.",
-        "type": "PubMed",
-        "volume": "14"
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-      "evidence": "Here, we show for the first time that the administration of D-ribose, the most active glycator among monosaccharides, produces high levels of advanced glycation end products (AGEs) and, importantly, triggers hyperphosphorylation of Tau in the brain of C57BL/6 mouse and neuroblastoma N2a cells.",
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           "Alonso AC",
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         "volume": "268"
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       "evidence": ">8 phosphates per tau molecules (vs 2 in adult healthy brain); can also be increased during development, hibernation and temperature, heat and oxydative stress These phosphorylated states are detected by specific antibodies and are targets of proline-directed kinases (SP motifs), non-proline kinases (KXGS motif) Weakens tau-MT interaction especially S261 in R1 and S214 in proline-rich domain",
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-          "El-Akkad E",
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-          "Grundke-Iqbal I",
-          "Iqbal K",
-          "Liang Z",
-          "Liu F",
-          "Shi J",
-          "Yin D"
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-        "first": "Liu F",
-        "last": "Gong CX",
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-        "pages": "6269-74",
-        "reference": "17078951",
-        "title": "PKA modulates GSK-3beta- and cdk5-catalyzed phosphorylation of tau in site- and kinase-specific manners.",
-        "type": "PubMed",
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-      "evidence": "Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396.",
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-          "Iqbal K",
-          "Liang Z",
-          "Liu F",
-          "Shi J",
-          "Yin D"
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-        "first": "Liu F",
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-        "pages": "6269-74",
-        "reference": "17078951",
-        "title": "PKA modulates GSK-3beta- and cdk5-catalyzed phosphorylation of tau in site- and kinase-specific manners.",
-        "type": "PubMed",
-        "volume": "580"
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-      "evidence": "Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396.",
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-          "Lu B",
-          "Malenka R",
-          "Polepalli J",
-          "Rajadas J",
-          "Wagh D",
-          "Yu W"
-        ],
-        "date": "2012-03-15",
-        "first": "Yu W",
-        "last": "Lu B",
-        "name": "Human molecular genetics",
-        "pages": "1384-90",
-        "reference": "22156579",
-        "title": "A critical role for the PAR-1/MARK-tau axis in mediating the toxic effects of Aβ on synapses and dendritic spines.",
-        "type": "PubMed",
-        "volume": "21"
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-      "evidence": "We first confirmed that expression of an MKI-GFP fusion protein in rat hippocampal neurons effectively attenuated MARK4-mediated phosphorylation of both endogenous tau (Fig. 3A) and transfected human tau at the 12E8 sites (Fig. 3B). Phosphorylation of tau at the PHF-1 site was also reduced by MKI (Fig. 3A). It is possible that the PHF-1 site is also targeted by PAR-1/MARKs in vivo, or that the phosphorylation of tau at the 12E8 sites is a prerequisite for PHF-1 site phosphorylation, as the 12E8 sites were previously shown to be required for tau phosphorylation at other sites",
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-        "authors": [
-          "Chai GS",
-          "Chen NN",
-          "Cheng XS",
-          "Duan DX",
-          "Hu Y",
-          "Liu GP",
-          "Luo Y",
-          "Ni ZF",
-          "Wang JZ"
-        ],
-        "date": "2013-01-01",
-        "first": "Duan DX",
-        "last": "Liu GP",
-        "name": "Journal of Alzheimer's disease : JAD",
-        "pages": "795-808",
-        "reference": "23948915",
-        "title": "Phosphorylation of tau by death-associated protein kinase 1 antagonizes the kinase-induced cell apoptosis.",
-        "type": "PubMed",
-        "volume": "37"
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-      "evidence": "These data suggest that tau hyperphosphorylation at Thr231, Ser262, and Ser396 by DAPK1 renders the cells more resistant to the kinase-induced apoptotic cell death, providing new insights into the tau-involved apoptotic abortion in the course of chronic neurodegeneration.",
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-          "Cavallaro RA",
-          "Ciraci V",
-          "Ferrer I",
-          "Fuso A",
-          "Nicolia V",
-          "Scarpa S"
-        ],
-        "date": "2017-01-01",
-        "first": "Nicolia V",
-        "last": "Fuso A",
-        "name": "Current Alzheimer research",
-        "pages": "753-759",
-        "reference": "28176663",
-        "title": "GSK3β 5'-flanking DNA Methylation and Expression in Alzheimer's Disease Patients.",
-        "type": "PubMed",
-        "volume": "14"
-      },
-      "evidence": "Here, we show for the first time that the administration of D-ribose, the most active glycator among monosaccharides, produces high levels of advanced glycation end products (AGEs) and, importantly, triggers hyperphosphorylation of Tau in the brain of C57BL/6 mouse and neuroblastoma N2a cells.",
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-      "citation": {
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-          "Boehm J",
-          "Bourgeois C",
-          "Dudilot A",
-          "Lauzon M",
-          "Leclerc N",
-          "Mondragón-Rodríguez S",
-          "Trillaud-Doppia E"
-        ],
-        "date": "2012-09-14",
-        "first": "Mondragón-Rodríguez S",
-        "last": "Boehm J",
-        "name": "The Journal of biological chemistry",
-        "pages": "32040-53",
-        "reference": "22833681",
-        "title": "Interaction of endogenous tau protein with synaptic proteins is regulated by N-methyl-D-aspartate receptor-dependent tau phosphorylation.",
-        "type": "PubMed",
-        "volume": "287"
-      },
-      "evidence": "Acute treatment of rTg4510 mice with an O-GlcNAcase inhibitor transiently reduced tau phosphorylation at epitopes implicated in tau pathology. More importantly, long-term inhibitor treatment strongly increased tau O-GlcNAcylation, reduced the number of dystrophic neurons, and protected against the formation of pathological tau species without altering the phosphorylation of non-pathological tau.",
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-        "authors": [
-          "Fan SJ",
-          "Huang FI",
-          "Liou JP",
-          "Yang CR"
-        ],
-        "date": "2018-05-29",
-        "first": "Fan SJ",
-        "last": "Yang CR",
-        "name": "Cell death &amp; disease",
-        "pages": "655",
-        "reference": "29844403",
-        "title": "The novel histone de acetylase 6 inhibitor, MPT0G211, ameliorates tau phosphorylation and cognitive deficits in an Alzheimer's disease model.",
-        "type": "PubMed",
-        "volume": "9"
-      },
-      "evidence": "This study aimed to investigate the protective effects and mechanism of the novel HDAC6 inhibitor, MPT0G211, using an AD model. Our results indicated that MPT0G211 significantly reduced tau phosphorylation and aggregation, the processes highly correlated with the formation of NFTs. This HDAC6 inhibitory activity resulted in an increase in acetylated Hsp90, which decreased Hsp90 and HDAC6 binding, causing ubiquitination of phosphorylated tau proteins. In addition, a significant increase of phospho-glycogen synthase kinase-3β (phospho-GSK3β) on Ser9 (the inactive form) through Akt phosphorylation was associated with the inhibition of phospho-tau Ser396 in response to MPT0G211 treatment.",
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-      "relation": "positiveCorrelation",
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     {
       "annotations": {
         "Cell_Line": {
           "N2a": true
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         "Method": {
           "Immunofluorescence": true,
           "Immunohistochemistry": true,
@@ -21773,32 +24866,35 @@
         "volume": "14"
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       "evidence": "The treatment of 10 mM D-ribose for 24 h resulted in a significant increase in active form of CaMKII (p-Thr286/287), yet simultaneously in a decrease in inactive form of CaMKII (p-Thr305/306) phosphorylation (Fig. 4e). The enzyme activity assay supported this result.",
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           "Immunohistochemistry": true,
@@ -21829,20 +24925,23 @@
         "volume": "14"
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       "evidence": "The treatment of 10 mM D-ribose for 24 h resulted in a significant increase in active form of CaMKII (p-Thr286/287), yet simultaneously in a decrease in inactive form of CaMKII (p-Thr305/306) phosphorylation (Fig. 4e). The enzyme activity assay supported this result.",
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           "N2a": true
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         "Method": {
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@@ -21874,16 +24973,19 @@
       },
       "evidence": "Here, we found that MG could induce tau hyperphosphorylation at multiple AD-related sites in neuroblastoma 2a cells under maintaining normal cell viability. MG treatment increased the level of advanced glycation end products (AGEs) and the receptor of AGEs (RAGE).",
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       "annotations": {
         "Cell_Line": {
           "N2a": true
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         "Method": {
           "Dot Blot": true,
           "ELISA": true,
@@ -21915,16 +25017,19 @@
       },
       "evidence": "Here, we found that MG could induce tau hyperphosphorylation at multiple AD-related sites in neuroblastoma 2a cells under maintaining normal cell viability. MG treatment increased the level of advanced glycation end products (AGEs) and the receptor of AGEs (RAGE).",
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         "Cell_Line": {
           "N2a": true
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         "Method": {
           "Dot Blot": true,
           "ELISA": true,
@@ -21956,16 +25061,19 @@
       },
       "evidence": "Here, we found that MG could induce tau hyperphosphorylation at multiple AD-related sites in neuroblastoma 2a cells under maintaining normal cell viability. MG treatment increased the level of advanced glycation end products (AGEs) and the receptor of AGEs (RAGE).",
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         "Cell_Line": {
           "N2a": true
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         "Method": {
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@@ -21997,16 +25105,19 @@
       },
       "evidence": "Here, we found that MG could induce tau hyperphosphorylation at multiple AD-related sites in neuroblastoma 2a cells under maintaining normal cell viability. MG treatment increased the level of advanced glycation end products (AGEs) and the receptor of AGEs (RAGE).",
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@@ -22038,17 +25149,20 @@
       },
       "evidence": "Here, we found that MG could induce tau hyperphosphorylation at multiple AD-related sites in neuroblastoma 2a cells under maintaining normal cell viability. MG treatment increased the level of advanced glycation end products (AGEs) and the receptor of AGEs (RAGE).",
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           "Immunofluorescence": true,
@@ -22079,16 +25193,19 @@
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       "evidence": "Here, we found that MG could induce tau hyperphosphorylation at multiple AD-related sites in neuroblastoma 2a cells under maintaining normal cell viability. MG treatment increased the level of advanced glycation end products (AGEs) and the receptor of AGEs (RAGE).",
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@@ -22120,16 +25237,19 @@
       },
       "evidence": "Here, we found that MG could induce tau hyperphosphorylation at multiple AD-related sites in neuroblastoma 2a cells under maintaining normal cell viability. MG treatment increased the level of advanced glycation end products (AGEs) and the receptor of AGEs (RAGE).",
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           "N2a": true
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         "Method": {
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@@ -22161,16 +25281,19 @@
       },
       "evidence": "Here, we found that MG could induce tau hyperphosphorylation at multiple AD-related sites in neuroblastoma 2a cells under maintaining normal cell viability. MG treatment increased the level of advanced glycation end products (AGEs) and the receptor of AGEs (RAGE).",
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         "Cell_Line": {
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         "Method": {
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@@ -22202,13 +25325,118 @@
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       "evidence": "Here, we found that MG could induce tau hyperphosphorylation at multiple AD-related sites in neuroblastoma 2a cells under maintaining normal cell viability. MG treatment increased the level of advanced glycation end products (AGEs) and the receptor of AGEs (RAGE).",
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+          "Wang JZ",
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       "evidence": "In accordance with the decreased efficiency of nitro-TPI we found a significant increase in methylglyoxal production (P50.05), independent of whether DHAP or GAP was used as substrate (Fig. 2E). Thus, nitrotyrosination of TPI results in reduced catalytic activity and increased occupancy of the enzyme by the substrate, and consequently, a higher production of the toxic methylglyoxal.",
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@@ -22326,13 +25630,16 @@
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       "evidence": "Interestingly, Syk upregulation in SH-SY5Y cells leads to a significant increase (1.7-fold) in phosphorylated tau at Y18 (Fig. 14c, p < 0.01) and at S396/404 (Fig. 14d, 3-fold, p < 0.0001) compared to control cells. Total tau levels are also significantly increased following Syk overexpression (Fig. 14e, 4.2-fold, p < 0.0001).",
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@@ -22483,9 +25799,9 @@
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@@ -22579,9 +25901,9 @@
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@@ -22627,9 +25952,9 @@
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@@ -22675,9 +26003,9 @@
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@@ -22771,9 +26105,9 @@
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@@ -22781,25 +26115,163 @@
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+          "Kügler S",
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+        "type": "PubMed",
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@@ -22831,9 +26303,9 @@
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@@ -22879,9 +26354,9 @@
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@@ -22927,9 +26405,9 @@
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@@ -22975,9 +26456,9 @@
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       "evidence": "Taken all together, we think that activation of GSK-3b and p38 should be responsible for MG-induced tau hyperphosphorylation.",
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@@ -23023,9 +26507,9 @@
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@@ -23071,9 +26558,9 @@
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       "evidence": "Taken all together, we think that activation of GSK-3b and p38 should be responsible for MG-induced tau hyperphosphorylation.",
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-          "Fluorescence Spectrophotometry": true,
-          "NBT colorimetric fructosamine assay": true
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       "citation": {
         "authors": [
-          "Chen L",
-          "He R",
-          "Wang X",
-          "Wei Y"
+          "Cheng XS",
+          "Du LL",
+          "Jiang X",
+          "Li XH",
+          "Lv BL",
+          "Wang JZ",
+          "Xie JZ",
+          "Zhang JY",
+          "Zhou XW"
         ],
-        "date": "2009-08-01",
-        "first": "Chen L",
-        "last": "He R",
-        "name": "Cellular and molecular life sciences : CMLS",
-        "pages": "2559-71",
-        "reference": "19517062",
-        "title": "D-Ribosylated Tau forms globular aggregates with high cytotoxicity.",
+        "date": "2012-12-01",
+        "first": "Li XH",
+        "last": "Zhou XW",
+        "name": "Neuromolecular medicine",
+        "pages": "338-48",
+        "reference": "22798221",
+        "title": "Methylglyoxal induces tau hyperphosphorylation via promoting AGEs formation.",
         "type": "PubMed",
-        "volume": "66"
+        "volume": "14"
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-      "evidence": "D-ribosylated Tau aggregates were highly toxic to SHSY5Y cells and resulted in both apoptosis and necrosis",
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         "Method": {
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           "Cell Viability Assay, MTT": true,
@@ -23198,156 +26705,61 @@
         "type": "PubMed",
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-          "Bažadona D",
-          "Buée L",
-          "Delalle I",
-          "Di Giovanni G",
-          "Harrington C",
-          "Hof PR",
-          "Jovanov-Milošević N",
-          "Wischik C",
-          "Wray S",
-          "de Silva R",
-          "Šimić G"
-        ],
-        "date": "2016-01-06",
-        "first": "Šimić G",
-        "last": "Hof PR",
-        "name": "Biomolecules",
-        "pages": "6",
-        "reference": "26751493",
-        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
-        "type": "PubMed",
-        "volume": "6"
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-      "evidence": "In the case of soluble monomeric or small oligomeric tau protein, the endocytosis appears to be clathrin-dependent (reviewed in [169]). In contrast, larger aggregates of tau could bind heparin in the extracellular matrix and be internalized through macropinocytosis [170]. As a result of exocytosis and endocytosis, the spreading of tau can occur in various neurodegenerative diseases (tauopathies) including AD. Three plausible mechanisms of tau spreading are shown schematically in Figure 6. Additionally, it appea rs that microglial cells may facilitate tau propagation by phagocytosis and exocytosis of tau protein [171].",
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-          "Di Giovanni G",
-          "Harrington C",
-          "Hof PR",
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-          "Wischik C",
-          "Wray S",
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-        "first": "Šimić G",
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-        "name": "Biomolecules",
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-        "type": "PubMed",
-        "volume": "6"
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-      "evidence": "Recently, it has been proposed that tau protein acetylation may be responsible for tau aggregation in AD. Grinberg and collaborators detected tau acetylation at Lys274 in all tauopathies (both primary and secondary), except in AgD",
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-          "Carlomagno Y",
-          "Castanedes-Casey M",
-          "Chung DC",
-          "Cook C",
-          "DeTure M",
-          "Dickson DW",
-          "Dunmore J",
-          "Madden BJ",
-          "Petrucelli L",
-          "Tong J",
-          "Yue M"
-        ],
-        "date": "2017-09-15",
-        "first": "Carlomagno Y",
-        "last": "Cook C",
-        "name": "The Journal of biological chemistry",
-        "pages": "15277-15286",
-        "reference": "28760828",
-        "title": "An acetylation-phosphorylation switch that regulates tau aggregation propensity and function.",
-        "type": "PubMed",
-        "volume": "292"
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-      "evidence": "Our findings indicate that several acetylation sites in tau are responsive to HDAC6 and that acetylation on Lys-321 (within a KCGS motif) is both essential for acetylation-mediated inhibition of tau aggregation in vitro and a molecular tactic for preventing phosphorylation on the downstream Ser-324 residue. Tau phosphorylation of Ser-324 (pSer-324) has not previously been evaluated in the context of tauopathy, and here we observed increased deposition of pSer-324-positive tau both in mouse models of tauopathy and in patients with Alzheimer's disease. These findings uncover a novel acetylation-phosphorylation switch at Lys-321/Ser-324 that coordinately regulates tau polymerization and function.",
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       "annotations": {
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         },
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+          "Flow Cytometry": true,
+          "Fluorescence Spectrophotometry": true,
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       "citation": {
         "authors": [
-          "Bennett RE",
-          "Carlson GA",
-          "Corjuc B",
-          "DeVos SL",
-          "Dujardin S",
-          "Frosch MP",
-          "Gonzalez J",
-          "Gor R",
-          "Hyman BT",
-          "Pitstick R",
-          "Roe AD"
+          "Chen L",
+          "He R",
+          "Wang X",
+          "Wei Y"
         ],
-        "date": "2017-07-01",
-        "first": "Bennett RE",
-        "last": "Hyman BT",
-        "name": "The American journal of pathology",
-        "pages": "1601-1612",
-        "reference": "28500862",
-        "title": "Enhanced Tau Aggregation in the Presence of Amyloid β.",
+        "date": "2009-08-01",
+        "first": "Chen L",
+        "last": "He R",
+        "name": "Cellular and molecular life sciences : CMLS",
+        "pages": "2559-71",
+        "reference": "19517062",
+        "title": "D-Ribosylated Tau forms globular aggregates with high cytotoxicity.",
         "type": "PubMed",
-        "volume": "187"
+        "volume": "66"
       },
-      "evidence": "In the HEK cell biosensor assay, tau from AD cases with plaques enhanced tau aggregates compared to tau from cases without plaques. In APP/PS1 cross with rTg4510 mice (P301L mutant human tau), tau seeding activity was threefold increased over the rTg4510 strain, without change in tau production or extracellular release.",
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+      "evidence": "Tau is rapidly glycated in the presence of D-ribose, resulting in oligomerization and polymerization with Glycated derivatives appearing after 24 h. Advanced glycation end-products (AGEs) were formed during initial stages of glycation. Thioflavin T-positive (ThT-positive) aggregations (day 4) indicated the globular-like features. Atomic force microscopy revealed that the surface morphology of ribosylated Tau40 was globular-like.",
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         "Method": {
           "Atomic Force Microscopy": true,
           "Cell Viability Assay, MTT": true,
@@ -23374,17 +26786,20 @@
         "volume": "66"
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       "evidence": "Tau is rapidly glycated in the presence of D-ribose, resulting in oligomerization and polymerization with Glycated derivatives appearing after 24 h. Advanced glycation end-products (AGEs) were formed during initial stages of glycation. Thioflavin T-positive (ThT-positive) aggregations (day 4) indicated the globular-like features. Atomic force microscopy revealed that the surface morphology of ribosylated Tau40 was globular-like.",
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           "Atomic Force Microscopy": true,
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@@ -23411,14 +26826,29 @@
         "volume": "66"
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       "evidence": "Tau is rapidly glycated in the presence of D-ribose, resulting in oligomerization and polymerization with Glycated derivatives appearing after 24 h. Advanced glycation end-products (AGEs) were formed during initial stages of glycation. Thioflavin T-positive (ThT-positive) aggregations (day 4) indicated the globular-like features. Atomic force microscopy revealed that the surface morphology of ribosylated Tau40 was globular-like.",
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@@ -23620,28 +27053,43 @@
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       "evidence": "In accordance with the decreased efficiency of nitro-TPI we found a significant increase in methylglyoxal production (P50.05), independent of whether DHAP or GAP was used as substrate (Fig. 2E). Thus, nitrotyrosination of TPI results in reduced catalytic activity and increased occupancy of the enzyme by the substrate, and consequently, a higher production of the toxic methylglyoxal.",
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@@ -23680,56 +27128,16 @@
         "volume": "132"
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       "evidence": "Triosephosphate isomerase (TPI) is a key enzyme in cell metabolism that controls the glycolytic flow and energy production through the interconversion of dihydroxyacetone phosphate (DHAP) and D-glyceraldehyde 3-phosphate (G3P) (Richard, 1993). Notably, TPI is the only glycolytic enzyme whose functional deficiency is associated to neurodegeneration (Eber et al., 1991; Ovadi et al., 2004). In particular, inefficient glycolysis (Hoyer et al., 1988) and ATP depletion (Keil et al., 2004) are characteristic in Alzheimer’s disease brains.",
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-          "Iijima KM",
-          "Iijima-Ando K",
-          "Lu B",
-          "Maruko-Otake A",
-          "Ohtake Y",
-          "Sekiya M",
-          "Suzuki E"
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-        "first": "Iijima-Ando K",
-        "last": "Iijima KM",
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-        "title": "Loss of axonal mitochondria promotes tau-mediated neurodegeneration and Alzheimer's disease-related tau phosphorylation via PAR-1.",
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-      "evidence": "Using transgenic Drosophila expressing human tau, we found that RNAi-mediated knockdown of milton or Miro, an adaptor protein essential for axonal transport of mitochondria, enhanced human tau-induced neurodegeneration. Tau phosphorylation at an AD-related site Ser262 increased with knockdown of milton or Miro; and partitioning defective-1 (PAR-1), the Drosophila homolog of mammalian microtubule affinity-regulating kinase, mediated this increase of tau phosphorylation. Tau phosphorylation at Ser262 has been reported to promote tau detachment from microtubules, and we found that the levels of microtubule-unbound free tau increased by milton knockdown. Blocking tau phosphorylation at Ser262 site by PAR-1 knockdown or by mutating the Ser262 site to unphosphorylatable alanine suppressed the enhancement of tau-induced neurodegeneration caused by milton knockdown. Furthermore, knockdown of milton or Miro increased the levels of active PAR-1.",
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         "type": "PubMed",
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         "Method": {
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@@ -23814,70 +27225,56 @@
         "type": "PubMed",
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-      "evidence": "Nitration of Tyr164 and Tyr208 would destabilize the closed state of loop 6 because the interaction between Tyr208 and Ala176 through an H-bond would be compromised (Fig. 2A and B; Supplementary Fig. S2). Indeed, purified TPI after nitrotyrosination with a peroxynitrite donor (SIN-1) displayed a significant decrease in isomerase activity in both directions of the catalysis, i.e. using DHAP (Fig. 2C) or GAP (Fig. 2D) as substrate.",
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-          "Confocal Microscopy": true,
-          "Electron Microscopy, Transmission": true,
-          "Immunofluorescence": true,
-          "Immunohistochemistry": true,
-          "Immunoprecipitation": true,
-          "Turbidometric Analysis": true,
-          "Western Blot": true
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         "authors": [
-          "Bravo R",
-          "Coma M",
-          "Fernàndez-Busquets X",
-          "Guix FX",
-          "Ill-Raga G",
-          "Miscione GP",
-          "Muñoz FJ",
-          "Nakaya T",
-          "Suzuki T",
-          "Valverde MA",
-          "Villà-Freixa J",
-          "de Fabritiis G",
-          "de Strooper B"
+          "Iijima KM",
+          "Iijima-Ando K",
+          "Lu B",
+          "Maruko-Otake A",
+          "Ohtake Y",
+          "Sekiya M",
+          "Suzuki E"
         ],
-        "date": "2009-05-01",
-        "first": "Guix FX",
-        "last": "Muñoz FJ",
-        "name": "Brain : a journal of neurology",
-        "pages": "1335-45",
-        "reference": "19251756",
-        "title": "Amyloid-dependent triosephosphate isomerase nitrotyrosination induces glycation and tau fibrillation.",
+        "date": "2012-01-01",
+        "first": "Iijima-Ando K",
+        "last": "Iijima KM",
+        "name": "PLoS genetics",
+        "pages": "e1002918",
+        "reference": "22952452",
+        "title": "Loss of axonal mitochondria promotes tau-mediated neurodegeneration and Alzheimer's disease-related tau phosphorylation via PAR-1.",
         "type": "PubMed",
-        "volume": "132"
+        "volume": "8"
       },
-      "evidence": "Nitration of Tyr164 and Tyr208 would destabilize the closed state of loop 6 because the interaction between Tyr208 and Ala176 through an H-bond would be compromised (Fig. 2A and B; Supplementary Fig. S2). Indeed, purified TPI after nitrotyrosination with a peroxynitrite donor (SIN-1) displayed a significant decrease in isomerase activity in both directions of the catalysis, i.e. using DHAP (Fig. 2C) or GAP (Fig. 2D) as substrate.",
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+      "evidence": "Using transgenic Drosophila expressing human tau, we found that RNAi-mediated knockdown of milton or Miro, an adaptor protein essential for axonal transport of mitochondria, enhanced human tau-induced neurodegeneration. Tau phosphorylation at an AD-related site Ser262 increased with knockdown of milton or Miro; and partitioning defective-1 (PAR-1), the Drosophila homolog of mammalian microtubule affinity-regulating kinase, mediated this increase of tau phosphorylation. Tau phosphorylation at Ser262 has been reported to promote tau detachment from microtubules, and we found that the levels of microtubule-unbound free tau increased by milton knockdown. Blocking tau phosphorylation at Ser262 site by PAR-1 knockdown or by mutating the Ser262 site to unphosphorylatable alanine suppressed the enhancement of tau-induced neurodegeneration caused by milton knockdown. Furthermore, knockdown of milton or Miro increased the levels of active PAR-1.",
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@@ -23917,14 +27314,17 @@
         "volume": "132"
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       "evidence": "Ab induced nitro-oxidative stress on human neuroblastoma cells, resulting in nitrotyrosination of TPI. Moreover, higher levels of nitro-TPI were also detected in extracts from hippocampus (Fig. 1F) and frontal cortex (Fig. 1G) obtained from Alzheimer’s disease brains, compared with healthy subjects.",
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         "Method": {
           "Atomic Force Microscopy": true,
           "Confocal Microscopy": true,
@@ -23962,305 +27362,79 @@
         "type": "PubMed",
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-      "evidence": "Nitration of Tyr164 and Tyr208 would destabilize the closed state of loop 6 because the interaction between Tyr208 and Ala176 through an H-bond would be compromised (Fig. 2A and B; Supplementary Fig. S2). Indeed, purified TPI after nitrotyrosination with a peroxynitrite donor (SIN-1) displayed a significant decrease in isomerase activity in both directions of the catalysis, i.e. using DHAP (Fig. 2C) or GAP (Fig. 2D) as substrate.",
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+      "evidence": "Taupositive material was present in the immunoprecipitates indicating that tau becomes associated to nitroTPI in an Ab dose-dependent pattern (Fig. 5A).TPI and nitro-TPI were incubated with tau protein and samples were analysed by Atomic Force Microscopy (Fig. 7A–D) and TEM (Fig. 7F and G). Abundant paired helical filament-like structures were found in samples containing nitro-TPI plus tau",
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-          "Confocal Microscopy": true,
-          "Electron Microscopy, Transmission": true,
-          "Immunofluorescence": true,
-          "Immunohistochemistry": true,
-          "Immunoprecipitation": true,
-          "Turbidometric Analysis": true,
-          "Western Blot": true
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       "citation": {
         "authors": [
-          "Bravo R",
-          "Coma M",
-          "Fernàndez-Busquets X",
-          "Guix FX",
-          "Ill-Raga G",
-          "Miscione GP",
-          "Muñoz FJ",
-          "Nakaya T",
-          "Suzuki T",
-          "Valverde MA",
-          "Villà-Freixa J",
-          "de Fabritiis G",
-          "de Strooper B"
+          "Berry RW",
+          "Binder LI",
+          "Lukas TJ",
+          "Reynolds MR"
         ],
-        "date": "2009-05-01",
-        "first": "Guix FX",
-        "last": "Muñoz FJ",
-        "name": "Brain : a journal of neurology",
-        "pages": "1335-45",
-        "reference": "19251756",
-        "title": "Amyloid-dependent triosephosphate isomerase nitrotyrosination induces glycation and tau fibrillation.",
+        "date": "2006-04-04",
+        "first": "Reynolds MR",
+        "last": "Binder LI",
+        "name": "Biochemistry",
+        "pages": "4314-26",
+        "reference": "16566606",
+        "title": "Peroxynitrite-mediated tau modifications stabilize preformed filaments and destabilize microtubules through distinct mechanisms.",
         "type": "PubMed",
-        "volume": "132"
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-          "Suzuki T",
-          "Valverde MA",
-          "Villà-Freixa J",
-          "de Fabritiis G",
-          "de Strooper B"
+          "Berry RW",
+          "Binder LI",
+          "Lukas TJ",
+          "Reynolds MR"
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-        "name": "Brain : a journal of neurology",
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-        "title": "Amyloid-dependent triosephosphate isomerase nitrotyrosination induces glycation and tau fibrillation.",
+        "date": "2006-04-04",
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+        "name": "Biochemistry",
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+        "reference": "16566606",
+        "title": "Peroxynitrite-mediated tau modifications stabilize preformed filaments and destabilize microtubules through distinct mechanisms.",
         "type": "PubMed",
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-      "evidence": "Taupositive material was present in the immunoprecipitates indicating that tau becomes associated to nitroTPI in an Ab dose-dependent pattern (Fig. 5A).TPI and nitro-TPI were incubated with tau protein and samples were analysed by Atomic Force Microscopy (Fig. 7A–D) and TEM (Fig. 7F and G). Abundant paired helical filament-like structures were found in samples containing nitro-TPI plus tau",
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-      "evidence": "Taupositive material was present in the immunoprecipitates indicating that tau becomes associated to nitroTPI in an Ab dose-dependent pattern (Fig. 5A).TPI and nitro-TPI were incubated with tau protein and samples were analysed by Atomic Force Microscopy (Fig. 7A–D) and TEM (Fig. 7F and G). Abundant paired helical filament-like structures were found in samples containing nitro-TPI plus tau",
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-      "evidence": "Taupositive material was present in the immunoprecipitates indicating that tau becomes associated to nitroTPI in an Ab dose-dependent pattern (Fig. 5A).TPI and nitro-TPI were incubated with tau protein and samples were analysed by Atomic Force Microscopy (Fig. 7A–D) and TEM (Fig. 7F and G). Abundant paired helical filament-like structures were found in samples containing nitro-TPI plus tau",
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-      "evidence": "Taupositive material was present in the immunoprecipitates indicating that tau becomes associated to nitroTPI in an Ab dose-dependent pattern (Fig. 5A).TPI and nitro-TPI were incubated with tau protein and samples were analysed by Atomic Force Microscopy (Fig. 7A–D) and TEM (Fig. 7F and G). Abundant paired helical filament-like structures were found in samples containing nitro-TPI plus tau",
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-        "title": "Amyloid-dependent triosephosphate isomerase nitrotyrosination induces glycation and tau fibrillation.",
-        "type": "PubMed",
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-      "evidence": "Taupositive material was present in the immunoprecipitates indicating that tau becomes associated to nitroTPI in an Ab dose-dependent pattern (Fig. 5A).TPI and nitro-TPI were incubated with tau protein and samples were analysed by Atomic Force Microscopy (Fig. 7A–D) and TEM (Fig. 7F and G). Abundant paired helical filament-like structures were found in samples containing nitro-TPI plus tau",
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@@ -24279,11 +27453,11 @@
         "volume": "45"
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       "evidence": "During Abeta-associated inflammation, reactive nitrogen and oxygen species are generated that can cause neuronal dysfunction and death (34-37). Prevalent among these species is peroxynitrite (ONOO-)",
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       "annotations": {
@@ -24291,6 +27465,9 @@
           "cerebral cortex": true,
           "hippocampal formation": true
         },
+        "Confidence": {
+          "Medium": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true,
           "Down Syndrome": true
@@ -24325,49 +27502,94 @@
         "volume": "110"
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       "evidence": "Normalizing the gene dosage of Dyrk1A in the TS mouse rescued the density of senescent cells in the cingulate cortex, hippocampus and septum, prevented cholinergic neuron degeneration, and reduced App expression in the hippocampus, Aß load in the cortex and hippocampus, the expression of phosphorylated tau at the Ser202 residue in the hippocampus and cerebellum and the levels of total tau in the cortex, hippocampus and cerebellum.",
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     {
       "annotations": {
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+          "Medium": true
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       },
       "citation": {
         "authors": [
           "Ait-Ghezala G",
-          "Bachmeier C",
           "Beaulieu-Abdelahad D",
           "Crawford F",
-          "Jin C",
-          "Laco G",
-          "Lin Y",
+          "Mouzon B",
           "Mullan M",
-          "Paris D"
+          "Paris D",
+          "Schweig JE",
+          "Yao H"
         ],
-        "date": "2014-12-05",
-        "first": "Paris D",
-        "last": "Mullan M",
-        "name": "The Journal of biological chemistry",
-        "pages": "33927-44",
-        "reference": "25331948",
-        "title": "The spleen tyrosine kinase (Syk) regulates Alzheimer amyloid-β production and Tau hyperphosphorylation.",
+        "date": "2017-09-06",
+        "first": "Schweig JE",
+        "last": "Paris D",
+        "name": "Acta neuropathologica communications",
+        "pages": "69",
+        "reference": "28877763",
+        "title": "Alzheimer's disease pathological lesions activate the spleen tyrosine kinase.",
         "type": "PubMed",
-        "volume": "289"
+        "volume": "5"
       },
-      "evidence": "We further validated Syk as a target-regulating Aβ by showing that pharmacological inhibition of Syk or down-regulation of Syk expression reduces Aβ production and increases the clearance of Aβ across the BBB mimicking (-)-nilvadipine effects. Moreover, treatment of transgenic mice overexpressing Aβ and transgenic Tau P301S mice with a selective Syk inhibitor respectively decreased brain Aβ accumulation and Tau hyperphosphorylation at multiple AD relevant epitopes.",
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+      "evidence": "Additionally, we show that Syk overexpression leads to increased tau accumulation and promotes tau hyperphosphorylation at multiple epitopes in human neuron-like SH-SY5Y cells, further supporting a role of Syk in the formation of tau pathogenic species. Collectively, our data show that Syk activation occurs following Aβ deposition and the formation of tau pathological species.",
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+    {
+      "annotations": {
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+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
+        "Research_Model": {
+          "APPPS1 mice": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Ait-Ghezala G",
+          "Beaulieu-Abdelahad D",
+          "Crawford F",
+          "Mouzon B",
+          "Mullan M",
+          "Paris D",
+          "Schweig JE",
+          "Yao H"
+        ],
+        "date": "2017-09-06",
+        "first": "Schweig JE",
+        "last": "Paris D",
+        "name": "Acta neuropathologica communications",
+        "pages": "69",
+        "reference": "28877763",
+        "title": "Alzheimer's disease pathological lesions activate the spleen tyrosine kinase.",
+        "type": "PubMed",
+        "volume": "5"
+      },
+      "evidence": "The upregulation of Syk activation observed in the brains of Tg APPsw and Tg PS1/APPsw is mainly attributable to pSyk accumulations in dystrophic neurites that are associated with Aβ plaques and increase with age and Aβ burden.",
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     },
     {
       "annotations": {
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         "Species": {
           "10116": true
         }
@@ -24401,58 +27623,73 @@
         "volume": "134"
       },
       "evidence": "Chronic Brain hypoperfusion (CBH) elevates nuclear factor-kB (NF-kB), which binds with the promoter sequences of miR-195 and negatively regulates its expression. Down-regulated miR-195 up-regulates APP and BACE1 and increases Aß levels. Some Aß then enter the intracellular space and activate calpain, promoting the conversion of Cdk5/p35 to Cdk5/p25 and catalyzes the degradation of IkB (inhibitor of NF-?B)and directly phosphorylates Tau. Down-regulated miR-195 up-regulates p35, which provides the active substrates of p25",
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-      "relation": "negativeCorrelation",
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+      "line": 2891,
+      "object": {
+        "modifier": "Activity"
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+      "relation": "increases",
+      "source": 12,
+      "subject": {
+        "location": {
+          "name": "Intracellular Space",
+          "namespace": "MESH"
+        }
+      },
+      "target": 352
     },
     {
       "annotations": {
+        "Anatomy": {
+          "hippocampal formation": true
+        },
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Neurons": true
+        },
         "Species": {
           "10116": true
         }
       },
       "citation": {
         "authors": [
-          "Ai J",
-          "Ban T",
-          "Bao YN",
-          "Chen QX",
-          "Hu XL",
-          "Jiang XM",
-          "Liu CD",
-          "Pei SC",
-          "Su XL",
-          "Sun LH",
-          "Sun LL",
-          "Wang X",
-          "Yan ML",
-          "Zhao LJ",
-          "Zong DK"
+          "Lu B",
+          "Malenka R",
+          "Polepalli J",
+          "Rajadas J",
+          "Wagh D",
+          "Yu W"
         ],
-        "date": "2015-09-01",
-        "first": "Sun LH",
-        "last": "Ai J",
-        "name": "Journal of neurochemistry",
-        "pages": "1139-51",
-        "reference": "26118667",
-        "title": "Activation of Cdk5/p25 and tau phosphorylation following chronic brain hypoperfusion in rats involves microRNA-195 down-regulation.",
+        "date": "2012-03-15",
+        "first": "Yu W",
+        "last": "Lu B",
+        "name": "Human molecular genetics",
+        "pages": "1384-90",
+        "reference": "22156579",
+        "title": "A critical role for the PAR-1/MARK-tau axis in mediating the toxic effects of Aβ on synapses and dendritic spines.",
         "type": "PubMed",
-        "volume": "134"
+        "volume": "21"
       },
-      "evidence": "Chronic Brain hypoperfusion (CBH) elevates nuclear factor-kB (NF-kB), which binds with the promoter sequences of miR-195 and negatively regulates its expression. Down-regulated miR-195 up-regulates APP and BACE1 and increases Aß levels. Some Aß then enter the intracellular space and activate calpain, promoting the conversion of Cdk5/p35 to Cdk5/p25 and catalyzes the degradation of IkB (inhibitor of NF-?B)and directly phosphorylates Tau. Down-regulated miR-195 up-regulates p35, which provides the active substrates of p25",
-      "key": "760aefcb7e5137db1b343f93c950290451cb09efc05228127a1a6216fe6e05cb7639d348b1f93e6a4562340dc4bd7ed380bf4734092122ccc8479201b07c9e7c",
-      "line": 2342,
+      "evidence": "Consistent with previous reports (11,34), treatment of rat hippocampal neurons with synthetic Aβ, prepared using a well-characterized procedure that enriches for Aβ oligomers (37), resulted in increased tau phosphorylation at the 12E8 sites (Fig. 2A), suggesting that Aβ treatment had activated MARK kinases. Increased phosphorylation of tau at a site recognized by the PHF-1 phospho-tau antibody was also observed (data not shown).",
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       "relation": "increases",
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-      "target": 760
+      "source": 12,
+      "target": 974
     },
     {
       "annotations": {
         "Anatomy": {
           "hippocampal formation": true
         },
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Neurons": true
+        },
         "Species": {
           "10116": true
         }
@@ -24477,17 +27714,23 @@
         "volume": "21"
       },
       "evidence": "Consistent with previous reports (11,34), treatment of rat hippocampal neurons with synthetic Aβ, prepared using a well-characterized procedure that enriches for Aβ oligomers (37), resulted in increased tau phosphorylation at the 12E8 sites (Fig. 2A), suggesting that Aβ treatment had activated MARK kinases. Increased phosphorylation of tau at a site recognized by the PHF-1 phospho-tau antibody was also observed (data not shown).",
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       "relation": "increases",
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-      "target": 635
+      "source": 12,
+      "target": 975
     },
     {
       "annotations": {
         "Anatomy": {
           "hippocampal formation": true
         },
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Neurons": true
+        },
         "Species": {
           "10116": true
         }
@@ -24512,54 +27755,99 @@
         "volume": "21"
       },
       "evidence": "Consistent with previous reports (11,34), treatment of rat hippocampal neurons with synthetic Aβ, prepared using a well-characterized procedure that enriches for Aβ oligomers (37), resulted in increased tau phosphorylation at the 12E8 sites (Fig. 2A), suggesting that Aβ treatment had activated MARK kinases. Increased phosphorylation of tau at a site recognized by the PHF-1 phospho-tau antibody was also observed (data not shown).",
-      "key": "05848719e271780a186556f64bb99893ac17a64b1f019938fa684e865b55047f3f5d343ca7384a359f58633d10849b1282d9626c91cfe8f74a0119876adda495",
-      "line": 2685,
-      "relation": "positiveCorrelation",
-      "source": 10,
-      "target": 116
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+      "line": 3321,
+      "object": {
+        "modifier": "Activity"
+      },
+      "relation": "increases",
+      "source": 12,
+      "target": 722
+    },
+    {
+      "annotations": {
+        "Anatomy": {
+          "hippocampal formation": true
+        },
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Neurons": true
+        },
+        "Species": {
+          "10116": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Lu B",
+          "Malenka R",
+          "Polepalli J",
+          "Rajadas J",
+          "Wagh D",
+          "Yu W"
+        ],
+        "date": "2012-03-15",
+        "first": "Yu W",
+        "last": "Lu B",
+        "name": "Human molecular genetics",
+        "pages": "1384-90",
+        "reference": "22156579",
+        "title": "A critical role for the PAR-1/MARK-tau axis in mediating the toxic effects of Aβ on synapses and dendritic spines.",
+        "type": "PubMed",
+        "volume": "21"
+      },
+      "evidence": "Consistent with previous reports (11,34), treatment of rat hippocampal neurons with synthetic Aβ, prepared using a well-characterized procedure that enriches for Aβ oligomers (37), resulted in increased tau phosphorylation at the 12E8 sites (Fig. 2A), suggesting that Aβ treatment had activated MARK kinases. Increased phosphorylation of tau at a site recognized by the PHF-1 phospho-tau antibody was also observed (data not shown).",
+      "key": "463d60e04402ce401035471b1f4e86656e6e20b948163b8ee1b83610b31337da0da32a25c4642f9056f6bbf237b22e77d84027f91be4265d888cc06a45379460",
+      "line": 3322,
+      "relation": "increases",
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+      "target": 418
     },
     {
       "annotations": {
         "Cell_Line": {
+          "BV2": true,
           "N2a": true
         },
-        "Species": {
-          "10090": true
+        "Confidence": {
+          "Medium": true
         }
       },
       "citation": {
         "authors": [
-          "Ando K",
-          "Brion JP",
-          "D'Amico E",
-          "Duyckaerts C",
-          "Erneux C",
-          "Jia Y",
-          "Leroy K",
-          "Luo HR",
-          "Pouillon V",
-          "Schurmans S",
-          "Stygelbout V"
+          "Bae D",
+          "Kim MJ",
+          "Kim S",
+          "Kim YJ",
+          "Lee YH",
+          "Na Y",
+          "Park SY",
+          "Yoon HG"
         ],
-        "date": "2014-02-01",
-        "first": "Stygelbout V",
-        "last": "Brion JP",
-        "name": "Brain : a journal of neurology",
-        "pages": "537-52",
-        "reference": "24401760",
-        "title": "Inositol trisphosphate 3-kinase B is increased in human Alzheimer brain and exacerbates mouse Alzheimer pathology.",
+        "date": "2015-04-01",
+        "first": "Park SY",
+        "last": "Yoon HG",
+        "name": "International journal of molecular medicine",
+        "pages": "1109-18",
+        "reference": "25672970",
+        "title": "Selective PCAF inhibitor ameliorates cognitive and behavioral deficits by suppressing NF-κB-mediated neuroinflammation induced by Aβ in a model of Alzheimer's disease.",
         "type": "PubMed",
-        "volume": "137"
+        "volume": "35"
       },
-      "evidence": "We show here that ITPKB protein level was increased 3-fold in the cerebral cortex of most patients with Alzheimer's disease compared with control subjects, and accumulated in dystrophic neurites associated to amyloid plaques. In mouse Neuro-2a neuroblastoma cells, Itpkb overexpression was associated with increased cell apoptosis and increased β-secretase 1 activity leading to overproduction of amyloid-β peptides. In this cellular model, an inhibitor of mitogen-activated kinase kinases 1/2 completely prevented overproduction of amyloid-β peptides. Transgenic overexpression of ITPKB in mouse forebrain neurons was not sufficient to induce amyloid plaque formation or tau hyperphosphorylation. However, in the 5X familial Alzheimer's disease mouse model, neuronal ITPKB overexpression significantly increased extracellular signal-regulated kinases 1/2 activation and β-secretase 1 activity, resulting in exacerbated Alzheimer's disease pathology as shown by increased astrogliosis, amyloid-β40 peptide production and tau hyperphosphorylation.",
-      "key": "f0782595fd697586a41e84439ccaff8e214622b044cebc7eb59f3b826d2e5900ee3035f4f8213e525a9f2ac375cf4959bb1860de98db874ebee23bd35106c10c",
-      "line": 2858,
-      "relation": "positiveCorrelation",
-      "source": 10,
-      "target": 771
+      "evidence": "In this study, we modified the PCAF inhibitor by chemical derivatization and selected compound C-30-27 as the most potent PCAF inhibitor. We demonstrated that C-30-27 selectively inhibited acetylation-dependent nuclear factor-κB (NF-κB) at Lys-122 and suppressed the NF-κB-mediated inflammatory response induced by lipopolysaccharide (LPS) or Aβ in both BV2 and Neuro-2A (N2A) cells. Finally, we demonstrated that C-30-27 improved cognitive deficits, as well as the capacity for locomotion and the damaged cholinergic system in the Aβ-treated rats.",
+      "key": "db58a374ea6950b918dcb6a62df15805b3ae07ba6560976b084ceaf1b06cc0f12afd475e66b0706ca13533fa7bec4858c730eccfdc7652c0d978507d2f20c6d5",
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+      "relation": "increases",
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+      "target": 197
     },
     {
       "annotations": {
+        "Confidence": {
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+        },
         "Species": {
           "7227": true
         }
@@ -24586,20 +27874,23 @@
         "volume": "7"
       },
       "evidence": "We have used a knock-out/knock-in strategy in Drosophila to generate a strain with hTau inserted into the endogenous fly tau locus and expressed under the control of the endogenous fly tau promoter, thus avoiding potential toxicity due to genetic over-expression. hTau knock-in (KI) proteins were expressed at normal, endogenous levels, bound to fly microtubules and were post-translationally modified, hence displaying physiological properties. We used this new model to investigate the effects of acetylation on hTau toxicity in vivo. The simultaneous pseudo-acetylation of hTau at lysines 163, 280, 281 and 369 drastically decreased hTau phosphorylation and significantly reduced its binding to microtubules in vivo. These molecular alterations were associated with ameliorated amyloid beta toxicity. Our results indicate acetylation of hTau on multiple sites regulates its biology and ameliorates amyloid beta toxicity in vivo.",
-      "key": "f72b2ab9c112b42ce234e1928e99c67b32ddfe49865e7ee7c28d28dcc9e2d826ee69fcee5c52f92ba297f70abca3f873fc23b42899cbc8acbda791de90a79940",
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       "relation": "negativeCorrelation",
-      "source": 10,
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       "subject": {
         "modifier": "Activity"
       },
-      "target": 247
+      "target": 573
     },
     {
       "annotations": {
         "Anatomy": {
           "hippocampal formation": true
         },
+        "Confidence": {
+          "Medium": true
+        },
         "Species": {
           "10116": true
         }
@@ -24632,14 +27923,17 @@
         "volume": "111"
       },
       "evidence": "Furthermore, the enhanced SUMO-immunoreactivity, costained with the hyperphosphorylated tau, is detected in cerebral cortex of the AD brains, and β-amyloid exposure of rat primary hippocampal neurons induces a dose-dependent SUMOylation of the hyperphosphorylated tau. Our findings suggest that tau SUMOylation reciprocally stimulates its phosphorylation and inhibits the ubiquitination-mediated tau degradation, which provides a new insight into the AD-like tau accumulation.",
-      "key": "c263b6b02720dbca8c09968f3a267bf7678e093a06a33fa9cd187d90b5128d56e9fb584c133a6d0ca642a494020e104b2c489b935460da378ed78ac71f15885a",
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       "relation": "increases",
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-      "target": 886
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+      "target": 969
     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "Research_Model": {
           "APP/PS1 x rTg4510 mice": true
         },
@@ -24673,510 +27967,886 @@
       },
       "evidence": "In the HEK cell biosensor assay, tau from AD cases with plaques enhanced tau aggregates compared to tau from cases without plaques. In APP/PS1 cross with rTg4510 mice (P301L mutant human tau), tau seeding activity was threefold increased over the rTg4510 strain, without change in tau production or extracellular release.",
       "key": "2a3b9a94af9db894289227ef4622cd38eda6d84468de47bc2e6265036bdb6b9f640928ed6502270dbc5d6d2c948e6f6c523a56641b39400758e305432277607d",
-      "line": 3583,
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       "relation": "positiveCorrelation",
-      "source": 10,
-      "target": 325
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+      "target": 402
     },
     {
       "annotations": {
-        "Cell_Line": {
-          "neural stem cell": true
-        },
-        "Method": {
-          "Electrophoretic Mobility Shift Assay": true,
-          "Immunofluorescence": true,
-          "RNA Interference, siRNA": true,
-          "RT-PCR": true,
-          "Western Blot": true
+        "Confidence": {
+          "Medium": true
         }
       },
       "citation": {
         "authors": [
-          "De Filippis D",
-          "Esposito G",
-          "Iuvone T",
-          "Lu J",
-          "Savani C",
-          "Scuderi C",
-          "Sheen V",
-          "Steardo L",
-          "Steardo L Jr"
+          "Sarge KD",
+          "Zhang YQ"
         ],
-        "date": "2008-06-01",
-        "first": "Esposito G",
-        "last": "Steardo L",
-        "name": "Journal of cellular and molecular medicine",
-        "pages": "914-27",
-        "reference": "18494933",
-        "title": "S100B induces tau protein hyperphosphorylation via Dickopff-1 up-regulation and disrupts the Wnt pathway in human neural stem cells.",
+        "date": "2008-10-03",
+        "first": "Zhang YQ",
+        "last": "Sarge KD",
+        "name": "Biochemical and biophysical research communications",
+        "pages": "673-8",
+        "reference": "18675254",
+        "title": "Sumoylation of amyloid precursor protein negatively regulates Abeta aggregate levels.",
         "type": "PubMed",
-        "volume": "12"
+        "volume": "374"
       },
-      "evidence": "Collectively, these studies demonstrate that the soluble, astroglial-derived S100B protein interacts with RAGE leading to the JNK phosphorylation and the pJNK-dependent up-regulation of c-Jun, a component of the AP-1 complex.",
-      "key": "48b2dc57989214d0dc8c6f19f478fcfbaf8d8de54b98204e7f59af4ab1b8896bc4f4998b8cd9f92bd2eb7c3444f99171176829fcf0d9a81f079b0a23d374eb62",
-      "line": 650,
-      "relation": "increases",
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-      "target": 292
+      "evidence": "Lysines 587 and 595 of APP, immediately adjacent to the site of beta-secretase cleavage, are covalently modified by SUMO proteins in vivo. Sumoylation of these lysine residues is associated with decreased levels of Abeta aggregates. The results demonstrate that the SUMO E2 enzyme (ubc9) is present within the endoplasmic reticulum, indicating how APP, and perhaps other proteins that enter this compartment, can be sumoylated.",
+      "key": "2870e99fd671fdd57d690a6e958f53230ef246e9c60d15b1ce3ce7c14f096df1a4f9a53b3d6d66480a4f05dc8fbe22f1baff7f45222c30216e6b4ac87d0849e8",
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+      "relation": "negativeCorrelation",
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     },
     {
       "annotations": {
-        "Cell_Line": {
-          "neural stem cell": true
-        },
-        "Method": {
-          "Electrophoretic Mobility Shift Assay": true,
-          "Immunofluorescence": true,
-          "RNA Interference, siRNA": true,
-          "RT-PCR": true,
-          "Western Blot": true
+        "Confidence": {
+          "Medium": true
         }
       },
       "citation": {
         "authors": [
-          "De Filippis D",
-          "Esposito G",
-          "Iuvone T",
-          "Lu J",
-          "Savani C",
-          "Scuderi C",
-          "Sheen V",
-          "Steardo L",
-          "Steardo L Jr"
+          "Sarge KD",
+          "Zhang YQ"
         ],
-        "date": "2008-06-01",
-        "first": "Esposito G",
-        "last": "Steardo L",
-        "name": "Journal of cellular and molecular medicine",
-        "pages": "914-27",
-        "reference": "18494933",
-        "title": "S100B induces tau protein hyperphosphorylation via Dickopff-1 up-regulation and disrupts the Wnt pathway in human neural stem cells.",
+        "date": "2008-10-03",
+        "first": "Zhang YQ",
+        "last": "Sarge KD",
+        "name": "Biochemical and biophysical research communications",
+        "pages": "673-8",
+        "reference": "18675254",
+        "title": "Sumoylation of amyloid precursor protein negatively regulates Abeta aggregate levels.",
         "type": "PubMed",
-        "volume": "12"
-      },
-      "evidence": "Collectively, these studies demonstrate that the soluble, astroglial-derived S100B protein interacts with RAGE leading to the JNK phosphorylation and the pJNK-dependent up-regulation of c-Jun, a component of the AP-1 complex.",
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-      "line": 652,
-      "object": {
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+        "volume": "374"
       },
-      "relation": "directlyIncreases",
-      "source": 673,
-      "target": 371
+      "evidence": "Lysines 587 and 595 of APP, immediately adjacent to the site of beta-secretase cleavage, are covalently modified by SUMO proteins in vivo. Sumoylation of these lysine residues is associated with decreased levels of Abeta aggregates. The results demonstrate that the SUMO E2 enzyme (ubc9) is present within the endoplasmic reticulum, indicating how APP, and perhaps other proteins that enter this compartment, can be sumoylated.",
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+      "line": 4572,
+      "relation": "negativeCorrelation",
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     },
     {
       "annotations": {
-        "Cell_Line": {
-          "neural stem cell": true
+        "Confidence": {
+          "Medium": true
         },
-        "Method": {
-          "Electrophoretic Mobility Shift Assay": true,
-          "Immunofluorescence": true,
-          "RNA Interference, siRNA": true,
-          "RT-PCR": true,
-          "Western Blot": true
+        "MeSHAnatomy": {
+          "Hippocampus": true
+        },
+        "Species": {
+          "10116": true
         }
       },
       "citation": {
         "authors": [
-          "De Filippis D",
-          "Esposito G",
-          "Iuvone T",
-          "Lu J",
-          "Savani C",
-          "Scuderi C",
-          "Sheen V",
-          "Steardo L",
-          "Steardo L Jr"
+          "Botezelli JD",
+          "Cintra DE",
+          "Gaspar RC",
+          "Gomes RJ",
+          "Kuga GK",
+          "Leme JACA",
+          "Muñoz VR",
+          "Nakandakari SCBR",
+          "Pauli JR",
+          "Ropelle ER",
+          "da Silva ASR",
+          "de Moura LP"
         ],
-        "date": "2008-06-01",
-        "first": "Esposito G",
-        "last": "Steardo L",
-        "name": "Journal of cellular and molecular medicine",
-        "pages": "914-27",
-        "reference": "18494933",
-        "title": "S100B induces tau protein hyperphosphorylation via Dickopff-1 up-regulation and disrupts the Wnt pathway in human neural stem cells.",
+        "date": "2018-04-01",
+        "first": "Kuga GK",
+        "last": "Pauli JR",
+        "name": "Experimental gerontology",
+        "pages": "66-71",
+        "reference": "29421605",
+        "title": "Impaired insulin signaling and spatial learning in middle-aged rats: The role of PTP1B.",
         "type": "PubMed",
-        "volume": "12"
+        "volume": "104"
       },
-      "evidence": "In addition, as revealed by Western blot, small interfering RNA and immunofluorescence analysis, S100B-induced JNK activation increased expression of Dickopff-1 that, in turn, promoted glycogen synthase kinase 3-beta phosphorylation and beta-catenin degradation, causing canonical Wnt pathway disruption and tau protein hyperphosphorylation.",
-      "key": "60dc743c75eca2bee8c766f626e8bf14559d9d84d2d34b2162ed5e34b855bc468ca8be77d25d9d6ba1f9d991e0010599cc065ce3f78c55f1088c2a951c01b38e",
-      "line": 663,
-      "relation": "decreases",
-      "source": 673,
-      "target": 170
+      "evidence": "Interestingly, the middle-aged rats have higher levels of PTP-1B, lower phosphorylation of IRS-1, Akt, GSK3β, mTOR, and TrkB. Also, the aging process increased Tau phosphorylation and β-amyloid content in the hippocampus region. In summary, this study provides new evidence that aging-related PTP1B increasing, contributing to insulin resistance and the onset of the AD.",
+      "key": "1d0107ba1b6b82658e4fc0398b4c9fc3f3a4833cb13955254ab6c3babc3ca16f793d38aeaa4b48e8e378c57ccec9d2004bc487e51042e653dafe5c1c9813dae9",
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+      "relation": "positiveCorrelation",
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     },
     {
       "annotations": {
-        "Cell_Line": {
-          "neural stem cell": true
+        "Confidence": {
+          "High": true
         },
         "Method": {
-          "Electrophoretic Mobility Shift Assay": true,
+          "Atomic Force Microscopy": true,
+          "Confocal Microscopy": true,
+          "Electron Microscopy, Transmission": true,
           "Immunofluorescence": true,
-          "RNA Interference, siRNA": true,
-          "RT-PCR": true,
+          "Immunohistochemistry": true,
+          "Immunoprecipitation": true,
+          "Turbidometric Analysis": true,
           "Western Blot": true
         }
       },
       "citation": {
         "authors": [
-          "De Filippis D",
-          "Esposito G",
-          "Iuvone T",
-          "Lu J",
-          "Savani C",
-          "Scuderi C",
-          "Sheen V",
-          "Steardo L",
-          "Steardo L Jr"
+          "Bravo R",
+          "Coma M",
+          "Fernàndez-Busquets X",
+          "Guix FX",
+          "Ill-Raga G",
+          "Miscione GP",
+          "Muñoz FJ",
+          "Nakaya T",
+          "Suzuki T",
+          "Valverde MA",
+          "Villà-Freixa J",
+          "de Fabritiis G",
+          "de Strooper B"
         ],
-        "date": "2008-06-01",
-        "first": "Esposito G",
-        "last": "Steardo L",
-        "name": "Journal of cellular and molecular medicine",
-        "pages": "914-27",
-        "reference": "18494933",
-        "title": "S100B induces tau protein hyperphosphorylation via Dickopff-1 up-regulation and disrupts the Wnt pathway in human neural stem cells.",
+        "date": "2009-05-01",
+        "first": "Guix FX",
+        "last": "Muñoz FJ",
+        "name": "Brain : a journal of neurology",
+        "pages": "1335-45",
+        "reference": "19251756",
+        "title": "Amyloid-dependent triosephosphate isomerase nitrotyrosination induces glycation and tau fibrillation.",
         "type": "PubMed",
-        "volume": "12"
+        "volume": "132"
       },
-      "evidence": "In addition, as revealed by Western blot, small interfering RNA and immunofluorescence analysis, S100B-induced JNK activation increased expression of Dickopff-1 that, in turn, promoted glycogen synthase kinase 3-beta phosphorylation and beta-catenin degradation, causing canonical Wnt pathway disruption and tau protein hyperphosphorylation.",
-      "key": "076a7b245cb524a5362115a7cd09e9ab116d97020e145b2804f4148fbbd7e2fec6c64f1656bcbaba797cc0a4e76b6e40758c350804e8ac794d98c149e54c1070",
-      "line": 664,
+      "evidence": "Ab induced nitro-oxidative stress on human neuroblastoma cells, resulting in nitrotyrosination of TPI. Moreover, higher levels of nitro-TPI were also detected in extracts from hippocampus (Fig. 1F) and frontal cortex (Fig. 1G) obtained from Alzheimer’s disease brains, compared with healthy subjects.",
+      "key": "2081a16b3bae9e07e3c0f86ad5037833627ba359f48dae52d07df1c789dcb85f472cfda6c1a0d493481629131c7c2d2b53de4e0f0a107407447eda4a26bb3fde",
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       "relation": "increases",
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-      "target": 538
+      "source": 207,
+      "target": 855
     },
     {
       "annotations": {
-        "Cell_Line": {
-          "neural stem cell": true
+        "Confidence": {
+          "High": true
         },
         "Method": {
-          "Electrophoretic Mobility Shift Assay": true,
+          "Atomic Force Microscopy": true,
+          "Confocal Microscopy": true,
+          "Electron Microscopy, Transmission": true,
           "Immunofluorescence": true,
-          "RNA Interference, siRNA": true,
-          "RT-PCR": true,
+          "Immunohistochemistry": true,
+          "Immunoprecipitation": true,
+          "Turbidometric Analysis": true,
           "Western Blot": true
         }
       },
       "citation": {
         "authors": [
-          "De Filippis D",
-          "Esposito G",
-          "Iuvone T",
-          "Lu J",
-          "Savani C",
-          "Scuderi C",
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-          "Lu J",
-          "Savani C",
-          "Scuderi C",
-          "Sheen V",
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+          "Hakala K",
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-          "Hashimoto Y",
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-          "Matsuoka M",
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-          "Toyama Y"
+          "Bravo R",
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+          "Fernàndez-Busquets X",
+          "Guix FX",
+          "Ill-Raga G",
+          "Miscione GP",
+          "Muñoz FJ",
+          "Nakaya T",
+          "Suzuki T",
+          "Valverde MA",
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+          "de Fabritiis G",
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-        "first": "Hashimoto Y",
-        "last": "Matsuoka M",
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-        "reference": "27068745",
-        "title": "An Alzheimer Disease-linked Rare Mutation Potentiates Netrin Receptor Uncoordinated-5C-induced Signaling That Merges with Amyloid β Precursor Protein Signaling.",
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         "authors": [
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-          "Kusakari S",
-          "Matsuoka M",
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-        "last": "Matsuoka M",
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-        "title": "An Alzheimer Disease-linked Rare Mutation Potentiates Netrin Receptor Uncoordinated-5C-induced Signaling That Merges with Amyloid β Precursor Protein Signaling.",
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         "type": "PubMed",
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+          "Muñoz FJ",
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-          "Goedert M"
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-        "title": "Phosphorylation of microtubule-associated protein tau by stress-activated protein kinases in intact cells.",
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-          "Michalski JC",
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-        "title": "Dysregulation of the nutrient/stress sensor O-GlcNAcylation is involved in the etiology of cardiovascular disorders, type-2 diabetes and Alzheimer's disease.",
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+        "volume": "282"
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-      "evidence": "Tau-nY18 did not label the classical pathological lesions of CBD or PSP but did label the neuronal lesions associated with PiD. Tau-nY29 revealed some, but not all classes of tau inclusions associated with both CBD and PSP but did label numerous Pick body inclusions in PiD. Tau-nY197 was restricted to the neuropil threads in both CBD and PSP; however, similar to Tau-nY29, extensive Pick body pathology was clearly labeled. Tau-nY394 did not detect any of the lesions associated with these disorders.",
-      "key": "2d5a49957a4ee27f4d85cbf75b3e79269be79a60f70fd8887942e7d81fbff2954dbbb821a6c91a41902d38b7be352531743704dec9e1ff5956ccf6669602c655",
-      "line": 815,
-      "relation": "positiveCorrelation",
-      "source": 918,
-      "target": 519
+      "evidence": "Acrolein and methylglyoxal were the most reactive compounds followed by glyoxal and malondialdehyde in terms of formation of Tau dimers and higher molecular weight oligomers. Analysis of the Tau aggregates by electron microscopy study showed that formation of fibrils using wild-type Tau and several Tau mutants could be observed with acrolein and methylglyoxal but not with glyoxal and malondialdehyde.",
+      "key": "0ca6c1a1dff198472ecb1756783f463c8ed7230b29451bd064cb6fab9fd5f4c22a6c04aa3fb0125b2032f0727703ea434e610efcf8ae9d8a808ed55dc8bea635",
+      "line": 808,
+      "relation": "causesNoChange",
+      "source": 70,
+      "target": 94
     },
     {
       "annotations": {
-        "Disease": {
-          "Alzheimer's disease": true
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
         }
       },
       "citation": {
         "authors": [
-          "Berry RW",
-          "Bigio EH",
-          "Binder LI",
-          "Fu Y",
-          "Guillozet-Bongaarts AL",
-          "Reyes JF",
-          "Reynolds MR"
+          "Gong CX",
+          "Li X",
+          "Lu F",
+          "Wang JZ"
         ],
-        "date": "2006-10-18",
-        "first": "Reynolds MR",
-        "last": "Binder LI",
-        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
-        "pages": "10636-45",
-        "reference": "17050703",
-        "title": "Tau nitration occurs at tyrosine 29 in the fibrillar lesions of Alzheimer's disease and other tauopathies.",
+        "date": "2006-04-01",
+        "first": "Li X",
+        "last": "Gong CX",
+        "name": "The European journal of neuroscience",
+        "pages": "2078-86",
+        "reference": "16630055",
+        "title": "Concurrent alterations of O-GlcNAcylation and phosphorylation of tau in mouse brains during fasting.",
         "type": "PubMed",
-        "volume": "26"
+        "volume": "23"
       },
-      "evidence": "Tau-nY29 detects soluble tau and paired helical filament tau from severely affected Alzheimer's brain but fails to recognize tau from normal aged brain. This observation suggests that nitration at Tyr29 is a disease-related event that may alter the intrinsic ability of tau to self-polymerize. In Alzheimer's brain, Tau-nY29 labels the fibrillar triad of tau lesions, including neurofibrillary tangles, neuritic plaques, and, to a lesser extent, neuropil threads. Intriguingly, although Tau-nY29 stains both the neuronal and glial tau pathology of Pick disease, it detects only the neuronal pathology in corticobasal degeneration and progressive supranuclear palsy without labeling the predominant glial pathology.",
-      "key": "10aef8709680aedb3de539edb197a9dcd9bc5a170beac9ae93a38525ce87e5815055df4ace08c6ea5f6f01a6745567a9f0151b4881e111ad4ca0b800100f15b7",
-      "line": 841,
-      "relation": "association",
-      "source": 918,
-      "target": 520
+      "evidence": "We recently discovered that the human brain tau is also modified by O-GlcNAcylation in addition to phosphorylation and that O-GlcNAcylation modulates phosphorylation of tau inversely (Liu et al.,2004a). We found that fasting induced a time-dependent decrease in tau O-GlcNAcylation and concurrent hyperphosphorylation of tau at most of the phosphorylation sites studied.",
+      "key": "c8488d2e4dd67eb26437bae5a03166a4b1e100e6428055079278b8eba9bb64645c3fad0785460158f9719fde10dabaa142a485937692f90d647f12449723011a",
+      "line": 819,
+      "relation": "negativeCorrelation",
+      "source": 596,
+      "target": 622
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "Research_Model": {
+          "rTg4510 mice": true
+        }
+      },
       "citation": {
         "authors": [
-          "Babić Leko M",
-          "Bažadona D",
-          "Buée L",
-          "Delalle I",
-          "Di Giovanni G",
-          "Harrington C",
-          "Hof PR",
-          "Jovanov-Milošević N",
-          "Wischik C",
-          "Wray S",
-          "de Silva R",
-          "Šimić G"
+          "Boehm J",
+          "Bourgeois C",
+          "Dudilot A",
+          "Lauzon M",
+          "Leclerc N",
+          "Mondragón-Rodríguez S",
+          "Trillaud-Doppia E"
         ],
-        "date": "2016-01-06",
-        "first": "Šimić G",
-        "last": "Hof PR",
-        "name": "Biomolecules",
-        "pages": "6",
-        "reference": "26751493",
-        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
+        "date": "2012-09-14",
+        "first": "Mondragón-Rodríguez S",
+        "last": "Boehm J",
+        "name": "The Journal of biological chemistry",
+        "pages": "32040-53",
+        "reference": "22833681",
+        "title": "Interaction of endogenous tau protein with synaptic proteins is regulated by N-methyl-D-aspartate receptor-dependent tau phosphorylation.",
         "type": "PubMed",
-        "volume": "6"
+        "volume": "287"
       },
-      "evidence": "On the other side, sarkosyl extracts from the filaments of PSP [129], corticobasal degeneration (CBD; [130]), argyrophilic grain disease (AgD; [131]), and some cases of FTDP-17, contain tau protein that separates as doublets of 64 and 69 kDa and are predominantly composed of tau isoforms with 4R (class II tauopathies), whereas sarkosyl extracts from filaments of Pick’s disease are characterized by the presence of pathological tau doublets of 60 and 64 kDa and contain mainly 3R tau isoforms (class III tauopathy).",
-      "key": "c50e994046aab899cabd6f57627394b555b822035bb523b627452c9cc3b116f517c0dbdfb8d1a6aaca739d67414c9bd9bdd4c337ea5f77d6ae5bc19bb95655be",
-      "line": 1648,
+      "evidence": "Acute treatment of rTg4510 mice with an O-GlcNAcase inhibitor transiently reduced tau phosphorylation at epitopes implicated in tau pathology. More importantly, long-term inhibitor treatment strongly increased tau O-GlcNAcylation, reduced the number of dystrophic neurons, and protected against the formation of pathological tau species without altering the phosphorylation of non-pathological tau.",
+      "key": "bb4409ddd643ba0bbacf5e96e9f564a7a37cbadeec45b750ad011a7670a26ce7a6a2e20a08cc5f498d44eaa5e0e864361cb7cd2b0687c2f91938dc2be629191a",
+      "line": 3089,
       "relation": "positiveCorrelation",
-      "source": 918,
-      "target": 307
+      "source": 596,
+      "target": 629
     },
     {
       "annotations": {
-        "Method": {
-          "Western Blot": true
+        "Confidence": {
+          "Medium": true
+        },
+        "Research_Model": {
+          "rTg4510 mice": true
         }
       },
       "citation": {
         "authors": [
-          "Adler CH",
-          "Beach TG",
-          "Braithwaite SP",
-          "Lee KW",
-          "Mouradian MM",
-          "Oh S",
-          "Park HJ",
-          "Stock JB",
-          "Voronkov M",
-          "Yan R",
-          "Zhang J"
+          "Boehm J",
+          "Bourgeois C",
+          "Dudilot A",
+          "Lauzon M",
+          "Leclerc N",
+          "Mondragón-Rodríguez S",
+          "Trillaud-Doppia E"
         ],
-        "date": "2018-02-01",
-        "first": "Park HJ",
-        "last": "Mouradian MM",
-        "name": "Journal of neuropathology and experimental neurology",
-        "pages": "139-148",
-        "reference": "29281045",
-        "title": "Protein Phosphatase 2A and Its Methylation Modulating Enzymes LCMT-1 and PME-1 Are Dysregulated in Tauopathies of Progressive Supranuclear Palsy and Alzheimer Disease.",
+        "date": "2012-09-14",
+        "first": "Mondragón-Rodríguez S",
+        "last": "Boehm J",
+        "name": "The Journal of biological chemistry",
+        "pages": "32040-53",
+        "reference": "22833681",
+        "title": "Interaction of endogenous tau protein with synaptic proteins is regulated by N-methyl-D-aspartate receptor-dependent tau phosphorylation.",
         "type": "PubMed",
-        "volume": "77"
+        "volume": "287"
       },
-      "evidence": "Western blot analyses showed a decrease of methyl-PP2A and an increase of demethyl-PP2A with a concomitant reduction in the methyl/demethyl PP2A ratio in both PSP (74%) and AD (76%) brains, associated with an LCMT-1 decrease and a demethylating enzyme increase, protein phosphatase methylesterase (PME-1), in both diseases.",
-      "key": "0476bf4cad124e43c143045b06c721f1daf01eb4f9fe84921c80833f69c710300c9746515e5789c8e4b7429bcf32c3e1d1ea6c20ae9a3c9be61be03fbb01ccfd",
-      "line": 3914,
-      "relation": "decreases",
-      "source": 918,
-      "target": 468
+      "evidence": "Acute treatment of rTg4510 mice with an O-GlcNAcase inhibitor transiently reduced tau phosphorylation at epitopes implicated in tau pathology. More importantly, long-term inhibitor treatment strongly increased tau O-GlcNAcylation, reduced the number of dystrophic neurons, and protected against the formation of pathological tau species without altering the phosphorylation of non-pathological tau.",
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+      "relation": "positiveCorrelation",
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+      "target": 663
     },
     {
       "annotations": {
-        "Method": {
-          "Western Blot": true
+        "Confidence": {
+          "Medium": true
+        },
+        "Research_Model": {
+          "rTg4510 mice": true
         }
       },
       "citation": {
         "authors": [
-          "Adler CH",
-          "Beach TG",
-          "Braithwaite SP",
-          "Lee KW",
-          "Mouradian MM",
-          "Oh S",
-          "Park HJ",
-          "Stock JB",
-          "Voronkov M",
-          "Yan R",
-          "Zhang J"
-        ],
-        "date": "2018-02-01",
-        "first": "Park HJ",
-        "last": "Mouradian MM",
-        "name": "Journal of neuropathology and experimental neurology",
-        "pages": "139-148",
-        "reference": "29281045",
-        "title": "Protein Phosphatase 2A and Its Methylation Modulating Enzymes LCMT-1 and PME-1 Are Dysregulated in Tauopathies of Progressive Supranuclear Palsy and Alzheimer Disease.",
+          "Boehm J",
+          "Bourgeois C",
+          "Dudilot A",
+          "Lauzon M",
+          "Leclerc N",
+          "Mondragón-Rodríguez S",
+          "Trillaud-Doppia E"
+        ],
+        "date": "2012-09-14",
+        "first": "Mondragón-Rodríguez S",
+        "last": "Boehm J",
+        "name": "The Journal of biological chemistry",
+        "pages": "32040-53",
+        "reference": "22833681",
+        "title": "Interaction of endogenous tau protein with synaptic proteins is regulated by N-methyl-D-aspartate receptor-dependent tau phosphorylation.",
         "type": "PubMed",
-        "volume": "77"
+        "volume": "287"
       },
-      "evidence": "Western blot analyses showed a decrease of methyl-PP2A and an increase of demethyl-PP2A with a concomitant reduction in the methyl/demethyl PP2A ratio in both PSP (74%) and AD (76%) brains, associated with an LCMT-1 decrease and a demethylating enzyme increase, protein phosphatase methylesterase (PME-1), in both diseases.",
-      "key": "aaf968df529ec44b7fe26dc26e09b9c35728c0f9a282db4be9818c85f214dc96b56d2edb28ba75fcec532479702dbed834f5d937d0bdc4a83fa0e9f6bb299914",
-      "line": 3916,
-      "relation": "increases",
-      "source": 918,
-      "target": 271
+      "evidence": "Acute treatment of rTg4510 mice with an O-GlcNAcase inhibitor transiently reduced tau phosphorylation at epitopes implicated in tau pathology. More importantly, long-term inhibitor treatment strongly increased tau O-GlcNAcylation, reduced the number of dystrophic neurons, and protected against the formation of pathological tau species without altering the phosphorylation of non-pathological tau.",
+      "key": "2d4109e569f1110503d59f93389a4dbbf15da57c25cb375384ac98702f838edd0970f22d3be4f5a40121eb78af20ca8dcd2474c29effeeeae3300ae47ff947c4",
+      "line": 3091,
+      "relation": "positiveCorrelation",
+      "source": 596,
+      "target": 642
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "Research_Model": {
+          "rTg4510 mice": true
+        }
+      },
       "citation": {
         "authors": [
-          "Halverson RA",
-          "Kim SY",
-          "Lee JM",
-          "Muma NA",
-          "Troncoso JC",
-          "Zemaitaitis MO"
+          "Boehm J",
+          "Bourgeois C",
+          "Dudilot A",
+          "Lauzon M",
+          "Leclerc N",
+          "Mondragón-Rodríguez S",
+          "Trillaud-Doppia E"
         ],
-        "date": "2003-02-01",
-        "first": "Zemaitaitis MO",
-        "last": "Muma NA",
-        "name": "Journal of neuropathology and experimental neurology",
-        "pages": "173-84",
-        "reference": "12578227",
-        "title": "Transglutaminase activity, protein, and mRNA expression are increased in progressive supranuclear palsy.",
+        "date": "2012-09-14",
+        "first": "Mondragón-Rodríguez S",
+        "last": "Boehm J",
+        "name": "The Journal of biological chemistry",
+        "pages": "32040-53",
+        "reference": "22833681",
+        "title": "Interaction of endogenous tau protein with synaptic proteins is regulated by N-methyl-D-aspartate receptor-dependent tau phosphorylation.",
         "type": "PubMed",
-        "volume": "62"
+        "volume": "287"
       },
-      "evidence": "Protein and mRNA levels of transglutaminase 1 were increased in globus pallidus of PSP as compared to controls. There were also significantly higher mRNA levels of the short form of transglutaminase 2 in globus pallidus of PSP (974% of control). Transglutaminase 1 mRNA and the long isoform of transglutaminase 2 mRNA (2212% of control) were significantly higher in PSP in the dentate of cerebellum. Together, these findings suggest that transglutaminase 1 and 2 enzymes may be involved in the formation and/or stabilization of neurofibrillary tangles in selectively vulnerable brain regions in PSP. These transglutaminases may be potential targets for therapeutic intervention.",
-      "key": "473798baef2f9104c9121d55c872d80f8e42952b9d6d60cbfc2a888500e61a736330e2df72fc126174728201703c1b1c64ad1e8d9b5dafdcdbf1ac5ee7c1f04d",
-      "line": 718,
+      "evidence": "Acute treatment of rTg4510 mice with an O-GlcNAcase inhibitor transiently reduced tau phosphorylation at epitopes implicated in tau pathology. More importantly, long-term inhibitor treatment strongly increased tau O-GlcNAcylation, reduced the number of dystrophic neurons, and protected against the formation of pathological tau species without altering the phosphorylation of non-pathological tau.",
+      "key": "49c2c8b48b5b8466f9c0a985470406fa950332e2cd01f1503752560573e4cebd4d278de13573ca62136dc8912dfc1435c4a4682a31a8be13b091d9fbc0777f08",
+      "line": 3092,
       "relation": "positiveCorrelation",
-      "source": 729,
-      "target": 80
+      "source": 596,
+      "target": 648
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+    {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "Research_Model": {
+          "rTg4510 mice": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Boehm J",
+          "Bourgeois C",
+          "Dudilot A",
+          "Lauzon M",
+          "Leclerc N",
+          "Mondragón-Rodríguez S",
+          "Trillaud-Doppia E"
+        ],
+        "date": "2012-09-14",
+        "first": "Mondragón-Rodríguez S",
+        "last": "Boehm J",
+        "name": "The Journal of biological chemistry",
+        "pages": "32040-53",
+        "reference": "22833681",
+        "title": "Interaction of endogenous tau protein with synaptic proteins is regulated by N-methyl-D-aspartate receptor-dependent tau phosphorylation.",
+        "type": "PubMed",
+        "volume": "287"
+      },
+      "evidence": "Acute treatment of rTg4510 mice with an O-GlcNAcase inhibitor transiently reduced tau phosphorylation at epitopes implicated in tau pathology. More importantly, long-term inhibitor treatment strongly increased tau O-GlcNAcylation, reduced the number of dystrophic neurons, and protected against the formation of pathological tau species without altering the phosphorylation of non-pathological tau.",
+      "key": "229eea8a082e3274da64c3ca4991dcfe6cba99502604f9286b486d23869734d334bad6f5ab3d238b192b0147ebcd0f0f4a45c67e369b22bac076f28db377ce2d",
+      "line": 3093,
+      "relation": "positiveCorrelation",
+      "source": 596,
+      "target": 649
+    },
+    {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        },
+        "Research_Model": {
+          "rTg4510 mice": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Boehm J",
+          "Bourgeois C",
+          "Dudilot A",
+          "Lauzon M",
+          "Leclerc N",
+          "Mondragón-Rodríguez S",
+          "Trillaud-Doppia E"
+        ],
+        "date": "2012-09-14",
+        "first": "Mondragón-Rodríguez S",
+        "last": "Boehm J",
+        "name": "The Journal of biological chemistry",
+        "pages": "32040-53",
+        "reference": "22833681",
+        "title": "Interaction of endogenous tau protein with synaptic proteins is regulated by N-methyl-D-aspartate receptor-dependent tau phosphorylation.",
+        "type": "PubMed",
+        "volume": "287"
+      },
+      "evidence": "This indicates that O-GlcNAcylation prevents the aggregation of tau in a manner that does not affect its normal phosphorylation state.",
+      "key": "0a957ba6dedd7f28f206a5d73bbffe2186535e6905cbc00016caef9f1311388e15e807fb0e107e230e1fc1366ecdeffbfa6a569abcc6a763177e4a797757e0d3",
+      "line": 3098,
+      "relation": "decreases",
+      "source": 596,
+      "target": 116
+    },
+    {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Dehennaut V",
+          "Drougat L",
+          "Guinez C",
+          "Lefebvre T",
+          "Michalski JC",
+          "Mir AM",
+          "Mortuaire M",
+          "Olivier S",
+          "Vercoutter-Edouart AS"
+        ],
+        "date": "2010-02-01",
+        "first": "Lefebvre T",
+        "last": "Michalski JC",
+        "name": "Biochimica et biophysica acta",
+        "pages": "67-79",
+        "reference": "19732809",
+        "title": "Dysregulation of the nutrient/stress sensor O-GlcNAcylation is involved in the etiology of cardiovascular disorders, type-2 diabetes and Alzheimer's disease.",
+        "type": "PubMed",
+        "volume": "1800"
+      },
+      "evidence": "These results are in accord with our previous study showing that Tau hyperphosphorylation is associated with a decrease in its O-GlcNAcylation level. A recent observation argues for the hypothesis that O-GlcNAcylation occurs first and that its modification reflects on the phosphorylation status.",
+      "key": "0c32ee0328f1023c42a5a861e2adaadfaa690a76c51bef8c14ea2d6b2e907a4295c02bfe6d53c69033db8e93f3400662bf714495f4d89b315ea493b7e9609630",
+      "line": 4258,
+      "relation": "negativeCorrelation",
+      "source": 596,
+      "target": 599
+    },
+    {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "Method": {
+          "Immunohistochemistry": true,
+          "Western Blot": true
+        },
+        "Species": {
+          "10090": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Gong CX",
+          "Li X",
+          "Lu F",
+          "Wang JZ"
+        ],
+        "date": "2006-04-01",
+        "first": "Li X",
+        "last": "Gong CX",
+        "name": "The European journal of neuroscience",
+        "pages": "2078-86",
+        "reference": "16630055",
+        "title": "Concurrent alterations of O-GlcNAcylation and phosphorylation of tau in mouse brains during fasting.",
+        "type": "PubMed",
+        "volume": "23"
+      },
+      "evidence": "We recently discovered that the human brain tau is also modified by O-GlcNAcylation in addition to phosphorylation and that O-GlcNAcylation modulates phosphorylation of tau inversely (Liu et al.,2004a). We found that fasting induced a time-dependent decrease in tau O-GlcNAcylation and concurrent hyperphosphorylation of tau at most of the phosphorylation sites studied.",
+      "key": "f51f4b37b05cef3b3c408dc4565b50406f5deeebac1423bf21b0640b87bc41e1682c8bfa8d1fa56e0ed9aa983a5b3b4fb0d3a75f9b5688bb74be7ce2b7213dd5",
+      "line": 823,
+      "relation": "decreases",
+      "source": 1032,
+      "target": 898
+    },
+    {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "Method": {
+          "Immunohistochemistry": true,
+          "Western Blot": true
+        },
+        "Species": {
+          "10090": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Gong CX",
+          "Li X",
+          "Lu F",
+          "Wang JZ"
+        ],
+        "date": "2006-04-01",
+        "first": "Li X",
+        "last": "Gong CX",
+        "name": "The European journal of neuroscience",
+        "pages": "2078-86",
+        "reference": "16630055",
+        "title": "Concurrent alterations of O-GlcNAcylation and phosphorylation of tau in mouse brains during fasting.",
+        "type": "PubMed",
+        "volume": "23"
+      },
+      "evidence": "We recently discovered that the human brain tau is also modified by O-GlcNAcylation in addition to phosphorylation and that O-GlcNAcylation modulates phosphorylation of tau inversely (Liu et al.,2004a). We found that fasting induced a time-dependent decrease in tau O-GlcNAcylation and concurrent hyperphosphorylation of tau at most of the phosphorylation sites studied.",
+      "key": "164c5d3be8959008b349f4e67965e77547fe3099f96935438907546f62a7197f18401c42e1bbc8ff096f26a98866bf7a5a7975deb44a6c8c6c4c792423d66239",
+      "line": 824,
+      "relation": "increases",
+      "source": 1032,
+      "target": 899
     },
     {
+      "annotations": {
+        "Anatomy": {
+          "globus pallidus": true
+        },
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "Halverson RA",
@@ -26130,16 +30079,19 @@
         "volume": "62"
       },
       "evidence": "Protein and mRNA levels of transglutaminase 1 were increased in globus pallidus of PSP as compared to controls. There were also significantly higher mRNA levels of the short form of transglutaminase 2 in globus pallidus of PSP (974% of control). Transglutaminase 1 mRNA and the long isoform of transglutaminase 2 mRNA (2212% of control) were significantly higher in PSP in the dentate of cerebellum. Together, these findings suggest that transglutaminase 1 and 2 enzymes may be involved in the formation and/or stabilization of neurofibrillary tangles in selectively vulnerable brain regions in PSP. These transglutaminases may be potential targets for therapeutic intervention.",
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+      "line": 849,
+      "relation": "increases",
+      "source": 1029,
+      "target": 819
     },
     {
       "annotations": {
         "Anatomy": {
           "globus pallidus": true
+        },
+        "Confidence": {
+          "Medium": true
         }
       },
       "citation": {
@@ -26162,13 +30114,21 @@
         "volume": "62"
       },
       "evidence": "Protein and mRNA levels of transglutaminase 1 were increased in globus pallidus of PSP as compared to controls. There were also significantly higher mRNA levels of the short form of transglutaminase 2 in globus pallidus of PSP (974% of control). Transglutaminase 1 mRNA and the long isoform of transglutaminase 2 mRNA (2212% of control) were significantly higher in PSP in the dentate of cerebellum. Together, these findings suggest that transglutaminase 1 and 2 enzymes may be involved in the formation and/or stabilization of neurofibrillary tangles in selectively vulnerable brain regions in PSP. These transglutaminases may be potential targets for therapeutic intervention.",
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-      "line": 713,
-      "relation": "isA",
-      "source": 922,
-      "target": 937
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+      "line": 850,
+      "relation": "increases",
+      "source": 1029,
+      "target": 1046
     },
     {
+      "annotations": {
+        "Anatomy": {
+          "globus pallidus": true
+        },
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "Halverson RA",
@@ -26189,55 +30149,21 @@
         "volume": "62"
       },
       "evidence": "Protein and mRNA levels of transglutaminase 1 were increased in globus pallidus of PSP as compared to controls. There were also significantly higher mRNA levels of the short form of transglutaminase 2 in globus pallidus of PSP (974% of control). Transglutaminase 1 mRNA and the long isoform of transglutaminase 2 mRNA (2212% of control) were significantly higher in PSP in the dentate of cerebellum. Together, these findings suggest that transglutaminase 1 and 2 enzymes may be involved in the formation and/or stabilization of neurofibrillary tangles in selectively vulnerable brain regions in PSP. These transglutaminases may be potential targets for therapeutic intervention.",
-      "key": "10cb66405d370844295872046890dfdd7e93c334314af94f6de9a1b9223fbc2143fecb32d407a45878c08a8c8ffe14131bf592ba4ee43edfb810b2a07ba0b841",
-      "line": 719,
-      "relation": "positiveCorrelation",
-      "source": 730,
-      "target": 80
+      "key": "bc83eb5c70ffec48024e15ae2f601bc39fb1aa7d69e1354909fa42aa108bd622a48837bde896d86a5115ed7c0be2b4a8dcce5c7b2f2992f7a37960cac9227284",
+      "line": 851,
+      "relation": "increases",
+      "source": 1029,
+      "target": 401
     },
     {
       "annotations": {
         "Anatomy": {
-          "prefrontal cortex": true
-        },
-        "Disease": {
-          "Alzheimer's disease": true
+          "dentate nucleus": true
         },
-        "Method": {
-          "Immunoblotting": true,
-          "Transglutaminase Assay": true
+        "Confidence": {
+          "Medium": true
         }
       },
-      "citation": {
-        "authors": [
-          "Cox TM",
-          "Johnson GV",
-          "Lockhart JP",
-          "Miller ML",
-          "Powers RE",
-          "Zinnerman MD"
-        ],
-        "date": "1997-03-21",
-        "first": "Johnson GV",
-        "last": "Powers RE",
-        "name": "Brain research",
-        "pages": "323-9",
-        "reference": "9099822",
-        "title": "Transglutaminase activity is increased in Alzheimer's disease brain.",
-        "type": "PubMed",
-        "volume": "751"
-      },
-      "evidence": "Total transglutaminase activity was significantly higher in the Alzheimer's disease prefrontal cortex compared to control. In addition the levels of tissue transglutaminase, as determined by quantitative immunoblotting, were elevated approximately 3-fold in Alzheimer's disease prefrontal cortex compared to control. To our knowledge, this is the first demonstration that transglutaminase is increased in Alzheimer's disease brain. There were no significant differences in transglutaminase activity or levels in the cerebellum between control and Alzheimer's disease cases. Because the elevation of transglutaminase in the Alzheimer's disease samples occurred in the prefrontal cortex, where neurofibrillary pathology is usually abundant, and not in the cerebellum, which is usually spared in Alzheimer's disease, it can be suggested that transglutaminase could be a contributing factor in neurofibrillary tangle formation.",
-      "key": "8878ceeb0b57a46e6d53029757bbd0e7a608e9f9f81a0d0890a7359c84a7299809f4e63ea0bd5188a24f1fff557b99801ba230e05cbd3ce1478a6f9d825dae95",
-      "line": 769,
-      "relation": "positiveCorrelation",
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-      "subject": {
-        "modifier": "Activity"
-      },
-      "target": 80
-    },
-    {
       "citation": {
         "authors": [
           "Halverson RA",
@@ -26258,107 +30184,20 @@
         "volume": "62"
       },
       "evidence": "Protein and mRNA levels of transglutaminase 1 were increased in globus pallidus of PSP as compared to controls. There were also significantly higher mRNA levels of the short form of transglutaminase 2 in globus pallidus of PSP (974% of control). Transglutaminase 1 mRNA and the long isoform of transglutaminase 2 mRNA (2212% of control) were significantly higher in PSP in the dentate of cerebellum. Together, these findings suggest that transglutaminase 1 and 2 enzymes may be involved in the formation and/or stabilization of neurofibrillary tangles in selectively vulnerable brain regions in PSP. These transglutaminases may be potential targets for therapeutic intervention.",
-      "key": "4a9c146c1a27049ef765a3bf1a73c8dfe12e19813db8cf9a4624e99959c4f05230e96853bd9332b6df0e7b320535bbdbc451f409430241b7bef0c43ff1e9acfb",
-      "line": 721,
-      "relation": "isA",
-      "source": 730,
-      "target": 267
-    },
-    {
-      "annotations": {
-        "Cell_Line": {
-          "SH-SY5Y": true
-        }
-      },
-      "citation": {
-        "authors": [
-          "Johnson GV",
-          "Kuret J",
-          "Tucholski J"
-        ],
-        "date": "1999-11-01",
-        "first": "Tucholski J",
-        "last": "Johnson GV",
-        "name": "Journal of neurochemistry",
-        "pages": "1871-80",
-        "reference": "10537045",
-        "title": "Tau is modified by tissue transglutaminase in situ: possible functional and metabolic effects of polyamination.",
-        "type": "PubMed",
-        "volume": "73"
-      },
-      "evidence": "For these studies, SH-SY5Y cells stably overexpressing tTG were used. tTG coimmunoprecipitated with tau, and elevating intracellular calcium levels with maitotoxin resulted in a 52 +/- 4% increase in the amount of tTG that coimmunoprecipitated with tau. The increase in association of tTG with tau after treatment with maitotoxin corresponded to a coimmunolocalization of tTG, tTG activity, and tau in the cells. Further, tau was modified by tTG in situ in response to maitotoxin treatment. In vitro polyaminated tau was significantly less susceptible to micro-calpain proteolysis; however, tTG-mediated polyamination of tau did not significantly alter the microtubule-binding capacity of tau.",
-      "key": "58bc2b78874c96563789e15c989a6fee251d44b2076664124c73b0515ff8174c19c7c9d0e7be9057c72462d3e0928810043819f1a232204cb2fb53d11b0a28de",
-      "line": 793,
-      "relation": "positiveCorrelation",
-      "source": 730,
-      "target": 486
-    },
-    {
-      "annotations": {
-        "Cell_Line": {
-          "SH-SY5Y": true
-        }
-      },
-      "citation": {
-        "authors": [
-          "Johnson GV",
-          "Kuret J",
-          "Tucholski J"
-        ],
-        "date": "1999-11-01",
-        "first": "Tucholski J",
-        "last": "Johnson GV",
-        "name": "Journal of neurochemistry",
-        "pages": "1871-80",
-        "reference": "10537045",
-        "title": "Tau is modified by tissue transglutaminase in situ: possible functional and metabolic effects of polyamination.",
-        "type": "PubMed",
-        "volume": "73"
-      },
-      "evidence": "For these studies, SH-SY5Y cells stably overexpressing tTG were used. tTG coimmunoprecipitated with tau, and elevating intracellular calcium levels with maitotoxin resulted in a 52 +/- 4% increase in the amount of tTG that coimmunoprecipitated with tau. The increase in association of tTG with tau after treatment with maitotoxin corresponded to a coimmunolocalization of tTG, tTG activity, and tau in the cells. Further, tau was modified by tTG in situ in response to maitotoxin treatment. In vitro polyaminated tau was significantly less susceptible to micro-calpain proteolysis; however, tTG-mediated polyamination of tau did not significantly alter the microtubule-binding capacity of tau.",
-      "key": "22cdd55e8bba7e40e98095e25358c20da2196b327e39fdfe3b9f209223d2677f6f82f15788d6814191cce055208fb2738e17afc0007a7f1ce4921f15cda1c2b7",
-      "line": 794,
-      "relation": "partOf",
-      "source": 730,
-      "target": 238
-    },
-    {
-      "annotations": {
-        "Cell_Line": {
-          "SH-SY5Y": true
-        }
-      },
-      "citation": {
-        "authors": [
-          "Johnson GV",
-          "Kuret J",
-          "Tucholski J"
-        ],
-        "date": "1999-11-01",
-        "first": "Tucholski J",
-        "last": "Johnson GV",
-        "name": "Journal of neurochemistry",
-        "pages": "1871-80",
-        "reference": "10537045",
-        "title": "Tau is modified by tissue transglutaminase in situ: possible functional and metabolic effects of polyamination.",
-        "type": "PubMed",
-        "volume": "73"
-      },
-      "evidence": "For these studies, SH-SY5Y cells stably overexpressing tTG were used. tTG coimmunoprecipitated with tau, and elevating intracellular calcium levels with maitotoxin resulted in a 52 +/- 4% increase in the amount of tTG that coimmunoprecipitated with tau. The increase in association of tTG with tau after treatment with maitotoxin corresponded to a coimmunolocalization of tTG, tTG activity, and tau in the cells. Further, tau was modified by tTG in situ in response to maitotoxin treatment. In vitro polyaminated tau was significantly less susceptible to micro-calpain proteolysis; however, tTG-mediated polyamination of tau did not significantly alter the microtubule-binding capacity of tau.",
-      "key": "057b3d0aede30ff81edafa0c000d50281908cace68e41756cf4b67fe4595b08550c45aa677bc9df25d3e0694bf65981838301db27cc0c4827d78efc1bdd6a3dc",
-      "line": 799,
-      "relation": "association",
-      "source": 730,
-      "subject": {
-        "modifier": "Activity"
-      },
-      "target": 129
+      "key": "9697f8dc2d8e4b45f366e1ea11f651c66d14719c41cd70808c2507b3616d1be1b2d7af51894517d14e76b35d2d427d2c723e6f128d20f83b33af1687e3146910",
+      "line": 855,
+      "relation": "increases",
+      "source": 1029,
+      "target": 1047
     },
     {
       "annotations": {
         "Anatomy": {
           "globus pallidus": true,
           "pons": true
+        },
+        "Confidence": {
+          "Medium": true
         }
       },
       "citation": {
@@ -26379,20 +30218,23 @@
         "volume": "59"
       },
       "evidence": "There were significantly higher levels of epsilon-(gamma-glutamyl) lysine cross-linking of PHF-tau in globus pallidus and pons regions of PSP cases compared to barely detectable cross-links in controls. The occipital cortex, an area spared from neurofibrillary pathology in PSP, showed no detectable cross-linking of PHF-tau protein in either PSP cases or control cases. Double-label immunofluorescence demonstrated the colocalization of the cross-link and PHF-tau in NFT in pons of PSP Previous studies and present data are consistent with the hypothesis that transglutaminase-induced cross-linking may be a factor contributing to the abnormal polymerization and stabilization of tau in straight and PHFs leading to neurofibrillary tangle formation in neurodegenerative diseases, including PSP and AD.",
-      "key": "e1754edfdd530861f7188118b4506efa5243d4162a587490d77ccd5827af6b2381bac7914d1dfbf4453735ba398bd4bbd3af6d261f40ddb3f6e22aacaddd7733",
-      "line": 731,
-      "relation": "positiveCorrelation",
-      "source": 267,
-      "subject": {
+      "key": "c5698264f739eb67cb96963e5b47bd38b29c610253797c6ee904012e5cc1b76396dbbf443ea32dd6a44fc4a1b270aedd2701122339477f73ed30c54feec937c3",
+      "line": 874,
+      "object": {
         "modifier": "Activity"
       },
-      "target": 918
+      "relation": "positiveCorrelation",
+      "source": 1029,
+      "target": 337
     },
     {
       "annotations": {
         "Anatomy": {
           "globus pallidus": true,
           "pons": true
+        },
+        "Confidence": {
+          "Medium": true
         }
       },
       "citation": {
@@ -26413,220 +30255,430 @@
         "volume": "59"
       },
       "evidence": "There were significantly higher levels of epsilon-(gamma-glutamyl) lysine cross-linking of PHF-tau in globus pallidus and pons regions of PSP cases compared to barely detectable cross-links in controls. The occipital cortex, an area spared from neurofibrillary pathology in PSP, showed no detectable cross-linking of PHF-tau protein in either PSP cases or control cases. Double-label immunofluorescence demonstrated the colocalization of the cross-link and PHF-tau in NFT in pons of PSP Previous studies and present data are consistent with the hypothesis that transglutaminase-induced cross-linking may be a factor contributing to the abnormal polymerization and stabilization of tau in straight and PHFs leading to neurofibrillary tangle formation in neurodegenerative diseases, including PSP and AD.",
-      "key": "9d5cbd9f6653c43868ff21c843d48b027373ed3a20c4b0a302f4df0220c692e2fdb36f0bb73cc1b2c02c4615c86165ebe291b34c941e6211bcb74aae960df2d1",
-      "line": 732,
+      "key": "cdbb78ae8a47c61a9d7b3a297a120aef886cda92cf39dfdb9b05d2c29efc4a868d6f65676aa02a97f5f6710a5708f602a3a33c45080ad59db6fa79ea7f03e767",
+      "line": 876,
       "relation": "positiveCorrelation",
-      "source": 267,
-      "subject": {
-        "modifier": "Activity"
-      },
-      "target": 80
+      "source": 1029,
+      "target": 94
     },
     {
       "annotations": {
         "Anatomy": {
-          "frontal cortex": true,
-          "parietal cortex": true
+          "neuropil": true
+        },
+        "Confidence": {
+          "High": true
         },
         "Disease": {
-          "Alzheimer's disease": true
+          "progressive supranuclear palsy": true
         },
-        "Method": {
-          "Confocal Microscopy": true,
-          "Fluorescence Microscopy": true,
-          "Immunoaffinity purification": true,
-          "Immunoblotting": true
+        "HBP_Disease": {
+          "Corticobasal Degeneration": true
         }
       },
       "citation": {
         "authors": [
-          "Lee JM",
-          "Muma NA",
-          "Norlund MA",
-          "Singer SM",
-          "Zainelli GM"
+          "Binder LI",
+          "Geula C",
+          "Reyes JF",
+          "Vana L"
         ],
-        "date": "2002-01-01",
-        "first": "Singer SM",
-        "last": "Muma NA",
-        "name": "Neurochemistry international",
-        "pages": "17-30",
-        "reference": "11738469",
-        "title": "Transglutaminase bonds in neurofibrillary tangles and paired helical filament tau early in Alzheimer's disease.",
+        "date": "2012-01-01",
+        "first": "Reyes JF",
+        "last": "Binder LI",
+        "name": "Acta neuropathologica",
+        "pages": "119-32",
+        "reference": "22057784",
+        "title": "Selective tau tyrosine nitration in non-AD tauopathies.",
         "type": "PubMed",
-        "volume": "40"
+        "volume": "123"
       },
-      "evidence": "The number of neurons that are immunoreactive with an antibody directed at the epsilon-(gamma-glutamyl)lysine bond was significantly higher in AD cortex compared with age-matched controls and schizophrenics. PHF tau-directed antibodies AT8, MC-1 and PHF-1 co-localized with epsilon(gamma-glutamyl)lysine immunolabeling in AD NFT. Immunoaffinity purification and immunoblotting experiments demonstrated that PHF tau contains epsilon(gamma-glutamyl)lysine bonds in parietal and frontal cortex in AD. In control cases with NFT present in the entorhinal cortex and hippocampus, indicative of Braak and Braak stage II, epsilon(gamma-glutamyl)lysine bonds were present in PHF tau in parietal and frontal cortex, despite the lack of microscopically detectable NFT or senile plaques in these cortical regions. The presence of PHF tau with epsilon(gamma-glutamyl)lysine bonds in brain regions devoid of NFT in stage II (but regions, which would be expected to contain NFT in stage III) suggests that these bonds occur early in the formation of NFT.",
-      "key": "9ea19ea9c2a382dace6d43a435c3c13c48e60e7211a710a3a1fad5c492c9cca79c62f29bdfbbf622d14fc5b9a1a298598b5052941c6ed1e0c2f195eb4a151e8c",
-      "line": 748,
+      "evidence": "Tau-nY18 did not label the classical pathological lesions of CBD or PSP but did label the neuronal lesions associated with PiD. Tau-nY29 revealed some, but not all classes of tau inclusions associated with both CBD and PSP but did label numerous Pick body inclusions in PiD. Tau-nY197 was restricted to the neuropil threads in both CBD and PSP; however, similar to Tau-nY29, extensive Pick body pathology was clearly labeled. Tau-nY394 did not detect any of the lesions associated with these disorders.",
+      "key": "2d5a49957a4ee27f4d85cbf75b3e79269be79a60f70fd8887942e7d81fbff2954dbbb821a6c91a41902d38b7be352531743704dec9e1ff5956ccf6669602c655",
+      "line": 969,
       "relation": "positiveCorrelation",
-      "source": 267,
-      "subject": {
-        "modifier": "Activity"
-      },
-      "target": 80
+      "source": 1029,
+      "target": 603
     },
     {
       "annotations": {
-        "Anatomy": {
-          "hippocampal formation": true
+        "Confidence": {
+          "Medium": true
         },
         "Disease": {
           "Alzheimer's disease": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
         }
       },
       "citation": {
         "authors": [
-          "Appelt DM",
-          "Balin BJ",
-          "Boyne LJ",
-          "Kopen GC"
+          "Berry RW",
+          "Bigio EH",
+          "Binder LI",
+          "Fu Y",
+          "Guillozet-Bongaarts AL",
+          "Reyes JF",
+          "Reynolds MR"
         ],
-        "date": "1996-12-01",
-        "first": "Appelt DM",
-        "last": "Balin BJ",
-        "name": "The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society",
-        "pages": "1421-7",
-        "reference": "8985134",
-        "title": "Localization of transglutaminase in hippocampal neurons: implications for Alzheimer's disease.",
-        "type": "PubMed",
-        "volume": "44"
-      },
-      "evidence": "Degenerating neurons from the AD hippocampus, compared to neurons from the normal aged hippocampus, exhibited increased immunoreactivity for TGase and demonstrated co-labeling for PHF1 and anti-TGase. Our results suggest that TGase may be associated with the neurofibrillary degeneration observed in AD, thereby implicating TGase as a potential factor in the pathogenesis of Alzheimer's disease.",
-      "key": "ed6314fbb45218ae5c0d8cbaecce2a2ef569db327e1718fd6296b42111c9628c65b39fb64e18365d7889702eedb4813104d2a9ddf32fd8fe31b49b060444e674",
-      "line": 782,
+        "date": "2006-10-18",
+        "first": "Reynolds MR",
+        "last": "Binder LI",
+        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
+        "pages": "10636-45",
+        "reference": "17050703",
+        "title": "Tau nitration occurs at tyrosine 29 in the fibrillar lesions of Alzheimer's disease and other tauopathies.",
+        "type": "PubMed",
+        "volume": "26"
+      },
+      "evidence": "Tau-nY29 detects soluble tau and paired helical filament tau from severely affected Alzheimer's brain but fails to recognize tau from normal aged brain. This observation suggests that nitration at Tyr29 is a disease-related event that may alter the intrinsic ability of tau to self-polymerize. In Alzheimer's brain, Tau-nY29 labels the fibrillar triad of tau lesions, including neurofibrillary tangles, neuritic plaques, and, to a lesser extent, neuropil threads. Intriguingly, although Tau-nY29 stains both the neuronal and glial tau pathology of Pick disease, it detects only the neuronal pathology in corticobasal degeneration and progressive supranuclear palsy without labeling the predominant glial pathology.",
+      "key": "10aef8709680aedb3de539edb197a9dcd9bc5a170beac9ae93a38525ce87e5815055df4ace08c6ea5f6f01a6745567a9f0151b4881e111ad4ca0b800100f15b7",
+      "line": 1003,
+      "relation": "association",
+      "source": 1029,
+      "target": 604
+    },
+    {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Babić Leko M",
+          "Bažadona D",
+          "Buée L",
+          "Delalle I",
+          "Di Giovanni G",
+          "Harrington C",
+          "Hof PR",
+          "Jovanov-Milošević N",
+          "Wischik C",
+          "Wray S",
+          "de Silva R",
+          "Šimić G"
+        ],
+        "date": "2016-01-06",
+        "first": "Šimić G",
+        "last": "Hof PR",
+        "name": "Biomolecules",
+        "pages": "6",
+        "reference": "26751493",
+        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
+        "type": "PubMed",
+        "volume": "6"
+      },
+      "evidence": "On the other side, sarkosyl extracts from the filaments of PSP [129], corticobasal degeneration (CBD; [130]), argyrophilic grain disease (AgD; [131]), and some cases of FTDP-17, contain tau protein that separates as doublets of 64 and 69 kDa and are predominantly composed of tau isoforms with 4R (class II tauopathies), whereas sarkosyl extracts from filaments of Pick’s disease are characterized by the presence of pathological tau doublets of 60 and 64 kDa and contain mainly 3R tau isoforms (class III tauopathy).",
+      "key": "c50e994046aab899cabd6f57627394b555b822035bb523b627452c9cc3b116f517c0dbdfb8d1a6aaca739d67414c9bd9bdd4c337ea5f77d6ae5bc19bb95655be",
+      "line": 1993,
       "relation": "positiveCorrelation",
-      "source": 267,
-      "subject": {
-        "modifier": "Activity"
+      "source": 1029,
+      "target": 386
+    },
+    {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "Method": {
+          "Western Blot": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Adler CH",
+          "Beach TG",
+          "Braithwaite SP",
+          "Lee KW",
+          "Mouradian MM",
+          "Oh S",
+          "Park HJ",
+          "Stock JB",
+          "Voronkov M",
+          "Yan R",
+          "Zhang J"
+        ],
+        "date": "2018-02-01",
+        "first": "Park HJ",
+        "last": "Mouradian MM",
+        "name": "Journal of neuropathology and experimental neurology",
+        "pages": "139-148",
+        "reference": "29281045",
+        "title": "Protein Phosphatase 2A and Its Methylation Modulating Enzymes LCMT-1 and PME-1 Are Dysregulated in Tauopathies of Progressive Supranuclear Palsy and Alzheimer Disease.",
+        "type": "PubMed",
+        "volume": "77"
       },
-      "target": 80
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+      "key": "39752f416ee5cf76fe22f3e1977d97ad370164bad03e06fe79913776c1838488ed727abdfdc9adb365deb4b3897db90e58f61b0e7c4386ec93060de2e076c91e",
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     {
       "annotations": {
-        "Anatomy": {
-          "frontal cortex": true,
-          "parietal cortex": true
+        "Confidence": {
+          "Medium": true
         },
-        "Disease": {
-          "Alzheimer's disease": true
+        "Method": {
+          "Western Blot": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Adler CH",
+          "Beach TG",
+          "Braithwaite SP",
+          "Lee KW",
+          "Mouradian MM",
+          "Oh S",
+          "Park HJ",
+          "Stock JB",
+          "Voronkov M",
+          "Yan R",
+          "Zhang J"
+        ],
+        "date": "2018-02-01",
+        "first": "Park HJ",
+        "last": "Mouradian MM",
+        "name": "Journal of neuropathology and experimental neurology",
+        "pages": "139-148",
+        "reference": "29281045",
+        "title": "Protein Phosphatase 2A and Its Methylation Modulating Enzymes LCMT-1 and PME-1 Are Dysregulated in Tauopathies of Progressive Supranuclear Palsy and Alzheimer Disease.",
+        "type": "PubMed",
+        "volume": "77"
+      },
+      "evidence": "Western blot analyses showed a decrease of methyl-PP2A and an increase of demethyl-PP2A with a concomitant reduction in the methyl/demethyl PP2A ratio in both PSP (74%) and AD (76%) brains, associated with an LCMT-1 decrease and a demethylating enzyme increase, protein phosphatase methylesterase (PME-1), in both diseases.",
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+      "line": 4882,
+      "relation": "decreases",
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+      "target": 549
+    },
+    {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
         },
         "Method": {
-          "Confocal Microscopy": true,
-          "Fluorescence Microscopy": true,
-          "Immunoaffinity purification": true,
-          "Immunoblotting": true
+          "Western Blot": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Adler CH",
+          "Beach TG",
+          "Braithwaite SP",
+          "Lee KW",
+          "Mouradian MM",
+          "Oh S",
+          "Park HJ",
+          "Stock JB",
+          "Voronkov M",
+          "Yan R",
+          "Zhang J"
+        ],
+        "date": "2018-02-01",
+        "first": "Park HJ",
+        "last": "Mouradian MM",
+        "name": "Journal of neuropathology and experimental neurology",
+        "pages": "139-148",
+        "reference": "29281045",
+        "title": "Protein Phosphatase 2A and Its Methylation Modulating Enzymes LCMT-1 and PME-1 Are Dysregulated in Tauopathies of Progressive Supranuclear Palsy and Alzheimer Disease.",
+        "type": "PubMed",
+        "volume": "77"
+      },
+      "evidence": "Western blot analyses showed a decrease of methyl-PP2A and an increase of demethyl-PP2A with a concomitant reduction in the methyl/demethyl PP2A ratio in both PSP (74%) and AD (76%) brains, associated with an LCMT-1 decrease and a demethylating enzyme increase, protein phosphatase methylesterase (PME-1), in both diseases.",
+      "key": "02f40c72c9706d345bd5cf0e17c05ba613a2c98a99d1652bceb8171a112d1b8b4cca02601718a787ffc7d458f230b75461f33d2bf7e8bd3e9e74f9a7e2da0c51",
+      "line": 4884,
+      "relation": "increases",
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+      "target": 741
+    },
+    {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHDisease": {
+          "Supranuclear Palsy, Progressive": true
         }
       },
       "citation": {
         "authors": [
+          "Halverson RA",
+          "Kim SY",
           "Lee JM",
           "Muma NA",
-          "Norlund MA",
-          "Singer SM",
-          "Zainelli GM"
+          "Troncoso JC",
+          "Zemaitaitis MO"
         ],
-        "date": "2002-01-01",
-        "first": "Singer SM",
+        "date": "2003-02-01",
+        "first": "Zemaitaitis MO",
         "last": "Muma NA",
-        "name": "Neurochemistry international",
-        "pages": "17-30",
-        "reference": "11738469",
-        "title": "Transglutaminase bonds in neurofibrillary tangles and paired helical filament tau early in Alzheimer's disease.",
+        "name": "Journal of neuropathology and experimental neurology",
+        "pages": "173-84",
+        "reference": "12578227",
+        "title": "Transglutaminase activity, protein, and mRNA expression are increased in progressive supranuclear palsy.",
         "type": "PubMed",
-        "volume": "40"
+        "volume": "62"
       },
-      "evidence": "The number of neurons that are immunoreactive with an antibody directed at the epsilon-(gamma-glutamyl)lysine bond was significantly higher in AD cortex compared with age-matched controls and schizophrenics. PHF tau-directed antibodies AT8, MC-1 and PHF-1 co-localized with epsilon(gamma-glutamyl)lysine immunolabeling in AD NFT. Immunoaffinity purification and immunoblotting experiments demonstrated that PHF tau contains epsilon(gamma-glutamyl)lysine bonds in parietal and frontal cortex in AD. In control cases with NFT present in the entorhinal cortex and hippocampus, indicative of Braak and Braak stage II, epsilon(gamma-glutamyl)lysine bonds were present in PHF tau in parietal and frontal cortex, despite the lack of microscopically detectable NFT or senile plaques in these cortical regions. The presence of PHF tau with epsilon(gamma-glutamyl)lysine bonds in brain regions devoid of NFT in stage II (but regions, which would be expected to contain NFT in stage III) suggests that these bonds occur early in the formation of NFT.",
-      "key": "60504bcc88a7051c20e9be9b1ca1f06f0effe28795c278319d79918a1b283a52da2fef2d58c51e962ac8273f575e254c5464ed41e6d272196a53faea1d21c818",
-      "line": 747,
+      "evidence": "Protein and mRNA levels of transglutaminase 1 were increased in globus pallidus of PSP as compared to controls. There were also significantly higher mRNA levels of the short form of transglutaminase 2 in globus pallidus of PSP (974% of control). Transglutaminase 1 mRNA and the long isoform of transglutaminase 2 mRNA (2212% of control) were significantly higher in PSP in the dentate of cerebellum. Together, these findings suggest that transglutaminase 1 and 2 enzymes may be involved in the formation and/or stabilization of neurofibrillary tangles in selectively vulnerable brain regions in PSP. These transglutaminases may be potential targets for therapeutic intervention.",
+      "key": "473798baef2f9104c9121d55c872d80f8e42952b9d6d60cbfc2a888500e61a736330e2df72fc126174728201703c1b1c64ad1e8d9b5dafdcdbf1ac5ee7c1f04d",
+      "line": 858,
       "relation": "positiveCorrelation",
-      "source": 267,
-      "subject": {
-        "modifier": "Activity"
-      },
-      "target": 908
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+      "target": 94
     },
     {
       "annotations": {
-        "Anatomy": {
-          "hippocampal formation": true
+        "Confidence": {
+          "Medium": true
         },
-        "Disease": {
-          "Alzheimer's disease": true
+        "MeSHDisease": {
+          "Supranuclear Palsy, Progressive": true
         }
       },
       "citation": {
         "authors": [
-          "Appelt DM",
-          "Balin BJ",
-          "Boyne LJ",
-          "Kopen GC"
+          "Halverson RA",
+          "Kim SY",
+          "Lee JM",
+          "Muma NA",
+          "Troncoso JC",
+          "Zemaitaitis MO"
         ],
-        "date": "1996-12-01",
-        "first": "Appelt DM",
-        "last": "Balin BJ",
-        "name": "The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society",
-        "pages": "1421-7",
-        "reference": "8985134",
-        "title": "Localization of transglutaminase in hippocampal neurons: implications for Alzheimer's disease.",
+        "date": "2003-02-01",
+        "first": "Zemaitaitis MO",
+        "last": "Muma NA",
+        "name": "Journal of neuropathology and experimental neurology",
+        "pages": "173-84",
+        "reference": "12578227",
+        "title": "Transglutaminase activity, protein, and mRNA expression are increased in progressive supranuclear palsy.",
         "type": "PubMed",
-        "volume": "44"
-      },
-      "evidence": "Degenerating neurons from the AD hippocampus, compared to neurons from the normal aged hippocampus, exhibited increased immunoreactivity for TGase and demonstrated co-labeling for PHF1 and anti-TGase. Our results suggest that TGase may be associated with the neurofibrillary degeneration observed in AD, thereby implicating TGase as a potential factor in the pathogenesis of Alzheimer's disease.",
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-      "line": 781,
-      "relation": "positiveCorrelation",
-      "source": 267,
-      "subject": {
-        "modifier": "Activity"
+        "volume": "62"
       },
-      "target": 908
+      "evidence": "Protein and mRNA levels of transglutaminase 1 were increased in globus pallidus of PSP as compared to controls. There were also significantly higher mRNA levels of the short form of transglutaminase 2 in globus pallidus of PSP (974% of control). Transglutaminase 1 mRNA and the long isoform of transglutaminase 2 mRNA (2212% of control) were significantly higher in PSP in the dentate of cerebellum. Together, these findings suggest that transglutaminase 1 and 2 enzymes may be involved in the formation and/or stabilization of neurofibrillary tangles in selectively vulnerable brain regions in PSP. These transglutaminases may be potential targets for therapeutic intervention.",
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-      "relation": "hasComponent",
-      "source": 238,
-      "target": 486
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+          "globus pallidus": true
+        },
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+          "Medium": true
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+      "citation": {
+        "authors": [
+          "Halverson RA",
+          "Kim SY",
+          "Lee JM",
+          "Muma NA",
+          "Troncoso JC",
+          "Zemaitaitis MO"
+        ],
+        "date": "2003-02-01",
+        "first": "Zemaitaitis MO",
+        "last": "Muma NA",
+        "name": "Journal of neuropathology and experimental neurology",
+        "pages": "173-84",
+        "reference": "12578227",
+        "title": "Transglutaminase activity, protein, and mRNA expression are increased in progressive supranuclear palsy.",
+        "type": "PubMed",
+        "volume": "62"
+      },
+      "evidence": "Protein and mRNA levels of transglutaminase 1 were increased in globus pallidus of PSP as compared to controls. There were also significantly higher mRNA levels of the short form of transglutaminase 2 in globus pallidus of PSP (974% of control). Transglutaminase 1 mRNA and the long isoform of transglutaminase 2 mRNA (2212% of control) were significantly higher in PSP in the dentate of cerebellum. Together, these findings suggest that transglutaminase 1 and 2 enzymes may be involved in the formation and/or stabilization of neurofibrillary tangles in selectively vulnerable brain regions in PSP. These transglutaminases may be potential targets for therapeutic intervention.",
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-      "relation": "hasComponent",
-      "source": 238,
-      "target": 730
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+          "Medium": true
+        },
+        "MeSHDisease": {
+          "Supranuclear Palsy, Progressive": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Halverson RA",
+          "Kim SY",
+          "Lee JM",
+          "Muma NA",
+          "Troncoso JC",
+          "Zemaitaitis MO"
+        ],
+        "date": "2003-02-01",
+        "first": "Zemaitaitis MO",
+        "last": "Muma NA",
+        "name": "Journal of neuropathology and experimental neurology",
+        "pages": "173-84",
+        "reference": "12578227",
+        "title": "Transglutaminase activity, protein, and mRNA expression are increased in progressive supranuclear palsy.",
+        "type": "PubMed",
+        "volume": "62"
+      },
+      "evidence": "Protein and mRNA levels of transglutaminase 1 were increased in globus pallidus of PSP as compared to controls. There were also significantly higher mRNA levels of the short form of transglutaminase 2 in globus pallidus of PSP (974% of control). Transglutaminase 1 mRNA and the long isoform of transglutaminase 2 mRNA (2212% of control) were significantly higher in PSP in the dentate of cerebellum. Together, these findings suggest that transglutaminase 1 and 2 enzymes may be involved in the formation and/or stabilization of neurofibrillary tangles in selectively vulnerable brain regions in PSP. These transglutaminases may be potential targets for therapeutic intervention.",
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     },
     {
       "annotations": {
-        "Cell_Line": {
-          "SH-SY5Y": true
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHDisease": {
+          "Supranuclear Palsy, Progressive": true
         }
       },
       "citation": {
         "authors": [
-          "Johnson GV",
-          "Kuret J",
-          "Tucholski J"
+          "Halverson RA",
+          "Kim SY",
+          "Lee JM",
+          "Muma NA",
+          "Troncoso JC",
+          "Zemaitaitis MO"
         ],
-        "date": "1999-11-01",
-        "first": "Tucholski J",
-        "last": "Johnson GV",
-        "name": "Journal of neurochemistry",
-        "pages": "1871-80",
-        "reference": "10537045",
-        "title": "Tau is modified by tissue transglutaminase in situ: possible functional and metabolic effects of polyamination.",
+        "date": "2003-02-01",
+        "first": "Zemaitaitis MO",
+        "last": "Muma NA",
+        "name": "Journal of neuropathology and experimental neurology",
+        "pages": "173-84",
+        "reference": "12578227",
+        "title": "Transglutaminase activity, protein, and mRNA expression are increased in progressive supranuclear palsy.",
         "type": "PubMed",
-        "volume": "73"
+        "volume": "62"
       },
-      "evidence": "For these studies, SH-SY5Y cells stably overexpressing tTG were used. tTG coimmunoprecipitated with tau, and elevating intracellular calcium levels with maitotoxin resulted in a 52 +/- 4% increase in the amount of tTG that coimmunoprecipitated with tau. The increase in association of tTG with tau after treatment with maitotoxin corresponded to a coimmunolocalization of tTG, tTG activity, and tau in the cells. Further, tau was modified by tTG in situ in response to maitotoxin treatment. In vitro polyaminated tau was significantly less susceptible to micro-calpain proteolysis; however, tTG-mediated polyamination of tau did not significantly alter the microtubule-binding capacity of tau.",
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-      "line": 797,
-      "relation": "positiveCorrelation",
-      "source": 238,
-      "target": 12
+      "evidence": "Protein and mRNA levels of transglutaminase 1 were increased in globus pallidus of PSP as compared to controls. There were also significantly higher mRNA levels of the short form of transglutaminase 2 in globus pallidus of PSP (974% of control). Transglutaminase 1 mRNA and the long isoform of transglutaminase 2 mRNA (2212% of control) were significantly higher in PSP in the dentate of cerebellum. Together, these findings suggest that transglutaminase 1 and 2 enzymes may be involved in the formation and/or stabilization of neurofibrillary tangles in selectively vulnerable brain regions in PSP. These transglutaminases may be potential targets for therapeutic intervention.",
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     },
     {
       "annotations": {
         "Cell_Line": {
           "SH-SY5Y": true
+        },
+        "Confidence": {
+          "High": true
         }
       },
       "citation": {
@@ -26646,16 +30698,19 @@
         "volume": "73"
       },
       "evidence": "For these studies, SH-SY5Y cells stably overexpressing tTG were used. tTG coimmunoprecipitated with tau, and elevating intracellular calcium levels with maitotoxin resulted in a 52 +/- 4% increase in the amount of tTG that coimmunoprecipitated with tau. The increase in association of tTG with tau after treatment with maitotoxin corresponded to a coimmunolocalization of tTG, tTG activity, and tau in the cells. Further, tau was modified by tTG in situ in response to maitotoxin treatment. In vitro polyaminated tau was significantly less susceptible to micro-calpain proteolysis; however, tTG-mediated polyamination of tau did not significantly alter the microtubule-binding capacity of tau.",
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-      "line": 796,
-      "relation": "increases",
-      "source": 152,
-      "target": 12
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+      "line": 946,
+      "relation": "positiveCorrelation",
+      "source": 820,
+      "target": 567
     },
     {
       "annotations": {
         "Cell_Line": {
           "SH-SY5Y": true
+        },
+        "Confidence": {
+          "High": true
         }
       },
       "citation": {
@@ -26675,19 +30730,19 @@
         "volume": "73"
       },
       "evidence": "For these studies, SH-SY5Y cells stably overexpressing tTG were used. tTG coimmunoprecipitated with tau, and elevating intracellular calcium levels with maitotoxin resulted in a 52 +/- 4% increase in the amount of tTG that coimmunoprecipitated with tau. The increase in association of tTG with tau after treatment with maitotoxin corresponded to a coimmunolocalization of tTG, tTG activity, and tau in the cells. Further, tau was modified by tTG in situ in response to maitotoxin treatment. In vitro polyaminated tau was significantly less susceptible to micro-calpain proteolysis; however, tTG-mediated polyamination of tau did not significantly alter the microtubule-binding capacity of tau.",
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-      "object": {
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-      "relation": "increases",
-      "source": 152,
-      "target": 730
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+      "relation": "partOf",
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     },
     {
       "annotations": {
         "Cell_Line": {
           "SH-SY5Y": true
+        },
+        "Confidence": {
+          "High": true
         }
       },
       "citation": {
@@ -26707,104 +30762,601 @@
         "volume": "73"
       },
       "evidence": "For these studies, SH-SY5Y cells stably overexpressing tTG were used. tTG coimmunoprecipitated with tau, and elevating intracellular calcium levels with maitotoxin resulted in a 52 +/- 4% increase in the amount of tTG that coimmunoprecipitated with tau. The increase in association of tTG with tau after treatment with maitotoxin corresponded to a coimmunolocalization of tTG, tTG activity, and tau in the cells. Further, tau was modified by tTG in situ in response to maitotoxin treatment. In vitro polyaminated tau was significantly less susceptible to micro-calpain proteolysis; however, tTG-mediated polyamination of tau did not significantly alter the microtubule-binding capacity of tau.",
-      "key": "702e9e1fcced2c75780dbf2928c0a771a0d92b24839196d082fc77ad64933b41a0bae0deb807a6e0d7f6895151daa5582c05bca485b211c7b5b61699dad792db",
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-    },
-    {
-      "citation": {
-        "authors": [
-          "Binder LI",
-          "Geula C",
-          "Reyes JF",
-          "Vana L"
-        ],
-        "date": "2012-01-01",
-        "first": "Reyes JF",
-        "last": "Binder LI",
-        "name": "Acta neuropathologica",
-        "pages": "119-32",
-        "reference": "22057784",
-        "title": "Selective tau tyrosine nitration in non-AD tauopathies.",
-        "type": "PubMed",
-        "volume": "123"
+      "key": "2054f4bfe37862cd71b1bd07eaa58c13ec0a6ce4d8d302776bb137eca6903651fa1c7e6a8bce2d35eb0171f66d4b679fc35e4ac6753d3d450c41c8e022ca5803",
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+      "relation": "association",
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+      "subject": {
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       },
-      "evidence": "Tau-nY18 did not label the classical pathological lesions of CBD or PSP but did label the neuronal lesions associated with PiD. Tau-nY29 revealed some, but not all classes of tau inclusions associated with both CBD and PSP but did label numerous Pick body inclusions in PiD. Tau-nY197 was restricted to the neuropil threads in both CBD and PSP; however, similar to Tau-nY29, extensive Pick body pathology was clearly labeled. Tau-nY394 did not detect any of the lesions associated with these disorders.",
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-      "line": 810,
-      "relation": "positiveCorrelation",
-      "source": 916,
-      "target": 518
+      "target": 437
     },
     {
+      "annotations": {
+        "Anatomy": {
+          "globus pallidus": true,
+          "pons": true
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       "citation": {
         "authors": [
-          "Binder LI",
-          "Geula C",
-          "Reyes JF",
-          "Vana L"
+          "Lee JM",
+          "Muma NA",
+          "Troncoso JC",
+          "Zemaitaitis MO"
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-        "first": "Reyes JF",
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-        "title": "Selective tau tyrosine nitration in non-AD tauopathies.",
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+        "first": "Zemaitaitis MO",
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         "type": "PubMed",
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       },
-      "evidence": "Tau-nY18 did not label the classical pathological lesions of CBD or PSP but did label the neuronal lesions associated with PiD. Tau-nY29 revealed some, but not all classes of tau inclusions associated with both CBD and PSP but did label numerous Pick body inclusions in PiD. Tau-nY197 was restricted to the neuropil threads in both CBD and PSP; however, similar to Tau-nY29, extensive Pick body pathology was clearly labeled. Tau-nY394 did not detect any of the lesions associated with these disorders.",
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         "authors": [
-          "Binder LI",
-          "Geula C",
-          "Reyes JF",
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+        "first": "Zemaitaitis MO",
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-      "evidence": "Tau-nY18 did not label the classical pathological lesions of CBD or PSP but did label the neuronal lesions associated with PiD. Tau-nY29 revealed some, but not all classes of tau inclusions associated with both CBD and PSP but did label numerous Pick body inclusions in PiD. Tau-nY197 was restricted to the neuropil threads in both CBD and PSP; however, similar to Tau-nY29, extensive Pick body pathology was clearly labeled. Tau-nY394 did not detect any of the lesions associated with these disorders.",
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+      "evidence": "The number of neurons that are immunoreactive with an antibody directed at the epsilon-(gamma-glutamyl)lysine bond was significantly higher in AD cortex compared with age-matched controls and schizophrenics. PHF tau-directed antibodies AT8, MC-1 and PHF-1 co-localized with epsilon(gamma-glutamyl)lysine immunolabeling in AD NFT. Immunoaffinity purification and immunoblotting experiments demonstrated that PHF tau contains epsilon(gamma-glutamyl)lysine bonds in parietal and frontal cortex in AD. In control cases with NFT present in the entorhinal cortex and hippocampus, indicative of Braak and Braak stage II, epsilon(gamma-glutamyl)lysine bonds were present in PHF tau in parietal and frontal cortex, despite the lack of microscopically detectable NFT or senile plaques in these cortical regions. The presence of PHF tau with epsilon(gamma-glutamyl)lysine bonds in brain regions devoid of NFT in stage II (but regions, which would be expected to contain NFT in stage III) suggests that these bonds occur early in the formation of NFT.",
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+          "Cox TM",
+          "Johnson GV",
+          "Lockhart JP",
+          "Miller ML",
+          "Powers RE",
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+      "evidence": "Total transglutaminase activity was significantly higher in the Alzheimer's disease prefrontal cortex compared to control. In addition the levels of tissue transglutaminase, as determined by quantitative immunoblotting, were elevated approximately 3-fold in Alzheimer's disease prefrontal cortex compared to control. To our knowledge, this is the first demonstration that transglutaminase is increased in Alzheimer's disease brain. There were no significant differences in transglutaminase activity or levels in the cerebellum between control and Alzheimer's disease cases. Because the elevation of transglutaminase in the Alzheimer's disease samples occurred in the prefrontal cortex, where neurofibrillary pathology is usually abundant, and not in the cerebellum, which is usually spared in Alzheimer's disease, it can be suggested that transglutaminase could be a contributing factor in neurofibrillary tangle formation.",
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+      "evidence": "For these studies, SH-SY5Y cells stably overexpressing tTG were used. tTG coimmunoprecipitated with tau, and elevating intracellular calcium levels with maitotoxin resulted in a 52 +/- 4% increase in the amount of tTG that coimmunoprecipitated with tau. The increase in association of tTG with tau after treatment with maitotoxin corresponded to a coimmunolocalization of tTG, tTG activity, and tau in the cells. Further, tau was modified by tTG in situ in response to maitotoxin treatment. In vitro polyaminated tau was significantly less susceptible to micro-calpain proteolysis; however, tTG-mediated polyamination of tau did not significantly alter the microtubule-binding capacity of tau.",
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+      "evidence": "For these studies, SH-SY5Y cells stably overexpressing tTG were used. tTG coimmunoprecipitated with tau, and elevating intracellular calcium levels with maitotoxin resulted in a 52 +/- 4% increase in the amount of tTG that coimmunoprecipitated with tau. The increase in association of tTG with tau after treatment with maitotoxin corresponded to a coimmunolocalization of tTG, tTG activity, and tau in the cells. Further, tau was modified by tTG in situ in response to maitotoxin treatment. In vitro polyaminated tau was significantly less susceptible to micro-calpain proteolysis; however, tTG-mediated polyamination of tau did not significantly alter the microtubule-binding capacity of tau.",
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+    {
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+        "Cell_Line": {
+          "SH-SY5Y": true
+        },
+        "Confidence": {
+          "High": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Johnson GV",
+          "Kuret J",
+          "Tucholski J"
+        ],
+        "date": "1999-11-01",
+        "first": "Tucholski J",
+        "last": "Johnson GV",
+        "name": "Journal of neurochemistry",
+        "pages": "1871-80",
+        "reference": "10537045",
+        "title": "Tau is modified by tissue transglutaminase in situ: possible functional and metabolic effects of polyamination.",
+        "type": "PubMed",
+        "volume": "73"
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+      "evidence": "For these studies, SH-SY5Y cells stably overexpressing tTG were used. tTG coimmunoprecipitated with tau, and elevating intracellular calcium levels with maitotoxin resulted in a 52 +/- 4% increase in the amount of tTG that coimmunoprecipitated with tau. The increase in association of tTG with tau after treatment with maitotoxin corresponded to a coimmunolocalization of tTG, tTG activity, and tau in the cells. Further, tau was modified by tTG in situ in response to maitotoxin treatment. In vitro polyaminated tau was significantly less susceptible to micro-calpain proteolysis; however, tTG-mediated polyamination of tau did not significantly alter the microtubule-binding capacity of tau.",
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+          "High": true
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+      "citation": {
+        "authors": [
+          "Babić Leko M",
+          "Bažadona D",
+          "Buée L",
+          "Delalle I",
+          "Di Giovanni G",
+          "Harrington C",
+          "Hof PR",
+          "Jovanov-Milošević N",
+          "Wischik C",
+          "Wray S",
+          "de Silva R",
+          "Šimić G"
+        ],
+        "date": "2016-01-06",
+        "first": "Šimić G",
+        "last": "Hof PR",
+        "name": "Biomolecules",
+        "pages": "6",
+        "reference": "26751493",
+        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
+        "type": "PubMed",
+        "volume": "6"
+      },
+      "evidence": "Apart from binding to MT, the repeat domains of tau also bind to tubulin deacetylase, histone deacetylase 6 (HDAC6) [68] and apolipoprotein E (apoE) more with the ",
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+          "High": true
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+          "Babić Leko M",
+          "Bažadona D",
+          "Buée L",
+          "Delalle I",
+          "Di Giovanni G",
+          "Harrington C",
+          "Hof PR",
+          "Jovanov-Milošević N",
+          "Wischik C",
+          "Wray S",
+          "de Silva R",
+          "Šimić G"
+        ],
+        "date": "2016-01-06",
+        "first": "Šimić G",
+        "last": "Hof PR",
+        "name": "Biomolecules",
+        "pages": "6",
+        "reference": "26751493",
+        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
+        "type": "PubMed",
+        "volume": "6"
+      },
+      "evidence": "Apart from binding to MT, the repeat domains of tau also bind to tubulin deacetylase, histone deacetylase 6 (HDAC6) [68] and apolipoprotein E (apoE) more with the ",
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+        "Confidence": {
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+        "Disease": {
           "progressive supranuclear palsy": true
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         "HBP_Disease": {
@@ -26830,15 +31382,21 @@
       },
       "evidence": "Tau-nY18 did not label the classical pathological lesions of CBD or PSP but did label the neuronal lesions associated with PiD. Tau-nY29 revealed some, but not all classes of tau inclusions associated with both CBD and PSP but did label numerous Pick body inclusions in PiD. Tau-nY197 was restricted to the neuropil threads in both CBD and PSP; however, similar to Tau-nY29, extensive Pick body pathology was clearly labeled. Tau-nY394 did not detect any of the lesions associated with these disorders.",
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     {
       "annotations": {
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         "Disease": {
           "Alzheimer's disease": true
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+        "MeSHAnatomy": {
+          "Brain": true
         }
       },
       "citation": {
@@ -26863,12 +31421,17 @@
       },
       "evidence": "Tau-nY29 detects soluble tau and paired helical filament tau from severely affected Alzheimer's brain but fails to recognize tau from normal aged brain. This observation suggests that nitration at Tyr29 is a disease-related event that may alter the intrinsic ability of tau to self-polymerize. In Alzheimer's brain, Tau-nY29 labels the fibrillar triad of tau lesions, including neurofibrillary tangles, neuritic plaques, and, to a lesser extent, neuropil threads. Intriguingly, although Tau-nY29 stains both the neuronal and glial tau pathology of Pick disease, it detects only the neuronal pathology in corticobasal degeneration and progressive supranuclear palsy without labeling the predominant glial pathology.",
       "key": "387d5259518ef7e7f92820fb266c6fdf14d6698ac8d12f5c7021951f7a1b8c26893dffc21d1d3ab3edf61b2cf1fba68d9d92bd07fdf675559230be10840391c1",
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       "relation": "association",
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     {
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       "citation": {
         "authors": [
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@@ -26896,12 +31459,17 @@
       },
       "evidence": "On the other side, sarkosyl extracts from the filaments of PSP [129], corticobasal degeneration (CBD; [130]), argyrophilic grain disease (AgD; [131]), and some cases of FTDP-17, contain tau protein that separates as doublets of 64 and 69 kDa and are predominantly composed of tau isoforms with 4R (class II tauopathies), whereas sarkosyl extracts from filaments of Pick’s disease are characterized by the presence of pathological tau doublets of 60 and 64 kDa and contain mainly 3R tau isoforms (class III tauopathy).",
       "key": "176b6dd210b6b40c32960551b396efe756d4556627c9de17b2ef1149e7d230db84cf5de4fde9dde79315a5d2c5b946381502c08a91423af9d1d190d7a66e0a65",
-      "line": 1646,
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       "relation": "positiveCorrelation",
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     {
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       "citation": {
         "authors": [
           "Cohen TJ",
@@ -26924,12 +31492,17 @@
       },
       "evidence": "Thus, K280 acetylation is a feature found in a variety of human 4R or 3R/4R tauopathies including AD, but not 3R-tauopathies such as PiD.",
       "key": "d1b4416c955ad7544b73188675400dce6f2ec41a406c7693b81a43644e5b574aead664a00fde0555274a194aacdd50d38d13561047756f8b167bc34dc9b8bcb7",
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       "relation": "positiveCorrelation",
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     {
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       "citation": {
         "authors": [
           "Cohen TJ",
@@ -26952,37 +31525,50 @@
       },
       "evidence": "Thus, K280 acetylation is a feature found in a variety of human 4R or 3R/4R tauopathies including AD, but not 3R-tauopathies such as PiD.",
       "key": "a432d29d204b43048c44f0f7480fa9ac2362b49a1cffcd0b7acf7e6a5d887a98f80f15f4dabd968380529a931f2e5dbdd3297c43195d9b44d9e1519abb7eb2d1",
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       "relation": "isA",
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+      "target": 999
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     {
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+          "High": true
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       "citation": {
         "authors": [
-          "Kawakami F",
-          "Ohtsuki K",
-          "Suzuki K"
+          "Cowburn RF",
+          "Dahllund L",
+          "Gustafsson E",
+          "Lund H",
+          "Malinowsky D",
+          "Strömberg K",
+          "Sunnemark D",
+          "Svensson A"
         ],
-        "date": "2008-02-01",
-        "first": "Kawakami F",
-        "last": "Ohtsuki K",
-        "name": "Biological &amp; pharmaceutical bulletin",
-        "pages": "193-200",
-        "reference": "18239272",
-        "title": "A novel consensus phosphorylation motif in sulfatide- and cholesterol-3-sulfate-binding protein substrates for CK1 in vitro.",
+        "date": "2013-07-01",
+        "first": "Lund H",
+        "last": "Sunnemark D",
+        "name": "Brain pathology (Zurich, Switzerland)",
+        "pages": "378-89",
+        "reference": "23088643",
+        "title": "Tau-tubulin kinase 1 expression, phosphorylation and co-localization with phospho-Ser422 tau in the Alzheimer's disease brain.",
         "type": "PubMed",
-        "volume": "31"
+        "volume": "23"
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       "evidence": "The pSer422 antibody displayed an almost identical pattern to that of AT8, in that it stained NFTs (Figure 5A–D), neuropil threads and neuritic plaques (Figure 5E–H)",
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     {
       "annotations": {
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         "Disease": {
           "progressive supranuclear palsy": true
         },
@@ -27012,12 +31598,17 @@
       },
       "evidence": "Tau-nY18 did not label the classical pathological lesions of CBD or PSP but did label the neuronal lesions associated with PiD. Tau-nY29 revealed some, but not all classes of tau inclusions associated with both CBD and PSP but did label numerous Pick body inclusions in PiD. Tau-nY197 was restricted to the neuropil threads in both CBD and PSP; however, similar to Tau-nY29, extensive Pick body pathology was clearly labeled. Tau-nY394 did not detect any of the lesions associated with these disorders.",
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       "citation": {
         "authors": [
           "Berry R",
@@ -27040,423 +31631,95 @@
       },
       "evidence": "This antibody detects nitrated tau in soluble preparations from both severe AD brains (Braak stage V, VI) and age-matched controls, suggesting that nitration at Tyr 18 may be linked to astrocyte activation, an early event associated with amyloid plaque formation",
       "key": "cbadb2965f2360b8e0c249c288b0078cda6e5bddb28d42e158dc0df2c0ae3fa79d9e863249035c072b4152ad362b22e87280a4620e1dcc432d72331f52d0374f",
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-          "Grassi E",
-          "Negri A",
-          "Nonnis S",
-          "Ronchi C",
-          "Ronchi S",
-          "Taverna F",
-          "Tedeschi G"
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-        "date": "2008-03-01",
-        "first": "Nonnis S",
-        "last": "Tedeschi G",
-        "name": "Neurochemical research",
-        "pages": "518-25",
-        "reference": "17768677",
-        "title": "Tau is endogenously nitrated in mouse brain: identification of a tyrosine residue modified in vivo by NO.",
-        "type": "PubMed",
-        "volume": "33"
-      },
-      "evidence": "It was possible to find nitrated Tyr 488 (numbers refer to mouse tau P10637 in the Swiss-Prot/ThEMBL data bank) which corresponds to Tyr 507 in rat tau (Table 1) in accordance with the data reported above for tau in PC12 cells.",
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-          "Taverna F",
-          "Tedeschi G"
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-        "last": "Tedeschi G",
-        "name": "Neurochemical research",
-        "pages": "518-25",
-        "reference": "17768677",
-        "title": "Tau is endogenously nitrated in mouse brain: identification of a tyrosine residue modified in vivo by NO.",
-        "type": "PubMed",
-        "volume": "33"
-      },
-      "evidence": "It was possible to find nitrated Tyr 488 (numbers refer to mouse tau P10637 in the Swiss-Prot/ThEMBL data bank) which corresponds to Tyr 507 in rat tau (Table 1) in accordance with the data reported above for tau in PC12 cells.",
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-          "Wang JZ",
-          "Wang Q",
-          "Xu YF",
-          "Yin J",
-          "Zhang YJ"
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-        "name": "FASEB journal : official publication of the Federation of American Societies for Experimental Biology",
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-        "title": "Peroxynitrite induces Alzheimer-like tau modifications and accumulation in rat brain and its underlying mechanisms.",
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-      "evidence": "In the present study we injected bilaterally 3-morpholino-sydnonimine (SIN-1), a recognized and widely used peroxynitrite donor (25–30), into rat hippocampus, and investigated whether or not peroxynitrite could induce simultaneously nitration and hyperphosphorylation of tau and the underlying mechanisms in vivo. The level of nitrated and hyperphosphorylated tau was markedly increased in rat hippocampus 24 h, and prevented by preinjection of uric acid, a natural scavenger of peroxynitrite. GSK-3beta and p38 MAPKs, including p38alpha, p38beta, and p38delta activity was increased, but no change in the activity of p38gamma, ERK, and c-Jun amino-terminal kinase (JNK). Both nitrated tau and hyperphosphorylated tau were aggregated in the hippocampus, with activity of 20S proteasome significantly arrested in SIN-1-injected rats. Hyperphosphorylated tau was degraded as efficiently as normal tau by 20S proteasome, but the nitrated tau with an unorderly secondary structure became more resistant to the proteolysis, providing evidence that peroxynitrite simultaneously induces tau hyperphosphorylation, nitration, and accumulation, and that activation of GSK-3beta, p38alpha, p38beta, p38delta isoforms and the inhibition of proteasome activity are respectively responsible for the peroxynitrite-induced tau hyperphosphorylation and accumulation.",
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-          "Wang JZ",
-          "Wang Q",
-          "Xu YF",
-          "Yin J",
-          "Zhang YJ"
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-        "name": "FASEB journal : official publication of the Federation of American Societies for Experimental Biology",
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-        "title": "Peroxynitrite induces Alzheimer-like tau modifications and accumulation in rat brain and its underlying mechanisms.",
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-      },
-      "evidence": "In the present study we injected bilaterally 3-morpholino-sydnonimine (SIN-1), a recognized and widely used peroxynitrite donor (25–30), into rat hippocampus, and investigated whether or not peroxynitrite could induce simultaneously nitration and hyperphosphorylation of tau and the underlying mechanisms in vivo. The level of nitrated and hyperphosphorylated tau was markedly increased in rat hippocampus 24 h, and prevented by preinjection of uric acid, a natural scavenger of peroxynitrite. GSK-3beta and p38 MAPKs, including p38alpha, p38beta, and p38delta activity was increased, but no change in the activity of p38gamma, ERK, and c-Jun amino-terminal kinase (JNK). Both nitrated tau and hyperphosphorylated tau were aggregated in the hippocampus, with activity of 20S proteasome significantly arrested in SIN-1-injected rats. Hyperphosphorylated tau was degraded as efficiently as normal tau by 20S proteasome, but the nitrated tau with an unorderly secondary structure became more resistant to the proteolysis, providing evidence that peroxynitrite simultaneously induces tau hyperphosphorylation, nitration, and accumulation, and that activation of GSK-3beta, p38alpha, p38beta, p38delta isoforms and the inhibition of proteasome activity are respectively responsible for the peroxynitrite-induced tau hyperphosphorylation and accumulation.",
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-        },
-        "ExpMethod": {
-          "in vivo": true
-        },
-        "Species": {
-          "10116": true
-        }
-      },
-      "citation": {
-        "authors": [
-          "Li HL",
-          "Liu YH",
-          "Wang JZ",
-          "Wang Q",
-          "Xu YF",
-          "Yin J",
-          "Zhang YJ"
-        ],
-        "date": "2006-07-01",
-        "first": "Zhang YJ",
-        "last": "Wang JZ",
-        "name": "FASEB journal : official publication of the Federation of American Societies for Experimental Biology",
-        "pages": "1431-42",
-        "reference": "16816118",
-        "title": "Peroxynitrite induces Alzheimer-like tau modifications and accumulation in rat brain and its underlying mechanisms.",
-        "type": "PubMed",
-        "volume": "20"
-      },
-      "evidence": "In the present study we injected bilaterally 3-morpholino-sydnonimine (SIN-1), a recognized and widely used peroxynitrite donor (25–30), into rat hippocampus, and investigated whether or not peroxynitrite could induce simultaneously nitration and hyperphosphorylation of tau and the underlying mechanisms in vivo. The level of nitrated and hyperphosphorylated tau was markedly increased in rat hippocampus 24 h, and prevented by preinjection of uric acid, a natural scavenger of peroxynitrite. GSK-3beta and p38 MAPKs, including p38alpha, p38beta, and p38delta activity was increased, but no change in the activity of p38gamma, ERK, and c-Jun amino-terminal kinase (JNK). Both nitrated tau and hyperphosphorylated tau were aggregated in the hippocampus, with activity of 20S proteasome significantly arrested in SIN-1-injected rats. Hyperphosphorylated tau was degraded as efficiently as normal tau by 20S proteasome, but the nitrated tau with an unorderly secondary structure became more resistant to the proteolysis, providing evidence that peroxynitrite simultaneously induces tau hyperphosphorylation, nitration, and accumulation, and that activation of GSK-3beta, p38alpha, p38beta, p38delta isoforms and the inhibition of proteasome activity are respectively responsible for the peroxynitrite-induced tau hyperphosphorylation and accumulation.",
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-      "relation": "hasVariant",
-      "source": 288,
-      "target": 289
+      "target": 602
     },
     {
       "annotations": {
-        "Anatomy": {
-          "dorsal root ganglion": true
+        "Confidence": {
+          "Medium": true
         }
       },
       "citation": {
         "authors": [
-          "Boutillier AL",
-          "Bradke F",
-          "Di Giovanni S",
-          "Gaub P",
-          "Hervera A",
-          "Joshi Y",
-          "Laskowski CJ",
-          "Lindner R",
-          "Nguyen T",
-          "Puttagunta R",
-          "Rathore KI",
-          "Schmandke A",
-          "Sória MG",
-          "Tedeschi A"
+          "Berry R",
+          "Binder LI",
+          "Fu Y",
+          "Guillozet-Bongaarts AL",
+          "Horowitz PM",
+          "Reyes JF",
+          "Reynolds MR"
         ],
-        "date": "2014-04-01",
-        "first": "Puttagunta R",
-        "last": "Di Giovanni S",
-        "name": "Nature communications",
-        "pages": "3527",
-        "reference": "24686445",
-        "title": "PCAF-dependent epigenetic changes promote axonal regeneration in the central nervous system.",
+        "date": "2008-08-01",
+        "first": "Reyes JF",
+        "last": "Binder LI",
+        "name": "Neurobiology of disease",
+        "pages": "198-208",
+        "reference": "18562203",
+        "title": "A possible link between astrocyte activation and tau nitration in Alzheimer's disease.",
         "type": "PubMed",
-        "volume": "5"
-      },
-      "evidence": "Here we show through systematic epigenetic studies that the histone acetyltransferase p300/CBP-associated factor (PCAF) promotes acetylation of histone 3 Lys 9 at the promoters of established key regeneration-associated genes following a peripheral but not a central axonal injury. Furthermore, we find that extracellular signal-regulated kinase (ERK)-mediated retrograde signalling is required for PCAF-dependent regenerative gene reprogramming. Finally, PCAF is necessary for conditioning-dependent axonal regeneration and also singularly promotes regeneration after spinal cord injury. ",
-      "key": "19f346d893fc0109f2a74f8ebba8bb544a0c854faa09e1d401e96ad2a36819ee6d7f1eb3a3d3f06dc6302bf5130b44f3256a084fd762a74a8be4be416ea420b8",
-      "line": 3238,
-      "object": {
-        "modifier": "Activity"
+        "volume": "31"
       },
-      "relation": "positiveCorrelation",
-      "source": 288,
+      "evidence": "This antibody detects nitrated tau in soluble preparations from both severe AD brains (Braak stage V, VI) and age-matched controls, suggesting that nitration at Tyr 18 may be linked to astrocyte activation, an early event associated with amyloid plaque formation",
+      "key": "bd83b49716b584449a1aa86771f11c11693814615012c0ecd2df3a4049f0007a39e1e92bf8459317adedbe110ec98365c2865e4e49d470268de08a8e80b212f7",
+      "line": 985,
+      "relation": "association",
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       "subject": {
         "modifier": "Activity"
       },
-      "target": 463
+      "target": 1027
     },
     {
       "annotations": {
-        "Anatomy": {
-          "hippocampal formation": true
+        "Confidence": {
+          "Medium": true
         },
-        "ExpMethod": {
-          "in vivo": true
+        "Disease": {
+          "Alzheimer's disease": true
         },
-        "Species": {
-          "10116": true
+        "MeSHAnatomy": {
+          "Brain": true
         }
       },
       "citation": {
         "authors": [
-          "Li HL",
-          "Liu YH",
-          "Wang JZ",
-          "Wang Q",
-          "Xu YF",
-          "Yin J",
-          "Zhang YJ"
+          "Berry RW",
+          "Bigio EH",
+          "Binder LI",
+          "Fu Y",
+          "Guillozet-Bongaarts AL",
+          "Reyes JF",
+          "Reynolds MR"
         ],
-        "date": "2006-07-01",
-        "first": "Zhang YJ",
-        "last": "Wang JZ",
-        "name": "FASEB journal : official publication of the Federation of American Societies for Experimental Biology",
-        "pages": "1431-42",
-        "reference": "16816118",
-        "title": "Peroxynitrite induces Alzheimer-like tau modifications and accumulation in rat brain and its underlying mechanisms.",
+        "date": "2006-10-18",
+        "first": "Reynolds MR",
+        "last": "Binder LI",
+        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
+        "pages": "10636-45",
+        "reference": "17050703",
+        "title": "Tau nitration occurs at tyrosine 29 in the fibrillar lesions of Alzheimer's disease and other tauopathies.",
         "type": "PubMed",
-        "volume": "20"
-      },
-      "evidence": "In the present study we injected bilaterally 3-morpholino-sydnonimine (SIN-1), a recognized and widely used peroxynitrite donor (25–30), into rat hippocampus, and investigated whether or not peroxynitrite could induce simultaneously nitration and hyperphosphorylation of tau and the underlying mechanisms in vivo. The level of nitrated and hyperphosphorylated tau was markedly increased in rat hippocampus 24 h, and prevented by preinjection of uric acid, a natural scavenger of peroxynitrite. GSK-3beta and p38 MAPKs, including p38alpha, p38beta, and p38delta activity was increased, but no change in the activity of p38gamma, ERK, and c-Jun amino-terminal kinase (JNK). Both nitrated tau and hyperphosphorylated tau were aggregated in the hippocampus, with activity of 20S proteasome significantly arrested in SIN-1-injected rats. Hyperphosphorylated tau was degraded as efficiently as normal tau by 20S proteasome, but the nitrated tau with an unorderly secondary structure became more resistant to the proteolysis, providing evidence that peroxynitrite simultaneously induces tau hyperphosphorylation, nitration, and accumulation, and that activation of GSK-3beta, p38alpha, p38beta, p38delta isoforms and the inhibition of proteasome activity are respectively responsible for the peroxynitrite-induced tau hyperphosphorylation and accumulation.",
-      "key": "7ed7bfc8ed54a6bab1186d6da6bfee27e5916c856b12fd45293ce67d6bd5191a7e7fecd284f602e27305b2589e570f03d1832a8492739b78150b2018500dc753",
-      "line": 891,
-      "relation": "negativeCorrelation",
-      "source": 305,
-      "subject": {
-        "modifier": "Activity"
+        "volume": "26"
       },
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+      "evidence": "Tau-nY29 detects soluble tau and paired helical filament tau from severely affected Alzheimer's brain but fails to recognize tau from normal aged brain. This observation suggests that nitration at Tyr29 is a disease-related event that may alter the intrinsic ability of tau to self-polymerize. In Alzheimer's brain, Tau-nY29 labels the fibrillar triad of tau lesions, including neurofibrillary tangles, neuritic plaques, and, to a lesser extent, neuropil threads. Intriguingly, although Tau-nY29 stains both the neuronal and glial tau pathology of Pick disease, it detects only the neuronal pathology in corticobasal degeneration and progressive supranuclear palsy without labeling the predominant glial pathology.",
+      "key": "df3683220d0a9a2a52d8fa9ff7fc02508583007abaf7219551ae862e0688002b38de7b4350bcc3ccdd261da536169a4db2db7bce49f961a5d85b985625947218",
+      "line": 996,
+      "relation": "association",
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     },
     {
       "annotations": {
-        "Anatomy": {
-          "hippocampal formation": true
-        },
-        "ExpMethod": {
-          "in vivo": true
-        },
-        "Species": {
-          "10116": true
+        "Confidence": {
+          "Medium": true
         }
       },
-      "citation": {
-        "authors": [
-          "Li HL",
-          "Liu YH",
-          "Wang JZ",
-          "Wang Q",
-          "Xu YF",
-          "Yin J",
-          "Zhang YJ"
-        ],
-        "date": "2006-07-01",
-        "first": "Zhang YJ",
-        "last": "Wang JZ",
-        "name": "FASEB journal : official publication of the Federation of American Societies for Experimental Biology",
-        "pages": "1431-42",
-        "reference": "16816118",
-        "title": "Peroxynitrite induces Alzheimer-like tau modifications and accumulation in rat brain and its underlying mechanisms.",
-        "type": "PubMed",
-        "volume": "20"
-      },
-      "evidence": "In the present study we injected bilaterally 3-morpholino-sydnonimine (SIN-1), a recognized and widely used peroxynitrite donor (25–30), into rat hippocampus, and investigated whether or not peroxynitrite could induce simultaneously nitration and hyperphosphorylation of tau and the underlying mechanisms in vivo. The level of nitrated and hyperphosphorylated tau was markedly increased in rat hippocampus 24 h, and prevented by preinjection of uric acid, a natural scavenger of peroxynitrite. GSK-3beta and p38 MAPKs, including p38alpha, p38beta, and p38delta activity was increased, but no change in the activity of p38gamma, ERK, and c-Jun amino-terminal kinase (JNK). Both nitrated tau and hyperphosphorylated tau were aggregated in the hippocampus, with activity of 20S proteasome significantly arrested in SIN-1-injected rats. Hyperphosphorylated tau was degraded as efficiently as normal tau by 20S proteasome, but the nitrated tau with an unorderly secondary structure became more resistant to the proteolysis, providing evidence that peroxynitrite simultaneously induces tau hyperphosphorylation, nitration, and accumulation, and that activation of GSK-3beta, p38alpha, p38beta, p38delta isoforms and the inhibition of proteasome activity are respectively responsible for the peroxynitrite-induced tau hyperphosphorylation and accumulation.",
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-    {
       "citation": {
         "authors": [
           "Berry RW",
@@ -27474,14 +31737,19 @@
         "type": "PubMed",
         "volume": "45"
       },
-      "evidence": "During Abeta-associated inflammation, reactive nitrogen and oxygen species are generated that can cause neuronal dysfunction and death (34-37). Prevalent among these species is peroxynitrite (ONOO-)",
-      "key": "c0236a96f442302ed86b70e47463bcc5afe9012acc22675c3c38d3625ec362a4fcf8e985518e86468cdced12739fe3155882d511554e552aff0cdb98b2b0e0b1",
-      "line": 903,
-      "relation": "increases",
-      "source": 184,
-      "target": 64
+      "evidence": "Select nitration of residues Tyr18, Tyr29, Tyr197, and Tyr394, events known to stabilize the pathological Alz-50 conformation inhibits the ability of monomeric tau to promote tubulin assembly, effect specific for the 3-NT modification, as mutant tau proteins pseudophosphorylated at each Tyr residue are fully competent to stabilize MTs, suggesting that ONOO(-)-mediated modifications stabilize tau filaments via 3,3'-DT bonding and destabilize MTs by site-selective nitration of tau monomers.",
+      "key": "dd830ffeacbcfab4fd4973197bd3b71c5037f612306121e0fef890ab34b792bad06c33cac3572cef431dfc8c21e005d6a862f81ca5910dbf8c690f740d861705",
+      "line": 1097,
+      "relation": "positiveCorrelation",
+      "source": 127,
+      "target": 604
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "Berry RW",
@@ -27501,12 +31769,17 @@
       },
       "evidence": "Select nitration of residues Tyr18, Tyr29, Tyr197, and Tyr394, events known to stabilize the pathological Alz-50 conformation inhibits the ability of monomeric tau to promote tubulin assembly, effect specific for the 3-NT modification, as mutant tau proteins pseudophosphorylated at each Tyr residue are fully competent to stabilize MTs, suggesting that ONOO(-)-mediated modifications stabilize tau filaments via 3,3'-DT bonding and destabilize MTs by site-selective nitration of tau monomers.",
       "key": "6e2b5369717c8f28489cdf71fbe551d1b2f2778589820fc6e282577fb3c2f9230feea873ac0186cd4e3bf38fe2eadd4e40cd9046e2e2db723bc823dbbd801553",
-      "line": 912,
+      "line": 1096,
       "relation": "positiveCorrelation",
-      "source": 131,
-      "target": 518
+      "source": 127,
+      "target": 602
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "Berry RW",
@@ -27525,13 +31798,18 @@
         "volume": "45"
       },
       "evidence": "Select nitration of residues Tyr18, Tyr29, Tyr197, and Tyr394, events known to stabilize the pathological Alz-50 conformation inhibits the ability of monomeric tau to promote tubulin assembly, effect specific for the 3-NT modification, as mutant tau proteins pseudophosphorylated at each Tyr residue are fully competent to stabilize MTs, suggesting that ONOO(-)-mediated modifications stabilize tau filaments via 3,3'-DT bonding and destabilize MTs by site-selective nitration of tau monomers.",
-      "key": "dd830ffeacbcfab4fd4973197bd3b71c5037f612306121e0fef890ab34b792bad06c33cac3572cef431dfc8c21e005d6a862f81ca5910dbf8c690f740d861705",
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+      "line": 1098,
       "relation": "positiveCorrelation",
-      "source": 131,
-      "target": 520
+      "source": 127,
+      "target": 603
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "Berry RW",
@@ -27550,13 +31828,18 @@
         "volume": "45"
       },
       "evidence": "Select nitration of residues Tyr18, Tyr29, Tyr197, and Tyr394, events known to stabilize the pathological Alz-50 conformation inhibits the ability of monomeric tau to promote tubulin assembly, effect specific for the 3-NT modification, as mutant tau proteins pseudophosphorylated at each Tyr residue are fully competent to stabilize MTs, suggesting that ONOO(-)-mediated modifications stabilize tau filaments via 3,3'-DT bonding and destabilize MTs by site-selective nitration of tau monomers.",
-      "key": "399fe5e756e4d08847f337abb5ed4911291c4878f043ed8f1e130ef1bcc6882cde293beb9da73f9f0bbed7a27a0399f7535564a4e2d595454e605ca414b565a8",
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+      "line": 1099,
       "relation": "positiveCorrelation",
-      "source": 131,
-      "target": 519
+      "source": 127,
+      "target": 605
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "Berry RW",
@@ -27575,24 +31858,63 @@
         "volume": "45"
       },
       "evidence": "Select nitration of residues Tyr18, Tyr29, Tyr197, and Tyr394, events known to stabilize the pathological Alz-50 conformation inhibits the ability of monomeric tau to promote tubulin assembly, effect specific for the 3-NT modification, as mutant tau proteins pseudophosphorylated at each Tyr residue are fully competent to stabilize MTs, suggesting that ONOO(-)-mediated modifications stabilize tau filaments via 3,3'-DT bonding and destabilize MTs by site-selective nitration of tau monomers.",
-      "key": "469248073c9e6dec273cf73c33da1eeaae50bc17b04b9309be2a135c8893355151011439077c53cc74c6f1e6433a13bba692f2937f295f84f0b4e217581dadde",
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+      "key": "c5c3e477e6b88a25b33428325b854dd2734a69922cc87b0a025fd6cedc620df992c6b61b1fa6834525038d45e9cc3700e15389a30abf06359fc71cd94db10338",
+      "line": 1109,
       "relation": "positiveCorrelation",
-      "source": 131,
-      "target": 521
+      "source": 127,
+      "target": 102
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
-          "Biernat J",
-          "Mandelkow E",
-          "Mandelkow EM",
-          "Schweers O"
+          "Hosomi N",
+          "Izumi Y",
+          "Maruyama H",
+          "Matsumoto M",
+          "Miyazaki Y",
+          "Nakamori M",
+          "Nishikawa T",
+          "Takahashi T"
         ],
-        "date": "1995-08-29",
-        "first": "Schweers O",
-        "last": "Mandelkow E",
-        "name": "Proceedings of the National Academy of Sciences of the United States of America",
+        "date": "2016-12-01",
+        "first": "Nishikawa T",
+        "last": "Matsumoto M",
+        "name": "Neuropathology and applied neurobiology",
+        "pages": "639-653",
+        "reference": "26501932",
+        "title": "The identification of raft-derived tau-associated vesicles that are incorporated into immature tangles and paired helical filaments.",
+        "type": "PubMed",
+        "volume": "42"
+      },
+      "evidence": "Pretangles contained either paired helical filaments (PHFs) or PtdIns(4,5)P2-immunopositive small vesicles (approximately 1 µm in diameter) with nearly identical topology to granulovacuolar degeneration (GVD) bodies. Various combinations of these vesicles and GVD bodies, the latter of which are pathological hallmarks observed within the neurons of AD patients, were found concurrently in neurons.These vesicles and GVD bodies were both immunopositive not only for PtdIns(4,5)P2, but also for several tau kinases such as glycogen synthase kinase-3ß and spleen tyrosine kinase.",
+      "key": "f3bfecdfdc652ce593744a73d7529f5dee36d4f623ccf4995489a2645e94d1791e939f091b1add8689ced9ef1e9c0e4dd17c2cfa802114590bad6c56b307f01d",
+      "line": 2729,
+      "relation": "partOf",
+      "source": 127,
+      "target": 139
+    },
+    {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Biernat J",
+          "Mandelkow E",
+          "Mandelkow EM",
+          "Schweers O"
+        ],
+        "date": "1995-08-29",
+        "first": "Schweers O",
+        "last": "Mandelkow E",
+        "name": "Proceedings of the National Academy of Sciences of the United States of America",
         "pages": "8463-7",
         "reference": "7667312",
         "title": "Oxidation of cysteine-322 in the repeat domain of microtubule-associated protein tau controls the in vitro assembly of paired helical filaments.",
@@ -27601,12 +31923,17 @@
       },
       "evidence": "Though whole tau assembled poorly, constructs containing three internal repeats (corresponding to the fetal tau isoform) formed PHFs reproducibly. This ability depended on intermolecular disulfide bridges formed by the single Cys-322. Blocking the SH group, mutating Cys for Ala, or keeping T in a reducing environment all inhibited assembly. On the other hand, Cys-322 can be oxidized, and this leads to PHF assembly (ref. 11; this report). In vitro this is achieved most easily by using constructs of the 'fetal' isoform of T (htau23) that has only three repeats. Conversely, reducing agents or the second repeat or T can be viewed as 'antidotes' against PHF assembly.The synthetic PHFs bound the dye thioflavin S used in Alzheimer disease diagnostics.",
       "key": "8eee2de7a12070b042ba5329a560e1a560c78157b3741e4dd8133098fd75f6124c8f3d01cd0ea50dbe75d6334ce0556bf5ce3c6030d2887bf59c14e75fa2b711",
-      "line": 2928,
+      "line": 3594,
       "relation": "positiveCorrelation",
-      "source": 131,
-      "target": 119
+      "source": 127,
+      "target": 120
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Biernat J",
@@ -27626,12 +31953,17 @@
       },
       "evidence": "Though whole tau assembled poorly, constructs containing three internal repeats (corresponding to the fetal tau isoform) formed PHFs reproducibly. This ability depended on intermolecular disulfide bridges formed by the single Cys-322. Blocking the SH group, mutating Cys for Ala, or keeping T in a reducing environment all inhibited assembly. On the other hand, Cys-322 can be oxidized, and this leads to PHF assembly (ref. 11; this report). In vitro this is achieved most easily by using constructs of the 'fetal' isoform of T (htau23) that has only three repeats. Conversely, reducing agents or the second repeat or T can be viewed as 'antidotes' against PHF assembly.The synthetic PHFs bound the dye thioflavin S used in Alzheimer disease diagnostics.",
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+        }
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       "citation": {
         "authors": [
           "Hasegawa M",
@@ -27653,12 +31985,17 @@
       },
       "evidence": "Ubiquitination occurs at lysines (K254, K257 K311) in repeat domain; participates in triage process",
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     {
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       "citation": {
         "authors": [
           "Hasegawa M",
@@ -27680,12 +32017,17 @@
       },
       "evidence": "Ubiquitination occurs at lysines (K254, K257 K311) in repeat domain; participates in triage process",
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       "citation": {
         "authors": [
           "Hasegawa M",
@@ -27707,1478 +32049,1354 @@
       },
       "evidence": "Ubiquitination occurs at lysines (K254, K257 K311) in repeat domain; participates in triage process",
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     {
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+        "Disease": {
+          "Alzheimer's disease": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        }
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       "citation": {
         "authors": [
-          "Ip NY",
-          "Lai KO",
-          "Liang Z",
-          "Plattner F",
-          "Shen Y",
-          "Wong CC",
-          "Yates JR 3rd",
-          "Zhan Y"
+          "Berry RW",
+          "Bigio EH",
+          "Binder LI",
+          "Fu Y",
+          "Guillozet-Bongaarts AL",
+          "Reyes JF",
+          "Reynolds MR"
         ],
-        "date": "2016-10-31",
-        "first": "Liang Z",
-        "last": "Ip NY",
-        "name": "Nature communications",
-        "pages": "13282",
-        "reference": "27796283",
-        "title": "The pseudokinase CaMKv is required for the activity-dependent maintenance of dendritic spines.",
+        "date": "2006-10-18",
+        "first": "Reynolds MR",
+        "last": "Binder LI",
+        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
+        "pages": "10636-45",
+        "reference": "17050703",
+        "title": "Tau nitration occurs at tyrosine 29 in the fibrillar lesions of Alzheimer's disease and other tauopathies.",
         "type": "PubMed",
-        "volume": "7"
-      },
-      "evidence": "Rac1 and RhoA are the best-studied members that regulate spine dynamics; their activation facilitates and prevents dendritic spine formation, respectively",
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+      "evidence": "Tau-nY29 detects soluble tau and paired helical filament tau from severely affected Alzheimer's brain but fails to recognize tau from normal aged brain. This observation suggests that nitration at Tyr29 is a disease-related event that may alter the intrinsic ability of tau to self-polymerize. In Alzheimer's brain, Tau-nY29 labels the fibrillar triad of tau lesions, including neurofibrillary tangles, neuritic plaques, and, to a lesser extent, neuropil threads. Intriguingly, although Tau-nY29 stains both the neuronal and glial tau pathology of Pick disease, it detects only the neuronal pathology in corticobasal degeneration and progressive supranuclear palsy without labeling the predominant glial pathology.",
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     {
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       "citation": {
         "authors": [
-          "Ip NY",
-          "Lai KO",
-          "Liang Z",
-          "Plattner F",
-          "Shen Y",
-          "Wong CC",
-          "Yates JR 3rd",
-          "Zhan Y"
+          "Cappelletti G",
+          "Grassi E",
+          "Negri A",
+          "Nonnis S",
+          "Ronchi C",
+          "Ronchi S",
+          "Taverna F",
+          "Tedeschi G"
         ],
-        "date": "2016-10-31",
-        "first": "Liang Z",
-        "last": "Ip NY",
-        "name": "Nature communications",
-        "pages": "13282",
-        "reference": "27796283",
-        "title": "The pseudokinase CaMKv is required for the activity-dependent maintenance of dendritic spines.",
+        "date": "2008-03-01",
+        "first": "Nonnis S",
+        "last": "Tedeschi G",
+        "name": "Neurochemical research",
+        "pages": "518-25",
+        "reference": "17768677",
+        "title": "Tau is endogenously nitrated in mouse brain: identification of a tyrosine residue modified in vivo by NO.",
         "type": "PubMed",
-        "volume": "7"
-      },
-      "evidence": "In contrast, much less is known about how RhoA is regulated by excitatory glutamate receptors. The Rho-GEF Lfc (also known as GEF-H1) is one notable link between RhoA activity and glutamate receptors18. Lfc is inhibited by AMPA receptors; Lfc and RhoA inhibition is implicated in spine maintenance10. RhoA hyperactivity can lead to spine loss and impaired synaptic function.",
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       },
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+      "evidence": "It was possible to find nitrated Tyr 488 (numbers refer to mouse tau P10637 in the Swiss-Prot/ThEMBL data bank) which corresponds to Tyr 507 in rat tau (Table 1) in accordance with the data reported above for tau in PC12 cells.",
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-          "Plattner F",
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-          "Yates JR 3rd",
-          "Zhan Y"
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-        "first": "Liang Z",
-        "last": "Ip NY",
-        "name": "Nature communications",
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-        "title": "The pseudokinase CaMKv is required for the activity-dependent maintenance of dendritic spines.",
-        "type": "PubMed",
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-      "evidence": "These observations suggest that CaMKv blocks RhoA activity by preventing its interaction with Lfc. These results demonstrate that CaMKv regulates spine maintenance through RhoA inhibition. The suppression of the Lfc/RhoA pathway by AMPA receptors is implicated in dendritic spine maintenance10. Given that CaMKv expression is upregulated by synaptic activity, CaMKv may be a key signalling protein that transduces the signals from AMPA receptors to suppress RhoA during activity-dependent spine maintenance. Corroborating this, the AMPA receptor blocker NBQX attenuated CaMKv expression in neurons (Fig. 3i,j). Importantly, CaMKv overexpression completely rescued NBQX-induced spine loss (Fig. 3k,l). These findings collectively reveal that activity-dependent CaMKv expression and the subsequent inhibition of Lfc/RhoA are required to mediate AMPA receptor function in spine maintenance.",
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-      "evidence": "In contrast, much less is known about how RhoA is regulated by excitatory glutamate receptors. The Rho-GEF Lfc (also known as GEF-H1) is one notable link between RhoA activity and glutamate receptors18. Lfc is inhibited by AMPA receptors; Lfc and RhoA inhibition is implicated in spine maintenance10. RhoA hyperactivity can lead to spine loss and impaired synaptic function.",
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-        "title": "The pseudokinase CaMKv is required for the activity-dependent maintenance of dendritic spines.",
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     {
       "annotations": {
         "Anatomy": {
           "hippocampal formation": true
         },
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       "citation": {
         "authors": [
-          "Boehm J",
-          "Bourgeois C",
-          "Dudilot A",
-          "Lauzon M",
-          "Leclerc N",
-          "Mondragón-Rodríguez S",
-          "Trillaud-Doppia E"
+          "Li HL",
+          "Liu YH",
+          "Wang JZ",
+          "Wang Q",
+          "Xu YF",
+          "Yin J",
+          "Zhang YJ"
         ],
-        "date": "2012-09-14",
-        "first": "Mondragón-Rodríguez S",
-        "last": "Boehm J",
-        "name": "The Journal of biological chemistry",
-        "pages": "32040-53",
-        "reference": "22833681",
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-          "Lai KO",
-          "Liang Z",
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-          "Shen Y",
-          "Wong CC",
-          "Yates JR 3rd",
-          "Zhan Y"
+          "Boutillier AL",
+          "Bradke F",
+          "Di Giovanni S",
+          "Gaub P",
+          "Hervera A",
+          "Joshi Y",
+          "Laskowski CJ",
+          "Lindner R",
+          "Nguyen T",
+          "Puttagunta R",
+          "Rathore KI",
+          "Schmandke A",
+          "Sória MG",
+          "Tedeschi A"
         ],
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-        "first": "Liang Z",
-        "last": "Ip NY",
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         "name": "Nature communications",
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-        "reference": "27796283",
-        "title": "The pseudokinase CaMKv is required for the activity-dependent maintenance of dendritic spines.",
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         "type": "PubMed",
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-          "Lai KO",
-          "Liang Z",
-          "Plattner F",
-          "Shen Y",
-          "Wong CC",
-          "Yates JR 3rd",
-          "Zhan Y"
+          "Arzberger T",
+          "Banzhaf-Strathmann J",
+          "Benito E",
+          "Edbauer D",
+          "Fischer A",
+          "Kretzschmar H",
+          "May S",
+          "Tahirovic S"
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-        "first": "Liang Z",
-        "last": "Ip NY",
-        "name": "Nature communications",
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-        "title": "The pseudokinase CaMKv is required for the activity-dependent maintenance of dendritic spines.",
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-        "name": "Nature communications",
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-        "title": "The pseudokinase CaMKv is required for the activity-dependent maintenance of dendritic spines.",
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-        "name": "Nature communications",
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-        "reference": "27796283",
-        "title": "The pseudokinase CaMKv is required for the activity-dependent maintenance of dendritic spines.",
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-          "Liang Z",
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-          "Yates JR 3rd",
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-        "first": "Liang Z",
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-        "reference": "27796283",
-        "title": "The pseudokinase CaMKv is required for the activity-dependent maintenance of dendritic spines.",
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       "citation": {
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-          "Gong CX",
-          "Grundke-Iqbal I",
-          "Iqbal K",
-          "Liang Z",
-          "Liu F",
-          "Shi J",
-          "Yin D"
+          "Berry RW",
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-        "title": "PKA modulates GSK-3beta- and cdk5-catalyzed phosphorylation of tau in site- and kinase-specific manners.",
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         "type": "PubMed",
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-          "Iqbal K",
-          "Liang Z",
-          "Liu F",
-          "Shi J",
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-        "title": "PKA modulates GSK-3beta- and cdk5-catalyzed phosphorylation of tau in site- and kinase-specific manners.",
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+        "title": "Peroxynitrite-mediated tau modifications stabilize preformed filaments and destabilize microtubules through distinct mechanisms.",
         "type": "PubMed",
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-      "evidence": "Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396.",
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       "citation": {
         "authors": [
-          "El-Akkad E",
-          "Gong CX",
-          "Grundke-Iqbal I",
-          "Iqbal K",
-          "Liang Z",
-          "Liu F",
-          "Shi J",
-          "Yin D"
+          "Babić Leko M",
+          "Bažadona D",
+          "Buée L",
+          "Delalle I",
+          "Di Giovanni G",
+          "Harrington C",
+          "Hof PR",
+          "Jovanov-Milošević N",
+          "Wischik C",
+          "Wray S",
+          "de Silva R",
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-        "title": "PKA modulates GSK-3beta- and cdk5-catalyzed phosphorylation of tau in site- and kinase-specific manners.",
+        "date": "2016-01-06",
+        "first": "Šimić G",
+        "last": "Hof PR",
+        "name": "Biomolecules",
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         "type": "PubMed",
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-          "Iqbal K",
-          "Liang Z",
-          "Liu F",
-          "Shi J",
-          "Yin D"
+          "Berry RW",
+          "Binder LI",
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-        "first": "Liu F",
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-        "title": "PKA modulates GSK-3beta- and cdk5-catalyzed phosphorylation of tau in site- and kinase-specific manners.",
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+        "pages": "4314-26",
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+        "title": "Peroxynitrite-mediated tau modifications stabilize preformed filaments and destabilize microtubules through distinct mechanisms.",
         "type": "PubMed",
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     {
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       "citation": {
         "authors": [
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-          "Gong CX",
-          "Grundke-Iqbal I",
-          "Iqbal K",
-          "Liang Z",
-          "Liu F",
-          "Shi J",
-          "Yin D"
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+          "Hof PR",
+          "Jovanov-Milošević N",
+          "Wischik C",
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-        "first": "Liu F",
-        "last": "Gong CX",
-        "name": "FEBS letters",
-        "pages": "6269-74",
-        "reference": "17078951",
-        "title": "PKA modulates GSK-3beta- and cdk5-catalyzed phosphorylation of tau in site- and kinase-specific manners.",
+        "date": "2016-01-06",
+        "first": "Šimić G",
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         "type": "PubMed",
-        "volume": "580"
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-          "Gong CX",
-          "Grundke-Iqbal I",
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-          "Liang Z",
-          "Liu F",
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-        "first": "Liu F",
-        "last": "Gong CX",
-        "name": "FEBS letters",
-        "pages": "6269-74",
-        "reference": "17078951",
-        "title": "PKA modulates GSK-3beta- and cdk5-catalyzed phosphorylation of tau in site- and kinase-specific manners.",
-        "type": "PubMed",
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-      },
-      "evidence": "Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396.",
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-      "line": 1139,
-      "relation": "increases",
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-      "subject": {
-        "modifier": "Activity"
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+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Neurons": true
+        }
       },
-      "target": 229
-    },
-    {
       "citation": {
         "authors": [
-          "El-Akkad E",
-          "Gong CX",
-          "Grundke-Iqbal I",
-          "Iqbal K",
-          "Liang Z",
-          "Liu F",
-          "Shi J",
-          "Yin D"
+          "Ait-Ghezala G",
+          "Beaulieu-Abdelahad D",
+          "Crawford F",
+          "Mouzon B",
+          "Mullan M",
+          "Paris D",
+          "Schweig JE",
+          "Yao H"
         ],
-        "date": "2006-11-13",
-        "first": "Liu F",
-        "last": "Gong CX",
-        "name": "FEBS letters",
-        "pages": "6269-74",
-        "reference": "17078951",
-        "title": "PKA modulates GSK-3beta- and cdk5-catalyzed phosphorylation of tau in site- and kinase-specific manners.",
+        "date": "2017-09-06",
+        "first": "Schweig JE",
+        "last": "Paris D",
+        "name": "Acta neuropathologica communications",
+        "pages": "69",
+        "reference": "28877763",
+        "title": "Alzheimer's disease pathological lesions activate the spleen tyrosine kinase.",
         "type": "PubMed",
-        "volume": "580"
-      },
-      "evidence": "Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396.",
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-      "line": 1141,
-      "relation": "increases",
-      "source": 400,
-      "subject": {
-        "modifier": "Activity"
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       },
-      "target": 232
+      "evidence": "We found an increase in Syk activation in DNs surrounding Aβ deposits as well as in neurons displaying an accumulation of phosphorylated Tau at Y18 and elevated levels of MC1 pathogenic tau conformers in AD brain sections whereas only weak immunoreactivity for pSyk was observed in brain sections from a non-demented control",
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     {
-      "citation": {
-        "authors": [
-          "El-Akkad E",
-          "Gong CX",
-          "Grundke-Iqbal I",
-          "Iqbal K",
-          "Liang Z",
-          "Liu F",
-          "Shi J",
-          "Yin D"
-        ],
-        "date": "2006-11-13",
-        "first": "Liu F",
-        "last": "Gong CX",
-        "name": "FEBS letters",
-        "pages": "6269-74",
-        "reference": "17078951",
-        "title": "PKA modulates GSK-3beta- and cdk5-catalyzed phosphorylation of tau in site- and kinase-specific manners.",
-        "type": "PubMed",
-        "volume": "580"
-      },
-      "evidence": "Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396.",
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-      "line": 1143,
-      "relation": "increases",
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-      "subject": {
-        "modifier": "Activity"
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       },
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-    {
       "citation": {
         "authors": [
-          "El-Akkad E",
-          "Gong CX",
-          "Grundke-Iqbal I",
-          "Iqbal K",
-          "Liang Z",
-          "Liu F",
-          "Shi J",
-          "Yin D"
+          "Berry RW",
+          "Binder LI",
+          "Lukas TJ",
+          "Reynolds MR"
         ],
-        "date": "2006-11-13",
-        "first": "Liu F",
-        "last": "Gong CX",
-        "name": "FEBS letters",
-        "pages": "6269-74",
-        "reference": "17078951",
-        "title": "PKA modulates GSK-3beta- and cdk5-catalyzed phosphorylation of tau in site- and kinase-specific manners.",
+        "date": "2006-04-04",
+        "first": "Reynolds MR",
+        "last": "Binder LI",
+        "name": "Biochemistry",
+        "pages": "4314-26",
+        "reference": "16566606",
+        "title": "Peroxynitrite-mediated tau modifications stabilize preformed filaments and destabilize microtubules through distinct mechanisms.",
         "type": "PubMed",
-        "volume": "580"
-      },
-      "evidence": "Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396.",
-      "key": "fe4badff6fcb23f84c4f8ec776ffe172e234658619f96a004da6d39de48cba0bd4597c09ddd87e4f0244de63a897c5100a3a6a63d41875cd27c13b6922777a5d",
-      "line": 1145,
-      "relation": "increases",
-      "source": 400,
-      "subject": {
-        "modifier": "Activity"
+        "volume": "45"
       },
-      "target": 231
+      "evidence": "Select nitration of residues Tyr18, Tyr29, Tyr197, and Tyr394, events known to stabilize the pathological Alz-50 conformation inhibits the ability of monomeric tau to promote tubulin assembly, effect specific for the 3-NT modification, as mutant tau proteins pseudophosphorylated at each Tyr residue are fully competent to stabilize MTs, suggesting that ONOO(-)-mediated modifications stabilize tau filaments via 3,3'-DT bonding and destabilize MTs by site-selective nitration of tau monomers.",
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     {
+      "annotations": {
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+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
-          "El-Akkad E",
-          "Gong CX",
-          "Grundke-Iqbal I",
-          "Iqbal K",
-          "Liang Z",
-          "Liu F",
-          "Shi J",
-          "Yin D"
+          "Berry RW",
+          "Binder LI",
+          "Lukas TJ",
+          "Reynolds MR"
         ],
-        "date": "2006-11-13",
-        "first": "Liu F",
-        "last": "Gong CX",
-        "name": "FEBS letters",
-        "pages": "6269-74",
-        "reference": "17078951",
-        "title": "PKA modulates GSK-3beta- and cdk5-catalyzed phosphorylation of tau in site- and kinase-specific manners.",
+        "date": "2006-04-04",
+        "first": "Reynolds MR",
+        "last": "Binder LI",
+        "name": "Biochemistry",
+        "pages": "4314-26",
+        "reference": "16566606",
+        "title": "Peroxynitrite-mediated tau modifications stabilize preformed filaments and destabilize microtubules through distinct mechanisms.",
         "type": "PubMed",
-        "volume": "580"
-      },
-      "evidence": "Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396.",
-      "key": "2f8946f37adac25000a2d256b271588b1e3fc63025e92e7611dbc27149681c16472b9d9d2f5f66cd1ca4af7783b657c0cdf6f44dea6af68eccf6b1167d26654b",
-      "line": 1147,
-      "relation": "increases",
-      "source": 400,
-      "subject": {
-        "modifier": "Activity"
+        "volume": "45"
       },
-      "target": 230
+      "evidence": "Select nitration of residues Tyr18, Tyr29, Tyr197, and Tyr394, events known to stabilize the pathological Alz-50 conformation inhibits the ability of monomeric tau to promote tubulin assembly, effect specific for the 3-NT modification, as mutant tau proteins pseudophosphorylated at each Tyr residue are fully competent to stabilize MTs, suggesting that ONOO(-)-mediated modifications stabilize tau filaments via 3,3'-DT bonding and destabilize MTs by site-selective nitration of tau monomers.",
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+      "line": 1106,
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     },
     {
       "annotations": {
-        "Duration": {
-          "2 hours": true
-        },
-        "Substrate_Concentration": {
-          "0.5 M": true
+        "Confidence": {
+          "Medium": true
         }
       },
       "citation": {
         "authors": [
-          "Ishiguro K",
-          "Kusubata M",
-          "Matsubara M",
-          "Taniguchi H",
-          "Titani K",
-          "Uchida T"
+          "Cowburn RF",
+          "Dahllund L",
+          "Gustafsson E",
+          "Lund H",
+          "Malinowsky D",
+          "Strömberg K",
+          "Sunnemark D",
+          "Svensson A"
         ],
-        "date": "1996-08-30",
-        "first": "Matsubara M",
-        "last": "Taniguchi H",
-        "name": "The Journal of biological chemistry",
-        "pages": "21108-13",
-        "reference": "8702879",
-        "title": "Site-specific phosphorylation of synapsin I by mitogen-activated protein kinase and Cdk5 and its effects on physiological functions.",
+        "date": "2013-07-01",
+        "first": "Lund H",
+        "last": "Sunnemark D",
+        "name": "Brain pathology (Zurich, Switzerland)",
+        "pages": "378-89",
+        "reference": "23088643",
+        "title": "Tau-tubulin kinase 1 expression, phosphorylation and co-localization with phospho-Ser422 tau in the Alzheimer's disease brain.",
         "type": "PubMed",
-        "volume": "271"
-      },
-      "evidence": "The phosphorylation sites were determined to be Ser551 and Ser553 with Cdk5-p23, and Ser62, Ser67, and Ser551 with MAP kinase. Upon phosphorylation with MAP kinase, synapsin I showed reduced F-actin bundling activity, while no significant effect on the interaction was observed with the protein phosphorylated with Cdk5-p23.",
-      "key": "4bdd2cedfc76ae3612c6cee85dcc078fb6785c4417fdb658fde22bf40ee4e700e71840eb468451170fac078abdc62657b2e2a45cec271965156ce58ab8313d16",
-      "line": 1211,
-      "relation": "increases",
-      "source": 400,
-      "subject": {
-        "modifier": "Activity"
+        "volume": "23"
       },
-      "target": 708
+      "evidence": "TTBK1 has been shown, by partial phosphopeptide mapping, to phosphorylate tau at serine residues 198, 199, 202 and 422 and at tyrosine 197 in vitro, sites that are also phosphorylated in AD PHFs (7, 12)",
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+      "line": 1546,
+      "relation": "positiveCorrelation",
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     },
     {
       "annotations": {
-        "Duration": {
-          "2 hours": true
+        "Confidence": {
+          "Medium": true
         },
-        "Substrate_Concentration": {
-          "0.5 M": true
+        "MeSHAnatomy": {
+          "Brain": true
+        },
+        "MeSHDisease": {
+          "Alzheimer Disease": true
         }
       },
       "citation": {
         "authors": [
-          "Ishiguro K",
-          "Kusubata M",
-          "Matsubara M",
-          "Taniguchi H",
-          "Titani K",
-          "Uchida T"
+          "Babić Leko M",
+          "Bažadona D",
+          "Buée L",
+          "Delalle I",
+          "Di Giovanni G",
+          "Harrington C",
+          "Hof PR",
+          "Jovanov-Milošević N",
+          "Wischik C",
+          "Wray S",
+          "de Silva R",
+          "Šimić G"
         ],
-        "date": "1996-08-30",
-        "first": "Matsubara M",
-        "last": "Taniguchi H",
-        "name": "The Journal of biological chemistry",
-        "pages": "21108-13",
-        "reference": "8702879",
-        "title": "Site-specific phosphorylation of synapsin I by mitogen-activated protein kinase and Cdk5 and its effects on physiological functions.",
+        "date": "2016-01-06",
+        "first": "Šimić G",
+        "last": "Hof PR",
+        "name": "Biomolecules",
+        "pages": "6",
+        "reference": "26751493",
+        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
         "type": "PubMed",
-        "volume": "271"
-      },
-      "evidence": "The phosphorylation sites were determined to be Ser551 and Ser553 with Cdk5-p23, and Ser62, Ser67, and Ser551 with MAP kinase. Upon phosphorylation with MAP kinase, synapsin I showed reduced F-actin bundling activity, while no significant effect on the interaction was observed with the protein phosphorylated with Cdk5-p23.",
-      "key": "1b7a9f6c27967f4a70d4d5990ab8226b90f1e0c8632163c67d8b2a9fb07c7a92f0e233e8c81eb22cd7e7ebfebe634c6a969574b855ae980c88f14448aa41fc32",
-      "line": 1212,
-      "relation": "increases",
-      "source": 400,
-      "subject": {
-        "modifier": "Activity"
+        "volume": "6"
       },
-      "target": 709
+      "evidence": "3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain.",
+      "key": "4cf017f9f7181d44b7eb217ad0fa36d664d0bb190a4587fbaffc1cf4ff2a3eff4a327e06ef6a6d49ea9854dcadf639312197d7a36f8f39084bceb9e316043b46",
+      "line": 1917,
+      "relation": "positiveCorrelation",
+      "source": 674,
+      "target": 1017
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
-          "Ai J",
-          "Ban T",
-          "Bao YN",
-          "Chen QX",
-          "Hu XL",
-          "Jiang XM",
-          "Liu CD",
-          "Pei SC",
-          "Su XL",
-          "Sun LH",
-          "Sun LL",
-          "Wang X",
-          "Yan ML",
-          "Zhao LJ",
-          "Zong DK"
+          "Berry RW",
+          "Binder LI",
+          "Lukas TJ",
+          "Reynolds MR"
         ],
-        "date": "2015-09-01",
-        "first": "Sun LH",
-        "last": "Ai J",
-        "name": "Journal of neurochemistry",
-        "pages": "1139-51",
-        "reference": "26118667",
-        "title": "Activation of Cdk5/p25 and tau phosphorylation following chronic brain hypoperfusion in rats involves microRNA-195 down-regulation.",
+        "date": "2006-04-04",
+        "first": "Reynolds MR",
+        "last": "Binder LI",
+        "name": "Biochemistry",
+        "pages": "4314-26",
+        "reference": "16566606",
+        "title": "Peroxynitrite-mediated tau modifications stabilize preformed filaments and destabilize microtubules through distinct mechanisms.",
         "type": "PubMed",
-        "volume": "134"
+        "volume": "45"
       },
-      "evidence": "To perform its function, Cdk5 must bind to the neuron-specific regulatory subunit protein p35, which is beneficial for neuronal development (Tsai et al. 1994; Chae et al. 1997). However, truncation of p35 and conversion to p25 (Patrick et al. 1999) is found in the forebrain of rats after focal cerebral ischemia and in AD patients, and these alterations are deleterious to the brain",
-      "key": "6313c481ac9459d16550f617ec63adc04e73b671cd77497d1c60700530ee6d6314fb2d09654eafe49dce1710f9b25919dd1be84bf12f0524ff4a03c460edc35c",
-      "line": 2298,
-      "relation": "increases",
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-      "target": 228
+      "evidence": "Select nitration of residues Tyr18, Tyr29, Tyr197, and Tyr394, events known to stabilize the pathological Alz-50 conformation inhibits the ability of monomeric tau to promote tubulin assembly, effect specific for the 3-NT modification, as mutant tau proteins pseudophosphorylated at each Tyr residue are fully competent to stabilize MTs, suggesting that ONOO(-)-mediated modifications stabilize tau filaments via 3,3'-DT bonding and destabilize MTs by site-selective nitration of tau monomers.",
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+      "line": 1109,
+      "relation": "positiveCorrelation",
+      "source": 102,
+      "target": 127
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
-          "Arzberger T",
-          "Banzhaf-Strathmann J",
-          "Benito E",
-          "Edbauer D",
-          "Fischer A",
-          "Kretzschmar H",
-          "May S",
-          "Tahirovic S"
+          "Ip NY",
+          "Lai KO",
+          "Liang Z",
+          "Plattner F",
+          "Shen Y",
+          "Wong CC",
+          "Yates JR 3rd",
+          "Zhan Y"
         ],
-        "date": "2014-08-01",
-        "first": "Banzhaf-Strathmann J",
-        "last": "Edbauer D",
-        "name": "The EMBO journal",
-        "pages": "1667-80",
-        "reference": "25001178",
-        "title": "MicroRNA-125b induces tau hyperphosphorylation and cognitive deficits in Alzheimer's disease.",
+        "date": "2016-10-31",
+        "first": "Liang Z",
+        "last": "Ip NY",
+        "name": "Nature communications",
+        "pages": "13282",
+        "reference": "27796283",
+        "title": "The pseudokinase CaMKv is required for the activity-dependent maintenance of dendritic spines.",
         "type": "PubMed",
-        "volume": "33"
+        "volume": "7"
       },
-      "evidence": "In primary neurons, overexpression of miR-125b causes tau hyperphosphorylation and an upregulation of p35, cdk5, and p44/42-MAPK signaling. In parallel, the phosphatases DUSP6 and PPP1CA and the anti-apoptotic factor Bcl-W are downregulated as direct targets of miR-125b. Knockdown of these phosphatases induces tau hyperphosphorylation, and overexpression of PPP1CA and Bcl-W prevents miR-125b-induced tau phosphorylation, suggesting that they mediate the effects of miR-125b on tau. Conversely, suppression of miR-125b in neurons by tough decoys reduces tau phosphorylation and kinase expression/activity. Injecting miR-125b into the hippocampus of mice impairs associative learning and is accompanied by downregulation of Bcl-W, DUSP6, and PPP1CA, resulting in increased tau phosphorylation in vivo. Importantly, DUSP6 and PPP1CA are also reduced in AD brains.",
-      "key": "286f291644eefdc8928d4e4da33dd76f5eb2926b41da1720603200d69fca7f6ef5335dc8f6bac39fefa738799012a983bfaebdef7f35b83996be9d0a21bc298b",
-      "line": 3903,
-      "relation": "directlyIncreases",
-      "source": 400,
+      "evidence": "Rac1 and RhoA are the best-studied members that regulate spine dynamics; their activation facilitates and prevents dendritic spine formation, respectively",
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+      "line": 1117,
+      "relation": "regulates",
+      "source": 762,
       "subject": {
-        "effect": {
-          "name": "kin",
-          "namespace": "bel"
-        },
         "modifier": "Activity"
       },
-      "target": 516
+      "target": 185
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
-          "Arzberger T",
-          "Banzhaf-Strathmann J",
-          "Benito E",
-          "Edbauer D",
-          "Fischer A",
-          "Kretzschmar H",
-          "May S",
-          "Tahirovic S"
+          "Ip NY",
+          "Lai KO",
+          "Liang Z",
+          "Plattner F",
+          "Shen Y",
+          "Wong CC",
+          "Yates JR 3rd",
+          "Zhan Y"
         ],
-        "date": "2014-08-01",
-        "first": "Banzhaf-Strathmann J",
-        "last": "Edbauer D",
-        "name": "The EMBO journal",
-        "pages": "1667-80",
-        "reference": "25001178",
-        "title": "MicroRNA-125b induces tau hyperphosphorylation and cognitive deficits in Alzheimer's disease.",
+        "date": "2016-10-31",
+        "first": "Liang Z",
+        "last": "Ip NY",
+        "name": "Nature communications",
+        "pages": "13282",
+        "reference": "27796283",
+        "title": "The pseudokinase CaMKv is required for the activity-dependent maintenance of dendritic spines.",
         "type": "PubMed",
-        "volume": "33"
+        "volume": "7"
       },
-      "evidence": "Since Erk1/2 activity has been shown to induce cdk5 (Harada et al, 2001), miR-125b-induced Erk1/2 activation through DUSP6 downregulation might ultimately stimulate aberrant cdk5/p35 activation and, consequently, enhance pathological tau phosphorylation at multiple sites",
-      "key": "9fbe4326cab7d2b3098ec7c4f71c8d6ad0319b5875cb88bfacd179a2e0d60ba17aa16cf4f8634e413e32c1597d57467f27c88bac7e3bdf1353558b0fc89c2238",
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+          "Lai KO",
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         "type": "PubMed",
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+          "Ip NY",
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         "type": "PubMed",
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-          "Farr SA",
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-          "Murphy MP",
-          "Niehoff ML",
-          "Platt TL",
-          "Ripley JL",
-          "Sultana R",
-          "Zhang Z"
+          "Boehm J",
+          "Bourgeois C",
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+          "Lauzon M",
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-        "title": "Antisense oligonucleotide against GSK-3β in brain of SAMP8 mice improves learning and memory and decreases oxidative stress: Involvement of transcription factor Nrf2 and implications for Alzheimer disease.",
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         "type": "PubMed",
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-      "evidence": "Nuclear factor erythroid-2-related factor 2 (Nrf2) is a transcription factor known to increase the level of many antioxidants, including glutathione-S transferase (GST), and is negatively regulated by the activity of GSK-3β. Our results indicated the increased nuclear localization of Nrf2 and level of GST, suggesting the increased activity of the transcription factor as a result of GSK-3β suppression, consistent with the decreased oxidative stress observed. Consistent with the improved learning and memory, and consistent with GSK-3b being a tau kinase, we observed decreased tau phosphorylation in brain of GAO-treated SAMP8 mice compared to that of RAO-treated SAMP8 mice.",
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         "type": "PubMed",
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       },
-      "evidence": "We studied underlying pathomechanisms in tauopathies using pR5 mice that express the P301L tau mutation found in familial forms of frontotemporal dementia. In a longitudinal study we investigated the functional status of glycogen synthase kinase-3 and correlated it with the appearance of distinct tau phospho-epitopes. Neurons displaying increases in activating phosphorylation of glycogen synthase kinase-3α/β at tyrosine 279/216 also showed an intense rather than moderate AT8 (phospho-Ser202/Thr205 tau) immunoreactivity, and immunoreactivity for AT100 (phospho-Ser212/Thr214 tau) and phosphorylated Ser422, phospho-epitopes associated with fibrillar tau pathology.",
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     {
       "annotations": {
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       },
       "citation": {
         "authors": [
-          "Dinekov M",
-          "Götz J",
-          "Köhler C"
+          "El-Akkad E",
+          "Gong CX",
+          "Grundke-Iqbal I",
+          "Iqbal K",
+          "Liang Z",
+          "Liu F",
+          "Shi J",
+          "Yin D"
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-        "first": "Köhler C",
-        "last": "Götz J",
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-        "pages": "1369-79",
-        "reference": "23294633",
-        "title": "Active glycogen synthase kinase-3 and tau pathology-related tyrosine phosphorylation in pR5 human tau transgenic mice.",
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+        "first": "Liu F",
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+        "name": "FEBS letters",
+        "pages": "6269-74",
+        "reference": "17078951",
+        "title": "PKA modulates GSK-3beta- and cdk5-catalyzed phosphorylation of tau in site- and kinase-specific manners.",
         "type": "PubMed",
-        "volume": "34"
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       },
-      "evidence": "We studied underlying pathomechanisms in tauopathies using pR5 mice that express the P301L tau mutation found in familial forms of frontotemporal dementia. In a longitudinal study we investigated the functional status of glycogen synthase kinase-3 and correlated it with the appearance of distinct tau phospho-epitopes. Neurons displaying increases in activating phosphorylation of glycogen synthase kinase-3α/β at tyrosine 279/216 also showed an intense rather than moderate AT8 (phospho-Ser202/Thr205 tau) immunoreactivity, and immunoreactivity for AT100 (phospho-Ser212/Thr214 tau) and phosphorylated Ser422, phospho-epitopes associated with fibrillar tau pathology.",
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     {
       "annotations": {
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       },
       "citation": {
         "authors": [
-          "Dinekov M",
-          "Götz J",
-          "Köhler C"
+          "El-Akkad E",
+          "Gong CX",
+          "Grundke-Iqbal I",
+          "Iqbal K",
+          "Liang Z",
+          "Liu F",
+          "Shi J",
+          "Yin D"
         ],
-        "date": "2013-05-01",
-        "first": "Köhler C",
-        "last": "Götz J",
-        "name": "Neurobiology of aging",
-        "pages": "1369-79",
-        "reference": "23294633",
-        "title": "Active glycogen synthase kinase-3 and tau pathology-related tyrosine phosphorylation in pR5 human tau transgenic mice.",
+        "date": "2006-11-13",
+        "first": "Liu F",
+        "last": "Gong CX",
+        "name": "FEBS letters",
+        "pages": "6269-74",
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+        "title": "PKA modulates GSK-3beta- and cdk5-catalyzed phosphorylation of tau in site- and kinase-specific manners.",
         "type": "PubMed",
-        "volume": "34"
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       },
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     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
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       "citation": {
         "authors": [
-          "Barghorn S",
-          "Biernat J",
-          "Li L",
-          "Mandelkow E",
-          "Mandelkow EM",
-          "Marx A",
-          "von Bergen M"
+          "El-Akkad E",
+          "Gong CX",
+          "Grundke-Iqbal I",
+          "Iqbal K",
+          "Liang Z",
+          "Liu F",
+          "Shi J",
+          "Yin D"
         ],
-        "date": "2001-12-21",
-        "first": "von Bergen M",
-        "last": "Mandelkow E",
-        "name": "The Journal of biological chemistry",
-        "pages": "48165-74",
-        "reference": "11606569",
-        "title": "Mutations of tau protein in frontotemporal dementia promote aggregation of paired helical filaments by enhancing local beta-structure.",
+        "date": "2006-11-13",
+        "first": "Liu F",
+        "last": "Gong CX",
+        "name": "FEBS letters",
+        "pages": "6269-74",
+        "reference": "17078951",
+        "title": "PKA modulates GSK-3beta- and cdk5-catalyzed phosphorylation of tau in site- and kinase-specific manners.",
         "type": "PubMed",
-        "volume": "276"
+        "volume": "580"
       },
-      "evidence": "We also show that two of the tau mutations found in hereditary frontotemporal dementias, DeltaK280 and P301L, have a much stronger tendency for PHF aggregation which correlates with their high propensity for beta-structure around the hexapeptide motifs.",
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-          "Barghorn S",
-          "Biernat J",
-          "Li L",
-          "Mandelkow E",
-          "Mandelkow EM",
-          "Marx A",
-          "von Bergen M"
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-        "date": "2001-12-21",
-        "first": "von Bergen M",
-        "last": "Mandelkow E",
-        "name": "The Journal of biological chemistry",
-        "pages": "48165-74",
-        "reference": "11606569",
-        "title": "Mutations of tau protein in frontotemporal dementia promote aggregation of paired helical filaments by enhancing local beta-structure.",
-        "type": "PubMed",
-        "volume": "276"
-      },
-      "evidence": "We also show that two of the tau mutations found in hereditary frontotemporal dementias, DeltaK280 and P301L, have a much stronger tendency for PHF aggregation which correlates with their high propensity for beta-structure around the hexapeptide motifs.",
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-          "Barton Whittle T",
-          "Castillo-Carranza DL",
-          "English KC",
-          "Gerson JE",
-          "Gupta P",
-          "Kayed R",
-          "Nicolas Crain C",
-          "Nilson AN",
-          "Sengupta U",
-          "Xue J",
-          "Zhang W"
-        ],
-        "date": "2017-01-01",
-        "first": "Nilson AN",
-        "last": "Kayed R",
-        "name": "Journal of Alzheimer's disease : JAD",
-        "pages": "1083-1099",
-        "reference": "27716675",
-        "title": "Tau Oligomers Associate with Inflammation in the Brain and Retina of Tauopathy Mice and in Neurodegenerative Diseases.",
-        "type": "PubMed",
-        "volume": "55"
+      "evidence": "Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396.",
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-      "evidence": "The tauopathy mice that we used contained the P301L mutation, which is implicated in some genetic tauopathies. In addition, this mutation, along with the related P301S mutation, has been associated with increased inflammation in the brain as well as retinal deficits",
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     {
       "annotations": {
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       "citation": {
         "authors": [
-          "Ando K",
-          "Brion JP",
-          "D'Amico E",
-          "Duyckaerts C",
-          "Erneux C",
-          "Jia Y",
-          "Leroy K",
-          "Luo HR",
-          "Pouillon V",
-          "Schurmans S",
-          "Stygelbout V"
+          "El-Akkad E",
+          "Gong CX",
+          "Grundke-Iqbal I",
+          "Iqbal K",
+          "Liang Z",
+          "Liu F",
+          "Shi J",
+          "Yin D"
         ],
-        "date": "2014-02-01",
-        "first": "Stygelbout V",
-        "last": "Brion JP",
-        "name": "Brain : a journal of neurology",
-        "pages": "537-52",
-        "reference": "24401760",
-        "title": "Inositol trisphosphate 3-kinase B is increased in human Alzheimer brain and exacerbates mouse Alzheimer pathology.",
+        "date": "2006-11-13",
+        "first": "Liu F",
+        "last": "Gong CX",
+        "name": "FEBS letters",
+        "pages": "6269-74",
+        "reference": "17078951",
+        "title": "PKA modulates GSK-3beta- and cdk5-catalyzed phosphorylation of tau in site- and kinase-specific manners.",
         "type": "PubMed",
-        "volume": "137"
+        "volume": "580"
       },
-      "evidence": "We show here that ITPKB protein level was increased 3-fold in the cerebral cortex of most patients with Alzheimer's disease compared with control subjects, and accumulated in dystrophic neurites associated to amyloid plaques. In mouse Neuro-2a neuroblastoma cells, Itpkb overexpression was associated with increased cell apoptosis and increased β-secretase 1 activity leading to overproduction of amyloid-β peptides. In this cellular model, an inhibitor of mitogen-activated kinase kinases 1/2 completely prevented overproduction of amyloid-β peptides. Transgenic overexpression of ITPKB in mouse forebrain neurons was not sufficient to induce amyloid plaque formation or tau hyperphosphorylation. However, in the 5X familial Alzheimer's disease mouse model, neuronal ITPKB overexpression significantly increased extracellular signal-regulated kinases 1/2 activation and β-secretase 1 activity, resulting in exacerbated Alzheimer's disease pathology as shown by increased astrogliosis, amyloid-β40 peptide production and tau hyperphosphorylation.",
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       "annotations": {
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         "authors": [
-          "Cuadrado A",
-          "Kügler S",
-          "Lastres-Becker I"
+          "El-Akkad E",
+          "Gong CX",
+          "Grundke-Iqbal I",
+          "Iqbal K",
+          "Liang Z",
+          "Liu F",
+          "Shi J",
+          "Yin D"
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-        "pages": "522-534",
-        "reference": "29121589",
-        "title": "Pharmacological targeting of GSK-3 and NRF2 provides neuroprotection in a preclinical model of tauopathy.",
+        "date": "2006-11-13",
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+        "name": "FEBS letters",
+        "pages": "6269-74",
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         "type": "PubMed",
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       },
-      "evidence": "Messenger RNA analysis of two pro-inflammatory markers such as IL-1β and inducible nitric oxide synthase (iNOS) indicate that TAUP301L expression induce Il-1β (Fig. 6D) and iNOS (Fig. 7D) mRNA expression in both genotypes and DMF treatment decreased this expression only in Nrf2+/+ mice.",
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         "authors": [
-          "Cuadrado A",
-          "Kügler S",
-          "Lastres-Becker I"
+          "Ishiguro K",
+          "Kusubata M",
+          "Matsubara M",
+          "Taniguchi H",
+          "Titani K",
+          "Uchida T"
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-        "last": "Lastres-Becker I",
-        "name": "Redox biology",
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-        "title": "Pharmacological targeting of GSK-3 and NRF2 provides neuroprotection in a preclinical model of tauopathy.",
+        "date": "1996-08-30",
+        "first": "Matsubara M",
+        "last": "Taniguchi H",
+        "name": "The Journal of biological chemistry",
+        "pages": "21108-13",
+        "reference": "8702879",
+        "title": "Site-specific phosphorylation of synapsin I by mitogen-activated protein kinase and Cdk5 and its effects on physiological functions.",
         "type": "PubMed",
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       },
-      "evidence": "Messenger RNA analysis of two pro-inflammatory markers such as IL-1β and inducible nitric oxide synthase (iNOS) indicate that TAUP301L expression induce Il-1β (Fig. 6D) and iNOS (Fig. 7D) mRNA expression in both genotypes and DMF treatment decreased this expression only in Nrf2+/+ mice.",
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       "citation": {
         "authors": [
-          "Allen ME",
-          "Bankston AN",
-          "Feng Y",
-          "Ku L",
-          "Li W",
-          "Liu G",
-          "Rui Y",
-          "Zheng JQ"
+          "Ishiguro K",
+          "Kusubata M",
+          "Matsubara M",
+          "Taniguchi H",
+          "Titani K",
+          "Uchida T"
         ],
-        "date": "2016-11-02",
-        "first": "Li W",
-        "last": "Feng Y",
-        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
-        "pages": "11283-11294",
-        "reference": "27807169",
-        "title": "p39 Is Responsible for Increasing Cdk5 Activity during Postnatal Neuron Differentiation and Governs Neuronal Network Formation and Epileptic Responses.",
+        "date": "1996-08-30",
+        "first": "Matsubara M",
+        "last": "Taniguchi H",
+        "name": "The Journal of biological chemistry",
+        "pages": "21108-13",
+        "reference": "8702879",
+        "title": "Site-specific phosphorylation of synapsin I by mitogen-activated protein kinase and Cdk5 and its effects on physiological functions.",
         "type": "PubMed",
-        "volume": "36"
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       },
-      "evidence": "p39, but not p35, is selectively upregulated by histone acetylation-mediated transcription, underlying the robust increase of Cdk5 activity during rat and mouse neuronal differentiation. Loss of p39 attenuates Cdk5 activity in neurons and preferentially affects phosphorylation of specific Cdk5 targets, leading to aberrant axonal growth and impaired dendritic spine and synapse formation.",
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+          "Benito E",
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-        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
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-        "name": "The Journal of biological chemistry",
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-        "title": "Early growth response 1 (Egr-1) regulates phosphorylation of microtubule-associated protein tau in mammalian brain.",
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-        "title": "A critical role for the PAR-1/MARK-tau axis in mediating the toxic effects of Aβ on synapses and dendritic spines.",
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-        "reference": "27807169",
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         ],
-        "date": "2012-03-15",
-        "first": "Yu W",
-        "last": "Lu B",
-        "name": "Human molecular genetics",
-        "pages": "1384-90",
-        "reference": "22156579",
-        "title": "A critical role for the PAR-1/MARK-tau axis in mediating the toxic effects of Aβ on synapses and dendritic spines.",
+        "date": "2018-04-01",
+        "first": "Cuadrado A",
+        "last": "Lastres-Becker I",
+        "name": "Redox biology",
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+        "title": "Pharmacological targeting of GSK-3 and NRF2 provides neuroprotection in a preclinical model of tauopathy.",
         "type": "PubMed",
-        "volume": "21"
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       },
-      "evidence": "Overexpression of MARK4 led to tau hyperphosphorylation, reduced expression of synaptic markers, and loss of dendritic spines and synapses, phenotypes also observed after Aβ treatment. Importantly, expression of a non-phosphorylatable form of tau with the PAR-1/MARK site mutated blocked the synaptic toxicity induced by MARK4 overexpression or Aβ treatment. To probe the involvement of endogenous MARK kinases in mediating the synaptic toxicity of Aβ, we employed a peptide inhibitor capable of effectively and specifically inhibiting the activities of all PAR-1/MARK family members. This inhibitor abrogated the toxic effects of Aβ oligomers on dendritic spines and synapses as assayed at the morphological and electrophysiological levels.",
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       "citation": {
         "authors": [
-          "Cuadrado-Tejedor M",
-          "Franco R",
-          "Garcia-Barroso C",
-          "Garcia-Osta A",
-          "Mederos S",
-          "Oyarzabal J",
-          "Perea G",
-          "Pérez-González M",
-          "Rabal O",
-          "Segura V",
-          "Sánchez-Arias JA",
-          "Ugarte A"
+          "Cuadrado A",
+          "Kügler S",
+          "Lastres-Becker I"
         ],
-        "date": "2017-01-01",
-        "first": "Cuadrado-Tejedor M",
-        "last": "Garcia-Osta A",
-        "name": "Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology",
-        "pages": "524-539",
-        "reference": "27550730",
-        "title": "A First-in-Class Small-Molecule that Acts as a Dual Inhibitor of HDAC and PDE5 and that Rescues Hippocampal Synaptic Impairment in Alzheimer's Disease Mice.",
+        "date": "2018-04-01",
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+        "title": "Pharmacological targeting of GSK-3 and NRF2 provides neuroprotection in a preclinical model of tauopathy.",
         "type": "PubMed",
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-      "evidence": "Here we report the discovery of a new first-in-class small-molecule (CM-414) that acts as a dual inhibitor of PDE5 and HDACs. We have used this compound as a chemical probe to validate this systems therapeutics strategy, where an increase in the activation of cAMP/cGMP-responsive element-binding protein (CREB) induced by PDE5 inhibition, combined with moderate HDAC class I inhibition, leads to efficient histone acetylation. This molecule rescued the impaired long-term potentiation evident in hippocampal slices from APP/PS1 mice. Chronic treatment of Tg2576 mice with CM-414 diminished brain Aβ and tau phosphorylation (pTau) levels, increased the inactive form of GSK3β, reverted the decrease in dendritic spine density on hippocampal neurons, and reversed their cognitive deficits, at least in part by inducing the expression of genes related to synaptic transmission.",
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         "authors": [
-          "DePaoli-Roach AA",
-          "Fiol CJ",
-          "Roach PJ",
-          "Wang QM"
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-        "last": "Roach PJ",
-        "name": "The Journal of biological chemistry",
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-        "title": "Glycogen synthase kinase-3 beta is a dual specificity kinase differentially regulated by tyrosine and serine/threonine phosphorylation.",
+        "date": "2018-04-01",
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+        "title": "Pharmacological targeting of GSK-3 and NRF2 provides neuroprotection in a preclinical model of tauopathy.",
         "type": "PubMed",
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         "authors": [
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-          "Fiol CJ",
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-        "name": "The Journal of biological chemistry",
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-        "title": "Glycogen synthase kinase-3 beta is a dual specificity kinase differentially regulated by tyrosine and serine/threonine phosphorylation.",
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         "type": "PubMed",
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         "authors": [
-          "DePaoli-Roach AA",
-          "Fiol CJ",
-          "Roach PJ",
-          "Wang QM"
+          "Butterfield DA",
+          "Farr SA",
+          "Kumar V",
+          "Morley JE",
+          "Murphy MP",
+          "Niehoff ML",
+          "Platt TL",
+          "Ripley JL",
+          "Sultana R",
+          "Zhang Z"
         ],
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-        "last": "Roach PJ",
-        "name": "The Journal of biological chemistry",
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+        "date": "2014-02-01",
+        "first": "Farr SA",
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+        "title": "Antisense oligonucleotide against GSK-3β in brain of SAMP8 mice improves learning and memory and decreases oxidative stress: Involvement of transcription factor Nrf2 and implications for Alzheimer disease.",
         "type": "PubMed",
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+      "evidence": "Nuclear factor erythroid-2-related factor 2 (Nrf2) is a transcription factor known to increase the level of many antioxidants, including glutathione-S transferase (GST), and is negatively regulated by the activity of GSK-3β. Our results indicated the increased nuclear localization of Nrf2 and level of GST, suggesting the increased activity of the transcription factor as a result of GSK-3β suppression, consistent with the decreased oxidative stress observed. Consistent with the improved learning and memory, and consistent with GSK-3b being a tau kinase, we observed decreased tau phosphorylation in brain of GAO-treated SAMP8 mice compared to that of RAO-treated SAMP8 mice.",
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-          "Fiol CJ",
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-        "title": "Glycogen synthase kinase-3 beta is a dual specificity kinase differentially regulated by tyrosine and serine/threonine phosphorylation.",
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-          "DePaoli-Roach AA",
-          "Fiol CJ",
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-        "name": "The Journal of biological chemistry",
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-        "title": "Glycogen synthase kinase-3 beta is a dual specificity kinase differentially regulated by tyrosine and serine/threonine phosphorylation.",
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         "type": "PubMed",
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       "citation": {
         "authors": [
-          "DePaoli-Roach AA",
-          "Fiol CJ",
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-          "Wang QM"
+          "Cuadrado A",
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-        "name": "The Journal of biological chemistry",
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-        "reference": "7514173",
-        "title": "Glycogen synthase kinase-3 beta is a dual specificity kinase differentially regulated by tyrosine and serine/threonine phosphorylation.",
+        "date": "2018-04-01",
+        "first": "Cuadrado A",
+        "last": "Lastres-Becker I",
+        "name": "Redox biology",
+        "pages": "522-534",
+        "reference": "29121589",
+        "title": "Pharmacological targeting of GSK-3 and NRF2 provides neuroprotection in a preclinical model of tauopathy.",
         "type": "PubMed",
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-      "evidence": "Vm (nM/min/mg) is 2400, 80, 106, 650, and 140; Km is 200, 59, 114, 16 (all uM) and 5mg/ml for phospho-CREB peptide, myelin basic protein, k-casein, phosphatase Inhibitor-2 and phosvitin",
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       "citation": {
         "authors": [
-          "DePaoli-Roach AA",
-          "Fiol CJ",
-          "Roach PJ",
-          "Wang QM"
+          "Berkovitch SS",
+          "Chattopadhyay S",
+          "Haggarty SJ",
+          "Huang JH",
+          "Iaconelli J",
+          "Karmacharya R",
+          "Mazitschek R",
+          "Schreiber SL"
         ],
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-        "first": "Wang QM",
-        "last": "Roach PJ",
-        "name": "The Journal of biological chemistry",
-        "pages": "14566-74",
-        "reference": "7514173",
-        "title": "Glycogen synthase kinase-3 beta is a dual specificity kinase differentially regulated by tyrosine and serine/threonine phosphorylation.",
+        "date": "2015-03-20",
+        "first": "Iaconelli J",
+        "last": "Karmacharya R",
+        "name": "ACS chemical biology",
+        "pages": "883-90",
+        "reference": "25546293",
+        "title": "HDAC6 inhibitors modulate Lys49 acetylation and membrane localization of β-catenin in human iPSC-derived neuronal cells.",
         "type": "PubMed",
-        "volume": "269"
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-      "evidence": "Vm (nM/min/mg) is 2400, 80, 106, 650, and 140; Km is 200, 59, 114, 16 (all uM) and 5mg/ml for phospho-CREB peptide, myelin basic protein, k-casein, phosphatase Inhibitor-2 and phosvitin",
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+      "evidence": "The N-terminus of β-catenin has phosphorylation, ubiquitination, and acetylation sites that regulate its stability and signaling. In the absence of a Wnt signal, Ser33, Ser37, and Thr41 are constitutively phosphorylated by glycogen synthase kinase 3β (GSK3β). β-Catenin phosphorylated at these sites is recognized by β-transducin repeat-containing protein (βTrCP), which results in ubiquitination and degradation by the ubiquitin-proteasome pathway. The N-terminal regulatory domain of β-catenin also includes Ser45, a phosphorylation site for Casein Kinase 1α (CK1α) and Lys49, which is acetylated by the acetyltransferase p300/CBP-associated factor (PCAF). The relevance of Lys49 acetylation and Ser45 phosphorylation to the function of β-catenin is an active area of investigation. We find that HDAC6 inhibitors increase Lys49 acetylation and Ser45 phosphorylation but do not affect Ser33, Ser37, and Thr41 phosphorylation. Lys49 acetylation results in decreased ubiquitination of β-catenin in the presence of proteasome inhibition. While increased Lys49 acetylation does not affect total levels of β-catenin, it results in increased membrane localization of β-catenin.",
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         "authors": [
-          "DePaoli-Roach AA",
-          "Fiol CJ",
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-          "Wang QM"
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         "type": "PubMed",
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         "authors": [
-          "El-Akkad E",
-          "Gong CX",
-          "Grundke-Iqbal I",
-          "Iqbal K",
-          "Liang Z",
-          "Liu F",
-          "Shi J",
-          "Yin D"
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-        "name": "FEBS letters",
-        "pages": "6269-74",
-        "reference": "17078951",
-        "title": "PKA modulates GSK-3beta- and cdk5-catalyzed phosphorylation of tau in site- and kinase-specific manners.",
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+        "title": "Pharmacological targeting of GSK-3 and NRF2 provides neuroprotection in a preclinical model of tauopathy.",
         "type": "PubMed",
-        "volume": "580"
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       },
-      "evidence": "Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396.",
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       "citation": {
         "authors": [
-          "Ait-Ghezala G",
-          "Bachmeier C",
-          "Beaulieu-Abdelahad D",
-          "Crawford F",
-          "Jin C",
-          "Laco G",
-          "Lin Y",
-          "Mullan M",
-          "Paris D"
+          "Cuadrado A",
+          "Kügler S",
+          "Lastres-Becker I"
         ],
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-        "first": "Paris D",
-        "last": "Mullan M",
-        "name": "The Journal of biological chemistry",
-        "pages": "33927-44",
-        "reference": "25331948",
-        "title": "The spleen tyrosine kinase (Syk) regulates Alzheimer amyloid-β production and Tau hyperphosphorylation.",
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         "type": "PubMed",
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       },
-      "evidence": "Western blot analyses of brain homogenates show that (−)-nilvadipine significantly reduces Tau phosphorylation in AT8 (phosphorylated Ser-199/Ser-202/Thr-205) and PHF-1 (phosphorylated Ser-396/Ser-404) epitopes",
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       "citation": {
         "authors": [
-          "Gamblin TC",
-          "Sun Q"
+          "Cuadrado A",
+          "Kügler S",
+          "Lastres-Becker I"
         ],
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-        "first": "Sun Q",
-        "last": "Gamblin TC",
-        "name": "Biochemistry",
-        "pages": "6002-11",
-        "reference": "19459590",
-        "title": "Pseudohyperphosphorylation causing AD-like changes in tau has significant effects on its polymerization.",
+        "date": "2018-04-01",
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+        "last": "Lastres-Becker I",
+        "name": "Redox biology",
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         "type": "PubMed",
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       },
-      "evidence": "Because S199/S202/T205E, S396/S404E, 6-Phos and 7-Phos all demonstrated an AD-like shift in mobility as a result of phosphorylation-like changes, we conclude that they have the characteristics of hyperphosphorylated tau. These mutants will therefore be referred to as pseudo-hyperphosphorylated tau throughout the manuscript. On the basis of the observations that pseudohyperphosphorylated tau has decreased affinity for microtubules and reduced inducer-initiated rates of nucleation and polymerization, we propose that this combination could be the cause of the increased cytotoxicity of hyperphosphorylated tau in Alzheimer's disease and also explain the potentially beneficial role of tau polymerization and NFT formation.",
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         "authors": [
-          "El-Akkad E",
-          "Gong CX",
-          "Grundke-Iqbal I",
-          "Iqbal K",
-          "Liang Z",
-          "Liu F",
-          "Shi J",
-          "Yin D"
+          "Fan SJ",
+          "Huang FI",
+          "Liou JP",
+          "Yang CR"
         ],
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-        "name": "FEBS letters",
-        "pages": "6269-74",
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-        "title": "PKA modulates GSK-3beta- and cdk5-catalyzed phosphorylation of tau in site- and kinase-specific manners.",
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+        "first": "Fan SJ",
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+        "title": "The novel histone de acetylase 6 inhibitor, MPT0G211, ameliorates tau phosphorylation and cognitive deficits in an Alzheimer's disease model.",
         "type": "PubMed",
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-          "Gong CX",
-          "Grundke-Iqbal I",
-          "Iqbal K",
-          "Liang Z",
-          "Liu F",
-          "Shi J",
-          "Yin D"
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+          "Kügler S",
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-        "name": "FEBS letters",
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-        "reference": "17078951",
-        "title": "PKA modulates GSK-3beta- and cdk5-catalyzed phosphorylation of tau in site- and kinase-specific manners.",
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+        "pages": "522-534",
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         "type": "PubMed",
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       },
-      "evidence": "Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396.",
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+      "relation": "hasVariant",
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     {
+      "annotations": {
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+        },
+        "Species": {
+          "10090": true
+        }
+      },
       "citation": {
         "authors": [
-          "Kawakami F",
-          "Ohtsuki K",
-          "Suzuki K"
+          "Cuadrado A",
+          "Kügler S",
+          "Lastres-Becker I"
         ],
-        "date": "2008-02-01",
-        "first": "Kawakami F",
-        "last": "Ohtsuki K",
-        "name": "Biological &amp; pharmaceutical bulletin",
-        "pages": "193-200",
-        "reference": "18239272",
-        "title": "A novel consensus phosphorylation motif in sulfatide- and cholesterol-3-sulfate-binding protein substrates for CK1 in vitro.",
+        "date": "2018-04-01",
+        "first": "Cuadrado A",
+        "last": "Lastres-Becker I",
+        "name": "Redox biology",
+        "pages": "522-534",
+        "reference": "29121589",
+        "title": "Pharmacological targeting of GSK-3 and NRF2 provides neuroprotection in a preclinical model of tauopathy.",
         "type": "PubMed",
-        "volume": "31"
+        "volume": "14"
       },
-      "evidence": "Epitopes S198, S199, S202, T205, S422 (Lund 2013)",
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+      "evidence": "Wild-type MEFs treated with DMF (20 μM) showed a time-dependent response effect activating phosphorylation of ERK (Fig. 2A, B) and p38 (Fig. 2A, C), that was maximal within 5 min. The Ser/Thr protein kinase AKT, an upstream regulator of GSK-3β, was also activated after 5 min as determined by increased phosphorylation of S473 (Fig. 2A, D)",
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     {
       "annotations": {
-        "Method": {
-          "Electron Microscopy, Transmission": true,
-          "NMR Spectroscopy": true,
-          "Thioflavin T Assay": true
+        "Confidence": {
+          "Medium": true
+        },
+        "Species": {
+          "10090": true
         }
       },
       "citation": {
         "authors": [
-          "Baulieu EE",
-          "Byrne C",
-          "Cantrelle FX",
-          "Chambraud B",
-          "Despres C",
-          "Huvent I",
-          "Jacquot Y",
-          "Landrieu I",
-          "Lippens G",
-          "Qi H",
-          "Smet-Nocca C"
+          "Cuadrado A",
+          "Kügler S",
+          "Lastres-Becker I"
         ],
-        "date": "2017-08-22",
-        "first": "Despres C",
-        "last": "Smet-Nocca C",
-        "name": "Proceedings of the National Academy of Sciences of the United States of America",
-        "pages": "9080-9085",
-        "reference": "28784767",
-        "title": "Identification of the Tau phosphorylation pattern that drives its aggregation.",
+        "date": "2018-04-01",
+        "first": "Cuadrado A",
+        "last": "Lastres-Becker I",
+        "name": "Redox biology",
+        "pages": "522-534",
+        "reference": "29121589",
+        "title": "Pharmacological targeting of GSK-3 and NRF2 provides neuroprotection in a preclinical model of tauopathy.",
         "type": "PubMed",
-        "volume": "114"
+        "volume": "14"
       },
-      "evidence": "When combined with ERK2 catalyzed phosphorylation, the turn-like disrupting G207V mutation in TauF8 hence leads to fast aggregation that already occurs during the phosphorylation reaction.",
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+      "evidence": "Wild-type MEFs treated with DMF (20 μM) showed a time-dependent response effect activating phosphorylation of ERK (Fig. 2A, B) and p38 (Fig. 2A, C), that was maximal within 5 min. The Ser/Thr protein kinase AKT, an upstream regulator of GSK-3β, was also activated after 5 min as determined by increased phosphorylation of S473 (Fig. 2A, D)",
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     {
       "annotations": {
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         "Species": {
           "10090": true
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       "citation": {
         "authors": [
-          "Ait-Ghezala G",
-          "Bachmeier C",
-          "Beaulieu-Abdelahad D",
-          "Crawford F",
-          "Jin C",
-          "Laco G",
-          "Lin Y",
-          "Mullan M",
-          "Paris D"
+          "Cuadrado A",
+          "Kügler S",
+          "Lastres-Becker I"
         ],
-        "date": "2014-12-05",
-        "first": "Paris D",
-        "last": "Mullan M",
-        "name": "The Journal of biological chemistry",
-        "pages": "33927-44",
-        "reference": "25331948",
-        "title": "The spleen tyrosine kinase (Syk) regulates Alzheimer amyloid-β production and Tau hyperphosphorylation.",
+        "date": "2018-04-01",
+        "first": "Cuadrado A",
+        "last": "Lastres-Becker I",
+        "name": "Redox biology",
+        "pages": "522-534",
+        "reference": "29121589",
+        "title": "Pharmacological targeting of GSK-3 and NRF2 provides neuroprotection in a preclinical model of tauopathy.",
         "type": "PubMed",
-        "volume": "289"
+        "volume": "14"
       },
-      "evidence": "We further validated Syk as a target-regulating Aβ by showing that pharmacological inhibition of Syk or down-regulation of Syk expression reduces Aβ production and increases the clearance of Aβ across the BBB mimicking (-)-nilvadipine effects. Moreover, treatment of transgenic mice overexpressing Aβ and transgenic Tau P301S mice with a selective Syk inhibitor respectively decreased brain Aβ accumulation and Tau hyperphosphorylation at multiple AD relevant epitopes.",
-      "key": "2710ccb8bf7e09fac02a578d26d2a292826064c69f3add3150a9a50b00f2c0ee405741d93015f78a7a1c5b0334e9985c5db1737265a15630e20dd7e122aba625",
-      "line": 2256,
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-      "target": 115
+      "evidence": "Wild-type MEFs treated with DMF (20 μM) showed a time-dependent response effect activating phosphorylation of ERK (Fig. 2A, B) and p38 (Fig. 2A, C), that was maximal within 5 min. The Ser/Thr protein kinase AKT, an upstream regulator of GSK-3β, was also activated after 5 min as determined by increased phosphorylation of S473 (Fig. 2A, D)",
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     {
       "annotations": {
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         "Species": {
-          "10116": true
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       },
       "citation": {
         "authors": [
-          "Ai J",
-          "Ban T",
-          "Bao YN",
-          "Chen QX",
-          "Hu XL",
-          "Jiang XM",
-          "Liu CD",
-          "Pei SC",
-          "Su XL",
-          "Sun LH",
-          "Sun LL",
-          "Wang X",
-          "Yan ML",
-          "Zhao LJ",
-          "Zong DK"
+          "Cuadrado A",
+          "Kügler S",
+          "Lastres-Becker I"
         ],
-        "date": "2015-09-01",
-        "first": "Sun LH",
-        "last": "Ai J",
-        "name": "Journal of neurochemistry",
-        "pages": "1139-51",
-        "reference": "26118667",
-        "title": "Activation of Cdk5/p25 and tau phosphorylation following chronic brain hypoperfusion in rats involves microRNA-195 down-regulation.",
+        "date": "2018-04-01",
+        "first": "Cuadrado A",
+        "last": "Lastres-Becker I",
+        "name": "Redox biology",
+        "pages": "522-534",
+        "reference": "29121589",
+        "title": "Pharmacological targeting of GSK-3 and NRF2 provides neuroprotection in a preclinical model of tauopathy.",
         "type": "PubMed",
-        "volume": "134"
+        "volume": "14"
       },
-      "evidence": "Endogenous miR-195 was knocked down using over-expression of its antisense molecule (pre-AMO-miR-195) via a lentivirus (lenti-pre-AMO-miR-195); this knockdown increased the tau phosphorylation at Ser202/Thr205, Ser262, Thr231, Ser422, and the Cdk5/p25 activation, but over-expression of miR-195 using lenti-pre-miR-195 decreased the tau phosphorylation and Cdk5/p25 activation.",
-      "key": "df20d0c28d944c873f143d0d0c4457c3fe4bbb2423c3f823a187d0ec78cc86a470a96ce08cb2306c8dc74e9fe23d8f59a60aa1bb684347e0a41752f542161d11",
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-      "source": 544,
-      "target": 264
+      "evidence": "Wild-type MEFs treated with DMF (20 μM) showed a time-dependent response effect activating phosphorylation of ERK (Fig. 2A, B) and p38 (Fig. 2A, C), that was maximal within 5 min. The Ser/Thr protein kinase AKT, an upstream regulator of GSK-3β, was also activated after 5 min as determined by increased phosphorylation of S473 (Fig. 2A, D)",
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     {
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+          "hippocampal formation": true
+        },
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+          "Medium": true
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+        "Species": {
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+        }
+      },
       "citation": {
         "authors": [
-          "Gamblin TC",
-          "Sun Q"
+          "Cuadrado A",
+          "Kügler S",
+          "Lastres-Becker I"
         ],
-        "date": "2009-06-30",
-        "first": "Sun Q",
-        "last": "Gamblin TC",
-        "name": "Biochemistry",
-        "pages": "6002-11",
-        "reference": "19459590",
-        "title": "Pseudohyperphosphorylation causing AD-like changes in tau has significant effects on its polymerization.",
+        "date": "2018-04-01",
+        "first": "Cuadrado A",
+        "last": "Lastres-Becker I",
+        "name": "Redox biology",
+        "pages": "522-534",
+        "reference": "29121589",
+        "title": "Pharmacological targeting of GSK-3 and NRF2 provides neuroprotection in a preclinical model of tauopathy.",
         "type": "PubMed",
-        "volume": "48"
+        "volume": "14"
       },
-      "evidence": "Because S199/S202/T205E, S396/S404E, 6-Phos and 7-Phos all demonstrated an AD-like shift in mobility as a result of phosphorylation-like changes, we conclude that they have the characteristics of hyperphosphorylated tau. These mutants will therefore be referred to as pseudo-hyperphosphorylated tau throughout the manuscript. On the basis of the observations that pseudohyperphosphorylated tau has decreased affinity for microtubules and reduced inducer-initiated rates of nucleation and polymerization, we propose that this combination could be the cause of the increased cytotoxicity of hyperphosphorylated tau in Alzheimer's disease and also explain the potentially beneficial role of tau polymerization and NFT formation.",
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-      "line": 2460,
-      "relation": "equivalentTo",
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+      "evidence": "DMF increased the phosphorylation levels of GSK-3βSer9 in both genotypes, indicating that this effect is upstream of NRF2 as shown in Fig. 3A.",
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     {
       "annotations": {
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-          "rTg4510 mice": true
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       },
       "citation": {
         "authors": [
-          "Boehm J",
-          "Bourgeois C",
-          "Dudilot A",
-          "Lauzon M",
-          "Leclerc N",
-          "Mondragón-Rodríguez S",
-          "Trillaud-Doppia E"
+          "Cuadrado A",
+          "Kügler S",
+          "Lastres-Becker I"
         ],
-        "date": "2012-09-14",
-        "first": "Mondragón-Rodríguez S",
-        "last": "Boehm J",
-        "name": "The Journal of biological chemistry",
-        "pages": "32040-53",
-        "reference": "22833681",
-        "title": "Interaction of endogenous tau protein with synaptic proteins is regulated by N-methyl-D-aspartate receptor-dependent tau phosphorylation.",
+        "date": "2018-04-01",
+        "first": "Cuadrado A",
+        "last": "Lastres-Becker I",
+        "name": "Redox biology",
+        "pages": "522-534",
+        "reference": "29121589",
+        "title": "Pharmacological targeting of GSK-3 and NRF2 provides neuroprotection in a preclinical model of tauopathy.",
         "type": "PubMed",
-        "volume": "287"
+        "volume": "14"
       },
-      "evidence": "Acute treatment of rTg4510 mice with an O-GlcNAcase inhibitor transiently reduced tau phosphorylation at epitopes implicated in tau pathology. More importantly, long-term inhibitor treatment strongly increased tau O-GlcNAcylation, reduced the number of dystrophic neurons, and protected against the formation of pathological tau species without altering the phosphorylation of non-pathological tau.",
-      "key": "65f36ef4b0f02c75ade243d3c727b69fa57984ab7b2e698116766238e5d9f86c18ccb30e164a2b062fec2375677e1c537c6d5bee6a177473ed73761efb2a0818",
-      "line": 2498,
-      "relation": "positiveCorrelation",
-      "source": 544,
-      "target": 513
+      "evidence": "Taken together, our results show that DMF reduces GSK-3 activity in vivo as determined by a significant and subtle reduction in the phosphorylation levels of its two substrates TAU and CRMP2 respectively.",
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+      "relation": "decreases",
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     },
     {
       "annotations": {
-        "Research_Model": {
-          "TPR50 mice": true
+        "Confidence": {
+          "Medium": true
         },
         "Species": {
           "10090": true
@@ -31860,36 +36310,31 @@
       },
       "citation": {
         "authors": [
-          "Hattori M",
-          "Horiguchi T",
-          "Iwashita H",
-          "Matsumoto Y",
-          "Nakamura K",
-          "Obayashi Y",
-          "Onishi T",
-          "Yano T"
+          "Cuadrado A",
+          "Kügler S",
+          "Lastres-Becker I"
         ],
-        "date": "2014-03-01",
-        "first": "Onishi T",
-        "last": "Iwashita H",
-        "name": "Neuroscience research",
-        "pages": "76-85",
-        "reference": "24406748",
-        "title": "Early-onset cognitive deficits and axonal transport dysfunction in P301S mutant tau transgenic mice.",
+        "date": "2018-04-01",
+        "first": "Cuadrado A",
+        "last": "Lastres-Becker I",
+        "name": "Redox biology",
+        "pages": "522-534",
+        "reference": "29121589",
+        "title": "Pharmacological targeting of GSK-3 and NRF2 provides neuroprotection in a preclinical model of tauopathy.",
         "type": "PubMed",
-        "volume": "80"
+        "volume": "14"
       },
-      "evidence": "We developed a transgenic mouse, named TPR50, harboring human P301S tau. Tau phosphorylation in the hippocampus of TPR50 mice increased with age, particularly at S202/T205. Therefore, cognitive dysfunction in TPR50 mice may result from early MT dysfunction and impaired axonal transport rather than accumulation of insoluble tau and neurodegeneration.",
-      "key": "3bd383265d263b43553760435fea9846a349c1cbae1c2c6fd7afb033032aac428ee67eb0ea6f625490bdb04080542352e6515350ef84bb7fad826301048a4af9",
-      "line": 2515,
-      "relation": "positiveCorrelation",
-      "source": 544,
-      "target": 626
+      "evidence": "Taken together, our results show that DMF reduces GSK-3 activity in vivo as determined by a significant and subtle reduction in the phosphorylation levels of its two substrates TAU and CRMP2 respectively.",
+      "key": "06e1cf85fa9d39d302e3c22d960a5c9a77f2522465efa945c78aa9be98002449ed69064d7f1d839ee39068b1a898e316f852b414674b53638fff36d282f2b4c8",
+      "line": 1236,
+      "relation": "decreases",
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+      "target": 900
     },
     {
       "annotations": {
-        "Research_Model": {
-          "pR5 mice": true
+        "Confidence": {
+          "Medium": true
         },
         "Species": {
           "10090": true
@@ -31897,37 +36342,31 @@
       },
       "citation": {
         "authors": [
-          "Dinekov M",
-          "Götz J",
-          "Köhler C"
+          "Cuadrado A",
+          "Kügler S",
+          "Lastres-Becker I"
         ],
-        "date": "2013-05-01",
-        "first": "Köhler C",
-        "last": "Götz J",
-        "name": "Neurobiology of aging",
-        "pages": "1369-79",
-        "reference": "23294633",
-        "title": "Active glycogen synthase kinase-3 and tau pathology-related tyrosine phosphorylation in pR5 human tau transgenic mice.",
+        "date": "2018-04-01",
+        "first": "Cuadrado A",
+        "last": "Lastres-Becker I",
+        "name": "Redox biology",
+        "pages": "522-534",
+        "reference": "29121589",
+        "title": "Pharmacological targeting of GSK-3 and NRF2 provides neuroprotection in a preclinical model of tauopathy.",
         "type": "PubMed",
-        "volume": "34"
+        "volume": "14"
       },
-      "evidence": "We studied underlying pathomechanisms in tauopathies using pR5 mice that express the P301L tau mutation found in familial forms of frontotemporal dementia. In a longitudinal study we investigated the functional status of glycogen synthase kinase-3 and correlated it with the appearance of distinct tau phospho-epitopes. Neurons displaying increases in activating phosphorylation of glycogen synthase kinase-3α/β at tyrosine 279/216 also showed an intense rather than moderate AT8 (phospho-Ser202/Thr205 tau) immunoreactivity, and immunoreactivity for AT100 (phospho-Ser212/Thr214 tau) and phosphorylated Ser422, phospho-epitopes associated with fibrillar tau pathology.",
-      "key": "001783fcf0cf1de501ebabd8f76e747aca963d8e5c573a47c1cbdf844d44d7adad2a4979f9ad6a065d0cb6f4e30d9ba6a84e66e3bdddbbc7055480505980bcf0",
-      "line": 2534,
-      "relation": "positiveCorrelation",
-      "source": 544,
-      "target": 625
+      "evidence": "Taken together, our results show that DMF reduces GSK-3 activity in vivo as determined by a significant and subtle reduction in the phosphorylation levels of its two substrates TAU and CRMP2 respectively.",
+      "key": "47fe30ac5229d7787ab4a4ed570190a269922303da364d270165be55d0fe37bf7468d6df77227631cc9ad1f25b46893bcae79856f9b1a50ffcbda8011dc83487",
+      "line": 1237,
+      "relation": "decreases",
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+      "target": 873
     },
     {
       "annotations": {
-        "Anatomy": {
-          "CA1 field of hippocampus": true,
-          "CA3 field of hippocampus": true,
-          "cerebral cortex": true,
-          "dentate gyrus granule cell layer": true
-        },
-        "Research_Model": {
-          "hTau E391 transgenic mice": true
+        "Confidence": {
+          "Medium": true
         },
         "Species": {
           "10090": true
@@ -31935,40 +36374,31 @@
       },
       "citation": {
         "authors": [
-          "Kraemer BC",
-          "Leverenz JB",
-          "McMillan PJ",
-          "Raskind M",
-          "Robinson L",
-          "Schellenberg G"
+          "Cuadrado A",
+          "Kügler S",
+          "Lastres-Becker I"
         ],
-        "date": "2011-11-01",
-        "first": "McMillan PJ",
-        "last": "Schellenberg G",
-        "name": "Journal of neuropathology and experimental neurology",
-        "pages": "1006-19",
-        "reference": "22002427",
-        "title": "Truncation of tau at E391 promotes early pathologic changes in transgenic mice.",
+        "date": "2018-04-01",
+        "first": "Cuadrado A",
+        "last": "Lastres-Becker I",
+        "name": "Redox biology",
+        "pages": "522-534",
+        "reference": "29121589",
+        "title": "Pharmacological targeting of GSK-3 and NRF2 provides neuroprotection in a preclinical model of tauopathy.",
         "type": "PubMed",
-        "volume": "70"
+        "volume": "14"
       },
-      "evidence": "E391-3610 mice (higher expressers) exhibit robust somatodendritic distribution of phospho- Ser 202/Thr 205 tau throughout the cortex, in hippocampal CA3 pyramidal neurons, CA1 apical dendrites and cell bodies and dentate granule cells.",
-      "key": "996ba4db2b821403912f6920c967d1348b549dd0ec073e22458dd9266755a5a3f15c255f93d557806fd8ce9cac7f8bc2c63defe8e833537cb84fa0e8784acbb8",
-      "line": 2570,
-      "relation": "positiveCorrelation",
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@@ -31976,1549 +36406,1619 @@
       },
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         "authors": [
-          "Kraemer BC",
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-          "Raskind M",
-          "Robinson L",
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-        "reference": "22002427",
-        "title": "Truncation of tau at E391 promotes early pathologic changes in transgenic mice.",
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         "type": "PubMed",
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-          "Sarmiento J",
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-      "evidence": "Phosphorylation at the epitope Ser202/Thr205 is regarded as a good marker for late-stage NFTs (5, 72). Hyman and colleagues (5) demonstrated that AT8 immunoreactivity is present primarily in eNFTs and in certain cases in iNFTs. These investigators also found that AT8 revealed dense neuropil thread staining.",
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         "authors": [
-          "Cornwell LB",
-          "Gylys KH",
-          "Henkins KM",
-          "Miller CA",
-          "Poon WW",
-          "Saing T",
-          "Sokolow S",
-          "Vinters HV"
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-        "reference": "22486774",
-        "title": "Extensive p-tau pathology and SDS-stable p-tau oligomers in Alzheimer's cortical synapses.",
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         "type": "PubMed",
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       "citation": {
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-        "name": "The Journal of biological chemistry",
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-        "reference": "16464864",
-        "title": "Small ubiquitin-like modifier (SUMO) modification of natively unfolded proteins tau and alpha-synuclein.",
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         "type": "PubMed",
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-      "evidence": "Both brain proteins were preferentially modified by SUMO1, as compared with SUMO2 or SUMO3. Tau contains two SUMO consensus sequences with Lys(340) as the major sumoylation site. Although both tau and alpha-synuclein are targets for proteasomal degradation, only tau sumoylation was affected by inhibitors of the proteasome pathway. Treatment with the phosphatase inhibitor, okadaic acid, or the microtubule depolymerizing drug, colchicine, up-regulated tau sumoylation.",
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-      "evidence": "Both brain proteins were preferentially modified by SUMO1, as compared with SUMO2 or SUMO3. Tau contains two SUMO consensus sequences with Lys(340) as the major sumoylation site. Although both tau and alpha-synuclein are targets for proteasomal degradation, only tau sumoylation was affected by inhibitors of the proteasome pathway. Treatment with the phosphatase inhibitor, okadaic acid, or the microtubule depolymerizing drug, colchicine, up-regulated tau sumoylation.",
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-          "Liu F",
-          "Shi J",
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-        "title": "PKA modulates GSK-3beta- and cdk5-catalyzed phosphorylation of tau in site- and kinase-specific manners.",
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-      "evidence": "Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396.",
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-          "Leroy A",
-          "Lippens G",
-          "Sibille N",
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-        "title": "Structural characterization by nuclear magnetic resonance of the impact of phosphorylation in the proline-rich region of the disordered Tau protein.",
-        "type": "PubMed",
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-      "evidence": "In this study, we address the structural impact of phosphorylation of the Tau protein by Nuclear Magnetic Resonance (NMR) spectroscopy on a functional fragment of Tau (Tau[Ser208-Ser324] = TauF4). TauF4 was phosphorylated by the proline-directed CDK2/CycA3 kinase on Thr231 (generating the AT180 epitope), Ser235, and equally on Thr212 and Thr217 in the Proline-rich region (Tau[Ser208-Gln244] or PRR). These modifications strongly decrease the capacity of TauF4 to polymerize tubulin into microtubules. While all the NMR parameters are consistent with a globally disordered Tau protein fragment, local clusters of structuration can be defined. The most salient result of our NMR analysis is that phosphorylation in the PRR stabilizes a short α-helix that runs from pSer235 till the very beginning of the microtubule-binding region (Tau[Thr245-Ser324] or MTBR of TauF4).",
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-          "Liang Z",
-          "Liu F",
-          "Shi J",
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         "type": "PubMed",
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-      "evidence": "Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396.",
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       "citation": {
         "authors": [
-          "Chai GS",
-          "Chen NN",
-          "Cheng XS",
-          "Duan DX",
-          "Hu Y",
-          "Liu GP",
-          "Luo Y",
-          "Ni ZF",
-          "Wang JZ"
+          "Cuadrado A",
+          "Kügler S",
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-        "date": "2013-01-01",
-        "first": "Duan DX",
-        "last": "Liu GP",
-        "name": "Journal of Alzheimer's disease : JAD",
-        "pages": "795-808",
-        "reference": "23948915",
-        "title": "Phosphorylation of tau by death-associated protein kinase 1 antagonizes the kinase-induced cell apoptosis.",
+        "date": "2018-04-01",
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+        "title": "Pharmacological targeting of GSK-3 and NRF2 provides neuroprotection in a preclinical model of tauopathy.",
         "type": "PubMed",
-        "volume": "37"
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       },
-      "evidence": "These data suggest that tau hyperphosphorylation at Thr231, Ser262, and Ser396 by DAPK1 renders the cells more resistant to the kinase-induced apoptotic cell death, providing new insights into the tau-involved apoptotic abortion in the course of chronic neurodegeneration.",
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     {
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       },
       "citation": {
         "authors": [
-          "Ai J",
-          "Ban T",
-          "Bao YN",
-          "Chen QX",
-          "Hu XL",
-          "Jiang XM",
-          "Liu CD",
-          "Pei SC",
-          "Su XL",
-          "Sun LH",
-          "Sun LL",
-          "Wang X",
-          "Yan ML",
-          "Zhao LJ",
-          "Zong DK"
+          "Nikkuni M",
+          "Ohshima T",
+          "Toba J",
+          "Watamura N",
+          "Yoshii A"
         ],
-        "date": "2015-09-01",
-        "first": "Sun LH",
-        "last": "Ai J",
-        "name": "Journal of neurochemistry",
-        "pages": "1139-51",
-        "reference": "26118667",
-        "title": "Activation of Cdk5/p25 and tau phosphorylation following chronic brain hypoperfusion in rats involves microRNA-195 down-regulation.",
+        "date": "2016-01-01",
+        "first": "Watamura N",
+        "last": "Ohshima T",
+        "name": "Journal of neuroscience research",
+        "pages": "15-26",
+        "reference": "26400044",
+        "title": "Colocalization of phosphorylated forms of WAVE1, CRMP2, and tau in Alzheimer's disease model mice: Involvement of Cdk5 phosphorylation and the effect of ATRA treatment.",
         "type": "PubMed",
-        "volume": "134"
+        "volume": "94"
       },
-      "evidence": "Endogenous miR-195 was knocked down using over-expression of its antisense molecule (pre-AMO-miR-195) via a lentivirus (lenti-pre-AMO-miR-195); this knockdown increased the tau phosphorylation at Ser202/Thr205, Ser262, Thr231, Ser422, and the Cdk5/p25 activation, but over-expression of miR-195 using lenti-pre-miR-195 decreased the tau phosphorylation and Cdk5/p25 activation.",
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+      "evidence": "First, we verified the colocalization of p-WAVE1 and pCRMP2 with aggregated hyperphosphorylated tau in the hippocampus at 23 months of age. Biochemical analysis revealed the inclusion of p-WAVE1, p-CRMP2, and tau in the sarkosyl-insoluble fractions of hippocampal homogenates",
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       "citation": {
         "authors": [
-          "Boehm J",
-          "Bourgeois C",
-          "Dudilot A",
-          "Lauzon M",
-          "Leclerc N",
-          "Mondragón-Rodríguez S",
-          "Trillaud-Doppia E"
+          "Nikkuni M",
+          "Ohshima T",
+          "Toba J",
+          "Watamura N",
+          "Yoshii A"
         ],
-        "date": "2012-09-14",
-        "first": "Mondragón-Rodríguez S",
-        "last": "Boehm J",
-        "name": "The Journal of biological chemistry",
-        "pages": "32040-53",
-        "reference": "22833681",
-        "title": "Interaction of endogenous tau protein with synaptic proteins is regulated by N-methyl-D-aspartate receptor-dependent tau phosphorylation.",
+        "date": "2016-01-01",
+        "first": "Watamura N",
+        "last": "Ohshima T",
+        "name": "Journal of neuroscience research",
+        "pages": "15-26",
+        "reference": "26400044",
+        "title": "Colocalization of phosphorylated forms of WAVE1, CRMP2, and tau in Alzheimer's disease model mice: Involvement of Cdk5 phosphorylation and the effect of ATRA treatment.",
         "type": "PubMed",
-        "volume": "287"
+        "volume": "94"
       },
-      "evidence": "Hence, LTD-inducing NMDA receptor activation leads to an increase in tau phosphorylation at sites PHF-1, AT180, as well as AT8 and to a reduction at AT100.",
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       "citation": {
         "authors": [
-          "Castillo-Carranza DL",
-          "Jackson GR",
-          "Kayed R",
-          "Lasagna-Reeves CA",
-          "Sarmiento J",
-          "Sengupta U",
-          "Troncoso J"
+          "Cuadrado A",
+          "Kügler S",
+          "Lastres-Becker I"
         ],
-        "date": "2012-05-01",
-        "first": "Lasagna-Reeves CA",
-        "last": "Kayed R",
-        "name": "FASEB journal : official publication of the Federation of American Societies for Experimental Biology",
-        "pages": "1946-59",
-        "reference": "22253473",
-        "title": "Identification of oligomers at early stages of tau aggregation in Alzheimer's disease.",
+        "date": "2018-04-01",
+        "first": "Cuadrado A",
+        "last": "Lastres-Becker I",
+        "name": "Redox biology",
+        "pages": "522-534",
+        "reference": "29121589",
+        "title": "Pharmacological targeting of GSK-3 and NRF2 provides neuroprotection in a preclinical model of tauopathy.",
         "type": "PubMed",
-        "volume": "26"
+        "volume": "14"
       },
-      "evidence": "This sequence (Fig. 3G–N) is supported by Western blot analysis, phosphorylated Thr231 in three AD cases and their age-matched controls, suggesting that tau phosphorylation at Thr231 occurs before the formation of oligomers (Fig. 3O).",
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+      "evidence": "Astrocytes displayed enlarged bodies and ramifications (Type B morphology), consistent with a reactive state after TAUP301L expression in Nrf2+/+ and Nrf2−/− mice (Fig. 6A left panels). However, only astrocytes from Nrf2+/+ mice treated with DMF were maintained in a resting morphology (Type A) (Fig. 6A right panels). Concerning microglia, TAUP301L expression induced a very significant increase in IBA1+ microglia at the ipsilateral hippocampal side of Nrf2+/+ and Nrf2−/− mice  (Fig. 7A), which was confirmed by stereological quantification (Fig. 7B). DMF treatment reduced significantly this microgliosis in Nrf2+/+ but not in Nrf2−/− mice, reinforcing the idea of NRF2-dependent anti-inflammatory effect",
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       "citation": {
         "authors": [
-          "Braidy N",
-          "Brew BJ",
-          "Cullen KM",
-          "Guillemin GJ",
-          "Rahman A",
-          "Ting K"
+          "Cuadrado A",
+          "Kügler S",
+          "Lastres-Becker I"
         ],
-        "date": "2009-07-22",
-        "first": "Rahman A",
-        "last": "Guillemin GJ",
-        "name": "PloS one",
-        "pages": "e6344",
-        "reference": "19623258",
-        "title": "The excitotoxin quinolinic acid induces tau phosphorylation in human neurons.",
+        "date": "2018-04-01",
+        "first": "Cuadrado A",
+        "last": "Lastres-Becker I",
+        "name": "Redox biology",
+        "pages": "522-534",
+        "reference": "29121589",
+        "title": "Pharmacological targeting of GSK-3 and NRF2 provides neuroprotection in a preclinical model of tauopathy.",
         "type": "PubMed",
-        "volume": "4"
+        "volume": "14"
       },
-      "evidence": "QA appears to act through NMDA receptor activation similar to other agonists, glutamate and NMDA and was abrogated by the NMDAR antagonist memantine. NMDA receptor agonists, glutamate and NMDA at equimolar concentrations (500 nM) increased tau phosphorylation at serine 199/202 (AT8) and threonine 231 (AT-180), similar to QA.",
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     {
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       "citation": {
         "authors": [
           "Ando K",
-          "Blum D",
-          "Bretteville A",
-          "Buée L",
-          "Bégard S",
-          "Bélarbi K",
-          "Caillet-Boudin ML",
-          "Demey-Thomas E",
-          "Dourlen P",
-          "Drobecq H",
-          "Eddarkaoui S",
-          "Galas MC",
-          "Ghestem A",
-          "Hamdane M",
-          "Landrieu I",
-          "Lippens G",
-          "Maurage CA",
-          "Melnyk P",
-          "Sambo AV",
-          "Sergeant N",
-          "Smet C",
-          "Verdier Y",
-          "Vingtdeux V",
-          "Vinh J"
+          "Brion JP",
+          "D'Amico E",
+          "Duyckaerts C",
+          "Erneux C",
+          "Jia Y",
+          "Leroy K",
+          "Luo HR",
+          "Pouillon V",
+          "Schurmans S",
+          "Stygelbout V"
         ],
-        "date": "2013-03-01",
-        "first": "Ando K",
-        "last": "Buée L",
-        "name": "Neurobiology of aging",
-        "pages": "757-69",
-        "reference": "22926167",
-        "title": "Tau pathology modulates Pin1 post-translational modifications and may be relevant as biomarker.",
+        "date": "2014-02-01",
+        "first": "Stygelbout V",
+        "last": "Brion JP",
+        "name": "Brain : a journal of neurology",
+        "pages": "537-52",
+        "reference": "24401760",
+        "title": "Inositol trisphosphate 3-kinase B is increased in human Alzheimer brain and exacerbates mouse Alzheimer pathology.",
         "type": "PubMed",
-        "volume": "34"
+        "volume": "137"
       },
-      "evidence": "Pin1 binds to phosphorylated Thr231 of tau and facilitates the dephosphorylation of phosphoThr231 through isomerization (Galas et al., 2006; Hamdane et al., 2006; Lu et al., 1999a). Phosphorylation at Thr231 on tau is associated with the early events of tau aggregation and NFT (Augustinack et al., 2002). Pin1 binds and isomerizes the proline imidic peptide bond following the phosphothreonine 231",
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+      "evidence": "We show here that ITPKB protein level was increased 3-fold in the cerebral cortex of most patients with Alzheimer's disease compared with control subjects, and accumulated in dystrophic neurites associated to amyloid plaques. In mouse Neuro-2a neuroblastoma cells, Itpkb overexpression was associated with increased cell apoptosis and increased β-secretase 1 activity leading to overproduction of amyloid-β peptides. In this cellular model, an inhibitor of mitogen-activated kinase kinases 1/2 completely prevented overproduction of amyloid-β peptides. Transgenic overexpression of ITPKB in mouse forebrain neurons was not sufficient to induce amyloid plaque formation or tau hyperphosphorylation. However, in the 5X familial Alzheimer's disease mouse model, neuronal ITPKB overexpression significantly increased extracellular signal-regulated kinases 1/2 activation and β-secretase 1 activity, resulting in exacerbated Alzheimer's disease pathology as shown by increased astrogliosis, amyloid-β40 peptide production and tau hyperphosphorylation.",
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       "citation": {
         "authors": [
-          "El-Akkad E",
-          "Gong CX",
-          "Grundke-Iqbal I",
-          "Iqbal K",
-          "Liang Z",
-          "Liu F",
-          "Shi J",
-          "Yin D"
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+          "Kügler S",
+          "Lastres-Becker I"
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-        "first": "Liu F",
-        "last": "Gong CX",
-        "name": "FEBS letters",
-        "pages": "6269-74",
-        "reference": "17078951",
-        "title": "PKA modulates GSK-3beta- and cdk5-catalyzed phosphorylation of tau in site- and kinase-specific manners.",
+        "date": "2018-04-01",
+        "first": "Cuadrado A",
+        "last": "Lastres-Becker I",
+        "name": "Redox biology",
+        "pages": "522-534",
+        "reference": "29121589",
+        "title": "Pharmacological targeting of GSK-3 and NRF2 provides neuroprotection in a preclinical model of tauopathy.",
         "type": "PubMed",
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-      "evidence": "Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396.",
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         "authors": [
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-          "Gong CX",
-          "Grundke-Iqbal I",
-          "Iqbal K",
-          "Liang Z",
-          "Liu F",
-          "Shi J",
-          "Yin D"
+          "Cuadrado A",
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+          "Lastres-Becker I"
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-        "first": "Liu F",
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-        "name": "FEBS letters",
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-        "reference": "17078951",
-        "title": "PKA modulates GSK-3beta- and cdk5-catalyzed phosphorylation of tau in site- and kinase-specific manners.",
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+        "pages": "522-534",
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+        "title": "Pharmacological targeting of GSK-3 and NRF2 provides neuroprotection in a preclinical model of tauopathy.",
         "type": "PubMed",
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       },
-      "evidence": "Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396.",
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+      "evidence": "Messenger RNA analysis of two pro-inflammatory markers such as IL-1β and inducible nitric oxide synthase (iNOS) indicate that TAUP301L expression induce Il-1β (Fig. 6D) and iNOS (Fig. 7D) mRNA expression in both genotypes and DMF treatment decreased this expression only in Nrf2+/+ mice.",
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       "citation": {
         "authors": [
-          "Buée-Scherrer V",
-          "Goedert M"
+          "Cuadrado A",
+          "Kügler S",
+          "Lastres-Becker I"
         ],
-        "date": "2002-03-27",
-        "first": "Buée-Scherrer V",
-        "last": "Goedert M",
-        "name": "FEBS letters",
-        "pages": "151-4",
-        "reference": "11943212",
-        "title": "Phosphorylation of microtubule-associated protein tau by stress-activated protein kinases in intact cells.",
+        "date": "2018-04-01",
+        "first": "Cuadrado A",
+        "last": "Lastres-Becker I",
+        "name": "Redox biology",
+        "pages": "522-534",
+        "reference": "29121589",
+        "title": "Pharmacological targeting of GSK-3 and NRF2 provides neuroprotection in a preclinical model of tauopathy.",
         "type": "PubMed",
-        "volume": "515"
+        "volume": "14"
       },
-      "evidence": "The AD2 epitope, which corresponds to phosphorylated S396 and S404 in tau, was generated most effectively by SAPK3/p38gamma and SAPK4/p38delta",
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       "citation": {
         "authors": [
-          "Lu B",
-          "Malenka R",
-          "Polepalli J",
-          "Rajadas J",
-          "Wagh D",
-          "Yu W"
+          "Cuadrado A",
+          "Kügler S",
+          "Lastres-Becker I"
         ],
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-        "first": "Yu W",
-        "last": "Lu B",
-        "name": "Human molecular genetics",
-        "pages": "1384-90",
-        "reference": "22156579",
-        "title": "A critical role for the PAR-1/MARK-tau axis in mediating the toxic effects of Aβ on synapses and dendritic spines.",
+        "date": "2018-04-01",
+        "first": "Cuadrado A",
+        "last": "Lastres-Becker I",
+        "name": "Redox biology",
+        "pages": "522-534",
+        "reference": "29121589",
+        "title": "Pharmacological targeting of GSK-3 and NRF2 provides neuroprotection in a preclinical model of tauopathy.",
         "type": "PubMed",
-        "volume": "21"
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       },
-      "evidence": "We first confirmed that expression of an MKI-GFP fusion protein in rat hippocampal neurons effectively attenuated MARK4-mediated phosphorylation of both endogenous tau (Fig. 3A) and transfected human tau at the 12E8 sites (Fig. 3B). Phosphorylation of tau at the PHF-1 site was also reduced by MKI (Fig. 3A). It is possible that the PHF-1 site is also targeted by PAR-1/MARKs in vivo, or that the phosphorylation of tau at the 12E8 sites is a prerequisite for PHF-1 site phosphorylation, as the 12E8 sites were previously shown to be required for tau phosphorylation at other sites",
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     {
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       "citation": {
         "authors": [
-          "El-Akkad E",
-          "Gong CX",
-          "Grundke-Iqbal I",
-          "Iqbal K",
-          "Liang Z",
-          "Liu F",
-          "Shi J",
-          "Yin D"
+          "Cuadrado A",
+          "Kügler S",
+          "Lastres-Becker I"
         ],
-        "date": "2006-11-13",
-        "first": "Liu F",
-        "last": "Gong CX",
-        "name": "FEBS letters",
-        "pages": "6269-74",
-        "reference": "17078951",
-        "title": "PKA modulates GSK-3beta- and cdk5-catalyzed phosphorylation of tau in site- and kinase-specific manners.",
+        "date": "2018-04-01",
+        "first": "Cuadrado A",
+        "last": "Lastres-Becker I",
+        "name": "Redox biology",
+        "pages": "522-534",
+        "reference": "29121589",
+        "title": "Pharmacological targeting of GSK-3 and NRF2 provides neuroprotection in a preclinical model of tauopathy.",
         "type": "PubMed",
-        "volume": "580"
+        "volume": "14"
       },
-      "evidence": "Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396.",
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     {
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+          "High": true
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       "citation": {
         "authors": [
-          "El-Akkad E",
-          "Gong CX",
-          "Grundke-Iqbal I",
-          "Iqbal K",
-          "Liang Z",
-          "Liu F",
-          "Shi J",
-          "Yin D"
+          "Babić Leko M",
+          "Bažadona D",
+          "Buée L",
+          "Delalle I",
+          "Di Giovanni G",
+          "Harrington C",
+          "Hof PR",
+          "Jovanov-Milošević N",
+          "Wischik C",
+          "Wray S",
+          "de Silva R",
+          "Šimić G"
         ],
-        "date": "2006-11-13",
-        "first": "Liu F",
-        "last": "Gong CX",
-        "name": "FEBS letters",
-        "pages": "6269-74",
-        "reference": "17078951",
-        "title": "PKA modulates GSK-3beta- and cdk5-catalyzed phosphorylation of tau in site- and kinase-specific manners.",
+        "date": "2016-01-06",
+        "first": "Šimić G",
+        "last": "Hof PR",
+        "name": "Biomolecules",
+        "pages": "6",
+        "reference": "26751493",
+        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
         "type": "PubMed",
-        "volume": "580"
+        "volume": "6"
       },
-      "evidence": "Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396.",
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+      "evidence": "Poorkaj et al. reported two exonic mutations (P301L and V337M) in two families with FTDP-17 [139], while Hutton et al. reported six different mutations in 10 families: three of these mutations (G272V, P301L and R406W) were missense mutations in exons, while the other three were in the 5' splice site of exon 10 [140].",
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     {
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       "citation": {
         "authors": [
-          "Amniai L",
-          "Fauquant C",
-          "Huvent I",
-          "Landrieu I",
-          "Leroy A",
-          "Lippens G",
-          "Sibille N",
-          "Verdegem D",
-          "Wieruszeski JM"
+          "Dinekov M",
+          "Götz J",
+          "Köhler C"
         ],
-        "date": "2012-02-01",
-        "first": "Sibille N",
-        "last": "Landrieu I",
-        "name": "Proteins",
-        "pages": "454-62",
-        "reference": "22072628",
-        "title": "Structural characterization by nuclear magnetic resonance of the impact of phosphorylation in the proline-rich region of the disordered Tau protein.",
+        "date": "2013-05-01",
+        "first": "Köhler C",
+        "last": "Götz J",
+        "name": "Neurobiology of aging",
+        "pages": "1369-79",
+        "reference": "23294633",
+        "title": "Active glycogen synthase kinase-3 and tau pathology-related tyrosine phosphorylation in pR5 human tau transgenic mice.",
         "type": "PubMed",
-        "volume": "80"
+        "volume": "34"
       },
-      "evidence": "In this study, we address the structural impact of phosphorylation of the Tau protein by Nuclear Magnetic Resonance (NMR) spectroscopy on a functional fragment of Tau (Tau[Ser208-Ser324] = TauF4). TauF4 was phosphorylated by the proline-directed CDK2/CycA3 kinase on Thr231 (generating the AT180 epitope), Ser235, and equally on Thr212 and Thr217 in the Proline-rich region (Tau[Ser208-Gln244] or PRR). These modifications strongly decrease the capacity of TauF4 to polymerize tubulin into microtubules. While all the NMR parameters are consistent with a globally disordered Tau protein fragment, local clusters of structuration can be defined. The most salient result of our NMR analysis is that phosphorylation in the PRR stabilizes a short α-helix that runs from pSer235 till the very beginning of the microtubule-binding region (Tau[Thr245-Ser324] or MTBR of TauF4).",
-      "key": "0437791b0113d2a1ee8966c1d57cd65f0a7c30ab84c089895def24193da0c037f9d91fc71ad8b638170916cc5a34be45a70aa1d3714ba362446b45bc45a1f24a",
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+      "evidence": "We studied underlying pathomechanisms in tauopathies using pR5 mice that express the P301L tau mutation found in familial forms of frontotemporal dementia. In a longitudinal study we investigated the functional status of glycogen synthase kinase-3 and correlated it with the appearance of distinct tau phospho-epitopes. Neurons displaying increases in activating phosphorylation of glycogen synthase kinase-3α/β at tyrosine 279/216 also showed an intense rather than moderate AT8 (phospho-Ser202/Thr205 tau) immunoreactivity, and immunoreactivity for AT100 (phospho-Ser212/Thr214 tau) and phosphorylated Ser422, phospho-epitopes associated with fibrillar tau pathology.",
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     {
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       "citation": {
         "authors": [
-          "El-Akkad E",
-          "Gong CX",
-          "Grundke-Iqbal I",
-          "Iqbal K",
-          "Liang Z",
-          "Liu F",
-          "Shi J",
-          "Yin D"
+          "Dinekov M",
+          "Götz J",
+          "Köhler C"
         ],
-        "date": "2006-11-13",
-        "first": "Liu F",
-        "last": "Gong CX",
-        "name": "FEBS letters",
-        "pages": "6269-74",
-        "reference": "17078951",
-        "title": "PKA modulates GSK-3beta- and cdk5-catalyzed phosphorylation of tau in site- and kinase-specific manners.",
+        "date": "2013-05-01",
+        "first": "Köhler C",
+        "last": "Götz J",
+        "name": "Neurobiology of aging",
+        "pages": "1369-79",
+        "reference": "23294633",
+        "title": "Active glycogen synthase kinase-3 and tau pathology-related tyrosine phosphorylation in pR5 human tau transgenic mice.",
         "type": "PubMed",
-        "volume": "580"
+        "volume": "34"
       },
-      "evidence": "Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396.",
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     {
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       "citation": {
         "authors": [
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-          "Gong CX",
-          "Grundke-Iqbal I",
-          "Iqbal K",
-          "Liang Z",
-          "Liu F",
-          "Shi J",
-          "Yin D"
+          "Dinekov M",
+          "Götz J",
+          "Köhler C"
         ],
-        "date": "2006-11-13",
-        "first": "Liu F",
-        "last": "Gong CX",
-        "name": "FEBS letters",
-        "pages": "6269-74",
-        "reference": "17078951",
-        "title": "PKA modulates GSK-3beta- and cdk5-catalyzed phosphorylation of tau in site- and kinase-specific manners.",
+        "date": "2013-05-01",
+        "first": "Köhler C",
+        "last": "Götz J",
+        "name": "Neurobiology of aging",
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+        "reference": "23294633",
+        "title": "Active glycogen synthase kinase-3 and tau pathology-related tyrosine phosphorylation in pR5 human tau transgenic mice.",
         "type": "PubMed",
-        "volume": "580"
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       },
-      "evidence": "Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396.",
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     {
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       "citation": {
         "authors": [
-          "El-Akkad E",
-          "Gong CX",
-          "Grundke-Iqbal I",
-          "Iqbal K",
-          "Liang Z",
-          "Liu F",
-          "Shi J",
-          "Yin D"
+          "Dinekov M",
+          "Götz J",
+          "Köhler C"
         ],
-        "date": "2006-11-13",
-        "first": "Liu F",
-        "last": "Gong CX",
-        "name": "FEBS letters",
-        "pages": "6269-74",
-        "reference": "17078951",
-        "title": "PKA modulates GSK-3beta- and cdk5-catalyzed phosphorylation of tau in site- and kinase-specific manners.",
+        "date": "2013-05-01",
+        "first": "Köhler C",
+        "last": "Götz J",
+        "name": "Neurobiology of aging",
+        "pages": "1369-79",
+        "reference": "23294633",
+        "title": "Active glycogen synthase kinase-3 and tau pathology-related tyrosine phosphorylation in pR5 human tau transgenic mice.",
         "type": "PubMed",
-        "volume": "580"
+        "volume": "34"
       },
-      "evidence": "Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396.",
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     {
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       "citation": {
         "authors": [
-          "El-Akkad E",
-          "Gong CX",
-          "Grundke-Iqbal I",
-          "Iqbal K",
-          "Liang Z",
-          "Liu F",
-          "Shi J",
-          "Yin D"
+          "Dinekov M",
+          "Götz J",
+          "Köhler C"
         ],
-        "date": "2006-11-13",
-        "first": "Liu F",
-        "last": "Gong CX",
-        "name": "FEBS letters",
-        "pages": "6269-74",
-        "reference": "17078951",
-        "title": "PKA modulates GSK-3beta- and cdk5-catalyzed phosphorylation of tau in site- and kinase-specific manners.",
+        "date": "2013-05-01",
+        "first": "Köhler C",
+        "last": "Götz J",
+        "name": "Neurobiology of aging",
+        "pages": "1369-79",
+        "reference": "23294633",
+        "title": "Active glycogen synthase kinase-3 and tau pathology-related tyrosine phosphorylation in pR5 human tau transgenic mice.",
         "type": "PubMed",
-        "volume": "580"
+        "volume": "34"
       },
-      "evidence": "Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396.",
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     {
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-          "Liu F",
-          "Shi J",
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+          "English KC",
+          "Gerson JE",
+          "Gupta P",
+          "Kayed R",
+          "Nicolas Crain C",
+          "Nilson AN",
+          "Sengupta U",
+          "Xue J",
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         "authors": [
-          "Agerman K",
-          "Eckersley S",
-          "Gu GJ",
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-          "Kvist AJ",
-          "Landegren U",
-          "Lund H",
-          "Milner R",
-          "Nilsson LN",
-          "Sunnemark D",
-          "Wu D"
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+          "Feng Y",
+          "Ku L",
+          "Li W",
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+          "Rui Y",
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-        "first": "Gu GJ",
-        "last": "Kamali-Moghaddam M",
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-        "title": "Elevated MARK2-dependent phosphorylation of Tau in Alzheimer's disease.",
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-          "Uchida T"
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+        "name": "The Journal of biological chemistry",
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       "annotations": {
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         "authors": [
-          "Delgado E",
-          "Domínguez JM",
-          "Fuertes A",
-          "Medina M",
-          "Orozco L",
-          "del Monte-Millán M"
+          "Han D",
+          "Li T",
+          "Lu Y",
+          "Paudel HK",
+          "Qureshi HY"
         ],
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-        "first": "Domínguez JM",
-        "last": "Medina M",
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+        "first": "Lu Y",
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         "name": "The Journal of biological chemistry",
-        "pages": "893-904",
-        "reference": "22102280",
-        "title": "Evidence for irreversible inhibition of glycogen synthase kinase-3β by tideglusib.",
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+        "title": "Early growth response 1 (Egr-1) regulates phosphorylation of microtubule-associated protein tau in mammalian brain.",
         "type": "PubMed",
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-      "evidence": "We report here that tideglusib inhibits GSK-3β irreversibly, as demonstrated by the lack of recovery in enzyme function after the unbound drug has been removed from the reaction medium and the fact that its dissociation rate constant is non-significantly different from zero.",
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-          "Delgado E",
-          "Domínguez JM",
-          "Fuertes A",
-          "Medina M",
-          "Orozco L",
-          "del Monte-Millán M"
+          "Allen ME",
+          "Bankston AN",
+          "Feng Y",
+          "Ku L",
+          "Li W",
+          "Liu G",
+          "Rui Y",
+          "Zheng JQ"
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-        "first": "Domínguez JM",
-        "last": "Medina M",
-        "name": "The Journal of biological chemistry",
-        "pages": "893-904",
-        "reference": "22102280",
-        "title": "Evidence for irreversible inhibition of glycogen synthase kinase-3β by tideglusib.",
+        "date": "2016-11-02",
+        "first": "Li W",
+        "last": "Feng Y",
+        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
+        "pages": "11283-11294",
+        "reference": "27807169",
+        "title": "p39 Is Responsible for Increasing Cdk5 Activity during Postnatal Neuron Differentiation and Governs Neuronal Network Formation and Epileptic Responses.",
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     {
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-          "Delgado E",
-          "Domínguez JM",
-          "Fuertes A",
-          "Medina M",
-          "Orozco L",
-          "del Monte-Millán M"
+          "Lu B",
+          "Malenka R",
+          "Polepalli J",
+          "Rajadas J",
+          "Wagh D",
+          "Yu W"
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-        "date": "2012-01-06",
-        "first": "Domínguez JM",
-        "last": "Medina M",
-        "name": "The Journal of biological chemistry",
-        "pages": "893-904",
-        "reference": "22102280",
-        "title": "Evidence for irreversible inhibition of glycogen synthase kinase-3β by tideglusib.",
+        "date": "2012-03-15",
+        "first": "Yu W",
+        "last": "Lu B",
+        "name": "Human molecular genetics",
+        "pages": "1384-90",
+        "reference": "22156579",
+        "title": "A critical role for the PAR-1/MARK-tau axis in mediating the toxic effects of Aβ on synapses and dendritic spines.",
         "type": "PubMed",
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-      "evidence": "Alsterpaullone showed identical results with the wild-type and the mutant enzymes, demonstrating that its mechanism of inhibition is independent of the presence of the Cys-199 residue.",
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-          "Sausville EA",
-          "Schultz C",
-          "Senderowicz AM",
-          "Snyder GL",
-          "Wu YZ",
-          "Zaharevitz DW"
+          "Allen ME",
+          "Bankston AN",
+          "Feng Y",
+          "Ku L",
+          "Li W",
+          "Liu G",
+          "Rui Y",
+          "Zheng JQ"
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-        "title": "Paullones are potent inhibitors of glycogen synthase kinase-3beta and cyclin-dependent kinase 5/p25.",
+        "date": "2016-11-02",
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+        "last": "Feng Y",
+        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
+        "pages": "11283-11294",
+        "reference": "27807169",
+        "title": "p39 Is Responsible for Increasing Cdk5 Activity during Postnatal Neuron Differentiation and Governs Neuronal Network Formation and Epileptic Responses.",
         "type": "PubMed",
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+          "Allen ME",
+          "Bankston AN",
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+          "Rui Y",
+          "Zheng JQ"
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+        "date": "2016-11-02",
+        "first": "Li W",
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+        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
+        "pages": "11283-11294",
+        "reference": "27807169",
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@@ -33526,53 +38026,46 @@
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       "citation": {
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-          "Schultz C",
-          "Senderowicz AM",
-          "Snyder GL",
-          "Wu YZ",
-          "Zaharevitz DW"
+          "Cuadrado-Tejedor M",
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+          "Oyarzabal J",
+          "Perea G",
+          "Pérez-González M",
+          "Rabal O",
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+        "first": "Cuadrado-Tejedor M",
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+        "pages": "524-539",
+        "reference": "27550730",
+        "title": "A First-in-Class Small-Molecule that Acts as a Dual Inhibitor of HDAC and PDE5 and that Rescues Hippocampal Synaptic Impairment in Alzheimer's Disease Mice.",
         "type": "PubMed",
-        "volume": "267"
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-      "evidence": "Alsterpaullone, the most active paullone, was demonstrated to act by competing with ATP for binding to GSK-3beta. Alsterpaullone inhibits the phosphorylation of tau in vivo at sites which are typically phosphorylated by GSK-3beta in Alzheimer's disease. Alsterpaullone also inhibits the CDK5/p25-dependent phosphorylation of DARPP-32 in mouse striatum slices in vitro. ",
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@@ -33580,73 +38073,139 @@
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-          "Schultz C",
-          "Senderowicz AM",
-          "Snyder GL",
-          "Wu YZ",
-          "Zaharevitz DW"
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+        "reference": "27550730",
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+        "volume": "42"
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+      "evidence": "Here we report the discovery of a new first-in-class small-molecule (CM-414) that acts as a dual inhibitor of PDE5 and HDACs. We have used this compound as a chemical probe to validate this systems therapeutics strategy, where an increase in the activation of cAMP/cGMP-responsive element-binding protein (CREB) induced by PDE5 inhibition, combined with moderate HDAC class I inhibition, leads to efficient histone acetylation. This molecule rescued the impaired long-term potentiation evident in hippocampal slices from APP/PS1 mice. Chronic treatment of Tg2576 mice with CM-414 diminished brain Aβ and tau phosphorylation (pTau) levels, increased the inactive form of GSK3β, reverted the decrease in dendritic spine density on hippocampal neurons, and reversed their cognitive deficits, at least in part by inducing the expression of genes related to synaptic transmission.",
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+      "source": 745,
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+      "relation": "hasVariant",
+      "source": 497,
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     },
     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
         "IC50": {
-          "5-50 nM": true
+          "50 mM": true
         }
       },
       "citation": {
         "authors": [
-          "Bibb JA",
-          "Biernat J",
-          "Eisenbrand G",
-          "Garnier M",
-          "Greengard P",
-          "Hoessel R",
-          "Leclerc S",
-          "Mandelkow EM",
-          "Marko D",
-          "Meijer L",
-          "Snyder GL",
-          "Wu YZ"
+          "DePaoli-Roach AA",
+          "Fiol CJ",
+          "Roach PJ",
+          "Wang QM"
         ],
-        "date": "2001-01-05",
-        "first": "Leclerc S",
-        "last": "Meijer L",
+        "date": "1994-05-20",
+        "first": "Wang QM",
+        "last": "Roach PJ",
         "name": "The Journal of biological chemistry",
-        "pages": "251-60",
-        "reference": "11013232",
-        "title": "Indirubins inhibit glycogen synthase kinase-3 beta and CDK5/p25, two protein kinases involved in abnormal tau phosphorylation in Alzheimer's disease. A property common to most cyclin-dependent kinase inhibitors?",
+        "pages": "14566-74",
+        "reference": "7514173",
+        "title": "Glycogen synthase kinase-3 beta is a dual specificity kinase differentially regulated by tyrosine and serine/threonine phosphorylation.",
         "type": "PubMed",
-        "volume": "276"
+        "volume": "269"
       },
-      "evidence": "We report here that indirubins are also powerful inhibitors (IC(50): 5-50 nm) of an evolutionarily related kinase, glycogen synthase kinase-3beta (GSK-3 beta).",
-      "key": "434a2fec3f6a7ad9fbf7f5409805fee57f69c2fb14c67dc5f6915384535dfe94b4beb49c9445960951b352541d2cc0d094252da2008ef7cef56cd8742d3fe87b",
-      "line": 1183,
+      "evidence": "Vm (nM/min/mg) is 2400, 80, 106, 650, and 140; Km is 200, 59, 114, 16 (all uM) and 5mg/ml for phospho-CREB peptide, myelin basic protein, k-casein, phosphatase Inhibitor-2 and phosvitin",
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       "object": {
         "effect": {
           "name": "kin",
@@ -33655,1182 +38214,1100 @@
         "modifier": "Activity"
       },
       "relation": "decreases",
-      "source": 149,
-      "target": 456
+      "source": 21,
+      "target": 537
     },
     {
       "annotations": {
-        "Anatomy": {
-          "striatum": true
-        },
-        "Ki": {
-          "4-80 nM": true
+        "Confidence": {
+          "High": true
         },
-        "Species": {
-          "10090": true
+        "IC50": {
+          "0.2 mM": true
         }
       },
       "citation": {
         "authors": [
-          "Bibb JA",
-          "Biernat J",
-          "Greengard P",
-          "Gussio R",
-          "Kunick C",
-          "Leost M",
-          "Link A",
-          "Mandelkow EM",
-          "Meijer L",
-          "Sausville EA",
-          "Schultz C",
-          "Senderowicz AM",
-          "Snyder GL",
-          "Wu YZ",
-          "Zaharevitz DW"
+          "DePaoli-Roach AA",
+          "Fiol CJ",
+          "Roach PJ",
+          "Wang QM"
         ],
-        "date": "2000-10-01",
-        "first": "Leost M",
-        "last": "Meijer L",
-        "name": "European journal of biochemistry",
-        "pages": "5983-94",
-        "reference": "10998059",
-        "title": "Paullones are potent inhibitors of glycogen synthase kinase-3beta and cyclin-dependent kinase 5/p25.",
+        "date": "1994-05-20",
+        "first": "Wang QM",
+        "last": "Roach PJ",
+        "name": "The Journal of biological chemistry",
+        "pages": "14566-74",
+        "reference": "7514173",
+        "title": "Glycogen synthase kinase-3 beta is a dual specificity kinase differentially regulated by tyrosine and serine/threonine phosphorylation.",
         "type": "PubMed",
-        "volume": "267"
+        "volume": "269"
       },
-      "evidence": "Alsterpaullone, the most active paullone, was demonstrated to act by competing with ATP for binding to GSK-3beta. Alsterpaullone inhibits the phosphorylation of tau in vivo at sites which are typically phosphorylated by GSK-3beta in Alzheimer's disease. Alsterpaullone also inhibits the CDK5/p25-dependent phosphorylation of DARPP-32 in mouse striatum slices in vitro. ",
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-      "line": 1198,
-      "relation": "increases",
-      "source": 777,
-      "subject": {
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         "modifier": "Activity"
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-      "target": 843
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+      "target": 537
     },
     {
       "annotations": {
-        "Anatomy": {
-          "hippocampal formation": true
+        "Confidence": {
+          "High": true
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-        "Species": {
-          "10090": true
+        "IC50": {
+          "0.6 mM": true
         }
       },
       "citation": {
         "authors": [
-          "Nikkuni M",
-          "Ohshima T",
-          "Toba J",
-          "Watamura N",
-          "Yoshii A"
+          "DePaoli-Roach AA",
+          "Fiol CJ",
+          "Roach PJ",
+          "Wang QM"
         ],
-        "date": "2016-01-01",
-        "first": "Watamura N",
-        "last": "Ohshima T",
-        "name": "Journal of neuroscience research",
-        "pages": "15-26",
-        "reference": "26400044",
-        "title": "Colocalization of phosphorylated forms of WAVE1, CRMP2, and tau in Alzheimer's disease model mice: Involvement of Cdk5 phosphorylation and the effect of ATRA treatment.",
+        "date": "1994-05-20",
+        "first": "Wang QM",
+        "last": "Roach PJ",
+        "name": "The Journal of biological chemistry",
+        "pages": "14566-74",
+        "reference": "7514173",
+        "title": "Glycogen synthase kinase-3 beta is a dual specificity kinase differentially regulated by tyrosine and serine/threonine phosphorylation.",
         "type": "PubMed",
-        "volume": "94"
+        "volume": "269"
       },
-      "evidence": "First, we verified the colocalization of p-WAVE1 and pCRMP2 with aggregated hyperphosphorylated tau in the hippocampus at 23 months of age. Biochemical analysis revealed the inclusion of p-WAVE1, p-CRMP2, and tau in the sarkosyl-insoluble fractions of hippocampal homogenates",
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     {
       "annotations": {
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       "citation": {
         "authors": [
-          "Nikkuni M",
-          "Ohshima T",
-          "Toba J",
-          "Watamura N",
-          "Yoshii A"
+          "DePaoli-Roach AA",
+          "Fiol CJ",
+          "Roach PJ",
+          "Wang QM"
         ],
-        "date": "2016-01-01",
-        "first": "Watamura N",
-        "last": "Ohshima T",
-        "name": "Journal of neuroscience research",
-        "pages": "15-26",
-        "reference": "26400044",
-        "title": "Colocalization of phosphorylated forms of WAVE1, CRMP2, and tau in Alzheimer's disease model mice: Involvement of Cdk5 phosphorylation and the effect of ATRA treatment.",
+        "date": "1994-05-20",
+        "first": "Wang QM",
+        "last": "Roach PJ",
+        "name": "The Journal of biological chemistry",
+        "pages": "14566-74",
+        "reference": "7514173",
+        "title": "Glycogen synthase kinase-3 beta is a dual specificity kinase differentially regulated by tyrosine and serine/threonine phosphorylation.",
         "type": "PubMed",
-        "volume": "94"
+        "volume": "269"
       },
-      "evidence": "First, we verified the colocalization of p-WAVE1 and pCRMP2 with aggregated hyperphosphorylated tau in the hippocampus at 23 months of age. Biochemical analysis revealed the inclusion of p-WAVE1, p-CRMP2, and tau in the sarkosyl-insoluble fractions of hippocampal homogenates",
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     {
       "annotations": {
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+          "0.4 mg/ml": true
         }
       },
       "citation": {
         "authors": [
-          "Ikezu S",
-          "Ikezu T"
+          "DePaoli-Roach AA",
+          "Fiol CJ",
+          "Roach PJ",
+          "Wang QM"
         ],
-        "date": "2014-01-01",
-        "first": "Ikezu S",
-        "last": "Ikezu T",
-        "name": "Frontiers in molecular neuroscience",
-        "pages": "33",
-        "reference": "24808823",
-        "title": "Tau-tubulin kinase.",
+        "date": "1994-05-20",
+        "first": "Wang QM",
+        "last": "Roach PJ",
+        "name": "The Journal of biological chemistry",
+        "pages": "14566-74",
+        "reference": "7514173",
+        "title": "Glycogen synthase kinase-3 beta is a dual specificity kinase differentially regulated by tyrosine and serine/threonine phosphorylation.",
         "type": "PubMed",
-        "volume": "7"
+        "volume": "269"
       },
-      "evidence": "Overexpression of TTBK1 was sufficient in inducing spatial learning impairment in mice, which is associated with enhanced Cdk5 activity and reduction in cell surface level of NR2B. Over-expressionof TTBK1 transgene in JNPL3 mice resulted in accumulation of pre-tangle forms of tau. Inaddition, TTBK1 expression plays a unique role in accelerating motor neuron degeneration and neuroinflammation in JNPL3mice.",
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     {
       "annotations": {
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       "citation": {
         "authors": [
-          "Chen X",
-          "Collins N",
-          "Dai X",
-          "Huang T",
-          "LaDu MJ",
-          "Lin L",
-          "Shen H",
-          "Wei Z",
-          "Wu X",
-          "Xiao N",
-          "York J",
-          "Zhang J",
-          "Zhou M",
-          "Zhu Y"
+          "DePaoli-Roach AA",
+          "Fiol CJ",
+          "Roach PJ",
+          "Wang QM"
         ],
-        "date": "2016-01-01",
-        "first": "Zhou M",
-        "last": "Chen X",
-        "name": "Current Alzheimer research",
-        "pages": "1048-55",
-        "reference": "27087442",
-        "title": "APOE4 Induces Site-Specific Tau Phosphorylation Through Calpain-CDK5 Signaling Pathway in EFAD-Tg Mice.",
+        "date": "1994-05-20",
+        "first": "Wang QM",
+        "last": "Roach PJ",
+        "name": "The Journal of biological chemistry",
+        "pages": "14566-74",
+        "reference": "7514173",
+        "title": "Glycogen synthase kinase-3 beta is a dual specificity kinase differentially regulated by tyrosine and serine/threonine phosphorylation.",
         "type": "PubMed",
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+        "volume": "269"
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-      "evidence": "Our data showed that CDK5 knock down induced an increase in p35 protein levels and Rac activity in triple transgenic Alzheimer's mice, which correlated with the recovery of cognitive function; these findings confirm that increased p35 and active Rac are involved in neuroprotection. In summary, our data suggest that p35 acts as a mediator of Rho GTPase activity and contributes to the neuroprotection induced by CDK5 RNAi.",
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+          "35 mM": true
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       "citation": {
         "authors": [
-          "Chen X",
-          "Collins N",
-          "Dai X",
-          "Huang T",
-          "LaDu MJ",
-          "Lin L",
-          "Shen H",
-          "Wei Z",
-          "Wu X",
-          "Xiao N",
-          "York J",
-          "Zhang J",
-          "Zhou M",
-          "Zhu Y"
+          "DePaoli-Roach AA",
+          "Fiol CJ",
+          "Roach PJ",
+          "Wang QM"
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-        "date": "2016-01-01",
-        "first": "Zhou M",
-        "last": "Chen X",
-        "name": "Current Alzheimer research",
-        "pages": "1048-55",
-        "reference": "27087442",
-        "title": "APOE4 Induces Site-Specific Tau Phosphorylation Through Calpain-CDK5 Signaling Pathway in EFAD-Tg Mice.",
+        "date": "1994-05-20",
+        "first": "Wang QM",
+        "last": "Roach PJ",
+        "name": "The Journal of biological chemistry",
+        "pages": "14566-74",
+        "reference": "7514173",
+        "title": "Glycogen synthase kinase-3 beta is a dual specificity kinase differentially regulated by tyrosine and serine/threonine phosphorylation.",
         "type": "PubMed",
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+        "volume": "269"
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-      "evidence": "Our data showed that CDK5 knock down induced an increase in p35 protein levels and Rac activity in triple transgenic Alzheimer's mice, which correlated with the recovery of cognitive function; these findings confirm that increased p35 and active Rac are involved in neuroprotection. In summary, our data suggest that p35 acts as a mediator of Rho GTPase activity and contributes to the neuroprotection induced by CDK5 RNAi.",
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     {
       "annotations": {
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       "citation": {
         "authors": [
-          "Chen X",
-          "Collins N",
-          "Dai X",
-          "Huang T",
-          "LaDu MJ",
-          "Lin L",
-          "Shen H",
-          "Wei Z",
-          "Wu X",
-          "Xiao N",
-          "York J",
-          "Zhang J",
-          "Zhou M",
-          "Zhu Y"
+          "DePaoli-Roach AA",
+          "Fiol CJ",
+          "Roach PJ",
+          "Wang QM"
         ],
-        "date": "2016-01-01",
-        "first": "Zhou M",
-        "last": "Chen X",
-        "name": "Current Alzheimer research",
-        "pages": "1048-55",
-        "reference": "27087442",
-        "title": "APOE4 Induces Site-Specific Tau Phosphorylation Through Calpain-CDK5 Signaling Pathway in EFAD-Tg Mice.",
+        "date": "1994-05-20",
+        "first": "Wang QM",
+        "last": "Roach PJ",
+        "name": "The Journal of biological chemistry",
+        "pages": "14566-74",
+        "reference": "7514173",
+        "title": "Glycogen synthase kinase-3 beta is a dual specificity kinase differentially regulated by tyrosine and serine/threonine phosphorylation.",
         "type": "PubMed",
-        "volume": "13"
+        "volume": "269"
       },
-      "evidence": "Our data showed that CDK5 knock down induced an increase in p35 protein levels and Rac activity in triple transgenic Alzheimer's mice, which correlated with the recovery of cognitive function; these findings confirm that increased p35 and active Rac are involved in neuroprotection. In summary, our data suggest that p35 acts as a mediator of Rho GTPase activity and contributes to the neuroprotection induced by CDK5 RNAi.",
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     {
       "annotations": {
-        "Species": {
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+          "High": true
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+        "IC50": {
+          "4.5 mM": true
         }
       },
       "citation": {
         "authors": [
-          "Chen X",
-          "Collins N",
-          "Dai X",
-          "Huang T",
-          "LaDu MJ",
-          "Lin L",
-          "Shen H",
-          "Wei Z",
-          "Wu X",
-          "Xiao N",
-          "York J",
-          "Zhang J",
-          "Zhou M",
-          "Zhu Y"
+          "DePaoli-Roach AA",
+          "Fiol CJ",
+          "Roach PJ",
+          "Wang QM"
         ],
-        "date": "2016-01-01",
-        "first": "Zhou M",
-        "last": "Chen X",
-        "name": "Current Alzheimer research",
-        "pages": "1048-55",
-        "reference": "27087442",
-        "title": "APOE4 Induces Site-Specific Tau Phosphorylation Through Calpain-CDK5 Signaling Pathway in EFAD-Tg Mice.",
+        "date": "1994-05-20",
+        "first": "Wang QM",
+        "last": "Roach PJ",
+        "name": "The Journal of biological chemistry",
+        "pages": "14566-74",
+        "reference": "7514173",
+        "title": "Glycogen synthase kinase-3 beta is a dual specificity kinase differentially regulated by tyrosine and serine/threonine phosphorylation.",
         "type": "PubMed",
-        "volume": "13"
+        "volume": "269"
       },
-      "evidence": "Our data showed that CDK5 knock down induced an increase in p35 protein levels and Rac activity in triple transgenic Alzheimer's mice, which correlated with the recovery of cognitive function; these findings confirm that increased p35 and active Rac are involved in neuroprotection. In summary, our data suggest that p35 acts as a mediator of Rho GTPase activity and contributes to the neuroprotection induced by CDK5 RNAi.",
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     {
       "annotations": {
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       },
       "citation": {
         "authors": [
-          "Cruz JC",
-          "Goldman JA",
-          "Shih H",
-          "Tsai LH",
-          "Tseng HC"
+          "El-Akkad E",
+          "Gong CX",
+          "Grundke-Iqbal I",
+          "Iqbal K",
+          "Liang Z",
+          "Liu F",
+          "Shi J",
+          "Yin D"
         ],
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-        "first": "Cruz JC",
-        "last": "Tsai LH",
-        "name": "Neuron",
-        "pages": "471-83",
-        "reference": "14642273",
-        "title": "Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles.",
+        "date": "2006-11-13",
+        "first": "Liu F",
+        "last": "Gong CX",
+        "name": "FEBS letters",
+        "pages": "6269-74",
+        "reference": "17078951",
+        "title": "PKA modulates GSK-3beta- and cdk5-catalyzed phosphorylation of tau in site- and kinase-specific manners.",
         "type": "PubMed",
-        "volume": "40"
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-      "evidence": "Tau peptides containing phosphorylated S202, T205, and T396 were found only in Tg mice, supporting our results using AT8 and PHF1 antibodies",
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       },
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+      "evidence": "Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396.",
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     {
       "annotations": {
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       },
       "citation": {
         "authors": [
-          "Cruz JC",
-          "Goldman JA",
-          "Shih H",
-          "Tsai LH",
-          "Tseng HC"
+          "Cowburn RF",
+          "Dahllund L",
+          "Gustafsson E",
+          "Lund H",
+          "Malinowsky D",
+          "Strömberg K",
+          "Sunnemark D",
+          "Svensson A"
         ],
-        "date": "2003-10-30",
-        "first": "Cruz JC",
-        "last": "Tsai LH",
-        "name": "Neuron",
-        "pages": "471-83",
-        "reference": "14642273",
-        "title": "Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles.",
+        "date": "2013-07-01",
+        "first": "Lund H",
+        "last": "Sunnemark D",
+        "name": "Brain pathology (Zurich, Switzerland)",
+        "pages": "378-89",
+        "reference": "23088643",
+        "title": "Tau-tubulin kinase 1 expression, phosphorylation and co-localization with phospho-Ser422 tau in the Alzheimer's disease brain.",
         "type": "PubMed",
-        "volume": "40"
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-      "evidence": "Tau peptides containing phosphorylated S202, T205, and T396 were found only in Tg mice, supporting our results using AT8 and PHF1 antibodies",
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       },
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       "annotations": {
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       "citation": {
         "authors": [
-          "Cruz JC",
-          "Goldman JA",
-          "Shih H",
-          "Tsai LH",
-          "Tseng HC"
+          "Cowburn RF",
+          "Dahllund L",
+          "Gustafsson E",
+          "Lund H",
+          "Malinowsky D",
+          "Strömberg K",
+          "Sunnemark D",
+          "Svensson A"
         ],
-        "date": "2003-10-30",
-        "first": "Cruz JC",
-        "last": "Tsai LH",
-        "name": "Neuron",
-        "pages": "471-83",
-        "reference": "14642273",
-        "title": "Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles.",
+        "date": "2013-07-01",
+        "first": "Lund H",
+        "last": "Sunnemark D",
+        "name": "Brain pathology (Zurich, Switzerland)",
+        "pages": "378-89",
+        "reference": "23088643",
+        "title": "Tau-tubulin kinase 1 expression, phosphorylation and co-localization with phospho-Ser422 tau in the Alzheimer's disease brain.",
         "type": "PubMed",
-        "volume": "40"
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-      "evidence": "Tau peptides containing phosphorylated S202, T205, and T396 were found only in Tg mice, supporting our results using AT8 and PHF1 antibodies",
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-        },
-        "modifier": "Activity"
+        "volume": "23"
       },
-      "target": 812
+      "evidence": "TTBK1 has been shown, by partial phosphopeptide mapping, to phosphorylate tau at serine residues 198, 199, 202 and 422 and at tyrosine 197 in vitro, sites that are also phosphorylated in AD PHFs (7, 12)",
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     {
       "annotations": {
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       "citation": {
         "authors": [
-          "Cruz JC",
-          "Goldman JA",
-          "Shih H",
-          "Tsai LH",
-          "Tseng HC"
+          "Ait-Ghezala G",
+          "Bachmeier C",
+          "Beaulieu-Abdelahad D",
+          "Crawford F",
+          "Jin C",
+          "Laco G",
+          "Lin Y",
+          "Mullan M",
+          "Paris D"
         ],
-        "date": "2003-10-30",
-        "first": "Cruz JC",
-        "last": "Tsai LH",
-        "name": "Neuron",
-        "pages": "471-83",
-        "reference": "14642273",
-        "title": "Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles.",
+        "date": "2014-12-05",
+        "first": "Paris D",
+        "last": "Mullan M",
+        "name": "The Journal of biological chemistry",
+        "pages": "33927-44",
+        "reference": "25331948",
+        "title": "The spleen tyrosine kinase (Syk) regulates Alzheimer amyloid-β production and Tau hyperphosphorylation.",
         "type": "PubMed",
-        "volume": "40"
-      },
-      "evidence": "Tau peptides containing phosphorylated S202, T205, and T396 were found only in Tg mice, supporting our results using AT8 and PHF1 antibodies",
-      "key": "51abaebefbffe4d966a71e652f3ec8529b95018941d0ee3c7ee892dda19b6815a99384ace95e6eb315d72dac858d8df5b2bb7e0293772e4955b434b424606396",
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-        "modifier": "Activity"
+        "volume": "289"
       },
-      "target": 813
+      "evidence": "Western blot analyses of brain homogenates show that (−)-nilvadipine significantly reduces Tau phosphorylation in AT8 (phosphorylated Ser-199/Ser-202/Thr-205) and PHF-1 (phosphorylated Ser-396/Ser-404) epitopes",
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     {
       "annotations": {
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+          "Medium": true
         },
         "Species": {
-          "10090": true
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       },
       "citation": {
         "authors": [
-          "Cruz JC",
-          "Goldman JA",
-          "Shih H",
-          "Tsai LH",
-          "Tseng HC"
+          "Boehm J",
+          "Bourgeois C",
+          "Dudilot A",
+          "Lauzon M",
+          "Leclerc N",
+          "Mondragón-Rodríguez S",
+          "Trillaud-Doppia E"
         ],
-        "date": "2003-10-30",
-        "first": "Cruz JC",
-        "last": "Tsai LH",
-        "name": "Neuron",
-        "pages": "471-83",
-        "reference": "14642273",
-        "title": "Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles.",
+        "date": "2012-09-14",
+        "first": "Mondragón-Rodríguez S",
+        "last": "Boehm J",
+        "name": "The Journal of biological chemistry",
+        "pages": "32040-53",
+        "reference": "22833681",
+        "title": "Interaction of endogenous tau protein with synaptic proteins is regulated by N-methyl-D-aspartate receptor-dependent tau phosphorylation.",
         "type": "PubMed",
-        "volume": "40"
-      },
-      "evidence": "Tau peptides containing phosphorylated S202, T205, and T396 were found only in Tg mice, supporting our results using AT8 and PHF1 antibodies",
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-        },
-        "modifier": "Activity"
+        "volume": "287"
       },
-      "target": 814
+      "evidence": "Hence, LTD-inducing NMDA receptor activation leads to an increase in tau phosphorylation at sites PHF-1, AT180, as well as AT8 and to a reduction at AT100.",
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       "annotations": {
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       },
       "citation": {
         "authors": [
-          "Cruz JC",
-          "Goldman JA",
-          "Shih H",
-          "Tsai LH",
-          "Tseng HC"
+          "Gamblin TC",
+          "Sun Q"
         ],
-        "date": "2003-10-30",
-        "first": "Cruz JC",
-        "last": "Tsai LH",
-        "name": "Neuron",
-        "pages": "471-83",
-        "reference": "14642273",
-        "title": "Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles.",
+        "date": "2009-06-30",
+        "first": "Sun Q",
+        "last": "Gamblin TC",
+        "name": "Biochemistry",
+        "pages": "6002-11",
+        "reference": "19459590",
+        "title": "Pseudohyperphosphorylation causing AD-like changes in tau has significant effects on its polymerization.",
         "type": "PubMed",
-        "volume": "40"
-      },
-      "evidence": "Tau peptides containing phosphorylated S202, T205, and T396 were found only in Tg mice, supporting our results using AT8 and PHF1 antibodies",
-      "key": "b698d67707a56d8dcfcbfc857bd51810ccb1ab80382428ac330ed90e34a1877343087b750ba9100c0d27f474fde4e518a0973e01c28154205de18dce7af7a0f6",
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+      "evidence": "Because S199/S202/T205E, S396/S404E, 6-Phos and 7-Phos all demonstrated an AD-like shift in mobility as a result of phosphorylation-like changes, we conclude that they have the characteristics of hyperphosphorylated tau. These mutants will therefore be referred to as pseudo-hyperphosphorylated tau throughout the manuscript. On the basis of the observations that pseudohyperphosphorylated tau has decreased affinity for microtubules and reduced inducer-initiated rates of nucleation and polymerization, we propose that this combination could be the cause of the increased cytotoxicity of hyperphosphorylated tau in Alzheimer's disease and also explain the potentially beneficial role of tau polymerization and NFT formation.",
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     {
       "annotations": {
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         },
         "Species": {
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       "citation": {
         "authors": [
-          "Cruz JC",
-          "Goldman JA",
-          "Shih H",
-          "Tsai LH",
-          "Tseng HC"
+          "Boehm J",
+          "Bourgeois C",
+          "Dudilot A",
+          "Lauzon M",
+          "Leclerc N",
+          "Mondragón-Rodríguez S",
+          "Trillaud-Doppia E"
         ],
-        "date": "2003-10-30",
-        "first": "Cruz JC",
-        "last": "Tsai LH",
-        "name": "Neuron",
-        "pages": "471-83",
-        "reference": "14642273",
-        "title": "Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles.",
+        "date": "2012-09-14",
+        "first": "Mondragón-Rodríguez S",
+        "last": "Boehm J",
+        "name": "The Journal of biological chemistry",
+        "pages": "32040-53",
+        "reference": "22833681",
+        "title": "Interaction of endogenous tau protein with synaptic proteins is regulated by N-methyl-D-aspartate receptor-dependent tau phosphorylation.",
         "type": "PubMed",
-        "volume": "40"
-      },
-      "evidence": "Tau peptides containing phosphorylated S202, T205, and T396 were found only in Tg mice, supporting our results using AT8 and PHF1 antibodies",
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-        "modifier": "Activity"
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       },
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+      "evidence": "This result is supported by recent studies showing that the interaction between Fyn and tau is regulated through tau phosphorylation at the AT8 site, increasing tau-Fyn interaction by 42-fold after tau is phosphorylated or bearing a phosphomimetic mutation at the AT8 site (63). In our experiments, tau phosphorylation at AT8 is strongly up-regulated through the activation of NMDA receptors (Fig. 3), suggesting that NMDA receptor activation could massively enhance the interaction between tau and Fyn.",
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     {
       "annotations": {
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       },
       "citation": {
         "authors": [
-          "Cruz JC",
-          "Goldman JA",
-          "Shih H",
-          "Tsai LH",
-          "Tseng HC"
+          "Andreadis A",
+          "Binder LI",
+          "Brady ST",
+          "Fu Y",
+          "Kanaan NM",
+          "LaPointe NE",
+          "Morfini GA",
+          "Patterson KR",
+          "Pigino GF",
+          "Song Y"
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-        "first": "Cruz JC",
-        "last": "Tsai LH",
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-        "title": "Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles.",
+        "date": "2011-07-06",
+        "first": "Kanaan NM",
+        "last": "Binder LI",
+        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
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+        "reference": "21734277",
+        "title": "Pathogenic forms of tau inhibit kinesin-dependent axonal transport through a mechanism involving activation of axonal phosphotransferases.",
         "type": "PubMed",
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         "authors": [
-          "Cruz JC",
-          "Goldman JA",
-          "Shih H",
-          "Tsai LH",
-          "Tseng HC"
+          "El-Akkad E",
+          "Gong CX",
+          "Grundke-Iqbal I",
+          "Iqbal K",
+          "Liang Z",
+          "Liu F",
+          "Shi J",
+          "Yin D"
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-        "title": "Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles.",
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+        "first": "Liu F",
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         "type": "PubMed",
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-          "Cruz JC",
-          "Goldman JA",
-          "Shih H",
-          "Tsai LH",
-          "Tseng HC"
+          "Cowburn RF",
+          "Dahllund L",
+          "Gustafsson E",
+          "Lund H",
+          "Malinowsky D",
+          "Strömberg K",
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+        "first": "Lund H",
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-          "Goldman JA",
-          "Shih H",
-          "Tsai LH",
-          "Tseng HC"
+          "Cowburn RF",
+          "Dahllund L",
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+        "first": "Lund H",
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-          "Goldman JA",
-          "Shih H",
-          "Tsai LH",
-          "Tseng HC"
+          "Baulieu EE",
+          "Byrne C",
+          "Cantrelle FX",
+          "Chambraud B",
+          "Despres C",
+          "Huvent I",
+          "Jacquot Y",
+          "Landrieu I",
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+          "Smet-Nocca C"
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-        "title": "Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles.",
+        "date": "2017-08-22",
+        "first": "Despres C",
+        "last": "Smet-Nocca C",
+        "name": "Proceedings of the National Academy of Sciences of the United States of America",
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         "type": "PubMed",
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-          "Goldman JA",
-          "Shih H",
-          "Tsai LH",
-          "Tseng HC"
+          "Ait-Ghezala G",
+          "Bachmeier C",
+          "Beaulieu-Abdelahad D",
+          "Crawford F",
+          "Jin C",
+          "Laco G",
+          "Lin Y",
+          "Mullan M",
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+        "first": "Paris D",
+        "last": "Mullan M",
+        "name": "The Journal of biological chemistry",
+        "pages": "33927-44",
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+        "title": "The spleen tyrosine kinase (Syk) regulates Alzheimer amyloid-β production and Tau hyperphosphorylation.",
         "type": "PubMed",
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         "authors": [
-          "Ishiguro K",
-          "Kusubata M",
-          "Matsubara M",
-          "Taniguchi H",
-          "Titani K",
-          "Uchida T"
+          "Boehm J",
+          "Bourgeois C",
+          "Dudilot A",
+          "Lauzon M",
+          "Leclerc N",
+          "Mondragón-Rodríguez S",
+          "Trillaud-Doppia E"
         ],
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-        "first": "Matsubara M",
-        "last": "Taniguchi H",
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+        "first": "Mondragón-Rodríguez S",
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         "name": "The Journal of biological chemistry",
-        "pages": "21108-13",
-        "reference": "8702879",
-        "title": "Site-specific phosphorylation of synapsin I by mitogen-activated protein kinase and Cdk5 and its effects on physiological functions.",
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+        "reference": "22833681",
+        "title": "Interaction of endogenous tau protein with synaptic proteins is regulated by N-methyl-D-aspartate receptor-dependent tau phosphorylation.",
         "type": "PubMed",
-        "volume": "271"
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-      "evidence": "The phosphorylation sites were determined to be Ser551 and Ser553 with Cdk5-p23, and Ser62, Ser67, and Ser551 with MAP kinase. Upon phosphorylation with MAP kinase, synapsin I showed reduced F-actin bundling activity, while no significant effect on the interaction was observed with the protein phosphorylated with Cdk5-p23.",
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+      "evidence": "Hence, LTD-inducing NMDA receptor activation leads to an increase in tau phosphorylation at sites PHF-1, AT180, as well as AT8 and to a reduction at AT100.",
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+          "NMR Spectroscopy": true,
+          "Thioflavin T Assay": true
+        }
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       "citation": {
         "authors": [
-          "Ishiguro K",
-          "Kusubata M",
-          "Matsubara M",
-          "Taniguchi H",
-          "Titani K",
-          "Uchida T"
+          "Baulieu EE",
+          "Byrne C",
+          "Cantrelle FX",
+          "Chambraud B",
+          "Despres C",
+          "Huvent I",
+          "Jacquot Y",
+          "Landrieu I",
+          "Lippens G",
+          "Qi H",
+          "Smet-Nocca C"
         ],
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-        "first": "Matsubara M",
-        "last": "Taniguchi H",
-        "name": "The Journal of biological chemistry",
-        "pages": "21108-13",
-        "reference": "8702879",
-        "title": "Site-specific phosphorylation of synapsin I by mitogen-activated protein kinase and Cdk5 and its effects on physiological functions.",
+        "date": "2017-08-22",
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+        "last": "Smet-Nocca C",
+        "name": "Proceedings of the National Academy of Sciences of the United States of America",
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+        "reference": "28784767",
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         "type": "PubMed",
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       "citation": {
         "authors": [
-          "Ishiguro K",
-          "Kusubata M",
-          "Matsubara M",
-          "Taniguchi H",
-          "Titani K",
-          "Uchida T"
+          "Ait-Ghezala G",
+          "Bachmeier C",
+          "Beaulieu-Abdelahad D",
+          "Crawford F",
+          "Jin C",
+          "Laco G",
+          "Lin Y",
+          "Mullan M",
+          "Paris D"
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-        "first": "Matsubara M",
-        "last": "Taniguchi H",
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+        "first": "Paris D",
+        "last": "Mullan M",
         "name": "The Journal of biological chemistry",
-        "pages": "21108-13",
-        "reference": "8702879",
-        "title": "Site-specific phosphorylation of synapsin I by mitogen-activated protein kinase and Cdk5 and its effects on physiological functions.",
+        "pages": "33927-44",
+        "reference": "25331948",
+        "title": "The spleen tyrosine kinase (Syk) regulates Alzheimer amyloid-β production and Tau hyperphosphorylation.",
         "type": "PubMed",
-        "volume": "271"
-      },
-      "evidence": "The phosphorylation sites were determined to be Ser551 and Ser553 with Cdk5-p23, and Ser62, Ser67, and Ser551 with MAP kinase. Upon phosphorylation with MAP kinase, synapsin I showed reduced F-actin bundling activity, while no significant effect on the interaction was observed with the protein phosphorylated with Cdk5-p23.",
-      "key": "8d1550dbbb2272219b625aad9d9068e8ae21457833cbd6ad46cee1d9e157235d63dcf3e7704bc1355c07e3059d5bfbe4f7c69434e9689e98d982002bb9482fa9",
-      "line": 1221,
-      "relation": "negativeCorrelation",
-      "source": 707,
-      "subject": {
-        "modifier": "Activity"
+        "volume": "289"
       },
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-    },
-    {
-      "key": "57cae75d6c0fdf0041d3ee1b9c0cb629187f1214690e27d1a57dbc85ee2250222ae1cc90bf352aece5b3a5b01dabc3003265fc9f9bffd655283257937084dfed",
-      "relation": "hasVariant",
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+      "evidence": "We further validated Syk as a target-regulating Aβ by showing that pharmacological inhibition of Syk or down-regulation of Syk expression reduces Aβ production and increases the clearance of Aβ across the BBB mimicking (-)-nilvadipine effects. Moreover, treatment of transgenic mice overexpressing Aβ and transgenic Tau P301S mice with a selective Syk inhibitor respectively decreased brain Aβ accumulation and Tau hyperphosphorylation at multiple AD relevant epitopes.",
+      "key": "1d1bb135d3be6c296f5e6f7503b0654ce5de1b00c7eb54861a658436ee11a3016e33a5fd006db8020a6c9601761ce1275bf8a8a30654916d0c980e10a9e7cb1c",
+      "line": 2779,
+      "relation": "equivalentTo",
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     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
-          "Ishiguro K",
-          "Kusubata M",
-          "Matsubara M",
-          "Taniguchi H",
-          "Titani K",
-          "Uchida T"
+          "Gamblin TC",
+          "Sun Q"
         ],
-        "date": "1996-08-30",
-        "first": "Matsubara M",
-        "last": "Taniguchi H",
-        "name": "The Journal of biological chemistry",
-        "pages": "21108-13",
-        "reference": "8702879",
-        "title": "Site-specific phosphorylation of synapsin I by mitogen-activated protein kinase and Cdk5 and its effects on physiological functions.",
+        "date": "2009-06-30",
+        "first": "Sun Q",
+        "last": "Gamblin TC",
+        "name": "Biochemistry",
+        "pages": "6002-11",
+        "reference": "19459590",
+        "title": "Pseudohyperphosphorylation causing AD-like changes in tau has significant effects on its polymerization.",
         "type": "PubMed",
-        "volume": "271"
-      },
-      "evidence": "The phosphorylation sites were determined to be Ser551 and Ser553 with Cdk5-p23, and Ser62, Ser67, and Ser551 with MAP kinase. Upon phosphorylation with MAP kinase, synapsin I showed reduced F-actin bundling activity, while no significant effect on the interaction was observed with the protein phosphorylated with Cdk5-p23.",
-      "key": "b84c7f94cd012daeddbbf04ed33afe7a3fdb9e1cb08f3116ea002f316783cc9ca9a4decfec2dc3915d20579976d58d6476d07efd969a499d6395d2efe31218f6",
-      "line": 1222,
-      "relation": "negativeCorrelation",
-      "source": 707,
-      "subject": {
-        "modifier": "Activity"
+        "volume": "48"
       },
-      "target": 711
-    },
-    {
-      "key": "e424f241b25481adb87435fedeb9d8b22e826e143143e9a0c50b71f7e333f40f7f4a8cd1970d783c4fe8e20cd687956f72fba840b4b88a8a7c8b3087b693a515",
-      "relation": "hasVariant",
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+      "evidence": "Because S199/S202/T205E, S396/S404E, 6-Phos and 7-Phos all demonstrated an AD-like shift in mobility as a result of phosphorylation-like changes, we conclude that they have the characteristics of hyperphosphorylated tau. These mutants will therefore be referred to as pseudo-hyperphosphorylated tau throughout the manuscript. On the basis of the observations that pseudohyperphosphorylated tau has decreased affinity for microtubules and reduced inducer-initiated rates of nucleation and polymerization, we propose that this combination could be the cause of the increased cytotoxicity of hyperphosphorylated tau in Alzheimer's disease and also explain the potentially beneficial role of tau polymerization and NFT formation.",
+      "key": "b7236e09a3447733472490960ef467e503cf5f110208dab77e0cf779b5023132bf8352e35d557e0ef122293ef667c9e53d0dcac6d6929c99bcf05d07dee4b679",
+      "line": 3034,
+      "relation": "decreases",
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     },
     {
+      "annotations": {
+        "Anatomy": {
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+        },
+        "Confidence": {
+          "Medium": true
+        },
+        "Species": {
+          "10116": true
+        }
+      },
       "citation": {
         "authors": [
-          "Ishiguro K",
-          "Kusubata M",
-          "Matsubara M",
-          "Taniguchi H",
-          "Titani K",
-          "Uchida T"
+          "Boehm J",
+          "Bourgeois C",
+          "Dudilot A",
+          "Lauzon M",
+          "Leclerc N",
+          "Mondragón-Rodríguez S",
+          "Trillaud-Doppia E"
         ],
-        "date": "1996-08-30",
-        "first": "Matsubara M",
-        "last": "Taniguchi H",
+        "date": "2012-09-14",
+        "first": "Mondragón-Rodríguez S",
+        "last": "Boehm J",
         "name": "The Journal of biological chemistry",
-        "pages": "21108-13",
-        "reference": "8702879",
-        "title": "Site-specific phosphorylation of synapsin I by mitogen-activated protein kinase and Cdk5 and its effects on physiological functions.",
+        "pages": "32040-53",
+        "reference": "22833681",
+        "title": "Interaction of endogenous tau protein with synaptic proteins is regulated by N-methyl-D-aspartate receptor-dependent tau phosphorylation.",
         "type": "PubMed",
-        "volume": "271"
+        "volume": "287"
       },
-      "evidence": "The phosphorylation sites were determined to be Ser551 and Ser553 with Cdk5-p23, and Ser62, Ser67, and Ser551 with MAP kinase. Upon phosphorylation with MAP kinase, synapsin I showed reduced F-actin bundling activity, while no significant effect on the interaction was observed with the protein phosphorylated with Cdk5-p23.",
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-      "line": 1217,
+      "evidence": "This result is supported by recent studies showing that the interaction between Fyn and tau is regulated through tau phosphorylation at the AT8 site, increasing tau-Fyn interaction by 42-fold after tau is phosphorylated or bearing a phosphomimetic mutation at the AT8 site (63). In our experiments, tau phosphorylation at AT8 is strongly up-regulated through the activation of NMDA receptors (Fig. 3), suggesting that NMDA receptor activation could massively enhance the interaction between tau and Fyn.",
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       "relation": "increases",
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-      "target": 710
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     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "Research_Model": {
+          "rTg4510 mice": true
+        }
+      },
       "citation": {
         "authors": [
-          "Ishiguro K",
-          "Kusubata M",
-          "Matsubara M",
-          "Taniguchi H",
-          "Titani K",
-          "Uchida T"
+          "Boehm J",
+          "Bourgeois C",
+          "Dudilot A",
+          "Lauzon M",
+          "Leclerc N",
+          "Mondragón-Rodríguez S",
+          "Trillaud-Doppia E"
         ],
-        "date": "1996-08-30",
-        "first": "Matsubara M",
-        "last": "Taniguchi H",
+        "date": "2012-09-14",
+        "first": "Mondragón-Rodríguez S",
+        "last": "Boehm J",
         "name": "The Journal of biological chemistry",
-        "pages": "21108-13",
-        "reference": "8702879",
-        "title": "Site-specific phosphorylation of synapsin I by mitogen-activated protein kinase and Cdk5 and its effects on physiological functions.",
+        "pages": "32040-53",
+        "reference": "22833681",
+        "title": "Interaction of endogenous tau protein with synaptic proteins is regulated by N-methyl-D-aspartate receptor-dependent tau phosphorylation.",
         "type": "PubMed",
-        "volume": "271"
-      },
-      "evidence": "The phosphorylation sites were determined to be Ser551 and Ser553 with Cdk5-p23, and Ser62, Ser67, and Ser551 with MAP kinase. Upon phosphorylation with MAP kinase, synapsin I showed reduced F-actin bundling activity, while no significant effect on the interaction was observed with the protein phosphorylated with Cdk5-p23.",
-      "key": "5bd41c125ea9f01fecee163009b066ebb0e707b469d2139902cdf51714e8ea1dae549c58ba7b66ed18b857759530cd2642f4476f7751af7071a26f17a081ec34",
-      "line": 1218,
-      "relation": "increases",
-      "source": 293,
-      "subject": {
-        "modifier": "Activity"
+        "volume": "287"
       },
-      "target": 711
+      "evidence": "Acute treatment of rTg4510 mice with an O-GlcNAcase inhibitor transiently reduced tau phosphorylation at epitopes implicated in tau pathology. More importantly, long-term inhibitor treatment strongly increased tau O-GlcNAcylation, reduced the number of dystrophic neurons, and protected against the formation of pathological tau species without altering the phosphorylation of non-pathological tau.",
+      "key": "65f36ef4b0f02c75ade243d3c727b69fa57984ab7b2e698116766238e5d9f86c18ccb30e164a2b062fec2375677e1c537c6d5bee6a177473ed73761efb2a0818",
+      "line": 3089,
+      "relation": "positiveCorrelation",
+      "source": 629,
+      "target": 596
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Hippocampus": true
+        },
+        "Research_Model": {
+          "TPR50 mice": true
+        },
+        "Species": {
+          "10090": true
+        }
+      },
       "citation": {
         "authors": [
-          "Ishiguro K",
-          "Kusubata M",
-          "Matsubara M",
-          "Taniguchi H",
-          "Titani K",
-          "Uchida T"
+          "Hattori M",
+          "Horiguchi T",
+          "Iwashita H",
+          "Matsumoto Y",
+          "Nakamura K",
+          "Obayashi Y",
+          "Onishi T",
+          "Yano T"
         ],
-        "date": "1996-08-30",
-        "first": "Matsubara M",
-        "last": "Taniguchi H",
-        "name": "The Journal of biological chemistry",
-        "pages": "21108-13",
-        "reference": "8702879",
-        "title": "Site-specific phosphorylation of synapsin I by mitogen-activated protein kinase and Cdk5 and its effects on physiological functions.",
+        "date": "2014-03-01",
+        "first": "Onishi T",
+        "last": "Iwashita H",
+        "name": "Neuroscience research",
+        "pages": "76-85",
+        "reference": "24406748",
+        "title": "Early-onset cognitive deficits and axonal transport dysfunction in P301S mutant tau transgenic mice.",
         "type": "PubMed",
-        "volume": "271"
-      },
-      "evidence": "The phosphorylation sites were determined to be Ser551 and Ser553 with Cdk5-p23, and Ser62, Ser67, and Ser551 with MAP kinase. Upon phosphorylation with MAP kinase, synapsin I showed reduced F-actin bundling activity, while no significant effect on the interaction was observed with the protein phosphorylated with Cdk5-p23.",
-      "key": "91c242e73631329776cfde9bcdc209dc6558559cb09527b6c10d2056b580fa64b25ebc78e04232f59021810d578674dfdbceeae0ef9d11ecde870143ae9a03c8",
-      "line": 1219,
-      "relation": "increases",
-      "source": 293,
-      "subject": {
-        "modifier": "Activity"
+        "volume": "80"
       },
-      "target": 708
-    },
-    {
-      "citation": {
-        "authors": [
-          "Ishiguro K",
-          "Kusubata M",
-          "Matsubara M",
-          "Taniguchi H",
-          "Titani K",
-          "Uchida T"
-        ],
-        "date": "1996-08-30",
-        "first": "Matsubara M",
-        "last": "Taniguchi H",
-        "name": "The Journal of biological chemistry",
-        "pages": "21108-13",
-        "reference": "8702879",
-        "title": "Site-specific phosphorylation of synapsin I by mitogen-activated protein kinase and Cdk5 and its effects on physiological functions.",
-        "type": "PubMed",
-        "volume": "271"
-      },
-      "evidence": "The phosphorylation sites were determined to be Ser551 and Ser553 with Cdk5-p23, and Ser62, Ser67, and Ser551 with MAP kinase. Upon phosphorylation with MAP kinase, synapsin I showed reduced F-actin bundling activity, while no significant effect on the interaction was observed with the protein phosphorylated with Cdk5-p23.",
-      "key": "e58925ab9292012990b73371144103371cfc74c838397b57ae721287135cbb018d4962ca65de6c5199cd9c6c9d7e1781a4b52ea684895e516a1c577c82c85471",
-      "line": 1221,
-      "object": {
-        "modifier": "Activity"
-      },
-      "relation": "negativeCorrelation",
-      "source": 710,
-      "target": 707
+      "evidence": "We developed a transgenic mouse, named TPR50, harboring human P301S tau. Tau phosphorylation in the hippocampus of TPR50 mice increased with age, particularly at S202/T205. Therefore, cognitive dysfunction in TPR50 mice may result from early MT dysfunction and impaired axonal transport rather than accumulation of insoluble tau and neurodegeneration.",
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     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "Research_Model": {
+          "pR5 mice": true
+        },
+        "Species": {
+          "10090": true
+        }
+      },
       "citation": {
         "authors": [
-          "Ishiguro K",
-          "Kusubata M",
-          "Matsubara M",
-          "Taniguchi H",
-          "Titani K",
-          "Uchida T"
+          "Dinekov M",
+          "Götz J",
+          "Köhler C"
         ],
-        "date": "1996-08-30",
-        "first": "Matsubara M",
-        "last": "Taniguchi H",
-        "name": "The Journal of biological chemistry",
-        "pages": "21108-13",
-        "reference": "8702879",
-        "title": "Site-specific phosphorylation of synapsin I by mitogen-activated protein kinase and Cdk5 and its effects on physiological functions.",
+        "date": "2013-05-01",
+        "first": "Köhler C",
+        "last": "Götz J",
+        "name": "Neurobiology of aging",
+        "pages": "1369-79",
+        "reference": "23294633",
+        "title": "Active glycogen synthase kinase-3 and tau pathology-related tyrosine phosphorylation in pR5 human tau transgenic mice.",
         "type": "PubMed",
-        "volume": "271"
-      },
-      "evidence": "The phosphorylation sites were determined to be Ser551 and Ser553 with Cdk5-p23, and Ser62, Ser67, and Ser551 with MAP kinase. Upon phosphorylation with MAP kinase, synapsin I showed reduced F-actin bundling activity, while no significant effect on the interaction was observed with the protein phosphorylated with Cdk5-p23.",
-      "key": "7635e4585b8e96b1cb90b1f76fbe1361ef1dc059550e9da0bf7dfb0946553626c76e85a80d5ad2610c87b64ee7cd5b364b84a92a11e6a08e280e88ea4b324f2c",
-      "line": 1222,
-      "object": {
-        "modifier": "Activity"
+        "volume": "34"
       },
-      "relation": "negativeCorrelation",
-      "source": 711,
-      "target": 707
+      "evidence": "We studied underlying pathomechanisms in tauopathies using pR5 mice that express the P301L tau mutation found in familial forms of frontotemporal dementia. In a longitudinal study we investigated the functional status of glycogen synthase kinase-3 and correlated it with the appearance of distinct tau phospho-epitopes. Neurons displaying increases in activating phosphorylation of glycogen synthase kinase-3α/β at tyrosine 279/216 also showed an intense rather than moderate AT8 (phospho-Ser202/Thr205 tau) immunoreactivity, and immunoreactivity for AT100 (phospho-Ser212/Thr214 tau) and phosphorylated Ser422, phospho-epitopes associated with fibrillar tau pathology.",
+      "key": "001783fcf0cf1de501ebabd8f76e747aca963d8e5c573a47c1cbdf844d44d7adad2a4979f9ad6a065d0cb6f4e30d9ba6a84e66e3bdddbbc7055480505980bcf0",
+      "line": 3134,
+      "relation": "positiveCorrelation",
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+      "target": 711
     },
     {
       "annotations": {
         "Anatomy": {
-          "hippocampal formation": true
+          "CA1 field of hippocampus": true,
+          "CA3 field of hippocampus": true,
+          "cerebral cortex": true,
+          "dentate gyrus granule cell layer": true
+        },
+        "Confidence": {
+          "Medium": true
+        },
+        "Research_Model": {
+          "hTau E391 transgenic mice": true
         },
         "Species": {
           "10090": true
@@ -34838,3445 +39315,3783 @@
       },
       "citation": {
         "authors": [
-          "Nikkuni M",
-          "Ohshima T",
-          "Toba J",
-          "Watamura N",
-          "Yoshii A"
+          "Kraemer BC",
+          "Leverenz JB",
+          "McMillan PJ",
+          "Raskind M",
+          "Robinson L",
+          "Schellenberg G"
         ],
-        "date": "2016-01-01",
-        "first": "Watamura N",
-        "last": "Ohshima T",
-        "name": "Journal of neuroscience research",
-        "pages": "15-26",
-        "reference": "26400044",
-        "title": "Colocalization of phosphorylated forms of WAVE1, CRMP2, and tau in Alzheimer's disease model mice: Involvement of Cdk5 phosphorylation and the effect of ATRA treatment.",
+        "date": "2011-11-01",
+        "first": "McMillan PJ",
+        "last": "Schellenberg G",
+        "name": "Journal of neuropathology and experimental neurology",
+        "pages": "1006-19",
+        "reference": "22002427",
+        "title": "Truncation of tau at E391 promotes early pathologic changes in transgenic mice.",
         "type": "PubMed",
-        "volume": "94"
+        "volume": "70"
       },
-      "evidence": "First, we verified the colocalization of p-WAVE1 and pCRMP2 with aggregated hyperphosphorylated tau in the hippocampus at 23 months of age. Biochemical analysis revealed the inclusion of p-WAVE1, p-CRMP2, and tau in the sarkosyl-insoluble fractions of hippocampal homogenates",
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-      "relation": "hasVariant",
-      "source": 854,
-      "target": 855
+      "evidence": "E391-3610 mice (higher expressers) exhibit robust somatodendritic distribution of phospho- Ser 202/Thr 205 tau throughout the cortex, in hippocampal CA3 pyramidal neurons, CA1 apical dendrites and cell bodies and dentate granule cells.",
+      "key": "996ba4db2b821403912f6920c967d1348b549dd0ec073e22458dd9266755a5a3f15c255f93d557806fd8ce9cac7f8bc2c63defe8e833537cb84fa0e8784acbb8",
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+      "relation": "positiveCorrelation",
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+      "target": 693
     },
     {
       "annotations": {
-        "Anatomy": {
-          "hippocampal formation": true
+        "Confidence": {
+          "High": true
         },
-        "Species": {
-          "10090": true
+        "Disease_Progression": {
+          "Late Stage": true
+        },
+        "MeSHDisease": {
+          "Alzheimer Disease": true
         }
       },
       "citation": {
         "authors": [
-          "Nikkuni M",
-          "Ohshima T",
-          "Toba J",
-          "Watamura N",
-          "Yoshii A"
+          "Castillo-Carranza DL",
+          "Jackson GR",
+          "Kayed R",
+          "Lasagna-Reeves CA",
+          "Sarmiento J",
+          "Sengupta U",
+          "Troncoso J"
         ],
-        "date": "2016-01-01",
-        "first": "Watamura N",
-        "last": "Ohshima T",
-        "name": "Journal of neuroscience research",
-        "pages": "15-26",
-        "reference": "26400044",
-        "title": "Colocalization of phosphorylated forms of WAVE1, CRMP2, and tau in Alzheimer's disease model mice: Involvement of Cdk5 phosphorylation and the effect of ATRA treatment.",
+        "date": "2012-05-01",
+        "first": "Lasagna-Reeves CA",
+        "last": "Kayed R",
+        "name": "FASEB journal : official publication of the Federation of American Societies for Experimental Biology",
+        "pages": "1946-59",
+        "reference": "22253473",
+        "title": "Identification of oligomers at early stages of tau aggregation in Alzheimer's disease.",
         "type": "PubMed",
-        "volume": "94"
+        "volume": "26"
       },
-      "evidence": "First, we verified the colocalization of p-WAVE1 and pCRMP2 with aggregated hyperphosphorylated tau in the hippocampus at 23 months of age. Biochemical analysis revealed the inclusion of p-WAVE1, p-CRMP2, and tau in the sarkosyl-insoluble fractions of hippocampal homogenates",
-      "key": "99164425b30d9eb358c25c0c37d1294356abed60519b45d5fd052465c31342b35dc90db560392d7f13a542cd20bd41bdb39487bd0901374ee2038901508b33de",
-      "line": 1235,
+      "evidence": "Phosphorylation at the epitope Ser202/Thr205 is regarded as a good marker for late-stage NFTs (5, 72). Hyman and colleagues (5) demonstrated that AT8 immunoreactivity is present primarily in eNFTs and in certain cases in iNFTs. These investigators also found that AT8 revealed dense neuropil thread staining.",
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     },
     {
       "annotations": {
-        "Anatomy": {
-          "cerebral cortex": true
+        "Confidence": {
+          "Medium": true
         },
-        "Species": {
-          "10090": true
+        "MeSHAnatomy": {
+          "Synapses": true
+        },
+        "MeSHDisease": {
+          "Alzheimer Disease": true
         }
       },
       "citation": {
         "authors": [
-          "Nikkuni M",
-          "Ohshima T",
-          "Toba J",
-          "Watamura N",
-          "Yoshii A"
+          "Cornwell LB",
+          "Gylys KH",
+          "Henkins KM",
+          "Miller CA",
+          "Poon WW",
+          "Saing T",
+          "Sokolow S",
+          "Vinters HV"
         ],
-        "date": "2016-01-01",
-        "first": "Watamura N",
-        "last": "Ohshima T",
-        "name": "Journal of neuroscience research",
-        "pages": "15-26",
-        "reference": "26400044",
-        "title": "Colocalization of phosphorylated forms of WAVE1, CRMP2, and tau in Alzheimer's disease model mice: Involvement of Cdk5 phosphorylation and the effect of ATRA treatment.",
+        "date": "2012-11-01",
+        "first": "Henkins KM",
+        "last": "Gylys KH",
+        "name": "Brain pathology (Zurich, Switzerland)",
+        "pages": "826-33",
+        "reference": "22486774",
+        "title": "Extensive p-tau pathology and SDS-stable p-tau oligomers in Alzheimer's cortical synapses.",
         "type": "PubMed",
-        "volume": "94"
+        "volume": "22"
       },
-      "evidence": "We found that the immunoreactivities of p-WAVE1 and pCRMP2 colocalized with p-tau and were located near peripheral amyloid plaques in the cerebral cortices of 23- month-old 33Tg (Fig. 3A) and 17-month-old APPswe/ PS1DE9 (Fig. 3B) mice.",
-      "key": "cd7433546d45f2939d3434943f5c164fea33363f96db0fc928697e6687e317f36fc7648676a011eb3611ffdb00d8b34e9bdf09a369e760fbff791d4ae23f2830",
-      "line": 1241,
-      "relation": "association",
-      "source": 243,
-      "target": 917
+      "evidence": "Oligomers positive for pS202/pT205 accumulate at synapses in AD",
+      "key": "1e53f6ac5a07cb870842c51ad62bc21cd3d7e5a4dcbcd0521a648b8a2370247597e7f1718a9fa777f315162c92be4fd173a5af12a43e4067cf1586334a80c223",
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     },
     {
       "annotations": {
-        "Species": {
-          "10090": true
+        "Confidence": {
+          "Medium": true
         }
       },
       "citation": {
         "authors": [
-          "Nikkuni M",
-          "Ohshima T",
-          "Toba J",
-          "Watamura N",
-          "Yoshii A"
+          "Andreadis A",
+          "Binder LI",
+          "Brady ST",
+          "Fu Y",
+          "Kanaan NM",
+          "LaPointe NE",
+          "Morfini GA",
+          "Patterson KR",
+          "Pigino GF",
+          "Song Y"
         ],
-        "date": "2016-01-01",
-        "first": "Watamura N",
-        "last": "Ohshima T",
-        "name": "Journal of neuroscience research",
-        "pages": "15-26",
-        "reference": "26400044",
-        "title": "Colocalization of phosphorylated forms of WAVE1, CRMP2, and tau in Alzheimer's disease model mice: Involvement of Cdk5 phosphorylation and the effect of ATRA treatment.",
+        "date": "2011-07-06",
+        "first": "Kanaan NM",
+        "last": "Binder LI",
+        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
+        "pages": "9858-68",
+        "reference": "21734277",
+        "title": "Pathogenic forms of tau inhibit kinesin-dependent axonal transport through a mechanism involving activation of axonal phosphotransferases.",
         "type": "PubMed",
-        "volume": "94"
+        "volume": "31"
       },
-      "evidence": "ATRA prevents the accumulation of amyloid plaques and APP processing into Ab through downregulation of Cdk5 in APP/PS1 mice. These results suggested that the administration of ATRA inhibited activity of Cdk5 and GSK3b and attenuated the formation of p-tau aggregation, including p-CRMP2 and p-WAVE1 in the 33Tg mouse brain.",
-      "key": "917f357e5b180ca4f87fcfb7723f688f891bfcce5d64c823c0dce2ef0ef37c83c4a473594a25c436180252ed6ca8d86e3fe7fc3b59c3a572b8b16a4e9ae57a8a",
-      "line": 1247,
-      "relation": "decreases",
-      "source": 9,
-      "target": 917
+      "evidence": "Filamentous, but not soluble, forms of wild-type tau inhibit anterograde, kinesin-based fast axonal transport (FAT) by activating axonal protein phosphatase 1 (PP1) and glycogen synthase kinase 3 (GSK3), independent of microtubule binding. Amino acids 2-18 of tau, comprising a phosphatase-activating domain (PAD), are necessary and sufficient for activation of this pathway. Various pathogenic forms of tau displaying increased exposure of PAD inhibited anterograde FAT in squid axoplasm. Immunohistochemical studies using a novel PAD-specific monoclonal antibody in human postmortem tissue indicated that increased PAD exposure represents an early pathogenic event in AD that closely associates in time with AT8 immunoreactivity. We propose a model of pathogenesis in which disease-associated changes in tau conformation lead to increased exposure of PAD, activation of PP1-GSK3, and inhibition of FAT",
+      "key": "d506aac1cca9f91fbe0593dfe31006b0265666df60f3a2f5237288216648e6819b066f2499866a393fdee1adf9658ac68e6a7c9504dd674d162110cd12d1956b",
+      "line": 4771,
+      "relation": "positiveCorrelation",
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     },
     {
       "annotations": {
-        "Species": {
-          "10090": true
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+          "Medium": true
         }
       },
       "citation": {
         "authors": [
-          "Nikkuni M",
-          "Ohshima T",
-          "Toba J",
-          "Watamura N",
-          "Yoshii A"
+          "El-Akkad E",
+          "Gong CX",
+          "Grundke-Iqbal I",
+          "Iqbal K",
+          "Liang Z",
+          "Liu F",
+          "Shi J",
+          "Yin D"
         ],
-        "date": "2016-01-01",
-        "first": "Watamura N",
-        "last": "Ohshima T",
-        "name": "Journal of neuroscience research",
-        "pages": "15-26",
-        "reference": "26400044",
-        "title": "Colocalization of phosphorylated forms of WAVE1, CRMP2, and tau in Alzheimer's disease model mice: Involvement of Cdk5 phosphorylation and the effect of ATRA treatment.",
+        "date": "2006-11-13",
+        "first": "Liu F",
+        "last": "Gong CX",
+        "name": "FEBS letters",
+        "pages": "6269-74",
+        "reference": "17078951",
+        "title": "PKA modulates GSK-3beta- and cdk5-catalyzed phosphorylation of tau in site- and kinase-specific manners.",
         "type": "PubMed",
-        "volume": "94"
+        "volume": "580"
       },
-      "evidence": "ATRA prevents the accumulation of amyloid plaques and APP processing into Ab through downregulation of Cdk5 in APP/PS1 mice. These results suggested that the administration of ATRA inhibited activity of Cdk5 and GSK3b and attenuated the formation of p-tau aggregation, including p-CRMP2 and p-WAVE1 in the 33Tg mouse brain.",
-      "key": "2ccae7b34edc8923aa7028506bfbcff7a489f8cc320c77bd4300de74e32fa812d1c8356b76d2f76182632886742f69f97c07e6ea7c2ea57713cf758d4f7d7583",
-      "line": 1248,
-      "relation": "decreases",
-      "source": 9,
-      "target": 91
+      "evidence": "Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396.",
+      "key": "4980742f27b19a5a74470c115046235d667a83cc1713c00fc3c79c9f2d96356a77a57a9ebeb2eb65a8b40dd45782ad87825c5f541733260dcbef517349218480",
+      "line": 1349,
+      "relation": "positiveCorrelation",
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+      "target": 372
     },
     {
       "annotations": {
-        "Species": {
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+          "High": true
         }
       },
       "citation": {
         "authors": [
-          "Nikkuni M",
-          "Ohshima T",
-          "Toba J",
-          "Watamura N",
-          "Yoshii A"
+          "Amniai L",
+          "Fauquant C",
+          "Huvent I",
+          "Landrieu I",
+          "Leroy A",
+          "Lippens G",
+          "Sibille N",
+          "Verdegem D",
+          "Wieruszeski JM"
         ],
-        "date": "2016-01-01",
-        "first": "Watamura N",
-        "last": "Ohshima T",
-        "name": "Journal of neuroscience research",
-        "pages": "15-26",
-        "reference": "26400044",
-        "title": "Colocalization of phosphorylated forms of WAVE1, CRMP2, and tau in Alzheimer's disease model mice: Involvement of Cdk5 phosphorylation and the effect of ATRA treatment.",
+        "date": "2012-02-01",
+        "first": "Sibille N",
+        "last": "Landrieu I",
+        "name": "Proteins",
+        "pages": "454-62",
+        "reference": "22072628",
+        "title": "Structural characterization by nuclear magnetic resonance of the impact of phosphorylation in the proline-rich region of the disordered Tau protein.",
         "type": "PubMed",
-        "volume": "94"
-      },
-      "evidence": "ATRA prevents the accumulation of amyloid plaques and APP processing into Ab through downregulation of Cdk5 in APP/PS1 mice. These results suggested that the administration of ATRA inhibited activity of Cdk5 and GSK3b and attenuated the formation of p-tau aggregation, including p-CRMP2 and p-WAVE1 in the 33Tg mouse brain.",
-      "key": "91035934e0f2ddb27b1e3313a3f7dc5bcfda3ae6f73f10554ce39ed6769e4cc577b76420f61c4496c3bdff1732f90a1c24991a020ed3b49518d7034103b00e32",
-      "line": 1249,
-      "object": {
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-          "name": "kin",
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-        "modifier": "Activity"
+        "volume": "80"
       },
-      "relation": "decreases",
-      "source": 9,
-      "target": 777
+      "evidence": "In this study, we address the structural impact of phosphorylation of the Tau protein by Nuclear Magnetic Resonance (NMR) spectroscopy on a functional fragment of Tau (Tau[Ser208-Ser324] = TauF4). TauF4 was phosphorylated by the proline-directed CDK2/CycA3 kinase on Thr231 (generating the AT180 epitope), Ser235, and equally on Thr212 and Thr217 in the Proline-rich region (Tau[Ser208-Gln244] or PRR). These modifications strongly decrease the capacity of TauF4 to polymerize tubulin into microtubules. While all the NMR parameters are consistent with a globally disordered Tau protein fragment, local clusters of structuration can be defined. The most salient result of our NMR analysis is that phosphorylation in the PRR stabilizes a short α-helix that runs from pSer235 till the very beginning of the microtubule-binding region (Tau[Thr245-Ser324] or MTBR of TauF4).",
+      "key": "d4bc0f406d860c51e6eefad6453085d8e65f00672cdc1966e59b81537046721d823e6e399051b292626f6e57c622ff45ed94feba0151e7aa791ea6759ae6d8d3",
+      "line": 3434,
+      "relation": "partOf",
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     },
     {
       "annotations": {
-        "Species": {
-          "10090": true
+        "Confidence": {
+          "Medium": true
         }
       },
       "citation": {
         "authors": [
-          "Nikkuni M",
-          "Ohshima T",
-          "Toba J",
-          "Watamura N",
-          "Yoshii A"
+          "El-Akkad E",
+          "Gong CX",
+          "Grundke-Iqbal I",
+          "Iqbal K",
+          "Liang Z",
+          "Liu F",
+          "Shi J",
+          "Yin D"
         ],
-        "date": "2016-01-01",
-        "first": "Watamura N",
-        "last": "Ohshima T",
-        "name": "Journal of neuroscience research",
-        "pages": "15-26",
-        "reference": "26400044",
-        "title": "Colocalization of phosphorylated forms of WAVE1, CRMP2, and tau in Alzheimer's disease model mice: Involvement of Cdk5 phosphorylation and the effect of ATRA treatment.",
+        "date": "2006-11-13",
+        "first": "Liu F",
+        "last": "Gong CX",
+        "name": "FEBS letters",
+        "pages": "6269-74",
+        "reference": "17078951",
+        "title": "PKA modulates GSK-3beta- and cdk5-catalyzed phosphorylation of tau in site- and kinase-specific manners.",
         "type": "PubMed",
-        "volume": "94"
-      },
-      "evidence": "ATRA prevents the accumulation of amyloid plaques and APP processing into Ab through downregulation of Cdk5 in APP/PS1 mice. These results suggested that the administration of ATRA inhibited activity of Cdk5 and GSK3b and attenuated the formation of p-tau aggregation, including p-CRMP2 and p-WAVE1 in the 33Tg mouse brain.",
-      "key": "767b96280366bcb8a960419a03722b5dc98d7bfd262a4c5e2e9f6feea0f48cb9da9b1aff37025b15f992c817599b2f2ace5c85c1dff6f5411fdf577821e1320f",
-      "line": 1250,
-      "object": {
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-          "name": "kin",
-          "namespace": "bel"
-        },
-        "modifier": "Activity"
+        "volume": "580"
       },
-      "relation": "decreases",
-      "source": 9,
-      "target": 794
+      "evidence": "Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396.",
+      "key": "a22d71720bf042cae00452bfe6cda72faf20cd60de111ba94acb03adebd2244eec268a0e85039c5ff9aef8f8666f123331ca4e3578688e263aa5d4dc289271d0",
+      "line": 1350,
+      "relation": "positiveCorrelation",
+      "source": 667,
+      "target": 372
     },
     {
       "annotations": {
-        "Species": {
-          "10090": true
+        "Confidence": {
+          "High": true
         }
       },
       "citation": {
         "authors": [
-          "Nikkuni M",
-          "Ohshima T",
-          "Toba J",
-          "Watamura N",
-          "Yoshii A"
+          "Chai GS",
+          "Chen NN",
+          "Cheng XS",
+          "Duan DX",
+          "Hu Y",
+          "Liu GP",
+          "Luo Y",
+          "Ni ZF",
+          "Wang JZ"
         ],
-        "date": "2016-01-01",
-        "first": "Watamura N",
-        "last": "Ohshima T",
-        "name": "Journal of neuroscience research",
-        "pages": "15-26",
-        "reference": "26400044",
-        "title": "Colocalization of phosphorylated forms of WAVE1, CRMP2, and tau in Alzheimer's disease model mice: Involvement of Cdk5 phosphorylation and the effect of ATRA treatment.",
+        "date": "2013-01-01",
+        "first": "Duan DX",
+        "last": "Liu GP",
+        "name": "Journal of Alzheimer's disease : JAD",
+        "pages": "795-808",
+        "reference": "23948915",
+        "title": "Phosphorylation of tau by death-associated protein kinase 1 antagonizes the kinase-induced cell apoptosis.",
         "type": "PubMed",
-        "volume": "94"
+        "volume": "37"
       },
-      "evidence": "ATRA prevents the accumulation of amyloid plaques and APP processing into Ab through downregulation of Cdk5 in APP/PS1 mice. These results suggested that the administration of ATRA inhibited activity of Cdk5 and GSK3b and attenuated the formation of p-tau aggregation, including p-CRMP2 and p-WAVE1 in the 33Tg mouse brain.",
-      "key": "8eab18b70e05b67c12998c4ebfd21ad610f7bdd9de3e60a72615ae626f80c2367b88c3d3445af344aca3ea64a0f080f52009382b416fa86628b80cd36dfc296a",
-      "line": 1251,
-      "relation": "decreases",
-      "source": 9,
-      "target": 243
+      "evidence": "These data suggest that tau hyperphosphorylation at Thr231, Ser262, and Ser396 by DAPK1 renders the cells more resistant to the kinase-induced apoptotic cell death, providing new insights into the tau-involved apoptotic abortion in the course of chronic neurodegeneration.",
+      "key": "a1ba7daa2d6be9f3cd5701f7d2548779703809c942a91b0f343e54702c56a0d5b8d104ea6398248f118bf8c1e78add5198a923b0214960f8e45b4ab50ec8031c",
+      "line": 2441,
+      "relation": "negativeCorrelation",
+      "source": 667,
+      "target": 173
     },
     {
       "annotations": {
-        "Ki": {
-          "39 nM": true
+        "Anatomy": {
+          "hippocampal formation": true
+        },
+        "Confidence": {
+          "Medium": true
+        },
+        "Species": {
+          "10116": true
         }
       },
       "citation": {
         "authors": [
-          "Albers RW",
-          "Amin N",
-          "Grant P",
-          "Pant HC",
-          "Shetty KT",
-          "Veeranna"
+          "Boehm J",
+          "Bourgeois C",
+          "Dudilot A",
+          "Lauzon M",
+          "Leclerc N",
+          "Mondragón-Rodríguez S",
+          "Trillaud-Doppia E"
         ],
-        "date": "1996-05-01",
-        "first": "Veeranna",
-        "last": "Pant HC",
-        "name": "Neurochemical research",
-        "pages": "629-36",
-        "reference": "8726973",
-        "title": "Inhibition of neuronal cyclin-dependent kinase-5 by staurosporine and purine analogs is independent of activation by Munc-18.",
+        "date": "2012-09-14",
+        "first": "Mondragón-Rodríguez S",
+        "last": "Boehm J",
+        "name": "The Journal of biological chemistry",
+        "pages": "32040-53",
+        "reference": "22833681",
+        "title": "Interaction of endogenous tau protein with synaptic proteins is regulated by N-methyl-D-aspartate receptor-dependent tau phosphorylation.",
         "type": "PubMed",
-        "volume": "21"
+        "volume": "287"
       },
-      "evidence": "The kinase activity was inhibited by staurosporine, isopentanyladenine and olomoucine in a dose dependent manner. Kinetic studies indicated Ki values of 39 nM, 38 microM and 8 microM, respectively for staurosporine, isopentanyladenine and olomoucine.",
-      "key": "2b4a4dab6928ae1fd6c414c908bcd2fce7ba04692497052fbcc0b41baf5bc55bf0286e6a92c67d724bf58898fe566b62c6d2603dc60b7f2712d1c2369510980d",
-      "line": 1258,
-      "object": {
-        "modifier": "Activity"
-      },
-      "relation": "decreases",
-      "source": 73,
-      "target": 400
+      "evidence": "Hence, LTD-inducing NMDA receptor activation leads to an increase in tau phosphorylation at sites PHF-1, AT180, as well as AT8 and to a reduction at AT100.",
+      "key": "bf907caf1b5742af725d50d7975be2a9ff01dfe93beeb26906d7e378c5b3a3886855d7114293d22a4f15ac2866c1643c7ebb884c2759c00adc11b9369a198879",
+      "line": 3057,
+      "relation": "equivalentTo",
+      "source": 667,
+      "target": 413
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        },
+        "Disease_Progression": {
+          "Early Stage": true
+        },
+        "MeSHDisease": {
+          "Alzheimer Disease": true
+        }
+      },
       "citation": {
         "authors": [
-          "Blokzijl A",
-          "Classon C",
-          "Gu GJ",
-          "Kamali-Moghaddam M",
-          "Landegren U",
-          "Lund H",
-          "Sunnemark D",
-          "Wu D",
-          "von Euler G"
+          "Castillo-Carranza DL",
+          "Jackson GR",
+          "Kayed R",
+          "Lasagna-Reeves CA",
+          "Sarmiento J",
+          "Sengupta U",
+          "Troncoso J"
         ],
-        "date": "2013-09-01",
-        "first": "Gu GJ",
-        "last": "Kamali-Moghaddam M",
-        "name": "Neuromolecular medicine",
-        "pages": "458-69",
-        "reference": "23666762",
-        "title": "Role of individual MARK isoforms in phosphorylation of tau at Ser²⁶² in Alzheimer's disease.",
+        "date": "2012-05-01",
+        "first": "Lasagna-Reeves CA",
+        "last": "Kayed R",
+        "name": "FASEB journal : official publication of the Federation of American Societies for Experimental Biology",
+        "pages": "1946-59",
+        "reference": "22253473",
+        "title": "Identification of oligomers at early stages of tau aggregation in Alzheimer's disease.",
         "type": "PubMed",
-        "volume": "15"
-      },
-      "evidence": "In parallel, phosphorylation of tau at Ser262 in MARK-transfected cells was investigated using a rabbit antibody recognizing phosphorylated Ser262 of tau (AGG5759) and a mouse anti-tau antibody (SC-21796) (Fig. S1a3). Tau was shown to interact with each of the transfected MARK isoforms (Fig. 1) and to be phosphorylated at Ser262 (Fig. 2). Staurosporine, a non-selective kinase inhibitor, significantly inhibited interactions between tau and each of the four MARK isoforms after treatment with 20 lM staurosporine for 1 h (Fig. 1; p = 0.02 for MARK1–, MARK2– and MARK3–tau interactions and p = 3 9 10-6 for MARK4–tau interaction). Treatment with staurosporine also significantly reduced PLA signals for tau phosphorylation at Ser262 (Fig. 2; p = 0.04 for MARK1- and p = 0.02 for MARK2- and MARK3- and p = 1 9 10-5 for MARK4-mediated tau phosphorylation)",
-      "key": "7a61d0d0f17b6fa2a6dcc8101060b094a5a9379091ce55567e1fba6b01b2bdea38c1f798df1c8e71fce084726c22af91131bbc866e01954d32b9ad015a7fa055",
-      "line": 1842,
-      "object": {
-        "effect": {
-          "name": "kin",
-          "namespace": "bel"
-        },
-        "modifier": "Activity"
+        "volume": "26"
       },
-      "relation": "decreases",
-      "source": 73,
-      "target": 759
+      "evidence": "This sequence (Fig. 3G–N) is supported by Western blot analysis, phosphorylated Thr231 in three AD cases and their age-matched controls, suggesting that tau phosphorylation at Thr231 occurs before the formation of oligomers (Fig. 3O).",
+      "key": "785d3d846aa7d3f302ec0c41e5a8c3f88ac74053fe2a194c6a7c9965a103e01d4c85bebb55fa72d0cbb16704221609ae926f8d39ee8807b0f9106240fb105896",
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     },
     {
       "annotations": {
-        "Cell_Line": {
-          "NIH/3T3": true
+        "Confidence": {
+          "Medium": true
         }
       },
       "citation": {
         "authors": [
-          "Agerman K",
-          "Eckersley S",
-          "Gu GJ",
-          "Kamali-Moghaddam M",
-          "Kvist AJ",
-          "Landegren U",
-          "Lund H",
-          "Milner R",
-          "Nilsson LN",
-          "Sunnemark D",
-          "Wu D"
+          "Ando K",
+          "Blum D",
+          "Bretteville A",
+          "Buée L",
+          "Bégard S",
+          "Bélarbi K",
+          "Caillet-Boudin ML",
+          "Demey-Thomas E",
+          "Dourlen P",
+          "Drobecq H",
+          "Eddarkaoui S",
+          "Galas MC",
+          "Ghestem A",
+          "Hamdane M",
+          "Landrieu I",
+          "Lippens G",
+          "Maurage CA",
+          "Melnyk P",
+          "Sambo AV",
+          "Sergeant N",
+          "Smet C",
+          "Verdier Y",
+          "Vingtdeux V",
+          "Vinh J"
         ],
-        "date": "2013-01-01",
-        "first": "Gu GJ",
-        "last": "Kamali-Moghaddam M",
-        "name": "Journal of Alzheimer's disease : JAD",
-        "pages": "699-713",
-        "reference": "23001711",
-        "title": "Elevated MARK2-dependent phosphorylation of Tau in Alzheimer's disease.",
+        "date": "2013-03-01",
+        "first": "Ando K",
+        "last": "Buée L",
+        "name": "Neurobiology of aging",
+        "pages": "757-69",
+        "reference": "22926167",
+        "title": "Tau pathology modulates Pin1 post-translational modifications and may be relevant as biomarker.",
         "type": "PubMed",
-        "volume": "33"
-      },
-      "evidence": "Several kinases such as microtubule-affinity regulating kinase (MARK), protein kinase A, calcium calmodulin kinase II, and checkpoint kinase 2 are known to phosphorylate tau on Ser(262) in vitro. In this study, we took advantage of the in situ proximity ligation assay to investigate the role of MARK2, one of the four MARK isoforms, in AD. We demonstrate that MARK2 interacts with tau and phosphorylates tau at Ser(262) in stably transfected NIH/3T3 cells expressing human recombinant tau. Staurosporine, a protein kinase inhibitor, significantly reduced the interaction between MARK2 and tau, and also phosphorylation of tau at Ser(262).",
-      "key": "92df9e300db62d7c2a9c542993b86c4f991615edc2d53d1e345f60985f0c21ea9f874167feeb753763d3777c6372bb5944f81b4d68799d1fd00b658c3990f41b",
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-        "modifier": "Activity"
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       },
-      "relation": "decreases",
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+      "evidence": "Pin1 binds to phosphorylated Thr231 of tau and facilitates the dephosphorylation of phosphoThr231 through isomerization (Galas et al., 2006; Hamdane et al., 2006; Lu et al., 1999a). Phosphorylation at Thr231 on tau is associated with the early events of tau aggregation and NFT (Augustinack et al., 2002). Pin1 binds and isomerizes the proline imidic peptide bond following the phosphothreonine 231",
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     },
     {
       "annotations": {
-        "Cell_Line": {
-          "NIH/3T3": true
+        "Confidence": {
+          "Medium": true
         }
       },
       "citation": {
         "authors": [
-          "Agerman K",
-          "Eckersley S",
-          "Gu GJ",
-          "Kamali-Moghaddam M",
-          "Kvist AJ",
-          "Landegren U",
-          "Lund H",
-          "Milner R",
-          "Nilsson LN",
-          "Sunnemark D",
-          "Wu D"
+          "Ando K",
+          "Blum D",
+          "Bretteville A",
+          "Buée L",
+          "Bégard S",
+          "Bélarbi K",
+          "Caillet-Boudin ML",
+          "Demey-Thomas E",
+          "Dourlen P",
+          "Drobecq H",
+          "Eddarkaoui S",
+          "Galas MC",
+          "Ghestem A",
+          "Hamdane M",
+          "Landrieu I",
+          "Lippens G",
+          "Maurage CA",
+          "Melnyk P",
+          "Sambo AV",
+          "Sergeant N",
+          "Smet C",
+          "Verdier Y",
+          "Vingtdeux V",
+          "Vinh J"
         ],
-        "date": "2013-01-01",
-        "first": "Gu GJ",
-        "last": "Kamali-Moghaddam M",
-        "name": "Journal of Alzheimer's disease : JAD",
-        "pages": "699-713",
-        "reference": "23001711",
-        "title": "Elevated MARK2-dependent phosphorylation of Tau in Alzheimer's disease.",
+        "date": "2013-03-01",
+        "first": "Ando K",
+        "last": "Buée L",
+        "name": "Neurobiology of aging",
+        "pages": "757-69",
+        "reference": "22926167",
+        "title": "Tau pathology modulates Pin1 post-translational modifications and may be relevant as biomarker.",
         "type": "PubMed",
-        "volume": "33"
+        "volume": "34"
       },
-      "evidence": "Several kinases such as microtubule-affinity regulating kinase (MARK), protein kinase A, calcium calmodulin kinase II, and checkpoint kinase 2 are known to phosphorylate tau on Ser(262) in vitro. In this study, we took advantage of the in situ proximity ligation assay to investigate the role of MARK2, one of the four MARK isoforms, in AD. We demonstrate that MARK2 interacts with tau and phosphorylates tau at Ser(262) in stably transfected NIH/3T3 cells expressing human recombinant tau. Staurosporine, a protein kinase inhibitor, significantly reduced the interaction between MARK2 and tau, and also phosphorylation of tau at Ser(262).",
-      "key": "f49227ef09e124976ddc76284a4c2d05c924e128b677207c7c15f71fa883200e631cdfd91d93f879f6958f424007a534a9254bdb3367bb83e4be99d8a512b2f1",
-      "line": 2769,
-      "relation": "decreases",
-      "source": 73,
-      "target": 557
+      "evidence": "Pin1 binds to phosphorylated Thr231 of tau and facilitates the dephosphorylation of phosphoThr231 through isomerization (Galas et al., 2006; Hamdane et al., 2006; Lu et al., 1999a). Phosphorylation at Thr231 on tau is associated with the early events of tau aggregation and NFT (Augustinack et al., 2002). Pin1 binds and isomerizes the proline imidic peptide bond following the phosphothreonine 231",
+      "key": "f201dad3bb69eba64ddb8d5d00c678da31b0c3eb3e76f45e669dd02bebafd9305b4ea34a77c63d8abadce24a5f17fdcd08e4670951a0b20425666b0376a7403d",
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+      "relation": "increases",
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+      "target": 94
     },
     {
       "annotations": {
-        "Ki": {
-          "38 μM": true
+        "Confidence": {
+          "Medium": true
         }
       },
       "citation": {
         "authors": [
-          "Albers RW",
-          "Amin N",
-          "Grant P",
-          "Pant HC",
-          "Shetty KT",
-          "Veeranna"
+          "El-Akkad E",
+          "Gong CX",
+          "Grundke-Iqbal I",
+          "Iqbal K",
+          "Liang Z",
+          "Liu F",
+          "Shi J",
+          "Yin D"
         ],
-        "date": "1996-05-01",
-        "first": "Veeranna",
-        "last": "Pant HC",
-        "name": "Neurochemical research",
-        "pages": "629-36",
-        "reference": "8726973",
-        "title": "Inhibition of neuronal cyclin-dependent kinase-5 by staurosporine and purine analogs is independent of activation by Munc-18.",
+        "date": "2006-11-13",
+        "first": "Liu F",
+        "last": "Gong CX",
+        "name": "FEBS letters",
+        "pages": "6269-74",
+        "reference": "17078951",
+        "title": "PKA modulates GSK-3beta- and cdk5-catalyzed phosphorylation of tau in site- and kinase-specific manners.",
         "type": "PubMed",
-        "volume": "21"
-      },
-      "evidence": "The kinase activity was inhibited by staurosporine, isopentanyladenine and olomoucine in a dose dependent manner. Kinetic studies indicated Ki values of 39 nM, 38 microM and 8 microM, respectively for staurosporine, isopentanyladenine and olomoucine.",
-      "key": "d526db59274ac0a83727b4103ea44301d3bcda39bed7764aac3d8ca5f79898eb84ea0312b391cc91f915a8ffe658d34cbba5d423caf0c805c65c7d1a92587e50",
-      "line": 1260,
-      "object": {
-        "modifier": "Activity"
+        "volume": "580"
       },
-      "relation": "decreases",
-      "source": 151,
-      "target": 400
+      "evidence": "Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396.",
+      "key": "c7e2d8a226012f214176cab21fe7ace67c63726033f393159552a6632373ab88975780fb571d1b053e3d6a6dda87a8d67cf8d8e217ce09e258a0cbdaa5e11b44",
+      "line": 1355,
+      "relation": "negativeCorrelation",
+      "source": 664,
+      "target": 372
     },
     {
       "annotations": {
-        "Ki": {
-          "8 μM": true
+        "Confidence": {
+          "High": true
         }
       },
       "citation": {
         "authors": [
-          "Albers RW",
-          "Amin N",
-          "Grant P",
-          "Pant HC",
-          "Shetty KT",
-          "Veeranna"
+          "Amniai L",
+          "Fauquant C",
+          "Huvent I",
+          "Landrieu I",
+          "Leroy A",
+          "Lippens G",
+          "Sibille N",
+          "Verdegem D",
+          "Wieruszeski JM"
         ],
-        "date": "1996-05-01",
-        "first": "Veeranna",
-        "last": "Pant HC",
-        "name": "Neurochemical research",
-        "pages": "629-36",
-        "reference": "8726973",
-        "title": "Inhibition of neuronal cyclin-dependent kinase-5 by staurosporine and purine analogs is independent of activation by Munc-18.",
+        "date": "2012-02-01",
+        "first": "Sibille N",
+        "last": "Landrieu I",
+        "name": "Proteins",
+        "pages": "454-62",
+        "reference": "22072628",
+        "title": "Structural characterization by nuclear magnetic resonance of the impact of phosphorylation in the proline-rich region of the disordered Tau protein.",
         "type": "PubMed",
-        "volume": "21"
-      },
-      "evidence": "The kinase activity was inhibited by staurosporine, isopentanyladenine and olomoucine in a dose dependent manner. Kinetic studies indicated Ki values of 39 nM, 38 microM and 8 microM, respectively for staurosporine, isopentanyladenine and olomoucine.",
-      "key": "a945316235161efc5922e19e32d2013f2f296516ba24d8b4269dbac43da6848caa14431f96ae53fa4d2565aa3bae3c7083d36d64adc41aa1434f183b8ab2cb44",
-      "line": 1262,
-      "object": {
-        "modifier": "Activity"
+        "volume": "80"
       },
-      "relation": "decreases",
-      "source": 155,
-      "target": 400
+      "evidence": "In this study, we address the structural impact of phosphorylation of the Tau protein by Nuclear Magnetic Resonance (NMR) spectroscopy on a functional fragment of Tau (Tau[Ser208-Ser324] = TauF4). TauF4 was phosphorylated by the proline-directed CDK2/CycA3 kinase on Thr231 (generating the AT180 epitope), Ser235, and equally on Thr212 and Thr217 in the Proline-rich region (Tau[Ser208-Gln244] or PRR). These modifications strongly decrease the capacity of TauF4 to polymerize tubulin into microtubules. While all the NMR parameters are consistent with a globally disordered Tau protein fragment, local clusters of structuration can be defined. The most salient result of our NMR analysis is that phosphorylation in the PRR stabilizes a short α-helix that runs from pSer235 till the very beginning of the microtubule-binding region (Tau[Thr245-Ser324] or MTBR of TauF4).",
+      "key": "0437791b0113d2a1ee8966c1d57cd65f0a7c30ab84c089895def24193da0c037f9d91fc71ad8b638170916cc5a34be45a70aa1d3714ba362446b45bc45a1f24a",
+      "line": 3433,
+      "relation": "partOf",
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     },
     {
       "annotations": {
-        "Km": {
-          "8-15 μM": true
-        },
-        "Km_ATP": {
-          "2 μM": true
-        },
-        "Vmax": {
-          "0.8-4 μM/min/mg": true
+        "Confidence": {
+          "Medium": true
         }
       },
       "citation": {
         "authors": [
-          "Kawakami F",
-          "Ohtsuki K",
-          "Suzuki K"
+          "El-Akkad E",
+          "Gong CX",
+          "Grundke-Iqbal I",
+          "Iqbal K",
+          "Liang Z",
+          "Liu F",
+          "Shi J",
+          "Yin D"
         ],
-        "date": "2008-02-01",
-        "first": "Kawakami F",
-        "last": "Ohtsuki K",
-        "name": "Biological &amp; pharmaceutical bulletin",
-        "pages": "193-200",
-        "reference": "18239272",
-        "title": "A novel consensus phosphorylation motif in sulfatide- and cholesterol-3-sulfate-binding protein substrates for CK1 in vitro.",
+        "date": "2006-11-13",
+        "first": "Liu F",
+        "last": "Gong CX",
+        "name": "FEBS letters",
+        "pages": "6269-74",
+        "reference": "17078951",
+        "title": "PKA modulates GSK-3beta- and cdk5-catalyzed phosphorylation of tau in site- and kinase-specific manners.",
         "type": "PubMed",
-        "volume": "31"
+        "volume": "580"
       },
-      "evidence": "Tau-phosphorylation properties dependent on co-factors (Km 8 to 15 uM, Vmax 0.8 to 4 uM/min/mg protein) and Km for ATP is 2uM",
-      "key": "6ad96a748c26f17f655c23eb65138c29eabad0ec3be35185b9cddc2d0564e3c153314a55fdc2758b39bcad64f4d935ced21f9b5d364a09c1daa41f76b0ed3129",
-      "line": 1271,
-      "relation": "increases",
-      "source": 413,
-      "target": 538
+      "evidence": "Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396.",
+      "key": "d153ea06f4c6df9733c87afdb60004ac3cadb0efd29f58105dece37838a4df2673cfb0bdf3466ceb14ecee4e89dee669a4fdc9d3cafe3d98215b161a04a11051",
+      "line": 1345,
+      "relation": "positiveCorrelation",
+      "source": 372,
+      "target": 661
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
-          "Alessi DR",
-          "Campbell DG",
-          "Cousin MA",
-          "Esoof N",
-          "Fritsch MJ",
-          "Gordon SL",
-          "Gourlay R",
-          "Macartney T",
-          "Peggie M",
-          "Velupillai S",
-          "Zhang N",
-          "van Aalten DM"
+          "El-Akkad E",
+          "Gong CX",
+          "Grundke-Iqbal I",
+          "Iqbal K",
+          "Liang Z",
+          "Liu F",
+          "Shi J",
+          "Yin D"
         ],
-        "date": "2015-02-11",
-        "first": "Zhang N",
-        "last": "Alessi DR",
-        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
-        "pages": "2492-507",
-        "reference": "25673844",
-        "title": "Phosphorylation of synaptic vesicle protein 2A at Thr84 by casein kinase 1 family kinases controls the specific retrieval of synaptotagmin-1.",
+        "date": "2006-11-13",
+        "first": "Liu F",
+        "last": "Gong CX",
+        "name": "FEBS letters",
+        "pages": "6269-74",
+        "reference": "17078951",
+        "title": "PKA modulates GSK-3beta- and cdk5-catalyzed phosphorylation of tau in site- and kinase-specific manners.",
         "type": "PubMed",
-        "volume": "35"
+        "volume": "580"
       },
-      "evidence": "The CK1 group of eukaryotic protein kinases are composed of seven CK1 isoforms (CK1α, CK1α2, CK1δ, CK1ε, CK1γ1, CK1γ2, and CK1γ3), two Tau–tubulin kinase isoforms (TTBK1 and TTBK2), and three VRK isoforms (VRK1, VRK2, and VRK3)",
-      "key": "548993e51c8577f30b1edb8fb592ff79b752a95edd1668fc0cd30b57277f5c753d714a662925a33b8cec1cbcd33cb146454a130977e563a1ff4eeb2eed289a46",
-      "line": 1393,
-      "relation": "isA",
-      "source": 413,
-      "target": 286
+      "evidence": "Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396.",
+      "key": "395166322fbf93a54b115c73c336bddd97ec407abb202ca40c2ce45f8a910f59f998cbe0fa78e5df2005a1cf50df23ea8f4e724595de24b39a4c6e8f350b782d",
+      "line": 1346,
+      "relation": "positiveCorrelation",
+      "source": 372,
+      "target": 628
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
-          "Kawakami F",
-          "Ohtsuki K",
-          "Suzuki K"
+          "El-Akkad E",
+          "Gong CX",
+          "Grundke-Iqbal I",
+          "Iqbal K",
+          "Liang Z",
+          "Liu F",
+          "Shi J",
+          "Yin D"
         ],
-        "date": "2008-02-01",
-        "first": "Kawakami F",
-        "last": "Ohtsuki K",
-        "name": "Biological &amp; pharmaceutical bulletin",
-        "pages": "193-200",
-        "reference": "18239272",
-        "title": "A novel consensus phosphorylation motif in sulfatide- and cholesterol-3-sulfate-binding protein substrates for CK1 in vitro.",
+        "date": "2006-11-13",
+        "first": "Liu F",
+        "last": "Gong CX",
+        "name": "FEBS letters",
+        "pages": "6269-74",
+        "reference": "17078951",
+        "title": "PKA modulates GSK-3beta- and cdk5-catalyzed phosphorylation of tau in site- and kinase-specific manners.",
         "type": "PubMed",
-        "volume": "31"
+        "volume": "580"
       },
-      "evidence": "Epitopes S198, S199, S202, T205, S422 (Lund 2013)",
-      "key": "5508ba1bdd36522fe015cc7ca4b0d8dbb9119530065ee42cbb571c0dc7fd43e15b2df3dd04cd64fd9f2a0c0655381139de88bdaef484cadd52cc5a7679d49fc3",
-      "line": 1280,
-      "relation": "increases",
-      "source": 734,
-      "target": 542
+      "evidence": "Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396.",
+      "key": "102bb970967ce9aa2b3b524963874120455a08919f4b62f44ad75ffbd8cd82fabf35ea828e42d637c25a390d21e442919f9ddbf3d47465f0ed5c4cc2001c371f",
+      "line": 1347,
+      "relation": "positiveCorrelation",
+      "source": 372,
+      "target": 629
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
-          "Kawakami F",
-          "Ohtsuki K",
-          "Suzuki K"
+          "El-Akkad E",
+          "Gong CX",
+          "Grundke-Iqbal I",
+          "Iqbal K",
+          "Liang Z",
+          "Liu F",
+          "Shi J",
+          "Yin D"
         ],
-        "date": "2008-02-01",
-        "first": "Kawakami F",
-        "last": "Ohtsuki K",
-        "name": "Biological &amp; pharmaceutical bulletin",
-        "pages": "193-200",
-        "reference": "18239272",
-        "title": "A novel consensus phosphorylation motif in sulfatide- and cholesterol-3-sulfate-binding protein substrates for CK1 in vitro.",
+        "date": "2006-11-13",
+        "first": "Liu F",
+        "last": "Gong CX",
+        "name": "FEBS letters",
+        "pages": "6269-74",
+        "reference": "17078951",
+        "title": "PKA modulates GSK-3beta- and cdk5-catalyzed phosphorylation of tau in site- and kinase-specific manners.",
         "type": "PubMed",
-        "volume": "31"
+        "volume": "580"
       },
-      "evidence": "Epitopes S198, S199, S202, T205, S422 (Lund 2013)",
-      "key": "b45370f48dc13b644f6914f349f84912b54b5a8f479c4c08f3d6de0558f82c32c34971f2b43788d0e607d96afa8f862b5d07cbc8da7a2747c988a57489ddded1",
-      "line": 1281,
-      "relation": "increases",
-      "source": 734,
-      "target": 543
+      "evidence": "Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396.",
+      "key": "0216d738c180b2131b290e3ca7881b2e4951400135ad58edf6933d33574269dc320dd13af2e9ae1a35bf4cdac5b86011775f2fd1284f452cc812ec2b1b23211a",
+      "line": 1364,
+      "relation": "decreases",
+      "source": 372,
+      "target": 629
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
-          "Kawakami F",
-          "Ohtsuki K",
-          "Suzuki K"
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+          "Gong CX",
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-        "first": "Kawakami F",
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-        "title": "A novel consensus phosphorylation motif in sulfatide- and cholesterol-3-sulfate-binding protein substrates for CK1 in vitro.",
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+        "first": "Liu F",
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         "type": "PubMed",
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       "citation": {
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+        "first": "Liu F",
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         "type": "PubMed",
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       "citation": {
         "authors": [
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       "annotations": {
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       "citation": {
         "authors": [
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-          "Bullido MJ",
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-        "first": "Vázquez-Higuera JL",
-        "last": "Combarros O",
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-        "title": "Genetic variations in tau-tubulin kinase-1 are linked to Alzheimer's disease in a Spanish case-control cohort.",
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+        "first": "Liu F",
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         "authors": [
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-        "first": "Bouskila M",
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-        "title": "TTBK2 kinase substrate specificity and the impact of spinocerebellar-ataxia-causing mutations on expression, activity, localization and development.",
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+        "first": "Liu F",
+        "last": "Gong CX",
+        "name": "FEBS letters",
+        "pages": "6269-74",
+        "reference": "17078951",
+        "title": "PKA modulates GSK-3beta- and cdk5-catalyzed phosphorylation of tau in site- and kinase-specific manners.",
         "type": "PubMed",
-        "volume": "437"
+        "volume": "580"
       },
-      "evidence": "TTBK1-Tg mice show significant age-dependent memory impairment as determined by radial arm water maze test, which is associated with enhancement of tau and neurofilament phosphorylation, increased levels of p25 and p35, both activators of cyclin-dependent protein kinase 5 (CDK5), enhanced calpain I activity, and reduced levels of hippocampal NMDA receptor types 2B (NR2B) and D. Enhanced CDK5/p35 complex formation is strongly correlated with dissociation of F-actin from p35, suggesting the inhibitory mechanism of CDK5/p35 complex formation by F-actin.",
-      "key": "d2ae1eed251fe01f251300a3910ee0fce466689b6b5cddc5fa78fce5f5b8d29a23d39178c5b5653c5252a8cc5da0167ce9b61f961d84bfce1eb6214b60fb56c1",
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+      "evidence": "Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396.",
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+      "relation": "decreases",
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     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
-          "Alessi DR",
-          "Campbell DG",
-          "Cousin MA",
-          "Esoof N",
-          "Fritsch MJ",
-          "Gordon SL",
-          "Gourlay R",
-          "Macartney T",
-          "Peggie M",
-          "Velupillai S",
-          "Zhang N",
-          "van Aalten DM"
+          "El-Akkad E",
+          "Gong CX",
+          "Grundke-Iqbal I",
+          "Iqbal K",
+          "Liang Z",
+          "Liu F",
+          "Shi J",
+          "Yin D"
         ],
-        "date": "2015-02-11",
-        "first": "Zhang N",
-        "last": "Alessi DR",
-        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
-        "pages": "2492-507",
-        "reference": "25673844",
-        "title": "Phosphorylation of synaptic vesicle protein 2A at Thr84 by casein kinase 1 family kinases controls the specific retrieval of synaptotagmin-1.",
+        "date": "2006-11-13",
+        "first": "Liu F",
+        "last": "Gong CX",
+        "name": "FEBS letters",
+        "pages": "6269-74",
+        "reference": "17078951",
+        "title": "PKA modulates GSK-3beta- and cdk5-catalyzed phosphorylation of tau in site- and kinase-specific manners.",
         "type": "PubMed",
-        "volume": "35"
+        "volume": "580"
       },
-      "evidence": "The CK1 group of eukaryotic protein kinases are composed of seven CK1 isoforms (CK1α, CK1α2, CK1δ, CK1ε, CK1γ1, CK1γ2, and CK1γ3), two Tau–tubulin kinase isoforms (TTBK1 and TTBK2), and three VRK isoforms (VRK1, VRK2, and VRK3)",
-      "key": "4d3521c09a565ec94acbde7458983b2ca06f74b9680de48d1ffb6ec2e7fb0fa6a738a6e197c65ae8b309d9977fb6e222668068c8a35b1af8241825114d228bc5",
-      "line": 1385,
-      "relation": "isA",
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-      "target": 312
+      "evidence": "Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396.",
+      "key": "bd402e9ec39a225e573d4a3a54267a05a4f60f749b7157c4c2ffb37bed41fd8128c6edac0133eeb75a8283c34feac4afe59ad7b1b1a765866b402ee5f2f963d7",
+      "line": 1355,
+      "relation": "negativeCorrelation",
+      "source": 372,
+      "target": 664
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
-          "Alessi DR",
-          "Campbell DG",
-          "Cousin MA",
-          "Esoof N",
-          "Fritsch MJ",
-          "Gordon SL",
-          "Gourlay R",
-          "Macartney T",
-          "Peggie M",
-          "Velupillai S",
-          "Zhang N",
-          "van Aalten DM"
+          "El-Akkad E",
+          "Gong CX",
+          "Grundke-Iqbal I",
+          "Iqbal K",
+          "Liang Z",
+          "Liu F",
+          "Shi J",
+          "Yin D"
         ],
-        "date": "2015-02-11",
-        "first": "Zhang N",
-        "last": "Alessi DR",
-        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
-        "pages": "2492-507",
-        "reference": "25673844",
-        "title": "Phosphorylation of synaptic vesicle protein 2A at Thr84 by casein kinase 1 family kinases controls the specific retrieval of synaptotagmin-1.",
+        "date": "2006-11-13",
+        "first": "Liu F",
+        "last": "Gong CX",
+        "name": "FEBS letters",
+        "pages": "6269-74",
+        "reference": "17078951",
+        "title": "PKA modulates GSK-3beta- and cdk5-catalyzed phosphorylation of tau in site- and kinase-specific manners.",
         "type": "PubMed",
-        "volume": "35"
+        "volume": "580"
       },
-      "evidence": "We demonstrate that Casein kinase 1 family members, including isoforms of Tau-tubulin protein kinases (TTBK1 and TTBK2), phosphorylate human SV2A at two constellations of residues, namely Cluster-1 (Ser42, Ser45, and Ser47) and Cluster-2 (Ser80, Ser81, and Thr84). These residues are also phosphorylated in vivo, and the phosphorylation of Thr84 within Cluster-2 is essential for triggering binding to the C2B domain of human synaptotagmin-1",
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-      "line": 1411,
-      "relation": "increases",
-      "source": 734,
-      "target": 696
+      "evidence": "Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396.",
+      "key": "e3ea750fc6fa4ee2d12488dd3c7b15a879900495c8ced1856d194dcce13640e28534ed0291762993a429ea9c584834207b2f6fdf556f726443eda50647181c73",
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     },
     {
+      "annotations": {
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+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
-          "Alessi DR",
-          "Campbell DG",
-          "Cousin MA",
-          "Esoof N",
-          "Fritsch MJ",
-          "Gordon SL",
-          "Gourlay R",
-          "Macartney T",
-          "Peggie M",
-          "Velupillai S",
-          "Zhang N",
-          "van Aalten DM"
+          "El-Akkad E",
+          "Gong CX",
+          "Grundke-Iqbal I",
+          "Iqbal K",
+          "Liang Z",
+          "Liu F",
+          "Shi J",
+          "Yin D"
         ],
-        "date": "2015-02-11",
-        "first": "Zhang N",
-        "last": "Alessi DR",
-        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
-        "pages": "2492-507",
-        "reference": "25673844",
-        "title": "Phosphorylation of synaptic vesicle protein 2A at Thr84 by casein kinase 1 family kinases controls the specific retrieval of synaptotagmin-1.",
+        "date": "2006-11-13",
+        "first": "Liu F",
+        "last": "Gong CX",
+        "name": "FEBS letters",
+        "pages": "6269-74",
+        "reference": "17078951",
+        "title": "PKA modulates GSK-3beta- and cdk5-catalyzed phosphorylation of tau in site- and kinase-specific manners.",
         "type": "PubMed",
-        "volume": "35"
+        "volume": "580"
       },
-      "evidence": "We demonstrate that Casein kinase 1 family members, including isoforms of Tau-tubulin protein kinases (TTBK1 and TTBK2), phosphorylate human SV2A at two constellations of residues, namely Cluster-1 (Ser42, Ser45, and Ser47) and Cluster-2 (Ser80, Ser81, and Thr84). These residues are also phosphorylated in vivo, and the phosphorylation of Thr84 within Cluster-2 is essential for triggering binding to the C2B domain of human synaptotagmin-1",
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+      "evidence": "Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396.",
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+      "relation": "regulates",
+      "source": 372,
+      "target": 537
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
-          "Alessi DR",
-          "Campbell DG",
-          "Cousin MA",
-          "Esoof N",
-          "Fritsch MJ",
-          "Gordon SL",
-          "Gourlay R",
-          "Macartney T",
-          "Peggie M",
-          "Velupillai S",
-          "Zhang N",
-          "van Aalten DM"
+          "El-Akkad E",
+          "Gong CX",
+          "Grundke-Iqbal I",
+          "Iqbal K",
+          "Liang Z",
+          "Liu F",
+          "Shi J",
+          "Yin D"
         ],
-        "date": "2015-02-11",
-        "first": "Zhang N",
-        "last": "Alessi DR",
-        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
-        "pages": "2492-507",
-        "reference": "25673844",
-        "title": "Phosphorylation of synaptic vesicle protein 2A at Thr84 by casein kinase 1 family kinases controls the specific retrieval of synaptotagmin-1.",
+        "date": "2006-11-13",
+        "first": "Liu F",
+        "last": "Gong CX",
+        "name": "FEBS letters",
+        "pages": "6269-74",
+        "reference": "17078951",
+        "title": "PKA modulates GSK-3beta- and cdk5-catalyzed phosphorylation of tau in site- and kinase-specific manners.",
         "type": "PubMed",
-        "volume": "35"
+        "volume": "580"
       },
-      "evidence": "We demonstrate that Casein kinase 1 family members, including isoforms of Tau-tubulin protein kinases (TTBK1 and TTBK2), phosphorylate human SV2A at two constellations of residues, namely Cluster-1 (Ser42, Ser45, and Ser47) and Cluster-2 (Ser80, Ser81, and Thr84). These residues are also phosphorylated in vivo, and the phosphorylation of Thr84 within Cluster-2 is essential for triggering binding to the C2B domain of human synaptotagmin-1",
-      "key": "0cad67cc207e241f3c9ede02c16f2c9c9e6afb516ef4952616eb292badf8a2c41aa6584ea616308add19334b1a67ab26aece2466e269b5ec6da6b3653bae5253",
-      "line": 1413,
-      "relation": "increases",
-      "source": 734,
-      "target": 698
+      "evidence": "Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396.",
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+      "object": {
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+      },
+      "relation": "regulates",
+      "source": 372,
+      "target": 478
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
-          "Alessi DR",
-          "Campbell DG",
-          "Cousin MA",
-          "Esoof N",
-          "Fritsch MJ",
-          "Gordon SL",
-          "Gourlay R",
-          "Macartney T",
-          "Peggie M",
-          "Velupillai S",
-          "Zhang N",
-          "van Aalten DM"
+          "Agerman K",
+          "Eckersley S",
+          "Gu GJ",
+          "Kamali-Moghaddam M",
+          "Kvist AJ",
+          "Landegren U",
+          "Lund H",
+          "Milner R",
+          "Nilsson LN",
+          "Sunnemark D",
+          "Wu D"
         ],
-        "date": "2015-02-11",
-        "first": "Zhang N",
-        "last": "Alessi DR",
-        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
-        "pages": "2492-507",
-        "reference": "25673844",
-        "title": "Phosphorylation of synaptic vesicle protein 2A at Thr84 by casein kinase 1 family kinases controls the specific retrieval of synaptotagmin-1.",
+        "date": "2013-01-01",
+        "first": "Gu GJ",
+        "last": "Kamali-Moghaddam M",
+        "name": "Journal of Alzheimer's disease : JAD",
+        "pages": "699-713",
+        "reference": "23001711",
+        "title": "Elevated MARK2-dependent phosphorylation of Tau in Alzheimer's disease.",
         "type": "PubMed",
-        "volume": "35"
+        "volume": "33"
       },
-      "evidence": "We demonstrate that Casein kinase 1 family members, including isoforms of Tau-tubulin protein kinases (TTBK1 and TTBK2), phosphorylate human SV2A at two constellations of residues, namely Cluster-1 (Ser42, Ser45, and Ser47) and Cluster-2 (Ser80, Ser81, and Thr84). These residues are also phosphorylated in vivo, and the phosphorylation of Thr84 within Cluster-2 is essential for triggering binding to the C2B domain of human synaptotagmin-1",
-      "key": "02aabb4a78aaf14036c37822d1f33d8c025be3f990f2d858e46c8b73e210dfc9767dc9c81e188a50178e082924068bc07cb5b3c13d1605a5f653bc3f5e0827aa",
-      "line": 1414,
-      "relation": "increases",
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-      "target": 699
+      "evidence": "Several kinases such as microtubule-affinity regulating kinase (MARK), protein kinase A, calcium calmodulin kinase II, and checkpoint kinase 2 are known to phosphorylate tau on Ser(262) in vitro. In this study, we took advantage of the in situ proximity ligation assay to investigate the role of MARK2, one of the four MARK isoforms, in AD. We demonstrate that MARK2 interacts with tau and phosphorylates tau at Ser(262) in stably transfected NIH/3T3 cells expressing human recombinant tau. Staurosporine, a protein kinase inhibitor, significantly reduced the interaction between MARK2 and tau, and also phosphorylation of tau at Ser(262).",
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+      "relation": "directlyIncreases",
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+      "subject": {
+        "effect": {
+          "name": "kin",
+          "namespace": "bel"
+        },
+        "modifier": "Activity"
+      },
+      "target": 642
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
-          "Alessi DR",
-          "Campbell DG",
-          "Cousin MA",
-          "Esoof N",
-          "Fritsch MJ",
-          "Gordon SL",
-          "Gourlay R",
-          "Macartney T",
-          "Peggie M",
-          "Velupillai S",
-          "Zhang N",
-          "van Aalten DM"
+          "Clelland CL",
+          "Duff KE",
+          "Emrani S",
+          "Goldberg AL",
+          "Kukushkin NV",
+          "Myeku N",
+          "Yu WH"
         ],
-        "date": "2015-02-11",
-        "first": "Zhang N",
-        "last": "Alessi DR",
-        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
-        "pages": "2492-507",
-        "reference": "25673844",
-        "title": "Phosphorylation of synaptic vesicle protein 2A at Thr84 by casein kinase 1 family kinases controls the specific retrieval of synaptotagmin-1.",
+        "date": "2016-01-01",
+        "first": "Myeku N",
+        "last": "Duff KE",
+        "name": "Nature medicine",
+        "pages": "46-53",
+        "reference": "26692334",
+        "title": "Tau-driven 26S proteasome impairment and cognitive dysfunction can be prevented early in disease by activating cAMP-PKA signaling.",
         "type": "PubMed",
-        "volume": "35"
+        "volume": "22"
       },
-      "evidence": "We demonstrate that Casein kinase 1 family members, including isoforms of Tau-tubulin protein kinases (TTBK1 and TTBK2), phosphorylate human SV2A at two constellations of residues, namely Cluster-1 (Ser42, Ser45, and Ser47) and Cluster-2 (Ser80, Ser81, and Thr84). These residues are also phosphorylated in vivo, and the phosphorylation of Thr84 within Cluster-2 is essential for triggering binding to the C2B domain of human synaptotagmin-1",
-      "key": "8dbbdd27da843de74b3a08cb869cf7e5084d8954e22eab2c5e6e2ef484402f985317c61a06c1c7796275cc638f607b182df217e56e93b9c734ee9c936d97446c",
-      "line": 1415,
+      "evidence": "Rolipram is a specific phosphodiesterase type 4 (PDE4) inhibitor that increases cAMP levels in multiple tissues in vivo. The chymotrypsin-like activity of the 26S proteasomes in crude extracts was elevated after administration of db-cAMP or rolipram but was blocked by epoxomicin Exposure of slices from the early-stage mice to rolipram or db-cAMP for 8 h reduced amounts of total and insoluble tau (Fig. 3a), including phosphorylated tau (Supplementary Fig. 4a,b). In contrast, epoxomicin treatment increased levels of phosphorylated tau (Supplementary Fig. 4), although the amount of total tau remained unchanged (Fig. 3a). PKA is known to phosphorylate tau at Ser214 (pS214)29. We therefore monitored the amount of pS214 tau to determine whether rolipram and db-cAMP activated PKA. The amount of pS214 tau was higher in db-cAMP– and rolipram-treated samples than in control (DMSO) and epoxomicin-treated slices (Fig. 3a).",
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+      "line": 4347,
       "relation": "increases",
-      "source": 734,
-      "target": 700
+      "source": 372,
+      "subject": {
+        "modifier": "Activity"
+      },
+      "target": 636
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
-          "Alessi DR",
-          "Campbell DG",
-          "Cousin MA",
-          "Esoof N",
-          "Fritsch MJ",
-          "Gordon SL",
-          "Gourlay R",
-          "Macartney T",
-          "Peggie M",
-          "Velupillai S",
-          "Zhang N",
-          "van Aalten DM"
+          "Clelland CL",
+          "Duff KE",
+          "Emrani S",
+          "Goldberg AL",
+          "Kukushkin NV",
+          "Myeku N",
+          "Yu WH"
         ],
-        "date": "2015-02-11",
-        "first": "Zhang N",
-        "last": "Alessi DR",
-        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
-        "pages": "2492-507",
-        "reference": "25673844",
-        "title": "Phosphorylation of synaptic vesicle protein 2A at Thr84 by casein kinase 1 family kinases controls the specific retrieval of synaptotagmin-1.",
+        "date": "2016-01-01",
+        "first": "Myeku N",
+        "last": "Duff KE",
+        "name": "Nature medicine",
+        "pages": "46-53",
+        "reference": "26692334",
+        "title": "Tau-driven 26S proteasome impairment and cognitive dysfunction can be prevented early in disease by activating cAMP-PKA signaling.",
         "type": "PubMed",
-        "volume": "35"
+        "volume": "22"
+      },
+      "evidence": "PKA stimulation attenuated proteasome dysfunction, probably through proteasome subunit phosphorylation resulting in lower levels of aggregated tau and improvements in cognitive performance.",
+      "key": "b48dd5e00df8563a18b6a942179776e017ae7123f2963bed4d390918414422bc489a3cb64574dc434913fbacf97fa5f7c21ca146125db9b238031cba77ef7541",
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       },
-      "evidence": "We demonstrate that Casein kinase 1 family members, including isoforms of Tau-tubulin protein kinases (TTBK1 and TTBK2), phosphorylate human SV2A at two constellations of residues, namely Cluster-1 (Ser42, Ser45, and Ser47) and Cluster-2 (Ser80, Ser81, and Thr84). These residues are also phosphorylated in vivo, and the phosphorylation of Thr84 within Cluster-2 is essential for triggering binding to the C2B domain of human synaptotagmin-1",
-      "key": "20fbf9a28429c6ab366f598cf78e6193464061e2b1a3fb1b67fbe02c8052cc37e532368f67363301444289cf093e4855f86a82073bd1eb9c60f4143326ea081e",
-      "line": 1416,
       "relation": "increases",
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-      "target": 701
+      "source": 372,
+      "subject": {
+        "modifier": "Activity"
+      },
+      "target": 234
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
-          "Bird TD",
-          "Ghetti B",
-          "Greenup L",
-          "Kraemer BC",
-          "Leverenz JB",
-          "Liachko NF",
-          "Loomis E",
-          "McMillan PJ",
-          "Montine TJ",
-          "Murrell JR",
-          "Raskind MA",
-          "Strovas TJ"
+          "Clelland CL",
+          "Duff KE",
+          "Emrani S",
+          "Goldberg AL",
+          "Kukushkin NV",
+          "Myeku N",
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-        "first": "Liachko NF",
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-        "title": "The tau tubulin kinases TTBK1/2 promote accumulation of pathological TDP-43.",
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-          "Montine TJ",
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+          "Duff KE",
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+          "Myeku N",
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         "authors": [
-          "Freeman D",
-          "Kraatz HB",
-          "Martić S",
-          "Rains MK"
+          "Imahori K",
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         "authors": [
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-          "Landrieu I",
-          "Lippens G",
-          "Qi H",
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-        "title": "Identification of the Tau phosphorylation pattern that drives its aggregation.",
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-          "Collins N",
-          "Dai X",
-          "Huang T",
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-          "Lin L",
-          "Shen H",
-          "Wei Z",
-          "Wu X",
-          "Xiao N",
-          "York J",
-          "Zhang J",
-          "Zhou M",
-          "Zhu Y"
+          "Delgado E",
+          "Domínguez JM",
+          "Fuertes A",
+          "Medina M",
+          "Orozco L",
+          "del Monte-Millán M"
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-        "first": "Zhou M",
-        "last": "Chen X",
-        "name": "Current Alzheimer research",
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-        "title": "APOE4 Induces Site-Specific Tau Phosphorylation Through Calpain-CDK5 Signaling Pathway in EFAD-Tg Mice.",
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+        "first": "Domínguez JM",
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-          "Campbell SN",
-          "Masliah E",
-          "Monte L",
-          "Rice KC",
-          "Rissman RA",
-          "Roe AD",
-          "Taché Y",
-          "Zhang C"
-        ],
-        "date": "2015-01-01",
-        "first": "Campbell SN",
-        "last": "Rissman RA",
-        "name": "Journal of Alzheimer's disease : JAD",
-        "pages": "967-76",
-        "reference": "25125464",
-        "title": "Increased tau phosphorylation and aggregation in the hippocampus of mice overexpressing corticotropin-releasing factor.",
-        "type": "PubMed",
-        "volume": "43"
-      },
-      "evidence": "CRF-OE mice had significantly elevated tau-P compared to wild type (WT) mice at the AT8 (S202/T204), PHF-1 (S396/404), S262, and S422 sites. Treating CRF-OE mice with R121919 blocked phosphorylation at the AT8 (S202/T204) and PHF-1 (S396/404) sites, but not at the S262 and S422 sites and reduced phosphorylation of c-Jun N Terminal Kinase (JNK).",
-      "key": "709375605236079d47502905dab02e943efeea459aa65b8a9356eefb6287d3f6582c096087b2c17baa74cfeddb5d2cefca538a0a682b3b282f6ef99fc4f6f859",
-      "line": 2416,
-      "relation": "positiveCorrelation",
-      "source": 336,
-      "target": 780
-    },
-    {
-      "citation": {
-        "authors": [
-          "Gamblin TC",
-          "Sun Q"
+          "Delgado E",
+          "Domínguez JM",
+          "Fuertes A",
+          "Medina M",
+          "Orozco L",
+          "del Monte-Millán M"
         ],
-        "date": "2009-06-30",
-        "first": "Sun Q",
-        "last": "Gamblin TC",
-        "name": "Biochemistry",
-        "pages": "6002-11",
-        "reference": "19459590",
-        "title": "Pseudohyperphosphorylation causing AD-like changes in tau has significant effects on its polymerization.",
+        "date": "2012-01-06",
+        "first": "Domínguez JM",
+        "last": "Medina M",
+        "name": "The Journal of biological chemistry",
+        "pages": "893-904",
+        "reference": "22102280",
+        "title": "Evidence for irreversible inhibition of glycogen synthase kinase-3β by tideglusib.",
         "type": "PubMed",
-        "volume": "48"
+        "volume": "287"
       },
-      "evidence": "Because S199/S202/T205E, S396/S404E, 6-Phos and 7-Phos all demonstrated an AD-like shift in mobility as a result of phosphorylation-like changes, we conclude that they have the characteristics of hyperphosphorylated tau. These mutants will therefore be referred to as pseudo-hyperphosphorylated tau throughout the manuscript. On the basis of the observations that pseudohyperphosphorylated tau has decreased affinity for microtubules and reduced inducer-initiated rates of nucleation and polymerization, we propose that this combination could be the cause of the increased cytotoxicity of hyperphosphorylated tau in Alzheimer's disease and also explain the potentially beneficial role of tau polymerization and NFT formation.",
-      "key": "fa4402b6ffbd9aa56ead97c94816e6fae0304e7240e06cdf968b7793c5dc8bed916845cd1cb3941d3a6c7caf31dfba5a340d34842c608827878bf572e790d0d3",
-      "line": 2458,
+      "evidence": "Inhibition caused by hypothemycin and tideglusib on a panel of selected human recombinant kinases",
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       "object": {
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         "modifier": "Activity"
       },
-      "relation": "negativeCorrelation",
-      "source": 336,
-      "target": 486
+      "relation": "decreases",
+      "source": 65,
+      "target": 537
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        },
+        "Ki": {
+          "40 nM": true
+        }
+      },
       "citation": {
         "authors": [
-          "Gamblin TC",
-          "Sun Q"
+          "Delgado E",
+          "Domínguez JM",
+          "Fuertes A",
+          "Medina M",
+          "Orozco L",
+          "del Monte-Millán M"
         ],
-        "date": "2009-06-30",
-        "first": "Sun Q",
-        "last": "Gamblin TC",
-        "name": "Biochemistry",
-        "pages": "6002-11",
-        "reference": "19459590",
-        "title": "Pseudohyperphosphorylation causing AD-like changes in tau has significant effects on its polymerization.",
+        "date": "2012-01-06",
+        "first": "Domínguez JM",
+        "last": "Medina M",
+        "name": "The Journal of biological chemistry",
+        "pages": "893-904",
+        "reference": "22102280",
+        "title": "Evidence for irreversible inhibition of glycogen synthase kinase-3β by tideglusib.",
         "type": "PubMed",
-        "volume": "48"
+        "volume": "287"
       },
-      "evidence": "Because S199/S202/T205E, S396/S404E, 6-Phos and 7-Phos all demonstrated an AD-like shift in mobility as a result of phosphorylation-like changes, we conclude that they have the characteristics of hyperphosphorylated tau. These mutants will therefore be referred to as pseudo-hyperphosphorylated tau throughout the manuscript. On the basis of the observations that pseudohyperphosphorylated tau has decreased affinity for microtubules and reduced inducer-initiated rates of nucleation and polymerization, we propose that this combination could be the cause of the increased cytotoxicity of hyperphosphorylated tau in Alzheimer's disease and also explain the potentially beneficial role of tau polymerization and NFT formation.",
-      "key": "777746edf61ce338343ccee16d099cc5ce3bbd29673fab840711634e2c077399ae9f9356d904c4e10edc38cc5c4d6d76f2011dd6c584141351e1ad720617b2cd",
-      "line": 2461,
+      "evidence": "Alsterpaullone showed identical results with the wild-type and the mutant enzymes, demonstrating that its mechanism of inhibition is independent of the presence of the Cys-199 residue.",
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       "object": {
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         "modifier": "Activity"
       },
       "relation": "decreases",
-      "source": 336,
-      "target": 486
+      "source": 50,
+      "target": 537
     },
     {
       "annotations": {
-        "Anatomy": {
-          "hippocampal formation": true
+        "Confidence": {
+          "Medium": true
         },
-        "Species": {
-          "10116": true
+        "Ki": {
+          "4-80 nM": true
         }
       },
       "citation": {
         "authors": [
-          "Boehm J",
-          "Bourgeois C",
-          "Dudilot A",
-          "Lauzon M",
-          "Leclerc N",
-          "Mondragón-Rodríguez S",
-          "Trillaud-Doppia E"
+          "Bibb JA",
+          "Biernat J",
+          "Greengard P",
+          "Gussio R",
+          "Kunick C",
+          "Leost M",
+          "Link A",
+          "Mandelkow EM",
+          "Meijer L",
+          "Sausville EA",
+          "Schultz C",
+          "Senderowicz AM",
+          "Snyder GL",
+          "Wu YZ",
+          "Zaharevitz DW"
         ],
-        "date": "2012-09-14",
-        "first": "Mondragón-Rodríguez S",
-        "last": "Boehm J",
-        "name": "The Journal of biological chemistry",
-        "pages": "32040-53",
-        "reference": "22833681",
-        "title": "Interaction of endogenous tau protein with synaptic proteins is regulated by N-methyl-D-aspartate receptor-dependent tau phosphorylation.",
+        "date": "2000-10-01",
+        "first": "Leost M",
+        "last": "Meijer L",
+        "name": "European journal of biochemistry",
+        "pages": "5983-94",
+        "reference": "10998059",
+        "title": "Paullones are potent inhibitors of glycogen synthase kinase-3beta and cyclin-dependent kinase 5/p25.",
         "type": "PubMed",
-        "volume": "287"
+        "volume": "267"
       },
-      "evidence": "This result is supported by recent studies showing that the interaction between Fyn and tau is regulated through tau phosphorylation at the AT8 site, increasing tau-Fyn interaction by 42-fold after tau is phosphorylated or bearing a phosphomimetic mutation at the AT8 site (63). In our experiments, tau phosphorylation at AT8 is strongly up-regulated through the activation of NMDA receptors (Fig. 3), suggesting that NMDA receptor activation could massively enhance the interaction between tau and Fyn.",
-      "key": "78e478f0a6b7a3005225f518a87fa202ea9ff13a36b015488678035d0424d04d7cf4c1e36198b474af806ebfef2e8f08cc6b2a2f45cdf46144ad457eb2e25a94",
-      "line": 2485,
-      "relation": "increases",
-      "source": 336,
-      "target": 237
+      "evidence": "Alsterpaullone, the most active paullone, was demonstrated to act by competing with ATP for binding to GSK-3beta. Alsterpaullone inhibits the phosphorylation of tau in vivo at sites which are typically phosphorylated by GSK-3beta in Alzheimer's disease. Alsterpaullone also inhibits the CDK5/p25-dependent phosphorylation of DARPP-32 in mouse striatum slices in vitro. ",
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+      "line": 1431,
+      "object": {
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+          "name": "kin",
+          "namespace": "bel"
+        },
+        "modifier": "Activity"
+      },
+      "relation": "decreases",
+      "source": 50,
+      "target": 537
     },
     {
       "annotations": {
-        "Disease_Progression": {
-          "Late Stage": true
+        "Confidence": {
+          "Medium": true
         },
-        "MeSHDisease": {
-          "Alzheimer Disease": true
+        "Ki": {
+          "4-80 nM": true
         }
       },
       "citation": {
         "authors": [
-          "Castillo-Carranza DL",
-          "Jackson GR",
-          "Kayed R",
-          "Lasagna-Reeves CA",
-          "Sarmiento J",
-          "Sengupta U",
-          "Troncoso J"
+          "Bibb JA",
+          "Biernat J",
+          "Greengard P",
+          "Gussio R",
+          "Kunick C",
+          "Leost M",
+          "Link A",
+          "Mandelkow EM",
+          "Meijer L",
+          "Sausville EA",
+          "Schultz C",
+          "Senderowicz AM",
+          "Snyder GL",
+          "Wu YZ",
+          "Zaharevitz DW"
         ],
-        "date": "2012-05-01",
-        "first": "Lasagna-Reeves CA",
-        "last": "Kayed R",
-        "name": "FASEB journal : official publication of the Federation of American Societies for Experimental Biology",
-        "pages": "1946-59",
-        "reference": "22253473",
-        "title": "Identification of oligomers at early stages of tau aggregation in Alzheimer's disease.",
+        "date": "2000-10-01",
+        "first": "Leost M",
+        "last": "Meijer L",
+        "name": "European journal of biochemistry",
+        "pages": "5983-94",
+        "reference": "10998059",
+        "title": "Paullones are potent inhibitors of glycogen synthase kinase-3beta and cyclin-dependent kinase 5/p25.",
         "type": "PubMed",
-        "volume": "26"
+        "volume": "267"
       },
-      "evidence": "Phosphorylation at the epitope Ser202/Thr205 is regarded as a good marker for late-stage NFTs (5, 72). Hyman and colleagues (5) demonstrated that AT8 immunoreactivity is present primarily in eNFTs and in certain cases in iNFTs. These investigators also found that AT8 revealed dense neuropil thread staining.",
-      "key": "7b6fb3cd18a605558c4a0ba6f81c5f1c61ac6afc1dcbf5f138253c60a8761cd8794ed3fc0587d5421d27535957e1b762ead069cb67ce0eb642fa9a9769da30ee",
-      "line": 2614,
-      "relation": "positiveCorrelation",
-      "source": 336,
-      "target": 169
+      "evidence": "Alsterpaullone, the most active paullone, was demonstrated to act by competing with ATP for binding to GSK-3beta. Alsterpaullone inhibits the phosphorylation of tau in vivo at sites which are typically phosphorylated by GSK-3beta in Alzheimer's disease. Alsterpaullone also inhibits the CDK5/p25-dependent phosphorylation of DARPP-32 in mouse striatum slices in vitro. ",
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+      "relation": "decreases",
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+      "target": 622
     },
     {
       "annotations": {
+        "Anatomy": {
+          "striatum": true
+        },
+        "Confidence": {
+          "Medium": true
+        },
+        "Ki": {
+          "4-80 nM": true
+        },
         "Species": {
           "10090": true
         }
       },
       "citation": {
         "authors": [
-          "Cho SH",
-          "Cole PA",
-          "Gan L",
-          "Haroutunian V",
-          "Huang EJ",
-          "Masliah E",
-          "Meyers D",
-          "Min SW",
-          "Mukherjee C",
-          "Ott M",
-          "Schroeder S",
-          "Seeley WW",
-          "Shen Y",
-          "Zhou Y"
+          "Bibb JA",
+          "Biernat J",
+          "Greengard P",
+          "Gussio R",
+          "Kunick C",
+          "Leost M",
+          "Link A",
+          "Mandelkow EM",
+          "Meijer L",
+          "Sausville EA",
+          "Schultz C",
+          "Senderowicz AM",
+          "Snyder GL",
+          "Wu YZ",
+          "Zaharevitz DW"
         ],
-        "date": "2010-09-23",
-        "first": "Min SW",
-        "last": "Gan L",
-        "name": "Neuron",
-        "pages": "953-66",
-        "reference": "20869593",
-        "title": "Acetylation of tau inhibits its degradation and contributes to tauopathy.",
+        "date": "2000-10-01",
+        "first": "Leost M",
+        "last": "Meijer L",
+        "name": "European journal of biochemistry",
+        "pages": "5983-94",
+        "reference": "10998059",
+        "title": "Paullones are potent inhibitors of glycogen synthase kinase-3beta and cyclin-dependent kinase 5/p25.",
         "type": "PubMed",
-        "volume": "67"
+        "volume": "267"
       },
-      "evidence": "Thus, the increase in ac-tau induced by SIRT1 deficiency is accompanied by accumulation of pathogenic p-tau in primary neurons. In mouse brains, deleting SIRT1, which elevated ac-tau, also increased AT8-positive p-tau.",
-      "key": "123bacf913592cb00bc29d22a76cdaca3e1c2734654fa8002d49a5b2911ec85a11ef0bb6edbfa11ac19970f9c51bdd40e33cf90a9e6bcdca285fa22ff20b5927",
-      "line": 3313,
-      "relation": "positiveCorrelation",
-      "source": 336,
-      "target": 490
+      "evidence": "Alsterpaullone, the most active paullone, was demonstrated to act by competing with ATP for binding to GSK-3beta. Alsterpaullone inhibits the phosphorylation of tau in vivo at sites which are typically phosphorylated by GSK-3beta in Alzheimer's disease. Alsterpaullone also inhibits the CDK5/p25-dependent phosphorylation of DARPP-32 in mouse striatum slices in vitro. ",
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+        "modifier": "Activity"
+      },
+      "relation": "decreases",
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+      "target": 867
     },
     {
       "annotations": {
+        "Anatomy": {
+          "striatum": true
+        },
+        "Confidence": {
+          "Medium": true
+        },
+        "Ki": {
+          "4-80 nM": true
+        },
         "Species": {
           "10090": true
         }
       },
       "citation": {
         "authors": [
-          "Cho SH",
-          "Cole PA",
-          "Gan L",
-          "Haroutunian V",
-          "Huang EJ",
-          "Masliah E",
-          "Meyers D",
-          "Min SW",
-          "Mukherjee C",
-          "Ott M",
-          "Schroeder S",
-          "Seeley WW",
-          "Shen Y",
-          "Zhou Y"
-        ],
-        "date": "2010-09-23",
-        "first": "Min SW",
-        "last": "Gan L",
-        "name": "Neuron",
-        "pages": "953-66",
-        "reference": "20869593",
-        "title": "Acetylation of tau inhibits its degradation and contributes to tauopathy.",
-        "type": "PubMed",
-        "volume": "67"
-      },
-      "evidence": "Thus, the increase in ac-tau induced by SIRT1 deficiency is accompanied by accumulation of pathogenic p-tau in primary neurons. In mouse brains, deleting SIRT1, which elevated ac-tau, also increased AT8-positive p-tau.",
-      "key": "f0d323f5ab20dca0b4e6c8279bae79fbd2e5e55dcff786913e1c2a64878ee41fbb50e5abd99f6719c654d47932d0740996c08ca8ee5f5147846640f7ef84b9cd",
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-      },
-      "relation": "negativeCorrelation",
-      "source": 336,
-      "target": 677
-    },
-    {
-      "citation": {
-        "authors": [
-          "Braidy N",
-          "Brew BJ",
-          "Cullen KM",
-          "Guillemin GJ",
-          "Rahman A",
-          "Ting K"
+          "Bibb JA",
+          "Biernat J",
+          "Greengard P",
+          "Gussio R",
+          "Kunick C",
+          "Leost M",
+          "Link A",
+          "Mandelkow EM",
+          "Meijer L",
+          "Sausville EA",
+          "Schultz C",
+          "Senderowicz AM",
+          "Snyder GL",
+          "Wu YZ",
+          "Zaharevitz DW"
         ],
-        "date": "2009-07-22",
-        "first": "Rahman A",
-        "last": "Guillemin GJ",
-        "name": "PloS one",
-        "pages": "e6344",
-        "reference": "19623258",
-        "title": "The excitotoxin quinolinic acid induces tau phosphorylation in human neurons.",
+        "date": "2000-10-01",
+        "first": "Leost M",
+        "last": "Meijer L",
+        "name": "European journal of biochemistry",
+        "pages": "5983-94",
+        "reference": "10998059",
+        "title": "Paullones are potent inhibitors of glycogen synthase kinase-3beta and cyclin-dependent kinase 5/p25.",
         "type": "PubMed",
-        "volume": "4"
+        "volume": "267"
       },
-      "evidence": "QA appears to act through NMDA receptor activation similar to other agonists, glutamate and NMDA and was abrogated by the NMDAR antagonist memantine. NMDA receptor agonists, glutamate and NMDA at equimolar concentrations (500 nM) increased tau phosphorylation at serine 199/202 (AT8) and threonine 231 (AT-180), similar to QA.",
-      "key": "36e37906425d87cc668fbc497e59b0656732013c100b1bb4bbced16daee47c1357f92421e458d7d59337b070d484364dcba96c7830123652867b6ba4f6f03601",
-      "line": 3871,
+      "evidence": "Alsterpaullone, the most active paullone, was demonstrated to act by competing with ATP for binding to GSK-3beta. Alsterpaullone inhibits the phosphorylation of tau in vivo at sites which are typically phosphorylated by GSK-3beta in Alzheimer's disease. Alsterpaullone also inhibits the CDK5/p25-dependent phosphorylation of DARPP-32 in mouse striatum slices in vitro. ",
+      "key": "29f819d62fea6d97967dfe8bc09f8831dcc444668d702c12ba7ec316a020d27c891384049e9dddc130765a29e3380d31416ecccfafc8376812f958dd79bb3d79",
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       "object": {
         "modifier": "Activity"
       },
-      "relation": "positiveCorrelation",
-      "source": 336,
-      "target": 209
+      "relation": "decreases",
+      "source": 50,
+      "target": 868
     },
     {
+      "annotations": {
+        "Anatomy": {
+          "striatum": true
+        },
+        "Confidence": {
+          "Medium": true
+        },
+        "Ki": {
+          "4-80 nM": true
+        },
+        "Species": {
+          "10090": true
+        }
+      },
       "citation": {
         "authors": [
-          "Kawakami F",
-          "Ohtsuki K",
-          "Suzuki K"
+          "Bibb JA",
+          "Biernat J",
+          "Greengard P",
+          "Gussio R",
+          "Kunick C",
+          "Leost M",
+          "Link A",
+          "Mandelkow EM",
+          "Meijer L",
+          "Sausville EA",
+          "Schultz C",
+          "Senderowicz AM",
+          "Snyder GL",
+          "Wu YZ",
+          "Zaharevitz DW"
         ],
-        "date": "2008-02-01",
-        "first": "Kawakami F",
-        "last": "Ohtsuki K",
-        "name": "Biological &amp; pharmaceutical bulletin",
-        "pages": "193-200",
-        "reference": "18239272",
-        "title": "A novel consensus phosphorylation motif in sulfatide- and cholesterol-3-sulfate-binding protein substrates for CK1 in vitro.",
+        "date": "2000-10-01",
+        "first": "Leost M",
+        "last": "Meijer L",
+        "name": "European journal of biochemistry",
+        "pages": "5983-94",
+        "reference": "10998059",
+        "title": "Paullones are potent inhibitors of glycogen synthase kinase-3beta and cyclin-dependent kinase 5/p25.",
         "type": "PubMed",
-        "volume": "31"
+        "volume": "267"
       },
-      "evidence": "These data suggest a role for TTBK1 in pre-tangle formation prior to the formation of fibrillar tau and strengthen the idea that tau is phosphorylated at Ser422 at an early intermediate stage in NFT formation.",
-      "key": "e1935a3800d76f6d018260507b9307e3b8a1b80be5107b30f1b5a0141d75f367b0c738db8807f10ed6e190f88b9495235e46d8abb7c2b4074b5be1f2af5ea9b1",
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-      "relation": "association",
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+      "evidence": "Alsterpaullone, the most active paullone, was demonstrated to act by competing with ATP for binding to GSK-3beta. Alsterpaullone inhibits the phosphorylation of tau in vivo at sites which are typically phosphorylated by GSK-3beta in Alzheimer's disease. Alsterpaullone also inhibits the CDK5/p25-dependent phosphorylation of DARPP-32 in mouse striatum slices in vitro. ",
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     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        },
+        "IC50": {
+          "5-50 nM": true
+        }
+      },
       "citation": {
         "authors": [
-          "Kawakami F",
-          "Ohtsuki K",
-          "Suzuki K"
+          "Bibb JA",
+          "Biernat J",
+          "Eisenbrand G",
+          "Garnier M",
+          "Greengard P",
+          "Hoessel R",
+          "Leclerc S",
+          "Mandelkow EM",
+          "Marko D",
+          "Meijer L",
+          "Snyder GL",
+          "Wu YZ"
         ],
-        "date": "2008-02-01",
-        "first": "Kawakami F",
-        "last": "Ohtsuki K",
-        "name": "Biological &amp; pharmaceutical bulletin",
-        "pages": "193-200",
-        "reference": "18239272",
-        "title": "A novel consensus phosphorylation motif in sulfatide- and cholesterol-3-sulfate-binding protein substrates for CK1 in vitro.",
+        "date": "2001-01-05",
+        "first": "Leclerc S",
+        "last": "Meijer L",
+        "name": "The Journal of biological chemistry",
+        "pages": "251-60",
+        "reference": "11013232",
+        "title": "Indirubins inhibit glycogen synthase kinase-3 beta and CDK5/p25, two protein kinases involved in abnormal tau phosphorylation in Alzheimer's disease. A property common to most cyclin-dependent kinase inhibitors?",
         "type": "PubMed",
-        "volume": "31"
+        "volume": "276"
       },
-      "evidence": "These data suggest a role for TTBK1 in pre-tangle formation prior to the formation of fibrillar tau and strengthen the idea that tau is phosphorylated at Ser422 at an early intermediate stage in NFT formation.",
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-      "line": 1302,
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+      "evidence": "We report here that indirubins are also powerful inhibitors (IC(50): 5-50 nm) of an evolutionarily related kinase, glycogen synthase kinase-3beta (GSK-3 beta).",
+      "key": "434a2fec3f6a7ad9fbf7f5409805fee57f69c2fb14c67dc5f6915384535dfe94b4beb49c9445960951b352541d2cc0d094252da2008ef7cef56cd8742d3fe87b",
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+          "namespace": "bel"
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+        "modifier": "Activity"
+      },
+      "relation": "decreases",
+      "source": 133,
+      "target": 537
     },
     {
+      "annotations": {
+        "Anatomy": {
+          "striatum": true
+        },
+        "Confidence": {
+          "Medium": true
+        },
+        "Ki": {
+          "4-80 nM": true
+        },
+        "Species": {
+          "10090": true
+        }
+      },
       "citation": {
         "authors": [
-          "Kawakami F",
-          "Ohtsuki K",
-          "Suzuki K"
+          "Bibb JA",
+          "Biernat J",
+          "Greengard P",
+          "Gussio R",
+          "Kunick C",
+          "Leost M",
+          "Link A",
+          "Mandelkow EM",
+          "Meijer L",
+          "Sausville EA",
+          "Schultz C",
+          "Senderowicz AM",
+          "Snyder GL",
+          "Wu YZ",
+          "Zaharevitz DW"
         ],
-        "date": "2008-02-01",
-        "first": "Kawakami F",
-        "last": "Ohtsuki K",
-        "name": "Biological &amp; pharmaceutical bulletin",
-        "pages": "193-200",
-        "reference": "18239272",
-        "title": "A novel consensus phosphorylation motif in sulfatide- and cholesterol-3-sulfate-binding protein substrates for CK1 in vitro.",
+        "date": "2000-10-01",
+        "first": "Leost M",
+        "last": "Meijer L",
+        "name": "European journal of biochemistry",
+        "pages": "5983-94",
+        "reference": "10998059",
+        "title": "Paullones are potent inhibitors of glycogen synthase kinase-3beta and cyclin-dependent kinase 5/p25.",
         "type": "PubMed",
-        "volume": "31"
+        "volume": "267"
       },
-      "evidence": "These data suggest a role for TTBK1 in pre-tangle formation prior to the formation of fibrillar tau and strengthen the idea that tau is phosphorylated at Ser422 at an early intermediate stage in NFT formation.",
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-      "line": 1303,
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+      "evidence": "Alsterpaullone, the most active paullone, was demonstrated to act by competing with ATP for binding to GSK-3beta. Alsterpaullone inhibits the phosphorylation of tau in vivo at sites which are typically phosphorylated by GSK-3beta in Alzheimer's disease. Alsterpaullone also inhibits the CDK5/p25-dependent phosphorylation of DARPP-32 in mouse striatum slices in vitro. ",
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+        "modifier": "Activity"
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+      "target": 935
     },
     {
       "annotations": {
-        "Study_Group": {
-          "Spanish cohort": true
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+          "Medium": true
+        },
+        "Species": {
+          "10090": true
         }
       },
       "citation": {
         "authors": [
-          "Berciano J",
-          "Bullido MJ",
-          "Combarros O",
-          "Frank A",
-          "Martínez-García A",
-          "Mateo I",
-          "Pozueta A",
-          "Rodríguez-Rodríguez E",
-          "Sánchez-Juan P",
-          "Valdivieso F",
-          "Vázquez-Higuera JL"
+          "Ikezu S",
+          "Ikezu T"
         ],
-        "date": "2011-03-01",
-        "first": "Vázquez-Higuera JL",
-        "last": "Combarros O",
-        "name": "Neurobiology of aging",
-        "pages": "550.e5-9",
-        "reference": "20096481",
-        "title": "Genetic variations in tau-tubulin kinase-1 are linked to Alzheimer's disease in a Spanish case-control cohort.",
+        "date": "2014-01-01",
+        "first": "Ikezu S",
+        "last": "Ikezu T",
+        "name": "Frontiers in molecular neuroscience",
+        "pages": "33",
+        "reference": "24808823",
+        "title": "Tau-tubulin kinase.",
         "type": "PubMed",
-        "volume": "32"
+        "volume": "7"
       },
-      "evidence": "Haplotype analysis of the block formed by rs2651206, rs10807287, and rs7764257 showed that the combination of the three frequent alleles (CTA) was significantly (p = 0.02) overrepresented in the AD group (67%) compared to the control group (63%), and this result was still significant after multiple testing corrections with 10,000 permutations (p = 0.05).",
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-      "line": 1316,
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+      "evidence": "Overexpression of TTBK1 was sufficient in inducing spatial learning impairment in mice, which is associated with enhanced Cdk5 activity and reduction in cell surface level of NR2B. Over-expressionof TTBK1 transgene in JNPL3 mice resulted in accumulation of pre-tangle forms of tau. Inaddition, TTBK1 expression plays a unique role in accelerating motor neuron degeneration and neuroinflammation in JNPL3mice.",
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     },
     {
       "annotations": {
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-          "Han chinese": true
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       },
       "citation": {
         "authors": [
-          "Alessi DR",
-          "Begley MJ",
-          "Bouskila M",
-          "Cantley LC",
-          "Deak M",
-          "Esoof N",
-          "Fang EH",
-          "Gay L",
-          "Prescott A",
-          "Storey KG"
+          "Ikezu S",
+          "Ikezu T"
         ],
-        "date": "2011-07-01",
-        "first": "Bouskila M",
-        "last": "Alessi DR",
-        "name": "The Biochemical journal",
-        "pages": "157-67",
-        "reference": "21548880",
-        "title": "TTBK2 kinase substrate specificity and the impact of spinocerebellar-ataxia-causing mutations on expression, activity, localization and development.",
+        "date": "2014-01-01",
+        "first": "Ikezu S",
+        "last": "Ikezu T",
+        "name": "Frontiers in molecular neuroscience",
+        "pages": "33",
+        "reference": "24808823",
+        "title": "Tau-tubulin kinase.",
         "type": "PubMed",
-        "volume": "437"
+        "volume": "7"
       },
-      "evidence": "Significant association with a reduced risk of LOAD (odds ratio/OR=0.69). rs2651206 polymorphism was strongly associated with LOAD (OR=0.72) (age, gender, and APOE adjusted). The TG haplotype, deriving from the two minor alleles, decreases risk of LOAD (OR=0.78, P=0.037).",
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       "relation": "positiveCorrelation",
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     {
       "annotations": {
-        "Study_Group": {
-          "Spanish cohort": true
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+          "Medium": true
+        },
+        "MeSHDisease": {
+          "Alzheimer Disease": true
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+        "Species": {
+          "10090": true
         }
       },
       "citation": {
         "authors": [
-          "Berciano J",
-          "Bullido MJ",
-          "Combarros O",
-          "Frank A",
-          "Martínez-García A",
-          "Mateo I",
-          "Pozueta A",
-          "Rodríguez-Rodríguez E",
-          "Sánchez-Juan P",
-          "Valdivieso F",
-          "Vázquez-Higuera JL"
+          "Chen X",
+          "Collins N",
+          "Dai X",
+          "Huang T",
+          "LaDu MJ",
+          "Lin L",
+          "Shen H",
+          "Wei Z",
+          "Wu X",
+          "Xiao N",
+          "York J",
+          "Zhang J",
+          "Zhou M",
+          "Zhu Y"
         ],
-        "date": "2011-03-01",
-        "first": "Vázquez-Higuera JL",
-        "last": "Combarros O",
-        "name": "Neurobiology of aging",
-        "pages": "550.e5-9",
-        "reference": "20096481",
-        "title": "Genetic variations in tau-tubulin kinase-1 are linked to Alzheimer's disease in a Spanish case-control cohort.",
+        "date": "2016-01-01",
+        "first": "Zhou M",
+        "last": "Chen X",
+        "name": "Current Alzheimer research",
+        "pages": "1048-55",
+        "reference": "27087442",
+        "title": "APOE4 Induces Site-Specific Tau Phosphorylation Through Calpain-CDK5 Signaling Pathway in EFAD-Tg Mice.",
         "type": "PubMed",
-        "volume": "32"
+        "volume": "13"
       },
-      "evidence": "Haplotype analysis of the block formed by rs2651206, rs10807287, and rs7764257 showed that the combination of the three frequent alleles (CTA) was significantly (p = 0.02) overrepresented in the AD group (67%) compared to the control group (63%), and this result was still significant after multiple testing corrections with 10,000 permutations (p = 0.05).",
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     {
       "annotations": {
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       "citation": {
         "authors": [
-          "Alessi DR",
-          "Begley MJ",
-          "Bouskila M",
-          "Cantley LC",
-          "Deak M",
-          "Esoof N",
-          "Fang EH",
-          "Gay L",
-          "Prescott A",
-          "Storey KG"
+          "Chen X",
+          "Collins N",
+          "Dai X",
+          "Huang T",
+          "LaDu MJ",
+          "Lin L",
+          "Shen H",
+          "Wei Z",
+          "Wu X",
+          "Xiao N",
+          "York J",
+          "Zhang J",
+          "Zhou M",
+          "Zhu Y"
         ],
-        "date": "2011-07-01",
-        "first": "Bouskila M",
-        "last": "Alessi DR",
-        "name": "The Biochemical journal",
-        "pages": "157-67",
-        "reference": "21548880",
-        "title": "TTBK2 kinase substrate specificity and the impact of spinocerebellar-ataxia-causing mutations on expression, activity, localization and development.",
+        "date": "2016-01-01",
+        "first": "Zhou M",
+        "last": "Chen X",
+        "name": "Current Alzheimer research",
+        "pages": "1048-55",
+        "reference": "27087442",
+        "title": "APOE4 Induces Site-Specific Tau Phosphorylation Through Calpain-CDK5 Signaling Pathway in EFAD-Tg Mice.",
         "type": "PubMed",
-        "volume": "437"
+        "volume": "13"
       },
-      "evidence": "Significant association with a reduced risk of LOAD (odds ratio/OR=0.69). rs2651206 polymorphism was strongly associated with LOAD (OR=0.72) (age, gender, and APOE adjusted). The TG haplotype, deriving from the two minor alleles, decreases risk of LOAD (OR=0.78, P=0.037).",
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     {
       "annotations": {
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       "citation": {
         "authors": [
-          "Berciano J",
-          "Bullido MJ",
-          "Combarros O",
-          "Frank A",
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-          "Mateo I",
-          "Pozueta A",
-          "Rodríguez-Rodríguez E",
-          "Sánchez-Juan P",
-          "Valdivieso F",
-          "Vázquez-Higuera JL"
+          "Chen X",
+          "Collins N",
+          "Dai X",
+          "Huang T",
+          "LaDu MJ",
+          "Lin L",
+          "Shen H",
+          "Wei Z",
+          "Wu X",
+          "Xiao N",
+          "York J",
+          "Zhang J",
+          "Zhou M",
+          "Zhu Y"
         ],
-        "date": "2011-03-01",
-        "first": "Vázquez-Higuera JL",
-        "last": "Combarros O",
-        "name": "Neurobiology of aging",
-        "pages": "550.e5-9",
-        "reference": "20096481",
-        "title": "Genetic variations in tau-tubulin kinase-1 are linked to Alzheimer's disease in a Spanish case-control cohort.",
+        "date": "2016-01-01",
+        "first": "Zhou M",
+        "last": "Chen X",
+        "name": "Current Alzheimer research",
+        "pages": "1048-55",
+        "reference": "27087442",
+        "title": "APOE4 Induces Site-Specific Tau Phosphorylation Through Calpain-CDK5 Signaling Pathway in EFAD-Tg Mice.",
         "type": "PubMed",
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       "annotations": {
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       "citation": {
         "authors": [
-          "Berciano J",
-          "Bullido MJ",
-          "Combarros O",
-          "Frank A",
-          "Martínez-García A",
-          "Mateo I",
-          "Pozueta A",
-          "Rodríguez-Rodríguez E",
-          "Sánchez-Juan P",
-          "Valdivieso F",
-          "Vázquez-Higuera JL"
+          "Chen X",
+          "Collins N",
+          "Dai X",
+          "Huang T",
+          "LaDu MJ",
+          "Lin L",
+          "Shen H",
+          "Wei Z",
+          "Wu X",
+          "Xiao N",
+          "York J",
+          "Zhang J",
+          "Zhou M",
+          "Zhu Y"
         ],
-        "date": "2011-03-01",
-        "first": "Vázquez-Higuera JL",
-        "last": "Combarros O",
-        "name": "Neurobiology of aging",
-        "pages": "550.e5-9",
-        "reference": "20096481",
-        "title": "Genetic variations in tau-tubulin kinase-1 are linked to Alzheimer's disease in a Spanish case-control cohort.",
+        "date": "2016-01-01",
+        "first": "Zhou M",
+        "last": "Chen X",
+        "name": "Current Alzheimer research",
+        "pages": "1048-55",
+        "reference": "27087442",
+        "title": "APOE4 Induces Site-Specific Tau Phosphorylation Through Calpain-CDK5 Signaling Pathway in EFAD-Tg Mice.",
         "type": "PubMed",
-        "volume": "32"
+        "volume": "13"
       },
-      "evidence": "Haplotype analysis of the block formed by rs2651206, rs10807287, and rs7764257 showed that the combination of the three frequent alleles (CTA) was significantly (p = 0.02) overrepresented in the AD group (67%) compared to the control group (63%), and this result was still significant after multiple testing corrections with 10,000 permutations (p = 0.05).",
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     },
     {
       "annotations": {
-        "Study_Group": {
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+          "Medium": true
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+          "p25 transgenic mice": true
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+        "Species": {
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       },
       "citation": {
         "authors": [
-          "Berciano J",
-          "Bullido MJ",
-          "Combarros O",
-          "Frank A",
-          "Martínez-García A",
-          "Mateo I",
-          "Pozueta A",
-          "Rodríguez-Rodríguez E",
-          "Sánchez-Juan P",
-          "Valdivieso F",
-          "Vázquez-Higuera JL"
+          "Cruz JC",
+          "Goldman JA",
+          "Shih H",
+          "Tsai LH",
+          "Tseng HC"
         ],
-        "date": "2011-03-01",
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+          "Mandelkow EM",
+          "Meijer L",
+          "Sausville EA",
+          "Schultz C",
+          "Senderowicz AM",
+          "Snyder GL",
+          "Wu YZ",
+          "Zaharevitz DW"
         ],
-        "date": "2015-08-31",
-        "first": "Watanabe T",
-        "last": "Kaibuchi K",
-        "name": "The Journal of cell biology",
-        "pages": "737-51",
-        "reference": "26323690",
-        "title": "TTBK2 with EB1/3 regulates microtubule dynamics in migrating cells through KIF2A phosphorylation.",
+        "date": "2000-10-01",
+        "first": "Leost M",
+        "last": "Meijer L",
+        "name": "European journal of biochemistry",
+        "pages": "5983-94",
+        "reference": "10998059",
+        "title": "Paullones are potent inhibitors of glycogen synthase kinase-3beta and cyclin-dependent kinase 5/p25.",
         "type": "PubMed",
-        "volume": "210"
+        "volume": "267"
       },
-      "evidence": "These findings indicate that TTBK2 with EB1/3 phosphorylates KIF2A and antagonizes KIF2A-induced depolymerization at MT plus ends for cell migration.",
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+      "evidence": "Alsterpaullone, the most active paullone, was demonstrated to act by competing with ATP for binding to GSK-3beta. Alsterpaullone inhibits the phosphorylation of tau in vivo at sites which are typically phosphorylated by GSK-3beta in Alzheimer's disease. Alsterpaullone also inhibits the CDK5/p25-dependent phosphorylation of DARPP-32 in mouse striatum slices in vitro. ",
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       "relation": "increases",
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     {
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       "citation": {
         "authors": [
-          "Arimura N",
-          "Hoshino M",
-          "Ishidate F",
-          "Kaibuchi K",
-          "Kakeno M",
-          "Matsui T",
-          "Matsuzawa K",
-          "Nishioka T",
-          "Shirahige A",
-          "Sugiyama I",
-          "Taya S",
-          "Watanabe T"
+          "Ciborowski P",
+          "Ikezu T",
+          "Jacobsen MT",
+          "Martinez LB",
+          "Okuyama S",
+          "Sato S",
+          "Schlautman JD",
+          "Swan RJ",
+          "Walsh SM",
+          "Xu J"
         ],
-        "date": "2015-08-31",
-        "first": "Watanabe T",
-        "last": "Kaibuchi K",
-        "name": "The Journal of cell biology",
-        "pages": "737-51",
-        "reference": "26323690",
-        "title": "TTBK2 with EB1/3 regulates microtubule dynamics in migrating cells through KIF2A phosphorylation.",
+        "date": "2008-12-31",
+        "first": "Sato S",
+        "last": "Ikezu T",
+        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
+        "pages": "14511-21",
+        "reference": "19118186",
+        "title": "Spatial learning impairment, enhanced CDK5/p35 activity, and downregulation of NMDA receptor expression in transgenic mice expressing tau-tubulin kinase 1.",
         "type": "PubMed",
-        "volume": "210"
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-      "evidence": "Upregulation of Na+Cl- coupled betaine/GABA transporter BGT1 for organic osmolytes",
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     {
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       "citation": {
         "authors": [
-          "Arimura N",
-          "Hoshino M",
-          "Ishidate F",
-          "Kaibuchi K",
-          "Kakeno M",
-          "Matsui T",
-          "Matsuzawa K",
-          "Nishioka T",
-          "Shirahige A",
-          "Sugiyama I",
-          "Taya S",
-          "Watanabe T"
+          "Chen X",
+          "Collins N",
+          "Dai X",
+          "Huang T",
+          "LaDu MJ",
+          "Lin L",
+          "Shen H",
+          "Wei Z",
+          "Wu X",
+          "Xiao N",
+          "York J",
+          "Zhang J",
+          "Zhou M",
+          "Zhu Y"
         ],
-        "date": "2015-08-31",
-        "first": "Watanabe T",
-        "last": "Kaibuchi K",
-        "name": "The Journal of cell biology",
-        "pages": "737-51",
-        "reference": "26323690",
-        "title": "TTBK2 with EB1/3 regulates microtubule dynamics in migrating cells through KIF2A phosphorylation.",
+        "date": "2016-01-01",
+        "first": "Zhou M",
+        "last": "Chen X",
+        "name": "Current Alzheimer research",
+        "pages": "1048-55",
+        "reference": "27087442",
+        "title": "APOE4 Induces Site-Specific Tau Phosphorylation Through Calpain-CDK5 Signaling Pathway in EFAD-Tg Mice.",
         "type": "PubMed",
-        "volume": "210"
-      },
-      "evidence": "Upregulation of SLC5A1 Na-copled Glucose transport",
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+      "evidence": "Our data showed that CDK5 knock down induced an increase in p35 protein levels and Rac activity in triple transgenic Alzheimer's mice, which correlated with the recovery of cognitive function; these findings confirm that increased p35 and active Rac are involved in neuroprotection. In summary, our data suggest that p35 acts as a mediator of Rho GTPase activity and contributes to the neuroprotection induced by CDK5 RNAi.",
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     {
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       "citation": {
         "authors": [
-          "Arimura N",
-          "Hoshino M",
-          "Ishidate F",
-          "Kaibuchi K",
-          "Kakeno M",
-          "Matsui T",
-          "Matsuzawa K",
-          "Nishioka T",
-          "Shirahige A",
-          "Sugiyama I",
-          "Taya S",
-          "Watanabe T"
+          "Ishiguro K",
+          "Kusubata M",
+          "Matsubara M",
+          "Taniguchi H",
+          "Titani K",
+          "Uchida T"
         ],
-        "date": "2015-08-31",
-        "first": "Watanabe T",
-        "last": "Kaibuchi K",
-        "name": "The Journal of cell biology",
-        "pages": "737-51",
-        "reference": "26323690",
-        "title": "TTBK2 with EB1/3 regulates microtubule dynamics in migrating cells through KIF2A phosphorylation.",
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+        "first": "Matsubara M",
+        "last": "Taniguchi H",
+        "name": "The Journal of biological chemistry",
+        "pages": "21108-13",
+        "reference": "8702879",
+        "title": "Site-specific phosphorylation of synapsin I by mitogen-activated protein kinase and Cdk5 and its effects on physiological functions.",
         "type": "PubMed",
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     {
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       "citation": {
         "authors": [
-          "Arimura N",
-          "Hoshino M",
-          "Ishidate F",
-          "Kaibuchi K",
-          "Kakeno M",
-          "Matsui T",
-          "Matsuzawa K",
-          "Nishioka T",
-          "Shirahige A",
-          "Sugiyama I",
-          "Taya S",
-          "Watanabe T"
+          "Ishiguro K",
+          "Kusubata M",
+          "Matsubara M",
+          "Taniguchi H",
+          "Titani K",
+          "Uchida T"
         ],
-        "date": "2015-08-31",
-        "first": "Watanabe T",
-        "last": "Kaibuchi K",
-        "name": "The Journal of cell biology",
-        "pages": "737-51",
-        "reference": "26323690",
-        "title": "TTBK2 with EB1/3 regulates microtubule dynamics in migrating cells through KIF2A phosphorylation.",
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+        "first": "Matsubara M",
+        "last": "Taniguchi H",
+        "name": "The Journal of biological chemistry",
+        "pages": "21108-13",
+        "reference": "8702879",
+        "title": "Site-specific phosphorylation of synapsin I by mitogen-activated protein kinase and Cdk5 and its effects on physiological functions.",
         "type": "PubMed",
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-      "evidence": "TTBK2 bound EB1 and Cep164 through its SxIP motifs and a proline-rich motif, respectively. Using TTBK2 variants that contained mutations in the SxIP or proline-rich motifs, we obtained evidence that Cep164, but not EB1, is essential for centriolar localization of TTBK2. Therefore, Cep164 binding is essential for the function of TTBK2 in promoting CP110 removal and ciliogenesis. We also provide evidence that TTBK2 has the potential to effectively phosphorylate Cep164 and Cep97 and inhibits the interaction between Cep164 and its binding partner Dishevelled-3 (an important regulator of ciliogenesis) in a kinase activity-dependent manner.",
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-          "Kaibuchi K",
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-          "Matsui T",
-          "Matsuzawa K",
-          "Nishioka T",
-          "Shirahige A",
-          "Sugiyama I",
-          "Taya S",
-          "Watanabe T"
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-        "last": "Kaibuchi K",
-        "name": "The Journal of cell biology",
-        "pages": "737-51",
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-        "title": "TTBK2 with EB1/3 regulates microtubule dynamics in migrating cells through KIF2A phosphorylation.",
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       "citation": {
         "authors": [
-          "Arimura N",
-          "Hoshino M",
-          "Ishidate F",
-          "Kaibuchi K",
-          "Kakeno M",
-          "Matsui T",
-          "Matsuzawa K",
-          "Nishioka T",
-          "Shirahige A",
-          "Sugiyama I",
-          "Taya S",
-          "Watanabe T"
+          "Ishiguro K",
+          "Kusubata M",
+          "Matsubara M",
+          "Taniguchi H",
+          "Titani K",
+          "Uchida T"
         ],
-        "date": "2015-08-31",
-        "first": "Watanabe T",
-        "last": "Kaibuchi K",
-        "name": "The Journal of cell biology",
-        "pages": "737-51",
-        "reference": "26323690",
-        "title": "TTBK2 with EB1/3 regulates microtubule dynamics in migrating cells through KIF2A phosphorylation.",
+        "date": "1996-08-30",
+        "first": "Matsubara M",
+        "last": "Taniguchi H",
+        "name": "The Journal of biological chemistry",
+        "pages": "21108-13",
+        "reference": "8702879",
+        "title": "Site-specific phosphorylation of synapsin I by mitogen-activated protein kinase and Cdk5 and its effects on physiological functions.",
         "type": "PubMed",
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       "citation": {
         "authors": [
-          "Arimura N",
-          "Hoshino M",
-          "Ishidate F",
-          "Kaibuchi K",
-          "Kakeno M",
-          "Matsui T",
-          "Matsuzawa K",
-          "Nishioka T",
-          "Shirahige A",
-          "Sugiyama I",
-          "Taya S",
-          "Watanabe T"
+          "Ishiguro K",
+          "Kusubata M",
+          "Matsubara M",
+          "Taniguchi H",
+          "Titani K",
+          "Uchida T"
         ],
-        "date": "2015-08-31",
-        "first": "Watanabe T",
-        "last": "Kaibuchi K",
-        "name": "The Journal of cell biology",
-        "pages": "737-51",
-        "reference": "26323690",
-        "title": "TTBK2 with EB1/3 regulates microtubule dynamics in migrating cells through KIF2A phosphorylation.",
+        "date": "1996-08-30",
+        "first": "Matsubara M",
+        "last": "Taniguchi H",
+        "name": "The Journal of biological chemistry",
+        "pages": "21108-13",
+        "reference": "8702879",
+        "title": "Site-specific phosphorylation of synapsin I by mitogen-activated protein kinase and Cdk5 and its effects on physiological functions.",
         "type": "PubMed",
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-      "evidence": "TTBK2 bound EB1 and Cep164 through its SxIP motifs and a proline-rich motif, respectively. Using TTBK2 variants that contained mutations in the SxIP or proline-rich motifs, we obtained evidence that Cep164, but not EB1, is essential for centriolar localization of TTBK2. Therefore, Cep164 binding is essential for the function of TTBK2 in promoting CP110 removal and ciliogenesis. We also provide evidence that TTBK2 has the potential to effectively phosphorylate Cep164 and Cep97 and inhibits the interaction between Cep164 and its binding partner Dishevelled-3 (an important regulator of ciliogenesis) in a kinase activity-dependent manner.",
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       "citation": {
         "authors": [
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-          "Hoshino M",
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-          "Kaibuchi K",
-          "Kakeno M",
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-          "Nishioka T",
-          "Shirahige A",
-          "Sugiyama I",
-          "Taya S",
-          "Watanabe T"
+          "Ishiguro K",
+          "Kusubata M",
+          "Matsubara M",
+          "Taniguchi H",
+          "Titani K",
+          "Uchida T"
         ],
-        "date": "2015-08-31",
-        "first": "Watanabe T",
-        "last": "Kaibuchi K",
-        "name": "The Journal of cell biology",
-        "pages": "737-51",
-        "reference": "26323690",
-        "title": "TTBK2 with EB1/3 regulates microtubule dynamics in migrating cells through KIF2A phosphorylation.",
+        "date": "1996-08-30",
+        "first": "Matsubara M",
+        "last": "Taniguchi H",
+        "name": "The Journal of biological chemistry",
+        "pages": "21108-13",
+        "reference": "8702879",
+        "title": "Site-specific phosphorylation of synapsin I by mitogen-activated protein kinase and Cdk5 and its effects on physiological functions.",
         "type": "PubMed",
-        "volume": "210"
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       },
-      "evidence": "TTBK2 bound EB1 and Cep164 through its SxIP motifs and a proline-rich motif, respectively. Using TTBK2 variants that contained mutations in the SxIP or proline-rich motifs, we obtained evidence that Cep164, but not EB1, is essential for centriolar localization of TTBK2. Therefore, Cep164 binding is essential for the function of TTBK2 in promoting CP110 removal and ciliogenesis. We also provide evidence that TTBK2 has the potential to effectively phosphorylate Cep164 and Cep97 and inhibits the interaction between Cep164 and its binding partner Dishevelled-3 (an important regulator of ciliogenesis) in a kinase activity-dependent manner.",
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       "relation": "increases",
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       "subject": {
         "modifier": "Activity"
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     {
       "annotations": {
-        "Method": {
-          "Electron Microscopy, Transmission": true,
-          "NMR Spectroscopy": true,
-          "Thioflavin T Assay": true
+        "Confidence": {
+          "Medium": true
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       },
       "citation": {
         "authors": [
-          "Baulieu EE",
-          "Byrne C",
-          "Cantrelle FX",
-          "Chambraud B",
-          "Despres C",
-          "Huvent I",
-          "Jacquot Y",
-          "Landrieu I",
-          "Lippens G",
-          "Qi H",
-          "Smet-Nocca C"
-        ],
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-        "first": "Despres C",
-        "last": "Smet-Nocca C",
-        "name": "Proceedings of the National Academy of Sciences of the United States of America",
-        "pages": "9080-9085",
-        "reference": "28784767",
-        "title": "Identification of the Tau phosphorylation pattern that drives its aggregation.",
+          "Ishiguro K",
+          "Kusubata M",
+          "Matsubara M",
+          "Taniguchi H",
+          "Titani K",
+          "Uchida T"
+        ],
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+        "first": "Matsubara M",
+        "last": "Taniguchi H",
+        "name": "The Journal of biological chemistry",
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+        "reference": "8702879",
+        "title": "Site-specific phosphorylation of synapsin I by mitogen-activated protein kinase and Cdk5 and its effects on physiological functions.",
         "type": "PubMed",
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       },
-      "evidence": "Only very recently has the crystal structure of its fragment antigen body (Fab) with different phosphorylated peptides suggested that a third phosphorylation event at position Ser208 might lead to an epitope with an even better affinity (15).",
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     {
       "annotations": {
-        "Method": {
-          "Electron Microscopy, Transmission": true,
-          "NMR Spectroscopy": true,
-          "Thioflavin T Assay": true
+        "Confidence": {
+          "Medium": true
         }
       },
       "citation": {
         "authors": [
-          "Baulieu EE",
-          "Byrne C",
-          "Cantrelle FX",
-          "Chambraud B",
-          "Despres C",
-          "Huvent I",
-          "Jacquot Y",
-          "Landrieu I",
-          "Lippens G",
-          "Qi H",
-          "Smet-Nocca C"
+          "Ishiguro K",
+          "Kusubata M",
+          "Matsubara M",
+          "Taniguchi H",
+          "Titani K",
+          "Uchida T"
         ],
-        "date": "2017-08-22",
-        "first": "Despres C",
-        "last": "Smet-Nocca C",
-        "name": "Proceedings of the National Academy of Sciences of the United States of America",
-        "pages": "9080-9085",
-        "reference": "28784767",
-        "title": "Identification of the Tau phosphorylation pattern that drives its aggregation.",
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+        "first": "Matsubara M",
+        "last": "Taniguchi H",
+        "name": "The Journal of biological chemistry",
+        "pages": "21108-13",
+        "reference": "8702879",
+        "title": "Site-specific phosphorylation of synapsin I by mitogen-activated protein kinase and Cdk5 and its effects on physiological functions.",
         "type": "PubMed",
-        "volume": "114"
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       },
-      "evidence": "Indeed, Tau phosphorylation at the three positions, Ser202/Thr205/Ser208, while not at Ser262, is sufficient to induce aggregation without the addition of any exogenous aggregation inducer.",
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     {
       "annotations": {
-        "MeSHDisease": {
-          "Alzheimer Disease": true
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+          "Medium": true
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       },
       "citation": {
         "authors": [
-          "Babić Leko M",
-          "Bažadona D",
-          "Buée L",
-          "Delalle I",
-          "Di Giovanni G",
-          "Harrington C",
-          "Hof PR",
-          "Jovanov-Milošević N",
-          "Wischik C",
-          "Wray S",
-          "de Silva R",
-          "Šimić G"
+          "Ishiguro K",
+          "Kusubata M",
+          "Matsubara M",
+          "Taniguchi H",
+          "Titani K",
+          "Uchida T"
         ],
-        "date": "2016-01-06",
-        "first": "Šimić G",
-        "last": "Hof PR",
-        "name": "Biomolecules",
-        "pages": "6",
-        "reference": "26751493",
-        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
+        "date": "1996-08-30",
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+        "last": "Taniguchi H",
+        "name": "The Journal of biological chemistry",
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         "type": "PubMed",
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-          "Bažadona D",
-          "Buée L",
-          "Delalle I",
-          "Di Giovanni G",
-          "Harrington C",
-          "Hof PR",
-          "Jovanov-Milošević N",
-          "Wischik C",
-          "Wray S",
-          "de Silva R",
-          "Šimić G"
+          "Ishiguro K",
+          "Kusubata M",
+          "Matsubara M",
+          "Taniguchi H",
+          "Titani K",
+          "Uchida T"
         ],
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-        "first": "Šimić G",
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-        "name": "Biomolecules",
-        "pages": "6",
-        "reference": "26751493",
-        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
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+        "name": "The Journal of biological chemistry",
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+        "reference": "8702879",
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         "type": "PubMed",
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       "citation": {
         "authors": [
-          "Fiol CJ",
-          "Mahrenholz AM",
-          "Roach PJ",
-          "Roeske RW",
-          "Wang Y"
+          "Ishiguro K",
+          "Kusubata M",
+          "Matsubara M",
+          "Taniguchi H",
+          "Titani K",
+          "Uchida T"
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-        "date": "1987-10-15",
-        "first": "Fiol CJ",
-        "last": "Roach PJ",
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         "name": "The Journal of biological chemistry",
-        "pages": "14042-8",
-        "reference": "2820993",
-        "title": "Formation of protein kinase recognition sites by covalent modification of the substrate. Molecular mechanism for the synergistic action of casein kinase II and glycogen synthase kinase 3.",
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         "type": "PubMed",
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-          "Deak M",
-          "Esoof N",
-          "Fang EH",
-          "Gay L",
-          "Prescott A",
-          "Storey KG"
+          "Nikkuni M",
+          "Ohshima T",
+          "Toba J",
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-        "title": "TTBK2 kinase substrate specificity and the impact of spinocerebellar-ataxia-causing mutations on expression, activity, localization and development.",
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+      "evidence": "ATRA prevents the accumulation of amyloid plaques and APP processing into Ab through downregulation of Cdk5 in APP/PS1 mice. These results suggested that the administration of ATRA inhibited activity of Cdk5 and GSK3b and attenuated the formation of p-tau aggregation, including p-CRMP2 and p-WAVE1 in the 33Tg mouse brain.",
+      "key": "a259bf27ac011efbaeae1496018403cb3b1de96a5375bbf62763c988940c90734a0650749f5f089f44c17b01c116a7a2850af19a64dd26b59b95a7e2f0344674",
+      "line": 1502,
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     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Neurons": true
+        }
+      },
       "citation": {
         "authors": [
-          "Alessi DR",
-          "Begley MJ",
-          "Bouskila M",
-          "Cantley LC",
-          "Deak M",
-          "Esoof N",
-          "Fang EH",
-          "Gay L",
-          "Prescott A",
-          "Storey KG"
+          "Chen CH",
+          "Ho Lee T",
+          "Kim BM",
+          "Suh J",
+          "Tanzi RE",
+          "You MH"
         ],
-        "date": "2011-07-01",
-        "first": "Bouskila M",
-        "last": "Alessi DR",
-        "name": "The Biochemical journal",
-        "pages": "157-67",
-        "reference": "21548880",
-        "title": "TTBK2 kinase substrate specificity and the impact of spinocerebellar-ataxia-causing mutations on expression, activity, localization and development.",
+        "date": "2016-06-15",
+        "first": "Kim BM",
+        "last": "Ho Lee T",
+        "name": "Human molecular genetics",
+        "pages": "2498-2513",
+        "reference": "27094130",
+        "title": "Inhibition of death-associated protein kinase 1 attenuates the phosphorylation and amyloidogenic processing of amyloid precursor protein.",
         "type": "PubMed",
-        "volume": "437"
+        "volume": "25"
       },
-      "evidence": "SCA11 truncating mutations promote TTBK2 protein expression, suppress kinase activity and lead to enhanced nuclear localization. Using a SCA11-mutation-carrying knockin mouse we show that this leads to inhibition of endogenous TTBK2 protein kinase activity.",
-      "key": "ac11857cf97228d7dd54c5d3924e6f23cb3ea86c29f5a6d3431e9731270c5a60baecf6c54965aa13fc16ce5203a108ed52493450f0b14905dff53385a0fbffef",
-      "line": 1352,
-      "object": {
-        "effect": {
-          "name": "kin",
-          "namespace": "bel"
+      "evidence": "DAPK1, but not its kinase deficient mutant (K42A), significantly increased human Aβ secretion in neuronal cell culture models. Moreover, knockdown of DAPK1 expression or inhibition of DAPK1 catalytic activity significantly decreased Aβ secretion. Furthermore, DAPK1, but not K42A, triggered Thr668 phosphorylation of APP, which may initiate and facilitate amyloidogenic APP processing leading to the generation of Aβ.",
+      "key": "be47b530f807fc8695593b4c8bc29a9eeefbec939762d353da2e84f1693fefa962978715c3e023112fbd9e21c01695272887dd717ec4dbe933a7a01e110eea3b",
+      "line": 2296,
+      "relation": "association",
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+      "annotations": {
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+          "Medium": true
         },
-        "modifier": "Activity"
+        "MeSHAnatomy": {
+          "Neurons": true
+        }
       },
-      "relation": "decreases",
-      "source": 737,
-      "target": 735
+      "citation": {
+        "authors": [
+          "Chen CH",
+          "Ho Lee T",
+          "Kim BM",
+          "Suh J",
+          "Tanzi RE",
+          "You MH"
+        ],
+        "date": "2016-06-15",
+        "first": "Kim BM",
+        "last": "Ho Lee T",
+        "name": "Human molecular genetics",
+        "pages": "2498-2513",
+        "reference": "27094130",
+        "title": "Inhibition of death-associated protein kinase 1 attenuates the phosphorylation and amyloidogenic processing of amyloid precursor protein.",
+        "type": "PubMed",
+        "volume": "25"
+      },
+      "evidence": "DAPK1, but not its kinase deficient mutant (K42A), significantly increased human Aβ secretion in neuronal cell culture models. Moreover, knockdown of DAPK1 expression or inhibition of DAPK1 catalytic activity significantly decreased Aβ secretion. Furthermore, DAPK1, but not K42A, triggered Thr668 phosphorylation of APP, which may initiate and facilitate amyloidogenic APP processing leading to the generation of Aβ.",
+      "key": "fcbc3ced92d6de6988e2ed713d83be120b0a8dc27d45b6da8227ac5898adbd2620fe55da1cac53e4cb3ba1744eca0d026fd94458bf4d7dd0d0fc99a1866a6889",
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     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        },
+        "Ki": {
+          "39 nM": true
+        }
+      },
       "citation": {
         "authors": [
-          "Alessi DR",
-          "Begley MJ",
-          "Bouskila M",
-          "Cantley LC",
-          "Deak M",
-          "Esoof N",
-          "Fang EH",
-          "Gay L",
-          "Prescott A",
-          "Storey KG"
+          "Albers RW",
+          "Amin N",
+          "Grant P",
+          "Pant HC",
+          "Shetty KT",
+          "Veeranna"
         ],
-        "date": "2011-07-01",
-        "first": "Bouskila M",
-        "last": "Alessi DR",
-        "name": "The Biochemical journal",
-        "pages": "157-67",
-        "reference": "21548880",
-        "title": "TTBK2 kinase substrate specificity and the impact of spinocerebellar-ataxia-causing mutations on expression, activity, localization and development.",
+        "date": "1996-05-01",
+        "first": "Veeranna",
+        "last": "Pant HC",
+        "name": "Neurochemical research",
+        "pages": "629-36",
+        "reference": "8726973",
+        "title": "Inhibition of neuronal cyclin-dependent kinase-5 by staurosporine and purine analogs is independent of activation by Munc-18.",
         "type": "PubMed",
-        "volume": "437"
+        "volume": "21"
       },
-      "evidence": "TTBK1-Tg mice show significant age-dependent memory impairment as determined by radial arm water maze test, which is associated with enhancement of tau and neurofilament phosphorylation, increased levels of p25 and p35, both activators of cyclin-dependent protein kinase 5 (CDK5), enhanced calpain I activity, and reduced levels of hippocampal NMDA receptor types 2B (NR2B) and D. Enhanced CDK5/p35 complex formation is strongly correlated with dissociation of F-actin from p35, suggesting the inhibitory mechanism of CDK5/p35 complex formation by F-actin.",
-      "key": "1dfef19beef4be18316aa0b51570c65fd7d965ae57c78f549dc7e309bca172743e49f1bfc7c55d1cd677d0e68e510d31856b3eee9659d91dc76c1523f8085f22",
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+      "evidence": "The kinase activity was inhibited by staurosporine, isopentanyladenine and olomoucine in a dose dependent manner. Kinetic studies indicated Ki values of 39 nM, 38 microM and 8 microM, respectively for staurosporine, isopentanyladenine and olomoucine.",
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       "object": {
         "modifier": "Activity"
       },
-      "relation": "increases",
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+      "source": 87,
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     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
-          "Ai J",
-          "Ban T",
-          "Bao YN",
-          "Chen QX",
-          "Hu XL",
-          "Jiang XM",
-          "Liu CD",
-          "Pei SC",
-          "Su XL",
-          "Sun LH",
-          "Sun LL",
-          "Wang X",
-          "Yan ML",
-          "Zhao LJ",
-          "Zong DK"
+          "Blokzijl A",
+          "Classon C",
+          "Gu GJ",
+          "Kamali-Moghaddam M",
+          "Landegren U",
+          "Lund H",
+          "Sunnemark D",
+          "Wu D",
+          "von Euler G"
         ],
-        "date": "2015-09-01",
-        "first": "Sun LH",
-        "last": "Ai J",
-        "name": "Journal of neurochemistry",
-        "pages": "1139-51",
-        "reference": "26118667",
-        "title": "Activation of Cdk5/p25 and tau phosphorylation following chronic brain hypoperfusion in rats involves microRNA-195 down-regulation.",
+        "date": "2013-09-01",
+        "first": "Gu GJ",
+        "last": "Kamali-Moghaddam M",
+        "name": "Neuromolecular medicine",
+        "pages": "458-69",
+        "reference": "23666762",
+        "title": "Role of individual MARK isoforms in phosphorylation of tau at Ser²⁶² in Alzheimer's disease.",
         "type": "PubMed",
-        "volume": "134"
+        "volume": "15"
       },
-      "evidence": "To perform its function, Cdk5 must bind to the neuron-specific regulatory subunit protein p35, which is beneficial for neuronal development (Tsai et al. 1994; Chae et al. 1997). However, truncation of p35 and conversion to p25 (Patrick et al. 1999) is found in the forebrain of rats after focal cerebral ischemia and in AD patients, and these alterations are deleterious to the brain",
-      "key": "c30715ad1e225bd3f5eff9a2351c52a1f86b0ceafc6b96fef73941ee5077dcc916f82fd138a94cf7ba4ecca1759abf787370589d7996bc6ac40acba7ee2c64d7",
-      "line": 2299,
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+      "evidence": "In parallel, phosphorylation of tau at Ser262 in MARK-transfected cells was investigated using a rabbit antibody recognizing phosphorylated Ser262 of tau (AGG5759) and a mouse anti-tau antibody (SC-21796) (Fig. S1a3). Tau was shown to interact with each of the transfected MARK isoforms (Fig. 1) and to be phosphorylated at Ser262 (Fig. 2). Staurosporine, a non-selective kinase inhibitor, significantly inhibited interactions between tau and each of the four MARK isoforms after treatment with 20 lM staurosporine for 1 h (Fig. 1; p = 0.02 for MARK1–, MARK2– and MARK3–tau interactions and p = 3 9 10-6 for MARK4–tau interaction). Treatment with staurosporine also significantly reduced PLA signals for tau phosphorylation at Ser262 (Fig. 2; p = 0.04 for MARK1- and p = 0.02 for MARK2- and MARK3- and p = 1 9 10-5 for MARK4-mediated tau phosphorylation)",
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     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
-          "Ai J",
-          "Ban T",
-          "Bao YN",
-          "Chen QX",
-          "Hu XL",
-          "Jiang XM",
-          "Liu CD",
-          "Pei SC",
-          "Su XL",
-          "Sun LH",
-          "Sun LL",
-          "Wang X",
-          "Yan ML",
-          "Zhao LJ",
-          "Zong DK"
+          "Blokzijl A",
+          "Classon C",
+          "Gu GJ",
+          "Kamali-Moghaddam M",
+          "Landegren U",
+          "Lund H",
+          "Sunnemark D",
+          "Wu D",
+          "von Euler G"
         ],
-        "date": "2015-09-01",
-        "first": "Sun LH",
-        "last": "Ai J",
-        "name": "Journal of neurochemistry",
-        "pages": "1139-51",
-        "reference": "26118667",
-        "title": "Activation of Cdk5/p25 and tau phosphorylation following chronic brain hypoperfusion in rats involves microRNA-195 down-regulation.",
+        "date": "2013-09-01",
+        "first": "Gu GJ",
+        "last": "Kamali-Moghaddam M",
+        "name": "Neuromolecular medicine",
+        "pages": "458-69",
+        "reference": "23666762",
+        "title": "Role of individual MARK isoforms in phosphorylation of tau at Ser²⁶² in Alzheimer's disease.",
         "type": "PubMed",
-        "volume": "134"
+        "volume": "15"
       },
-      "evidence": "To perform its function, Cdk5 must bind to the neuron-specific regulatory subunit protein p35, which is beneficial for neuronal development (Tsai et al. 1994; Chae et al. 1997). However, truncation of p35 and conversion to p25 (Patrick et al. 1999) is found in the forebrain of rats after focal cerebral ischemia and in AD patients, and these alterations are deleterious to the brain",
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-      "line": 2301,
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-      "target": 311
+      "evidence": "In parallel, phosphorylation of tau at Ser262 in MARK-transfected cells was investigated using a rabbit antibody recognizing phosphorylated Ser262 of tau (AGG5759) and a mouse anti-tau antibody (SC-21796) (Fig. S1a3). Tau was shown to interact with each of the transfected MARK isoforms (Fig. 1) and to be phosphorylated at Ser262 (Fig. 2). Staurosporine, a non-selective kinase inhibitor, significantly inhibited interactions between tau and each of the four MARK isoforms after treatment with 20 lM staurosporine for 1 h (Fig. 1; p = 0.02 for MARK1–, MARK2– and MARK3–tau interactions and p = 3 9 10-6 for MARK4–tau interaction). Treatment with staurosporine also significantly reduced PLA signals for tau phosphorylation at Ser262 (Fig. 2; p = 0.04 for MARK1- and p = 0.02 for MARK2- and MARK3- and p = 1 9 10-5 for MARK4-mediated tau phosphorylation)",
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     {
-      "key": "1cdd48fda869945529a8aaaa6d6b9375e991f4594450df5d699e16b2abfa5af9fc8fbc25c4b6dd1478361ca4fb7739a825b0cc381152a5347d81bd16974f1b2b",
-      "relation": "hasVariant",
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-      "target": 402
+      "annotations": {
+        "Cell_Line": {
+          "NIH/3T3": true
+        },
+        "Confidence": {
+          "Medium": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Agerman K",
+          "Eckersley S",
+          "Gu GJ",
+          "Kamali-Moghaddam M",
+          "Kvist AJ",
+          "Landegren U",
+          "Lund H",
+          "Milner R",
+          "Nilsson LN",
+          "Sunnemark D",
+          "Wu D"
+        ],
+        "date": "2013-01-01",
+        "first": "Gu GJ",
+        "last": "Kamali-Moghaddam M",
+        "name": "Journal of Alzheimer's disease : JAD",
+        "pages": "699-713",
+        "reference": "23001711",
+        "title": "Elevated MARK2-dependent phosphorylation of Tau in Alzheimer's disease.",
+        "type": "PubMed",
+        "volume": "33"
+      },
+      "evidence": "Several kinases such as microtubule-affinity regulating kinase (MARK), protein kinase A, calcium calmodulin kinase II, and checkpoint kinase 2 are known to phosphorylate tau on Ser(262) in vitro. In this study, we took advantage of the in situ proximity ligation assay to investigate the role of MARK2, one of the four MARK isoforms, in AD. We demonstrate that MARK2 interacts with tau and phosphorylates tau at Ser(262) in stably transfected NIH/3T3 cells expressing human recombinant tau. Staurosporine, a protein kinase inhibitor, significantly reduced the interaction between MARK2 and tau, and also phosphorylation of tau at Ser(262).",
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     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
-          "Alessi DR",
-          "Begley MJ",
-          "Bouskila M",
-          "Cantley LC",
-          "Deak M",
-          "Esoof N",
-          "Fang EH",
-          "Gay L",
-          "Prescott A",
-          "Storey KG"
+          "Blokzijl A",
+          "Classon C",
+          "Gu GJ",
+          "Kamali-Moghaddam M",
+          "Landegren U",
+          "Lund H",
+          "Sunnemark D",
+          "Wu D",
+          "von Euler G"
         ],
-        "date": "2011-07-01",
-        "first": "Bouskila M",
-        "last": "Alessi DR",
-        "name": "The Biochemical journal",
-        "pages": "157-67",
-        "reference": "21548880",
-        "title": "TTBK2 kinase substrate specificity and the impact of spinocerebellar-ataxia-causing mutations on expression, activity, localization and development.",
+        "date": "2013-09-01",
+        "first": "Gu GJ",
+        "last": "Kamali-Moghaddam M",
+        "name": "Neuromolecular medicine",
+        "pages": "458-69",
+        "reference": "23666762",
+        "title": "Role of individual MARK isoforms in phosphorylation of tau at Ser²⁶² in Alzheimer's disease.",
         "type": "PubMed",
-        "volume": "437"
-      },
-      "evidence": "TTBK1-Tg mice show significant age-dependent memory impairment as determined by radial arm water maze test, which is associated with enhancement of tau and neurofilament phosphorylation, increased levels of p25 and p35, both activators of cyclin-dependent protein kinase 5 (CDK5), enhanced calpain I activity, and reduced levels of hippocampal NMDA receptor types 2B (NR2B) and D. Enhanced CDK5/p35 complex formation is strongly correlated with dissociation of F-actin from p35, suggesting the inhibitory mechanism of CDK5/p35 complex formation by F-actin.",
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-      "line": 1366,
-      "relation": "positiveCorrelation",
-      "source": 273,
-      "subject": {
-        "modifier": "Activity"
+        "volume": "15"
       },
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+      "evidence": "In parallel, phosphorylation of tau at Ser262 in MARK-transfected cells was investigated using a rabbit antibody recognizing phosphorylated Ser262 of tau (AGG5759) and a mouse anti-tau antibody (SC-21796) (Fig. S1a3). Tau was shown to interact with each of the transfected MARK isoforms (Fig. 1) and to be phosphorylated at Ser262 (Fig. 2). Staurosporine, a non-selective kinase inhibitor, significantly inhibited interactions between tau and each of the four MARK isoforms after treatment with 20 lM staurosporine for 1 h (Fig. 1; p = 0.02 for MARK1–, MARK2– and MARK3–tau interactions and p = 3 9 10-6 for MARK4–tau interaction). Treatment with staurosporine also significantly reduced PLA signals for tau phosphorylation at Ser262 (Fig. 2; p = 0.04 for MARK1- and p = 0.02 for MARK2- and MARK3- and p = 1 9 10-5 for MARK4-mediated tau phosphorylation)",
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+      "line": 2242,
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     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
-          "Alessi DR",
-          "Begley MJ",
-          "Bouskila M",
-          "Cantley LC",
-          "Deak M",
-          "Esoof N",
-          "Fang EH",
-          "Gay L",
-          "Prescott A",
-          "Storey KG"
+          "Blokzijl A",
+          "Classon C",
+          "Gu GJ",
+          "Kamali-Moghaddam M",
+          "Landegren U",
+          "Lund H",
+          "Sunnemark D",
+          "Wu D",
+          "von Euler G"
         ],
-        "date": "2011-07-01",
-        "first": "Bouskila M",
-        "last": "Alessi DR",
-        "name": "The Biochemical journal",
-        "pages": "157-67",
-        "reference": "21548880",
-        "title": "TTBK2 kinase substrate specificity and the impact of spinocerebellar-ataxia-causing mutations on expression, activity, localization and development.",
+        "date": "2013-09-01",
+        "first": "Gu GJ",
+        "last": "Kamali-Moghaddam M",
+        "name": "Neuromolecular medicine",
+        "pages": "458-69",
+        "reference": "23666762",
+        "title": "Role of individual MARK isoforms in phosphorylation of tau at Ser²⁶² in Alzheimer's disease.",
         "type": "PubMed",
-        "volume": "437"
+        "volume": "15"
       },
-      "evidence": "TTBK1-Tg mice show significant age-dependent memory impairment as determined by radial arm water maze test, which is associated with enhancement of tau and neurofilament phosphorylation, increased levels of p25 and p35, both activators of cyclin-dependent protein kinase 5 (CDK5), enhanced calpain I activity, and reduced levels of hippocampal NMDA receptor types 2B (NR2B) and D. Enhanced CDK5/p35 complex formation is strongly correlated with dissociation of F-actin from p35, suggesting the inhibitory mechanism of CDK5/p35 complex formation by F-actin.",
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-      "line": 1367,
-      "relation": "negativeCorrelation",
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+      "evidence": "In parallel, phosphorylation of tau at Ser262 in MARK-transfected cells was investigated using a rabbit antibody recognizing phosphorylated Ser262 of tau (AGG5759) and a mouse anti-tau antibody (SC-21796) (Fig. S1a3). Tau was shown to interact with each of the transfected MARK isoforms (Fig. 1) and to be phosphorylated at Ser262 (Fig. 2). Staurosporine, a non-selective kinase inhibitor, significantly inhibited interactions between tau and each of the four MARK isoforms after treatment with 20 lM staurosporine for 1 h (Fig. 1; p = 0.02 for MARK1–, MARK2– and MARK3–tau interactions and p = 3 9 10-6 for MARK4–tau interaction). Treatment with staurosporine also significantly reduced PLA signals for tau phosphorylation at Ser262 (Fig. 2; p = 0.04 for MARK1- and p = 0.02 for MARK2- and MARK3- and p = 1 9 10-5 for MARK4-mediated tau phosphorylation)",
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+      "line": 2243,
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+      "target": 287
     },
     {
+      "annotations": {
+        "Cell_Line": {
+          "NIH/3T3": true
+        },
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
-          "Alessi DR",
-          "Begley MJ",
-          "Bouskila M",
-          "Cantley LC",
-          "Deak M",
-          "Esoof N",
-          "Fang EH",
-          "Gay L",
-          "Prescott A",
-          "Storey KG"
+          "Agerman K",
+          "Eckersley S",
+          "Gu GJ",
+          "Kamali-Moghaddam M",
+          "Kvist AJ",
+          "Landegren U",
+          "Lund H",
+          "Milner R",
+          "Nilsson LN",
+          "Sunnemark D",
+          "Wu D"
         ],
-        "date": "2011-07-01",
-        "first": "Bouskila M",
-        "last": "Alessi DR",
-        "name": "The Biochemical journal",
-        "pages": "157-67",
-        "reference": "21548880",
-        "title": "TTBK2 kinase substrate specificity and the impact of spinocerebellar-ataxia-causing mutations on expression, activity, localization and development.",
+        "date": "2013-01-01",
+        "first": "Gu GJ",
+        "last": "Kamali-Moghaddam M",
+        "name": "Journal of Alzheimer's disease : JAD",
+        "pages": "699-713",
+        "reference": "23001711",
+        "title": "Elevated MARK2-dependent phosphorylation of Tau in Alzheimer's disease.",
         "type": "PubMed",
-        "volume": "437"
+        "volume": "33"
       },
-      "evidence": "TTBK1-Tg mice show significant age-dependent memory impairment as determined by radial arm water maze test, which is associated with enhancement of tau and neurofilament phosphorylation, increased levels of p25 and p35, both activators of cyclin-dependent protein kinase 5 (CDK5), enhanced calpain I activity, and reduced levels of hippocampal NMDA receptor types 2B (NR2B) and D. Enhanced CDK5/p35 complex formation is strongly correlated with dissociation of F-actin from p35, suggesting the inhibitory mechanism of CDK5/p35 complex formation by F-actin.",
-      "key": "0d84013a93308c5371674d116da9e4e9ea579ea80e9023e47b6b4b3ca72bc5ddd6bd5db2ad3d8d4b6c9324a194e776f67294e475bbc15d5f5a432d71d2efbb5b",
-      "line": 1368,
-      "relation": "negativeCorrelation",
-      "source": 455,
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+      "evidence": "Several kinases such as microtubule-affinity regulating kinase (MARK), protein kinase A, calcium calmodulin kinase II, and checkpoint kinase 2 are known to phosphorylate tau on Ser(262) in vitro. In this study, we took advantage of the in situ proximity ligation assay to investigate the role of MARK2, one of the four MARK isoforms, in AD. We demonstrate that MARK2 interacts with tau and phosphorylates tau at Ser(262) in stably transfected NIH/3T3 cells expressing human recombinant tau. Staurosporine, a protein kinase inhibitor, significantly reduced the interaction between MARK2 and tau, and also phosphorylation of tau at Ser(262).",
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+      "target": 720
     },
     {
+      "annotations": {
+        "Cell_Line": {
+          "NIH/3T3": true
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+        "Confidence": {
+          "Medium": true
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       "citation": {
         "authors": [
-          "Alessi DR",
-          "Campbell DG",
-          "Cousin MA",
-          "Esoof N",
-          "Fritsch MJ",
-          "Gordon SL",
-          "Gourlay R",
-          "Macartney T",
-          "Peggie M",
-          "Velupillai S",
-          "Zhang N",
-          "van Aalten DM"
+          "Agerman K",
+          "Eckersley S",
+          "Gu GJ",
+          "Kamali-Moghaddam M",
+          "Kvist AJ",
+          "Landegren U",
+          "Lund H",
+          "Milner R",
+          "Nilsson LN",
+          "Sunnemark D",
+          "Wu D"
         ],
-        "date": "2015-02-11",
-        "first": "Zhang N",
-        "last": "Alessi DR",
-        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
-        "pages": "2492-507",
-        "reference": "25673844",
-        "title": "Phosphorylation of synaptic vesicle protein 2A at Thr84 by casein kinase 1 family kinases controls the specific retrieval of synaptotagmin-1.",
+        "date": "2013-01-01",
+        "first": "Gu GJ",
+        "last": "Kamali-Moghaddam M",
+        "name": "Journal of Alzheimer's disease : JAD",
+        "pages": "699-713",
+        "reference": "23001711",
+        "title": "Elevated MARK2-dependent phosphorylation of Tau in Alzheimer's disease.",
         "type": "PubMed",
-        "volume": "35"
+        "volume": "33"
       },
-      "evidence": "The CK1 group of eukaryotic protein kinases are composed of seven CK1 isoforms (CK1α, CK1α2, CK1δ, CK1ε, CK1γ1, CK1γ2, and CK1γ3), two Tau–tubulin kinase isoforms (TTBK1 and TTBK2), and three VRK isoforms (VRK1, VRK2, and VRK3)",
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-      "line": 1387,
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-      "target": 312
+      "evidence": "Several kinases such as microtubule-affinity regulating kinase (MARK), protein kinase A, calcium calmodulin kinase II, and checkpoint kinase 2 are known to phosphorylate tau on Ser(262) in vitro. In this study, we took advantage of the in situ proximity ligation assay to investigate the role of MARK2, one of the four MARK isoforms, in AD. We demonstrate that MARK2 interacts with tau and phosphorylates tau at Ser(262) in stably transfected NIH/3T3 cells expressing human recombinant tau. Staurosporine, a protein kinase inhibitor, significantly reduced the interaction between MARK2 and tau, and also phosphorylation of tau at Ser(262).",
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     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        },
+        "Ki": {
+          "38 μM": true
+        }
+      },
       "citation": {
         "authors": [
-          "Alessi DR",
-          "Campbell DG",
-          "Cousin MA",
-          "Esoof N",
-          "Fritsch MJ",
-          "Gordon SL",
-          "Gourlay R",
-          "Macartney T",
-          "Peggie M",
-          "Velupillai S",
-          "Zhang N",
-          "van Aalten DM"
+          "Albers RW",
+          "Amin N",
+          "Grant P",
+          "Pant HC",
+          "Shetty KT",
+          "Veeranna"
         ],
-        "date": "2015-02-11",
-        "first": "Zhang N",
-        "last": "Alessi DR",
-        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
-        "pages": "2492-507",
-        "reference": "25673844",
-        "title": "Phosphorylation of synaptic vesicle protein 2A at Thr84 by casein kinase 1 family kinases controls the specific retrieval of synaptotagmin-1.",
+        "date": "1996-05-01",
+        "first": "Veeranna",
+        "last": "Pant HC",
+        "name": "Neurochemical research",
+        "pages": "629-36",
+        "reference": "8726973",
+        "title": "Inhibition of neuronal cyclin-dependent kinase-5 by staurosporine and purine analogs is independent of activation by Munc-18.",
         "type": "PubMed",
-        "volume": "35"
+        "volume": "21"
       },
-      "evidence": "The CK1 group of eukaryotic protein kinases are composed of seven CK1 isoforms (CK1α, CK1α2, CK1δ, CK1ε, CK1γ1, CK1γ2, and CK1γ3), two Tau–tubulin kinase isoforms (TTBK1 and TTBK2), and three VRK isoforms (VRK1, VRK2, and VRK3)",
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-      "relation": "isA",
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+      "evidence": "The kinase activity was inhibited by staurosporine, isopentanyladenine and olomoucine in a dose dependent manner. Kinetic studies indicated Ki values of 39 nM, 38 microM and 8 microM, respectively for staurosporine, isopentanyladenine and olomoucine.",
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     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        },
+        "Ki": {
+          "8 μM": true
+        }
+      },
       "citation": {
         "authors": [
-          "Alessi DR",
-          "Campbell DG",
-          "Cousin MA",
-          "Esoof N",
-          "Fritsch MJ",
-          "Gordon SL",
-          "Gourlay R",
-          "Macartney T",
-          "Peggie M",
-          "Velupillai S",
-          "Zhang N",
-          "van Aalten DM"
+          "Albers RW",
+          "Amin N",
+          "Grant P",
+          "Pant HC",
+          "Shetty KT",
+          "Veeranna"
         ],
-        "date": "2015-02-11",
-        "first": "Zhang N",
-        "last": "Alessi DR",
-        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
-        "pages": "2492-507",
-        "reference": "25673844",
-        "title": "Phosphorylation of synaptic vesicle protein 2A at Thr84 by casein kinase 1 family kinases controls the specific retrieval of synaptotagmin-1.",
+        "date": "1996-05-01",
+        "first": "Veeranna",
+        "last": "Pant HC",
+        "name": "Neurochemical research",
+        "pages": "629-36",
+        "reference": "8726973",
+        "title": "Inhibition of neuronal cyclin-dependent kinase-5 by staurosporine and purine analogs is independent of activation by Munc-18.",
         "type": "PubMed",
-        "volume": "35"
+        "volume": "21"
       },
-      "evidence": "The CK1 group of eukaryotic protein kinases are composed of seven CK1 isoforms (CK1α, CK1α2, CK1δ, CK1ε, CK1γ1, CK1γ2, and CK1γ3), two Tau–tubulin kinase isoforms (TTBK1 and TTBK2), and three VRK isoforms (VRK1, VRK2, and VRK3)",
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-      "relation": "isA",
-      "source": 751,
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+      "evidence": "The kinase activity was inhibited by staurosporine, isopentanyladenine and olomoucine in a dose dependent manner. Kinetic studies indicated Ki values of 39 nM, 38 microM and 8 microM, respectively for staurosporine, isopentanyladenine and olomoucine.",
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     {
+      "annotations": {
+        "Confidence": {
+          "High": true
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+        "Km": {
+          "8-15 μM": true
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+        "Km_ATP": {
+          "2 μM": true
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+        "Vmax": {
+          "0.8-4 μM/min/mg": true
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       "citation": {
         "authors": [
-          "Alessi DR",
-          "Campbell DG",
-          "Cousin MA",
-          "Esoof N",
-          "Fritsch MJ",
-          "Gordon SL",
-          "Gourlay R",
-          "Macartney T",
-          "Peggie M",
-          "Velupillai S",
-          "Zhang N",
-          "van Aalten DM"
+          "Kawakami F",
+          "Ohtsuki K",
+          "Suzuki K"
         ],
-        "date": "2015-02-11",
-        "first": "Zhang N",
-        "last": "Alessi DR",
-        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
-        "pages": "2492-507",
-        "reference": "25673844",
-        "title": "Phosphorylation of synaptic vesicle protein 2A at Thr84 by casein kinase 1 family kinases controls the specific retrieval of synaptotagmin-1.",
+        "date": "2008-02-01",
+        "first": "Kawakami F",
+        "last": "Ohtsuki K",
+        "name": "Biological &amp; pharmaceutical bulletin",
+        "pages": "193-200",
+        "reference": "18239272",
+        "title": "A novel consensus phosphorylation motif in sulfatide- and cholesterol-3-sulfate-binding protein substrates for CK1 in vitro.",
         "type": "PubMed",
-        "volume": "35"
+        "volume": "31"
       },
-      "evidence": "The CK1 group of eukaryotic protein kinases are composed of seven CK1 isoforms (CK1α, CK1α2, CK1δ, CK1ε, CK1γ1, CK1γ2, and CK1γ3), two Tau–tubulin kinase isoforms (TTBK1 and TTBK2), and three VRK isoforms (VRK1, VRK2, and VRK3)",
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-      "relation": "isA",
-      "source": 286,
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+      "evidence": "Tau-phosphorylation properties dependent on co-factors (Km 8 to 15 uM, Vmax 0.8 to 4 uM/min/mg protein) and Km for ATP is 2uM",
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     {
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+          "High": true
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       "citation": {
         "authors": [
           "Alessi DR",
@@ -38754,225 +43691,418 @@
         "type": "PubMed",
         "volume": "35"
       },
-      "evidence": "We demonstrate that Casein kinase 1 family members, including isoforms of Tau-tubulin protein kinases (TTBK1 and TTBK2), phosphorylate human SV2A at two constellations of residues, namely Cluster-1 (Ser42, Ser45, and Ser47) and Cluster-2 (Ser80, Ser81, and Thr84). These residues are also phosphorylated in vivo, and the phosphorylation of Thr84 within Cluster-2 is essential for triggering binding to the C2B domain of human synaptotagmin-1",
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     {
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+          "Medium": true
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       "citation": {
         "authors": [
-          "Alessi DR",
-          "Campbell DG",
-          "Cousin MA",
-          "Esoof N",
-          "Fritsch MJ",
-          "Gordon SL",
-          "Gourlay R",
-          "Macartney T",
-          "Peggie M",
-          "Velupillai S",
-          "Zhang N",
-          "van Aalten DM"
+          "Cowburn RF",
+          "Dahllund L",
+          "Gustafsson E",
+          "Lund H",
+          "Malinowsky D",
+          "Strömberg K",
+          "Sunnemark D",
+          "Svensson A"
         ],
-        "date": "2015-02-11",
-        "first": "Zhang N",
-        "last": "Alessi DR",
-        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
-        "pages": "2492-507",
-        "reference": "25673844",
-        "title": "Phosphorylation of synaptic vesicle protein 2A at Thr84 by casein kinase 1 family kinases controls the specific retrieval of synaptotagmin-1.",
+        "date": "2013-07-01",
+        "first": "Lund H",
+        "last": "Sunnemark D",
+        "name": "Brain pathology (Zurich, Switzerland)",
+        "pages": "378-89",
+        "reference": "23088643",
+        "title": "Tau-tubulin kinase 1 expression, phosphorylation and co-localization with phospho-Ser422 tau in the Alzheimer's disease brain.",
         "type": "PubMed",
-        "volume": "35"
+        "volume": "23"
       },
-      "evidence": "We demonstrate that Casein kinase 1 family members, including isoforms of Tau-tubulin protein kinases (TTBK1 and TTBK2), phosphorylate human SV2A at two constellations of residues, namely Cluster-1 (Ser42, Ser45, and Ser47) and Cluster-2 (Ser80, Ser81, and Thr84). These residues are also phosphorylated in vivo, and the phosphorylation of Thr84 within Cluster-2 is essential for triggering binding to the C2B domain of human synaptotagmin-1",
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     {
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+          "Medium": true
+        }
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       "citation": {
         "authors": [
-          "Alessi DR",
-          "Campbell DG",
-          "Cousin MA",
-          "Esoof N",
-          "Fritsch MJ",
-          "Gordon SL",
-          "Gourlay R",
-          "Macartney T",
-          "Peggie M",
-          "Velupillai S",
-          "Zhang N",
-          "van Aalten DM"
+          "Cowburn RF",
+          "Dahllund L",
+          "Gustafsson E",
+          "Lund H",
+          "Malinowsky D",
+          "Strömberg K",
+          "Sunnemark D",
+          "Svensson A"
         ],
-        "date": "2015-02-11",
-        "first": "Zhang N",
-        "last": "Alessi DR",
-        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
-        "pages": "2492-507",
-        "reference": "25673844",
-        "title": "Phosphorylation of synaptic vesicle protein 2A at Thr84 by casein kinase 1 family kinases controls the specific retrieval of synaptotagmin-1.",
+        "date": "2013-07-01",
+        "first": "Lund H",
+        "last": "Sunnemark D",
+        "name": "Brain pathology (Zurich, Switzerland)",
+        "pages": "378-89",
+        "reference": "23088643",
+        "title": "Tau-tubulin kinase 1 expression, phosphorylation and co-localization with phospho-Ser422 tau in the Alzheimer's disease brain.",
         "type": "PubMed",
-        "volume": "35"
+        "volume": "23"
       },
-      "evidence": "We demonstrate that Casein kinase 1 family members, including isoforms of Tau-tubulin protein kinases (TTBK1 and TTBK2), phosphorylate human SV2A at two constellations of residues, namely Cluster-1 (Ser42, Ser45, and Ser47) and Cluster-2 (Ser80, Ser81, and Thr84). These residues are also phosphorylated in vivo, and the phosphorylation of Thr84 within Cluster-2 is essential for triggering binding to the C2B domain of human synaptotagmin-1",
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     {
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+        }
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       "citation": {
         "authors": [
-          "Alessi DR",
-          "Campbell DG",
-          "Cousin MA",
-          "Esoof N",
-          "Fritsch MJ",
-          "Gordon SL",
-          "Gourlay R",
-          "Macartney T",
-          "Peggie M",
-          "Velupillai S",
-          "Zhang N",
-          "van Aalten DM"
+          "Cowburn RF",
+          "Dahllund L",
+          "Gustafsson E",
+          "Lund H",
+          "Malinowsky D",
+          "Strömberg K",
+          "Sunnemark D",
+          "Svensson A"
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-        "date": "2015-02-11",
-        "first": "Zhang N",
-        "last": "Alessi DR",
-        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
-        "pages": "2492-507",
-        "reference": "25673844",
-        "title": "Phosphorylation of synaptic vesicle protein 2A at Thr84 by casein kinase 1 family kinases controls the specific retrieval of synaptotagmin-1.",
+        "date": "2013-07-01",
+        "first": "Lund H",
+        "last": "Sunnemark D",
+        "name": "Brain pathology (Zurich, Switzerland)",
+        "pages": "378-89",
+        "reference": "23088643",
+        "title": "Tau-tubulin kinase 1 expression, phosphorylation and co-localization with phospho-Ser422 tau in the Alzheimer's disease brain.",
         "type": "PubMed",
-        "volume": "35"
+        "volume": "23"
       },
-      "evidence": "We demonstrate that Casein kinase 1 family members, including isoforms of Tau-tubulin protein kinases (TTBK1 and TTBK2), phosphorylate human SV2A at two constellations of residues, namely Cluster-1 (Ser42, Ser45, and Ser47) and Cluster-2 (Ser80, Ser81, and Thr84). These residues are also phosphorylated in vivo, and the phosphorylation of Thr84 within Cluster-2 is essential for triggering binding to the C2B domain of human synaptotagmin-1",
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     {
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       "citation": {
         "authors": [
-          "Alessi DR",
-          "Campbell DG",
-          "Cousin MA",
-          "Esoof N",
-          "Fritsch MJ",
-          "Gordon SL",
-          "Gourlay R",
-          "Macartney T",
-          "Peggie M",
-          "Velupillai S",
-          "Zhang N",
-          "van Aalten DM"
+          "Cowburn RF",
+          "Dahllund L",
+          "Gustafsson E",
+          "Lund H",
+          "Malinowsky D",
+          "Strömberg K",
+          "Sunnemark D",
+          "Svensson A"
         ],
-        "date": "2015-02-11",
-        "first": "Zhang N",
-        "last": "Alessi DR",
-        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
-        "pages": "2492-507",
-        "reference": "25673844",
-        "title": "Phosphorylation of synaptic vesicle protein 2A at Thr84 by casein kinase 1 family kinases controls the specific retrieval of synaptotagmin-1.",
+        "date": "2013-07-01",
+        "first": "Lund H",
+        "last": "Sunnemark D",
+        "name": "Brain pathology (Zurich, Switzerland)",
+        "pages": "378-89",
+        "reference": "23088643",
+        "title": "Tau-tubulin kinase 1 expression, phosphorylation and co-localization with phospho-Ser422 tau in the Alzheimer's disease brain.",
         "type": "PubMed",
-        "volume": "35"
+        "volume": "23"
       },
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     {
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       "citation": {
         "authors": [
-          "Alessi DR",
-          "Campbell DG",
-          "Cousin MA",
-          "Esoof N",
-          "Fritsch MJ",
-          "Gordon SL",
-          "Gourlay R",
-          "Macartney T",
-          "Peggie M",
-          "Velupillai S",
-          "Zhang N",
-          "van Aalten DM"
+          "Freeman D",
+          "Kraatz HB",
+          "Martić S",
+          "Rains MK"
         ],
-        "date": "2015-02-11",
-        "first": "Zhang N",
-        "last": "Alessi DR",
-        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
-        "pages": "2492-507",
-        "reference": "25673844",
-        "title": "Phosphorylation of synaptic vesicle protein 2A at Thr84 by casein kinase 1 family kinases controls the specific retrieval of synaptotagmin-1.",
+        "date": "2013-08-21",
+        "first": "Rains MK",
+        "last": "Kraatz HB",
+        "name": "ACS chemical neuroscience",
+        "pages": "1194-203",
+        "reference": "23687953",
+        "title": "Electrochemical investigations into kinase-catalyzed transformations of tau protein.",
         "type": "PubMed",
-        "volume": "35"
+        "volume": "4"
       },
-      "evidence": "We demonstrate that Casein kinase 1 family members, including isoforms of Tau-tubulin protein kinases (TTBK1 and TTBK2), phosphorylate human SV2A at two constellations of residues, namely Cluster-1 (Ser42, Ser45, and Ser47) and Cluster-2 (Ser80, Ser81, and Thr84). These residues are also phosphorylated in vivo, and the phosphorylation of Thr84 within Cluster-2 is essential for triggering binding to the C2B domain of human synaptotagmin-1",
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+          "Cowburn RF",
+          "Dahllund L",
+          "Gustafsson E",
+          "Lund H",
+          "Malinowsky D",
+          "Strömberg K",
+          "Sunnemark D",
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+        "first": "Lund H",
+        "last": "Sunnemark D",
+        "name": "Brain pathology (Zurich, Switzerland)",
+        "pages": "378-89",
+        "reference": "23088643",
+        "title": "Tau-tubulin kinase 1 expression, phosphorylation and co-localization with phospho-Ser422 tau in the Alzheimer's disease brain.",
+        "type": "PubMed",
+        "volume": "23"
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       "annotations": {
-        "Method": {
-          "Electron Microscopy, Transmission": true,
-          "NMR Spectroscopy": true,
-          "Thioflavin T Assay": true
+        "Confidence": {
+          "Medium": true
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       },
       "citation": {
         "authors": [
-          "Baulieu EE",
-          "Byrne C",
-          "Cantrelle FX",
-          "Chambraud B",
-          "Despres C",
-          "Huvent I",
-          "Jacquot Y",
-          "Landrieu I",
-          "Lippens G",
-          "Qi H",
-          "Smet-Nocca C"
+          "Cowburn RF",
+          "Dahllund L",
+          "Gustafsson E",
+          "Lund H",
+          "Malinowsky D",
+          "Strömberg K",
+          "Sunnemark D",
+          "Svensson A"
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-        "date": "2017-08-22",
-        "first": "Despres C",
-        "last": "Smet-Nocca C",
-        "name": "Proceedings of the National Academy of Sciences of the United States of America",
-        "pages": "9080-9085",
-        "reference": "28784767",
-        "title": "Identification of the Tau phosphorylation pattern that drives its aggregation.",
+        "date": "2013-07-01",
+        "first": "Lund H",
+        "last": "Sunnemark D",
+        "name": "Brain pathology (Zurich, Switzerland)",
+        "pages": "378-89",
+        "reference": "23088643",
+        "title": "Tau-tubulin kinase 1 expression, phosphorylation and co-localization with phospho-Ser422 tau in the Alzheimer's disease brain.",
         "type": "PubMed",
-        "volume": "114"
+        "volume": "23"
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-      "evidence": "Phosphorylation at Ser208 might be catalyzed by Casein kinase 1 (44), and its identification as a potential site for O-GlcNacylation (45) points to the important role of this residue.",
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+          "Dahllund L",
+          "Gustafsson E",
+          "Lund H",
+          "Malinowsky D",
+          "Strömberg K",
+          "Sunnemark D",
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+        "last": "Sunnemark D",
+        "name": "Brain pathology (Zurich, Switzerland)",
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+        "reference": "23088643",
+        "title": "Tau-tubulin kinase 1 expression, phosphorylation and co-localization with phospho-Ser422 tau in the Alzheimer's disease brain.",
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+          "Malinowsky D",
+          "Strömberg K",
+          "Sunnemark D",
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+        "last": "Sunnemark D",
+        "name": "Brain pathology (Zurich, Switzerland)",
+        "pages": "378-89",
+        "reference": "23088643",
+        "title": "Tau-tubulin kinase 1 expression, phosphorylation and co-localization with phospho-Ser422 tau in the Alzheimer's disease brain.",
+        "type": "PubMed",
+        "volume": "23"
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+      "evidence": "These data suggest a role for TTBK1 in pre-tangle formation prior to the formation of fibrillar tau and strengthen the idea that tau is phosphorylated at Ser422 at an early intermediate stage in NFT formation.",
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+          "Spanish cohort": true
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+      "citation": {
+        "authors": [
+          "Berciano J",
+          "Bullido MJ",
+          "Combarros O",
+          "Frank A",
+          "Martínez-García A",
+          "Mateo I",
+          "Pozueta A",
+          "Rodríguez-Rodríguez E",
+          "Sánchez-Juan P",
+          "Valdivieso F",
+          "Vázquez-Higuera JL"
+        ],
+        "date": "2011-03-01",
+        "first": "Vázquez-Higuera JL",
+        "last": "Combarros O",
+        "name": "Neurobiology of aging",
+        "pages": "550.e5-9",
+        "reference": "20096481",
+        "title": "Genetic variations in tau-tubulin kinase-1 are linked to Alzheimer's disease in a Spanish case-control cohort.",
+        "type": "PubMed",
+        "volume": "32"
+      },
+      "evidence": "Activates cdk5 and GSK3; genetic variation protects against AD in Spanish cohort",
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+          "Berciano J",
+          "Bullido MJ",
+          "Combarros O",
+          "Frank A",
+          "Martínez-García A",
+          "Mateo I",
+          "Pozueta A",
+          "Rodríguez-Rodríguez E",
+          "Sánchez-Juan P",
+          "Valdivieso F",
+          "Vázquez-Higuera JL"
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+        "first": "Vázquez-Higuera JL",
+        "last": "Combarros O",
+        "name": "Neurobiology of aging",
+        "pages": "550.e5-9",
+        "reference": "20096481",
+        "title": "Genetic variations in tau-tubulin kinase-1 are linked to Alzheimer's disease in a Spanish case-control cohort.",
+        "type": "PubMed",
+        "volume": "32"
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+      "evidence": "Activates cdk5 and GSK3; genetic variation protects against AD in Spanish cohort",
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       "citation": {
         "authors": [
           "Alessi DR",
@@ -38999,13 +44129,18 @@
         "volume": "35"
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       "evidence": "The CK1 group of eukaryotic protein kinases are composed of seven CK1 isoforms (CK1α, CK1α2, CK1δ, CK1ε, CK1γ1, CK1γ2, and CK1γ3), two Tau–tubulin kinase isoforms (TTBK1 and TTBK2), and three VRK isoforms (VRK1, VRK2, and VRK3)",
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       "citation": {
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           "Alessi DR",
@@ -39031,14 +44166,19 @@
         "type": "PubMed",
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-      "evidence": "The CK1 group of eukaryotic protein kinases are composed of seven CK1 isoforms (CK1α, CK1α2, CK1δ, CK1ε, CK1γ1, CK1γ2, and CK1γ3), two Tau–tubulin kinase isoforms (TTBK1 and TTBK2), and three VRK isoforms (VRK1, VRK2, and VRK3)",
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@@ -39064,14 +44204,19 @@
         "type": "PubMed",
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+      "evidence": "We demonstrate that Casein kinase 1 family members, including isoforms of Tau-tubulin protein kinases (TTBK1 and TTBK2), phosphorylate human SV2A at two constellations of residues, namely Cluster-1 (Ser42, Ser45, and Ser47) and Cluster-2 (Ser80, Ser81, and Thr84). These residues are also phosphorylated in vivo, and the phosphorylation of Thr84 within Cluster-2 is essential for triggering binding to the C2B domain of human synaptotagmin-1",
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@@ -39097,14 +44242,19 @@
         "type": "PubMed",
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+      "evidence": "We demonstrate that Casein kinase 1 family members, including isoforms of Tau-tubulin protein kinases (TTBK1 and TTBK2), phosphorylate human SV2A at two constellations of residues, namely Cluster-1 (Ser42, Ser45, and Ser47) and Cluster-2 (Ser80, Ser81, and Thr84). These residues are also phosphorylated in vivo, and the phosphorylation of Thr84 within Cluster-2 is essential for triggering binding to the C2B domain of human synaptotagmin-1",
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         "authors": [
           "Alessi DR",
@@ -39130,56 +44280,19 @@
         "type": "PubMed",
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           "Alessi DR",
@@ -39206,13 +44319,18 @@
         "volume": "35"
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       "evidence": "We demonstrate that Casein kinase 1 family members, including isoforms of Tau-tubulin protein kinases (TTBK1 and TTBK2), phosphorylate human SV2A at two constellations of residues, namely Cluster-1 (Ser42, Ser45, and Ser47) and Cluster-2 (Ser80, Ser81, and Thr84). These residues are also phosphorylated in vivo, and the phosphorylation of Thr84 within Cluster-2 is essential for triggering binding to the C2B domain of human synaptotagmin-1",
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       "citation": {
         "authors": [
           "Alessi DR",
@@ -39239,1451 +44357,1796 @@
         "volume": "35"
       },
       "evidence": "We demonstrate that Casein kinase 1 family members, including isoforms of Tau-tubulin protein kinases (TTBK1 and TTBK2), phosphorylate human SV2A at two constellations of residues, namely Cluster-1 (Ser42, Ser45, and Ser47) and Cluster-2 (Ser80, Ser81, and Thr84). These residues are also phosphorylated in vivo, and the phosphorylation of Thr84 within Cluster-2 is essential for triggering binding to the C2B domain of human synaptotagmin-1",
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       "citation": {
         "authors": [
-          "Chen F",
-          "Gong CX",
-          "Gu J",
-          "Hu W",
-          "Iqbal K",
-          "Liu F",
-          "Miao S",
-          "Wang W",
-          "Wu F"
+          "Bird TD",
+          "Ghetti B",
+          "Greenup L",
+          "Kraemer BC",
+          "Leverenz JB",
+          "Liachko NF",
+          "Loomis E",
+          "McMillan PJ",
+          "Montine TJ",
+          "Murrell JR",
+          "Raskind MA",
+          "Strovas TJ"
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-        "date": "2018-02-01",
-        "first": "Gu J",
-        "last": "Liu F",
-        "name": "FEBS letters",
-        "pages": "402-410",
-        "reference": "29334120",
-        "title": "Protein Phosphatase 1 dephosphorylates TDP-43 and suppresses its function in tau exon 10 inclusion.",
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+        "first": "Liachko NF",
+        "last": "Kraemer BC",
+        "name": "PLoS genetics",
+        "pages": "e1004803",
+        "reference": "25473830",
+        "title": "The tau tubulin kinases TTBK1/2 promote accumulation of pathological TDP-43.",
         "type": "PubMed",
-        "volume": "592"
-      },
-      "evidence": "We recently found that overexpression of TDP-43 enhances tau exon 10 inclusion and tau mRNA instability. Overexpression of PP1α and PP1γ, but not PP1β, suppressed TDP-43 phosphorylation at Ser403/404 and Ser409/410 and TDP-43-induced tau exon 10 inclusion.",
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+      "evidence": "Using refined methodology, we demonstrate TTBK1 and TTBK2 directly phosphorylate TDP-43 in vitro and promote TDP-43 phosphorylation in mammalian cultured cells. TTBK1/2 overexpression drives phosphorylation and relocalization of TDP-43 from the nucleus to cytoplasmic inclusions reminiscent of neuropathologic changes in disease states.",
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         "authors": [
-          "Lang F",
-          "Matschke V",
-          "Meuth SG",
-          "Nieding K",
-          "Seebohm G",
-          "Strutz-Seebohm N"
+          "Bird TD",
+          "Ghetti B",
+          "Greenup L",
+          "Kraemer BC",
+          "Leverenz JB",
+          "Liachko NF",
+          "Loomis E",
+          "McMillan PJ",
+          "Montine TJ",
+          "Murrell JR",
+          "Raskind MA",
+          "Strovas TJ"
         ],
-        "date": "2016-01-01",
-        "first": "Nieding K",
-        "last": "Strutz-Seebohm N",
-        "name": "Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology",
-        "pages": "1444-52",
-        "reference": "27607061",
-        "title": "Tau Tubulin Kinase TTBK2 Sensitivity of Glutamate Receptor GluK2.",
+        "date": "2014-12-01",
+        "first": "Liachko NF",
+        "last": "Kraemer BC",
+        "name": "PLoS genetics",
+        "pages": "e1004803",
+        "reference": "25473830",
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         "type": "PubMed",
-        "volume": "39"
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     {
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       "citation": {
         "authors": [
-          "Lang F",
-          "Matschke V",
-          "Meuth SG",
-          "Nieding K",
-          "Seebohm G",
-          "Strutz-Seebohm N"
+          "Cowburn RF",
+          "Dahllund L",
+          "Gustafsson E",
+          "Lund H",
+          "Malinowsky D",
+          "Strömberg K",
+          "Sunnemark D",
+          "Svensson A"
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-        "reference": "27607061",
-        "title": "Tau Tubulin Kinase TTBK2 Sensitivity of Glutamate Receptor GluK2.",
+        "date": "2013-07-01",
+        "first": "Lund H",
+        "last": "Sunnemark D",
+        "name": "Brain pathology (Zurich, Switzerland)",
+        "pages": "378-89",
+        "reference": "23088643",
+        "title": "Tau-tubulin kinase 1 expression, phosphorylation and co-localization with phospho-Ser422 tau in the Alzheimer's disease brain.",
         "type": "PubMed",
-        "volume": "39"
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-          "Lang F",
-          "Matschke V",
-          "Meuth SG",
-          "Nieding K",
-          "Seebohm G",
-          "Strutz-Seebohm N"
+          "Cowburn RF",
+          "Dahllund L",
+          "Gustafsson E",
+          "Lund H",
+          "Malinowsky D",
+          "Strömberg K",
+          "Sunnemark D",
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-        "name": "Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology",
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-        "reference": "27607061",
-        "title": "Tau Tubulin Kinase TTBK2 Sensitivity of Glutamate Receptor GluK2.",
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+        "first": "Lund H",
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+      "evidence": "The pSer422 antibody displayed an almost identical pattern to that of AT8, in that it stained NFTs (Figure 5A–D), neuropil threads and neuritic plaques (Figure 5E–H)",
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       "citation": {
         "authors": [
-          "Babić Leko M",
-          "Bažadona D",
-          "Buée L",
-          "Delalle I",
-          "Di Giovanni G",
-          "Harrington C",
-          "Hof PR",
-          "Jovanov-Milošević N",
-          "Wischik C",
-          "Wray S",
-          "de Silva R",
-          "Šimić G"
+          "Cowburn RF",
+          "Dahllund L",
+          "Gustafsson E",
+          "Lund H",
+          "Malinowsky D",
+          "Strömberg K",
+          "Sunnemark D",
+          "Svensson A"
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-        "date": "2016-01-06",
-        "first": "Šimić G",
-        "last": "Hof PR",
-        "name": "Biomolecules",
-        "pages": "6",
-        "reference": "26751493",
-        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
+        "date": "2013-07-01",
+        "first": "Lund H",
+        "last": "Sunnemark D",
+        "name": "Brain pathology (Zurich, Switzerland)",
+        "pages": "378-89",
+        "reference": "23088643",
+        "title": "Tau-tubulin kinase 1 expression, phosphorylation and co-localization with phospho-Ser422 tau in the Alzheimer's disease brain.",
         "type": "PubMed",
-        "volume": "6"
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-      "evidence": "In the case of soluble monomeric or small oligomeric tau protein, the endocytosis appears to be clathrin-dependent (reviewed in [169]). In contrast, larger aggregates of tau could bind heparin in the extracellular matrix and be internalized through macropinocytosis [170]. As a result of exocytosis and endocytosis, the spreading of tau can occur in various neurodegenerative diseases (tauopathies) including AD. Three plausible mechanisms of tau spreading are shown schematically in Figure 6. Additionally, it appea rs that microglial cells may facilitate tau propagation by phagocytosis and exocytosis of tau protein [171].",
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       "citation": {
         "authors": [
-          "Babić Leko M",
-          "Bažadona D",
-          "Buée L",
-          "Delalle I",
-          "Di Giovanni G",
-          "Harrington C",
-          "Hof PR",
-          "Jovanov-Milošević N",
-          "Wischik C",
-          "Wray S",
-          "de Silva R",
-          "Šimić G"
+          "Cowburn RF",
+          "Dahllund L",
+          "Gustafsson E",
+          "Lund H",
+          "Malinowsky D",
+          "Strömberg K",
+          "Sunnemark D",
+          "Svensson A"
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-        "date": "2016-01-06",
-        "first": "Šimić G",
-        "last": "Hof PR",
-        "name": "Biomolecules",
-        "pages": "6",
-        "reference": "26751493",
-        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
+        "date": "2013-07-01",
+        "first": "Lund H",
+        "last": "Sunnemark D",
+        "name": "Brain pathology (Zurich, Switzerland)",
+        "pages": "378-89",
+        "reference": "23088643",
+        "title": "Tau-tubulin kinase 1 expression, phosphorylation and co-localization with phospho-Ser422 tau in the Alzheimer's disease brain.",
         "type": "PubMed",
-        "volume": "6"
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-      "evidence": "In the case of soluble monomeric or small oligomeric tau protein, the endocytosis appears to be clathrin-dependent (reviewed in [169]). In contrast, larger aggregates of tau could bind heparin in the extracellular matrix and be internalized through macropinocytosis [170]. As a result of exocytosis and endocytosis, the spreading of tau can occur in various neurodegenerative diseases (tauopathies) including AD. Three plausible mechanisms of tau spreading are shown schematically in Figure 6. Additionally, it appea rs that microglial cells may facilitate tau propagation by phagocytosis and exocytosis of tau protein [171].",
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       "citation": {
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-          "Arimura N",
-          "Hoshino M",
-          "Ishidate F",
-          "Kaibuchi K",
-          "Kakeno M",
-          "Matsui T",
-          "Matsuzawa K",
-          "Nishioka T",
-          "Shirahige A",
-          "Sugiyama I",
-          "Taya S",
-          "Watanabe T"
+          "Baulieu EE",
+          "Byrne C",
+          "Cantrelle FX",
+          "Chambraud B",
+          "Despres C",
+          "Huvent I",
+          "Jacquot Y",
+          "Landrieu I",
+          "Lippens G",
+          "Qi H",
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-        "first": "Watanabe T",
-        "last": "Kaibuchi K",
-        "name": "The Journal of cell biology",
-        "pages": "737-51",
-        "reference": "26323690",
-        "title": "TTBK2 with EB1/3 regulates microtubule dynamics in migrating cells through KIF2A phosphorylation.",
+        "date": "2017-08-22",
+        "first": "Despres C",
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+        "name": "Proceedings of the National Academy of Sciences of the United States of America",
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+        "reference": "28784767",
+        "title": "Identification of the Tau phosphorylation pattern that drives its aggregation.",
         "type": "PubMed",
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       "citation": {
         "authors": [
-          "Arimura N",
-          "Hoshino M",
-          "Ishidate F",
-          "Kaibuchi K",
-          "Kakeno M",
-          "Matsui T",
-          "Matsuzawa K",
-          "Nishioka T",
-          "Shirahige A",
-          "Sugiyama I",
-          "Taya S",
-          "Watanabe T"
+          "Baulieu EE",
+          "Byrne C",
+          "Cantrelle FX",
+          "Chambraud B",
+          "Despres C",
+          "Huvent I",
+          "Jacquot Y",
+          "Landrieu I",
+          "Lippens G",
+          "Qi H",
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-        "first": "Watanabe T",
-        "last": "Kaibuchi K",
-        "name": "The Journal of cell biology",
-        "pages": "737-51",
-        "reference": "26323690",
-        "title": "TTBK2 with EB1/3 regulates microtubule dynamics in migrating cells through KIF2A phosphorylation.",
+        "date": "2017-08-22",
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+        "name": "Proceedings of the National Academy of Sciences of the United States of America",
+        "pages": "9080-9085",
+        "reference": "28784767",
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+        "MeSHDisease": {
+          "Alzheimer Disease": true
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       "citation": {
         "authors": [
-          "Arimura N",
-          "Hoshino M",
-          "Ishidate F",
-          "Kaibuchi K",
-          "Kakeno M",
-          "Matsui T",
-          "Matsuzawa K",
-          "Nishioka T",
-          "Shirahige A",
-          "Sugiyama I",
-          "Taya S",
-          "Watanabe T"
+          "Chen X",
+          "Collins N",
+          "Dai X",
+          "Huang T",
+          "LaDu MJ",
+          "Lin L",
+          "Shen H",
+          "Wei Z",
+          "Wu X",
+          "Xiao N",
+          "York J",
+          "Zhang J",
+          "Zhou M",
+          "Zhu Y"
         ],
-        "date": "2015-08-31",
-        "first": "Watanabe T",
-        "last": "Kaibuchi K",
-        "name": "The Journal of cell biology",
-        "pages": "737-51",
-        "reference": "26323690",
-        "title": "TTBK2 with EB1/3 regulates microtubule dynamics in migrating cells through KIF2A phosphorylation.",
+        "date": "2016-01-01",
+        "first": "Zhou M",
+        "last": "Chen X",
+        "name": "Current Alzheimer research",
+        "pages": "1048-55",
+        "reference": "27087442",
+        "title": "APOE4 Induces Site-Specific Tau Phosphorylation Through Calpain-CDK5 Signaling Pathway in EFAD-Tg Mice.",
         "type": "PubMed",
-        "volume": "210"
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       "citation": {
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-          "Hoshino M",
-          "Ishidate F",
-          "Kaibuchi K",
-          "Kakeno M",
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-          "Matsuzawa K",
-          "Nishioka T",
-          "Shirahige A",
-          "Sugiyama I",
-          "Taya S",
-          "Watanabe T"
+          "Castillo-Carranza DL",
+          "Jackson GR",
+          "Kayed R",
+          "Lasagna-Reeves CA",
+          "Sarmiento J",
+          "Sengupta U",
+          "Troncoso J"
         ],
-        "date": "2015-08-31",
-        "first": "Watanabe T",
-        "last": "Kaibuchi K",
-        "name": "The Journal of cell biology",
-        "pages": "737-51",
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+        "date": "2012-05-01",
+        "first": "Lasagna-Reeves CA",
+        "last": "Kayed R",
+        "name": "FASEB journal : official publication of the Federation of American Societies for Experimental Biology",
+        "pages": "1946-59",
+        "reference": "22253473",
+        "title": "Identification of oligomers at early stages of tau aggregation in Alzheimer's disease.",
         "type": "PubMed",
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-      "evidence": "Upregulation of SLC5A1 Na-copled Glucose transport",
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+      "evidence": "Phosphorylation at the epitope Ser202/Thr205 is regarded as a good marker for late-stage NFTs (5, 72). Hyman and colleagues (5) demonstrated that AT8 immunoreactivity is present primarily in eNFTs and in certain cases in iNFTs. These investigators also found that AT8 revealed dense neuropil thread staining.",
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-        "name": "The Journal of cell biology",
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+          "Cho SH",
+          "Cole PA",
+          "Gan L",
+          "Haroutunian V",
+          "Huang EJ",
+          "Masliah E",
+          "Meyers D",
+          "Min SW",
+          "Mukherjee C",
+          "Ott M",
+          "Schroeder S",
+          "Seeley WW",
+          "Shen Y",
+          "Zhou Y"
+        ],
+        "date": "2010-09-23",
+        "first": "Min SW",
+        "last": "Gan L",
+        "name": "Neuron",
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+        "title": "Acetylation of tau inhibits its degradation and contributes to tauopathy.",
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-          "Hoshino M",
-          "Ishidate F",
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-          "Matsuzawa K",
-          "Nishioka T",
-          "Shirahige A",
-          "Sugiyama I",
-          "Taya S",
-          "Watanabe T"
+          "Cho SH",
+          "Cole PA",
+          "Gan L",
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+          "Huang EJ",
+          "Masliah E",
+          "Meyers D",
+          "Min SW",
+          "Mukherjee C",
+          "Ott M",
+          "Schroeder S",
+          "Seeley WW",
+          "Shen Y",
+          "Zhou Y"
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-        "first": "Watanabe T",
-        "last": "Kaibuchi K",
-        "name": "The Journal of cell biology",
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-        "title": "TTBK2 with EB1/3 regulates microtubule dynamics in migrating cells through KIF2A phosphorylation.",
+        "date": "2010-09-23",
+        "first": "Min SW",
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-          "Hoshino M",
-          "Ishidate F",
-          "Kaibuchi K",
-          "Kakeno M",
-          "Matsui T",
-          "Matsuzawa K",
-          "Nishioka T",
-          "Shirahige A",
-          "Sugiyama I",
-          "Taya S",
-          "Watanabe T"
+          "Cowburn RF",
+          "Dahllund L",
+          "Gustafsson E",
+          "Lund H",
+          "Malinowsky D",
+          "Strömberg K",
+          "Sunnemark D",
+          "Svensson A"
         ],
-        "date": "2015-08-31",
-        "first": "Watanabe T",
-        "last": "Kaibuchi K",
-        "name": "The Journal of cell biology",
-        "pages": "737-51",
-        "reference": "26323690",
-        "title": "TTBK2 with EB1/3 regulates microtubule dynamics in migrating cells through KIF2A phosphorylation.",
+        "date": "2013-07-01",
+        "first": "Lund H",
+        "last": "Sunnemark D",
+        "name": "Brain pathology (Zurich, Switzerland)",
+        "pages": "378-89",
+        "reference": "23088643",
+        "title": "Tau-tubulin kinase 1 expression, phosphorylation and co-localization with phospho-Ser422 tau in the Alzheimer's disease brain.",
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-        "volume": "210"
+        "volume": "23"
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       "citation": {
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-          "Hoshino M",
-          "Ishidate F",
-          "Kaibuchi K",
-          "Kakeno M",
-          "Matsui T",
-          "Matsuzawa K",
-          "Nishioka T",
-          "Shirahige A",
-          "Sugiyama I",
-          "Taya S",
-          "Watanabe T"
+          "Cowburn RF",
+          "Dahllund L",
+          "Gustafsson E",
+          "Lund H",
+          "Malinowsky D",
+          "Strömberg K",
+          "Sunnemark D",
+          "Svensson A"
         ],
-        "date": "2015-08-31",
-        "first": "Watanabe T",
-        "last": "Kaibuchi K",
-        "name": "The Journal of cell biology",
-        "pages": "737-51",
-        "reference": "26323690",
-        "title": "TTBK2 with EB1/3 regulates microtubule dynamics in migrating cells through KIF2A phosphorylation.",
+        "date": "2013-07-01",
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+        "first": "Vázquez-Higuera JL",
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         "type": "PubMed",
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       },
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       "citation": {
         "authors": [
-          "Ikezu S",
-          "Ikezu T"
+          "Berciano J",
+          "Bullido MJ",
+          "Combarros O",
+          "Frank A",
+          "Martínez-García A",
+          "Mateo I",
+          "Pozueta A",
+          "Rodríguez-Rodríguez E",
+          "Sánchez-Juan P",
+          "Valdivieso F",
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         ],
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-        "first": "Ikezu S",
-        "last": "Ikezu T",
-        "name": "Frontiers in molecular neuroscience",
-        "pages": "33",
-        "reference": "24808823",
-        "title": "Tau-tubulin kinase.",
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+        "first": "Vázquez-Higuera JL",
+        "last": "Combarros O",
+        "name": "Neurobiology of aging",
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+        "title": "Genetic variations in tau-tubulin kinase-1 are linked to Alzheimer's disease in a Spanish case-control cohort.",
         "type": "PubMed",
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       "citation": {
         "authors": [
-          "Butterfield DA",
-          "Farr SA",
-          "Kumar V",
-          "Morley JE",
-          "Murphy MP",
-          "Niehoff ML",
-          "Platt TL",
-          "Ripley JL",
-          "Sultana R",
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-        "title": "Antisense oligonucleotide against GSK-3β in brain of SAMP8 mice improves learning and memory and decreases oxidative stress: Involvement of transcription factor Nrf2 and implications for Alzheimer disease.",
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-      "evidence": "Nuclear factor erythroid-2-related factor 2 (Nrf2) is a transcription factor known to increase the level of many antioxidants, including glutathione-S transferase (GST), and is negatively regulated by the activity of GSK-3β. Our results indicated the increased nuclear localization of Nrf2 and level of GST, suggesting the increased activity of the transcription factor as a result of GSK-3β suppression, consistent with the decreased oxidative stress observed. Consistent with the improved learning and memory, and consistent with GSK-3b being a tau kinase, we observed decreased tau phosphorylation in brain of GAO-treated SAMP8 mice compared to that of RAO-treated SAMP8 mice.",
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-          "Devidze N",
-          "Gan L",
-          "Gestwicki JE",
-          "Johnson JR",
-          "Krogan NJ",
-          "Li Y",
-          "Masliah E",
-          "Min SW",
-          "Mok SA",
-          "Sohn PD"
+          "Berciano J",
+          "Bullido MJ",
+          "Combarros O",
+          "Frank A",
+          "Martínez-García A",
+          "Mateo I",
+          "Pozueta A",
+          "Rodríguez-Rodríguez E",
+          "Sánchez-Juan P",
+          "Valdivieso F",
+          "Vázquez-Higuera JL"
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-        "first": "Min SW",
-        "last": "Gan L",
-        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
-        "pages": "3680-3688",
-        "reference": "29540553",
-        "title": "SIRT1 Deacetylates Tau and Reduces Pathogenic Tau Spread in a Mouse Model of Tauopathy.",
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+        "first": "Vázquez-Higuera JL",
+        "last": "Combarros O",
+        "name": "Neurobiology of aging",
+        "pages": "550.e5-9",
+        "reference": "20096481",
+        "title": "Genetic variations in tau-tubulin kinase-1 are linked to Alzheimer's disease in a Spanish case-control cohort.",
         "type": "PubMed",
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     {
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       },
       "citation": {
         "authors": [
-          "Brown JT",
-          "Cimarosti H",
-          "Henley JM",
-          "McMillan LE"
+          "Berciano J",
+          "Bullido MJ",
+          "Combarros O",
+          "Frank A",
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+          "Mateo I",
+          "Pozueta A",
+          "Rodríguez-Rodríguez E",
+          "Sánchez-Juan P",
+          "Valdivieso F",
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-        "first": "McMillan LE",
-        "last": "Cimarosti H",
-        "name": "Neuroscience letters",
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-        "reference": "21843595",
-        "title": "Profiles of SUMO and ubiquitin conjugation in an Alzheimer's disease model.",
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+        "first": "Vázquez-Higuera JL",
+        "last": "Combarros O",
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-        "first": "Ikezu S",
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-        "name": "Frontiers in molecular neuroscience",
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-        "title": "Tau-tubulin kinase.",
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+        "last": "Combarros O",
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         "type": "PubMed",
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-      "evidence": "Overexpression of TTBK1 was sufficient in inducing spatial learning impairment in mice, which is associated with enhanced Cdk5 activity and reduction in cell surface level of NR2B. Over-expressionof TTBK1 transgene in JNPL3 mice resulted in accumulation of pre-tangle forms of tau. Inaddition, TTBK1 expression plays a unique role in accelerating motor neuron degeneration and neuroinflammation in JNPL3mice.",
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         "authors": [
-          "Buée-Scherrer V",
-          "Goedert M"
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+          "Morita H",
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+          "Takahashi H",
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         "type": "PubMed",
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         "authors": [
-          "Buée-Scherrer V",
-          "Goedert M"
+          "Alessi DR",
+          "Campbell DG",
+          "Cousin MA",
+          "Esoof N",
+          "Fritsch MJ",
+          "Gordon SL",
+          "Gourlay R",
+          "Macartney T",
+          "Peggie M",
+          "Velupillai S",
+          "Zhang N",
+          "van Aalten DM"
         ],
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-        "first": "Buée-Scherrer V",
-        "last": "Goedert M",
-        "name": "FEBS letters",
-        "pages": "151-4",
-        "reference": "11943212",
-        "title": "Phosphorylation of microtubule-associated protein tau by stress-activated protein kinases in intact cells.",
+        "date": "2015-02-11",
+        "first": "Zhang N",
+        "last": "Alessi DR",
+        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
+        "pages": "2492-507",
+        "reference": "25673844",
+        "title": "Phosphorylation of synaptic vesicle protein 2A at Thr84 by casein kinase 1 family kinases controls the specific retrieval of synaptotagmin-1.",
         "type": "PubMed",
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+        "last": "Boehm J",
+        "name": "The Journal of biological chemistry",
+        "pages": "32040-53",
+        "reference": "22833681",
+        "title": "Interaction of endogenous tau protein with synaptic proteins is regulated by N-methyl-D-aspartate receptor-dependent tau phosphorylation.",
         "type": "PubMed",
-        "volume": "114"
+        "volume": "287"
       },
-      "evidence": "Our finding that the resulting Tau species with phosphorylation at Ser202/Th205, but with a disrupted turn-like structure, forms abundant fibers detectable by thioflavin fluorescence or electron microscopy (Figs. 2 and 4) suggests the initial turn-like structure induced by the phosphorylation of only Ser202 and Thr205 is protective against aggregation.",
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-      "line": 1544,
-      "relation": "decreases",
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-      "target": 201
+      "evidence": "Hence, LTD-inducing NMDA receptor activation leads to an increase in tau phosphorylation at sites PHF-1, AT180, as well as AT8 and to a reduction at AT100.",
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     {
       "annotations": {
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+        },
         "Method": {
           "Electron Microscopy, Transmission": true,
           "NMR Spectroscopy": true,
@@ -40956,94 +46259,22 @@
         "volume": "114"
       },
       "evidence": "Indeed, Tau phosphorylation at the three positions, Ser202/Thr205/Ser208, while not at Ser262, is sufficient to induce aggregation without the addition of any exogenous aggregation inducer.",
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-      "annotations": {
-        "Method": {
-          "Electron Microscopy, Transmission": true,
-          "NMR Spectroscopy": true,
-          "Thioflavin T Assay": true
-        }
-      },
-      "citation": {
-        "authors": [
-          "Baulieu EE",
-          "Byrne C",
-          "Cantrelle FX",
-          "Chambraud B",
-          "Despres C",
-          "Huvent I",
-          "Jacquot Y",
-          "Landrieu I",
-          "Lippens G",
-          "Qi H",
-          "Smet-Nocca C"
-        ],
-        "date": "2017-08-22",
-        "first": "Despres C",
-        "last": "Smet-Nocca C",
-        "name": "Proceedings of the National Academy of Sciences of the United States of America",
-        "pages": "9080-9085",
-        "reference": "28784767",
-        "title": "Identification of the Tau phosphorylation pattern that drives its aggregation.",
-        "type": "PubMed",
-        "volume": "114"
-      },
-      "evidence": "When combined with ERK2 catalyzed phosphorylation, the turn-like disrupting G207V mutation in TauF8 hence leads to fast aggregation that already occurs during the phosphorylation reaction.",
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-      "annotations": {
-        "Method": {
-          "Electron Microscopy, Transmission": true,
-          "NMR Spectroscopy": true,
-          "Thioflavin T Assay": true
-        }
-      },
-      "citation": {
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-          "Baulieu EE",
-          "Byrne C",
-          "Cantrelle FX",
-          "Chambraud B",
-          "Despres C",
-          "Huvent I",
-          "Jacquot Y",
-          "Landrieu I",
-          "Lippens G",
-          "Qi H",
-          "Smet-Nocca C"
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-        "date": "2017-08-22",
-        "first": "Despres C",
-        "last": "Smet-Nocca C",
-        "name": "Proceedings of the National Academy of Sciences of the United States of America",
-        "pages": "9080-9085",
-        "reference": "28784767",
-        "title": "Identification of the Tau phosphorylation pattern that drives its aggregation.",
-        "type": "PubMed",
-        "volume": "114"
-      },
-      "evidence": "Indeed, Tau phosphorylation at the three positions, Ser202/Thr205/Ser208, while not at Ser262, is sufficient to induce aggregation without the addition of any exogenous aggregation inducer.",
-      "key": "0aca94050bc354228ff2fab06728b2b74aa181c9b23f32e792da595fc726f11186a359d5ed6c692d097c6b7f1062d580761b0fdea8e31467453dc82bbc74587e",
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     },
     {
       "annotations": {
-        "Species": {
-          "10090": true
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
+        "MeSHDisease": {
+          "Alzheimer Disease": true
         }
       },
       "citation": {
@@ -41071,53 +46302,60 @@
         "type": "PubMed",
         "volume": "6"
       },
-      "evidence": "Using the same tau-1 monoclonal antibody and electron microscopy with colloidal gold-labeled secondary antibodies, tau was also found in very low amounts in astrocytes [16] and oligodendrocytes [17], and this was confirmed by tau mRNA expression analysis in the mouse brain [18].",
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+      "evidence": "3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain.",
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+      "relation": "positiveCorrelation",
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     },
     {
       "annotations": {
+        "Anatomy": {
+          "hippocampal formation": true
+        },
+        "Confidence": {
+          "Medium": true
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         "Species": {
-          "10090": true
+          "10116": true
         }
       },
       "citation": {
         "authors": [
-          "Babić Leko M",
-          "Bažadona D",
-          "Buée L",
-          "Delalle I",
-          "Di Giovanni G",
-          "Harrington C",
-          "Hof PR",
-          "Jovanov-Milošević N",
-          "Wischik C",
-          "Wray S",
-          "de Silva R",
-          "Šimić G"
+          "Boehm J",
+          "Bourgeois C",
+          "Dudilot A",
+          "Lauzon M",
+          "Leclerc N",
+          "Mondragón-Rodríguez S",
+          "Trillaud-Doppia E"
         ],
-        "date": "2016-01-06",
-        "first": "Šimić G",
-        "last": "Hof PR",
-        "name": "Biomolecules",
-        "pages": "6",
-        "reference": "26751493",
-        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
+        "date": "2012-09-14",
+        "first": "Mondragón-Rodríguez S",
+        "last": "Boehm J",
+        "name": "The Journal of biological chemistry",
+        "pages": "32040-53",
+        "reference": "22833681",
+        "title": "Interaction of endogenous tau protein with synaptic proteins is regulated by N-methyl-D-aspartate receptor-dependent tau phosphorylation.",
         "type": "PubMed",
-        "volume": "6"
+        "volume": "287"
       },
-      "evidence": "Using the same tau-1 monoclonal antibody and electron microscopy with colloidal gold-labeled secondary antibodies, tau was also found in very low amounts in astrocytes [16] and oligodendrocytes [17], and this was confirmed by tau mRNA expression analysis in the mouse brain [18].",
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+      "evidence": "This result is supported by recent studies showing that the interaction between Fyn and tau is regulated through tau phosphorylation at the AT8 site, increasing tau-Fyn interaction by 42-fold after tau is phosphorylated or bearing a phosphomimetic mutation at the AT8 site (63). In our experiments, tau phosphorylation at AT8 is strongly up-regulated through the activation of NMDA receptors (Fig. 3), suggesting that NMDA receptor activation could massively enhance the interaction between tau and Fyn.",
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     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
@@ -41148,2178 +46386,2606 @@
         "volume": "6"
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       "evidence": "3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain.",
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-          "Ait-Ghezala G",
-          "Beaulieu-Abdelahad D",
-          "Crawford F",
-          "Mouzon B",
-          "Mullan M",
-          "Paris D",
-          "Schweig JE",
-          "Yao H"
-        ],
-        "date": "2017-09-06",
-        "first": "Schweig JE",
-        "last": "Paris D",
-        "name": "Acta neuropathologica communications",
-        "pages": "69",
-        "reference": "28877763",
-        "title": "Alzheimer's disease pathological lesions activate the spleen tyrosine kinase.",
-        "type": "PubMed",
-        "volume": "5"
-      },
-      "evidence": "We found an increase in Syk activation in DNs surrounding Aβ deposits as well as in neurons displaying an accumulation of phosphorylated Tau at Y18 and elevated levels of MC1 pathogenic tau conformers in AD brain sections whereas only weak immunoreactivity for pSyk was observed in brain sections from a non-demented control",
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       "relation": "positiveCorrelation",
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     {
       "annotations": {
-        "MeSHDisease": {
-          "Alzheimer Disease": true
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+          "High": true
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       },
       "citation": {
         "authors": [
-          "Babić Leko M",
-          "Bažadona D",
-          "Buée L",
-          "Delalle I",
-          "Di Giovanni G",
-          "Harrington C",
-          "Hof PR",
-          "Jovanov-Milošević N",
-          "Wischik C",
-          "Wray S",
-          "de Silva R",
-          "Šimić G"
+          "Fiol CJ",
+          "Mahrenholz AM",
+          "Roach PJ",
+          "Roeske RW",
+          "Wang Y"
         ],
-        "date": "2016-01-06",
-        "first": "Šimić G",
-        "last": "Hof PR",
-        "name": "Biomolecules",
-        "pages": "6",
-        "reference": "26751493",
-        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
+        "date": "1987-10-15",
+        "first": "Fiol CJ",
+        "last": "Roach PJ",
+        "name": "The Journal of biological chemistry",
+        "pages": "14042-8",
+        "reference": "2820993",
+        "title": "Formation of protein kinase recognition sites by covalent modification of the substrate. Molecular mechanism for the synergistic action of casein kinase II and glycogen synthase kinase 3.",
         "type": "PubMed",
-        "volume": "6"
+        "volume": "262"
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-      "evidence": "3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain.",
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-      "line": 1572,
-      "relation": "positiveCorrelation",
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+      "evidence": "The results provide a molecular basis to explain the synergistic action of casein kinase II and GSK-3 that is also observed with native glycogen synthase.",
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     {
       "annotations": {
-        "MeSHDisease": {
-          "Alzheimer Disease": true
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+          "High": true
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       },
       "citation": {
         "authors": [
-          "Babić Leko M",
-          "Bažadona D",
-          "Buée L",
-          "Delalle I",
-          "Di Giovanni G",
-          "Harrington C",
-          "Hof PR",
-          "Jovanov-Milošević N",
-          "Wischik C",
-          "Wray S",
-          "de Silva R",
-          "Šimić G"
+          "Alessi DR",
+          "Begley MJ",
+          "Bouskila M",
+          "Cantley LC",
+          "Deak M",
+          "Esoof N",
+          "Fang EH",
+          "Gay L",
+          "Prescott A",
+          "Storey KG"
         ],
-        "date": "2016-01-06",
-        "first": "Šimić G",
-        "last": "Hof PR",
-        "name": "Biomolecules",
-        "pages": "6",
-        "reference": "26751493",
-        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
+        "date": "2011-07-01",
+        "first": "Bouskila M",
+        "last": "Alessi DR",
+        "name": "The Biochemical journal",
+        "pages": "157-67",
+        "reference": "21548880",
+        "title": "TTBK2 kinase substrate specificity and the impact of spinocerebellar-ataxia-causing mutations on expression, activity, localization and development.",
         "type": "PubMed",
-        "volume": "6"
+        "volume": "437"
       },
-      "evidence": "3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain.",
-      "key": "e0ddd3dc7ad26d80f50c57a146496ec96ea7275550900e90301cd17b7e880e44eef88c8da39c478955f9307dbfd86eae242e2b69e9eecdf40e2d29825cfdd3ec",
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+      "evidence": "SCA11 truncating mutations promote TTBK2 protein expression, suppress kinase activity and lead to enhanced nuclear localization. Using a SCA11-mutation-carrying knockin mouse we show that this leads to inhibition of endogenous TTBK2 protein kinase activity.",
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       "relation": "positiveCorrelation",
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+      "source": 828,
+      "target": 1005
     },
     {
       "annotations": {
-        "MeSHDisease": {
-          "Alzheimer Disease": true
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+          "High": true
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       },
       "citation": {
         "authors": [
-          "Babić Leko M",
-          "Bažadona D",
-          "Buée L",
-          "Delalle I",
-          "Di Giovanni G",
-          "Harrington C",
-          "Hof PR",
-          "Jovanov-Milošević N",
-          "Wischik C",
-          "Wray S",
-          "de Silva R",
-          "Šimić G"
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-        "date": "2016-01-06",
-        "first": "Šimić G",
-        "last": "Hof PR",
-        "name": "Biomolecules",
-        "pages": "6",
-        "reference": "26751493",
-        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
+          "Alessi DR",
+          "Begley MJ",
+          "Bouskila M",
+          "Cantley LC",
+          "Deak M",
+          "Esoof N",
+          "Fang EH",
+          "Gay L",
+          "Prescott A",
+          "Storey KG"
+        ],
+        "date": "2011-07-01",
+        "first": "Bouskila M",
+        "last": "Alessi DR",
+        "name": "The Biochemical journal",
+        "pages": "157-67",
+        "reference": "21548880",
+        "title": "TTBK2 kinase substrate specificity and the impact of spinocerebellar-ataxia-causing mutations on expression, activity, localization and development.",
         "type": "PubMed",
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+      "evidence": "SCA11 truncating mutations promote TTBK2 protein expression, suppress kinase activity and lead to enhanced nuclear localization. Using a SCA11-mutation-carrying knockin mouse we show that this leads to inhibition of endogenous TTBK2 protein kinase activity.",
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     {
       "annotations": {
-        "MeSHDisease": {
-          "Alzheimer Disease": true
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         }
       },
       "citation": {
         "authors": [
-          "Babić Leko M",
-          "Bažadona D",
-          "Buée L",
-          "Delalle I",
-          "Di Giovanni G",
-          "Harrington C",
-          "Hof PR",
-          "Jovanov-Milošević N",
-          "Wischik C",
-          "Wray S",
-          "de Silva R",
-          "Šimić G"
+          "Alessi DR",
+          "Begley MJ",
+          "Bouskila M",
+          "Cantley LC",
+          "Deak M",
+          "Esoof N",
+          "Fang EH",
+          "Gay L",
+          "Prescott A",
+          "Storey KG"
         ],
-        "date": "2016-01-06",
-        "first": "Šimić G",
-        "last": "Hof PR",
-        "name": "Biomolecules",
-        "pages": "6",
-        "reference": "26751493",
-        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
+        "date": "2011-07-01",
+        "first": "Bouskila M",
+        "last": "Alessi DR",
+        "name": "The Biochemical journal",
+        "pages": "157-67",
+        "reference": "21548880",
+        "title": "TTBK2 kinase substrate specificity and the impact of spinocerebellar-ataxia-causing mutations on expression, activity, localization and development.",
         "type": "PubMed",
-        "volume": "6"
+        "volume": "437"
       },
-      "evidence": "3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain.",
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+      "evidence": "SCA11 truncating mutations promote TTBK2 protein expression, suppress kinase activity and lead to enhanced nuclear localization. Using a SCA11-mutation-carrying knockin mouse we show that this leads to inhibition of endogenous TTBK2 protein kinase activity.",
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     },
     {
       "annotations": {
-        "MeSHDisease": {
-          "Alzheimer Disease": true
+        "Confidence": {
+          "High": true
         }
       },
       "citation": {
         "authors": [
-          "Babić Leko M",
-          "Bažadona D",
-          "Buée L",
-          "Delalle I",
-          "Di Giovanni G",
-          "Harrington C",
-          "Hof PR",
-          "Jovanov-Milošević N",
-          "Wischik C",
-          "Wray S",
-          "de Silva R",
-          "Šimić G"
+          "Alessi DR",
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+          "Schlautman JD",
+          "Swan RJ",
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-        "first": "Šimić G",
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-        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
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         "authors": [
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-          "Dong XP",
-          "Gong HS",
-          "Guo Y",
-          "Liu Y",
-          "Shi Q",
-          "Tian C",
-          "Wang SB",
-          "Xie WL",
-          "Xu Y",
-          "Zhang BY",
-          "Zhang J"
+          "Ciborowski P",
+          "Ikezu T",
+          "Jacobsen MT",
+          "Martinez LB",
+          "Okuyama S",
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+          "Schlautman JD",
+          "Swan RJ",
+          "Walsh SM",
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-        "last": "Dong XP",
-        "name": "International journal of molecular medicine",
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-        "title": "Reduction of protein kinase MARK4 in the brains of experimental scrapie rodents and human prion disease correlates with deposits of PrP(Sc).",
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         "type": "PubMed",
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         "authors": [
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-          "Wagh D",
-          "Yu W"
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-        "reference": "22156579",
-        "title": "A critical role for the PAR-1/MARK-tau axis in mediating the toxic effects of Aβ on synapses and dendritic spines.",
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-        "title": "A critical role for the PAR-1/MARK-tau axis in mediating the toxic effects of Aβ on synapses and dendritic spines.",
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       "citation": {
         "authors": [
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-          "Chen NN",
-          "Cheng XS",
-          "Duan DX",
-          "Hu Y",
-          "Liu GP",
-          "Luo Y",
-          "Ni ZF",
-          "Wang JZ"
+          "Ikezu S",
+          "Ikezu T"
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-        "last": "Liu GP",
-        "name": "Journal of Alzheimer's disease : JAD",
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-        "reference": "23948915",
-        "title": "Phosphorylation of tau by death-associated protein kinase 1 antagonizes the kinase-induced cell apoptosis.",
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       "citation": {
         "authors": [
-          "Ai J",
-          "Ban T",
-          "Bao YN",
-          "Chen QX",
-          "Hu XL",
-          "Jiang XM",
-          "Liu CD",
-          "Pei SC",
-          "Su XL",
-          "Sun LH",
-          "Sun LL",
-          "Wang X",
-          "Yan ML",
-          "Zhao LJ",
-          "Zong DK"
+          "Ikezu S",
+          "Ikezu T"
         ],
-        "date": "2015-09-01",
-        "first": "Sun LH",
-        "last": "Ai J",
-        "name": "Journal of neurochemistry",
-        "pages": "1139-51",
-        "reference": "26118667",
-        "title": "Activation of Cdk5/p25 and tau phosphorylation following chronic brain hypoperfusion in rats involves microRNA-195 down-regulation.",
+        "date": "2014-01-01",
+        "first": "Ikezu S",
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         "type": "PubMed",
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       },
-      "evidence": "Endogenous miR-195 was knocked down using over-expression of its antisense molecule (pre-AMO-miR-195) via a lentivirus (lenti-pre-AMO-miR-195); this knockdown increased the tau phosphorylation at Ser202/Thr205, Ser262, Thr231, Ser422, and the Cdk5/p25 activation, but over-expression of miR-195 using lenti-pre-miR-195 decreased the tau phosphorylation and Cdk5/p25 activation.",
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+      "evidence": "Overexpression of TTBK1 was sufficient in inducing spatial learning impairment in mice, which is associated with enhanced Cdk5 activity and reduction in cell surface level of NR2B. Over-expressionof TTBK1 transgene in JNPL3 mice resulted in accumulation of pre-tangle forms of tau. Inaddition, TTBK1 expression plays a unique role in accelerating motor neuron degeneration and neuroinflammation in JNPL3mice.",
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     },
     {
       "annotations": {
-        "Research_Model": {
-          "rTg4510 mice": true
+        "Confidence": {
+          "Medium": true
+        },
+        "Species": {
+          "10090": true
         }
       },
       "citation": {
         "authors": [
-          "Boehm J",
-          "Bourgeois C",
-          "Dudilot A",
-          "Lauzon M",
-          "Leclerc N",
-          "Mondragón-Rodríguez S",
-          "Trillaud-Doppia E"
+          "Ikezu S",
+          "Ikezu T"
         ],
-        "date": "2012-09-14",
-        "first": "Mondragón-Rodríguez S",
-        "last": "Boehm J",
-        "name": "The Journal of biological chemistry",
-        "pages": "32040-53",
-        "reference": "22833681",
-        "title": "Interaction of endogenous tau protein with synaptic proteins is regulated by N-methyl-D-aspartate receptor-dependent tau phosphorylation.",
+        "date": "2014-01-01",
+        "first": "Ikezu S",
+        "last": "Ikezu T",
+        "name": "Frontiers in molecular neuroscience",
+        "pages": "33",
+        "reference": "24808823",
+        "title": "Tau-tubulin kinase.",
         "type": "PubMed",
-        "volume": "287"
+        "volume": "7"
+      },
+      "evidence": "Overexpression of TTBK1 was sufficient in inducing spatial learning impairment in mice, which is associated with enhanced Cdk5 activity and reduction in cell surface level of NR2B. Over-expressionof TTBK1 transgene in JNPL3 mice resulted in accumulation of pre-tangle forms of tau. Inaddition, TTBK1 expression plays a unique role in accelerating motor neuron degeneration and neuroinflammation in JNPL3mice.",
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+      "line": 1798,
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       },
-      "evidence": "Acute treatment of rTg4510 mice with an O-GlcNAcase inhibitor transiently reduced tau phosphorylation at epitopes implicated in tau pathology. More importantly, long-term inhibitor treatment strongly increased tau O-GlcNAcylation, reduced the number of dystrophic neurons, and protected against the formation of pathological tau species without altering the phosphorylation of non-pathological tau.",
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-      "line": 2500,
       "relation": "positiveCorrelation",
-      "source": 557,
-      "target": 513
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     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "Species": {
-          "7227": true
+          "10090": true
         }
       },
       "citation": {
         "authors": [
-          "Iijima KM",
-          "Iijima-Ando K",
-          "Lu B",
-          "Maruko-Otake A",
-          "Ohtake Y",
-          "Sekiya M",
-          "Suzuki E"
+          "Ciborowski P",
+          "Ikezu T",
+          "Jacobsen MT",
+          "Martinez LB",
+          "Okuyama S",
+          "Sato S",
+          "Schlautman JD",
+          "Swan RJ",
+          "Walsh SM",
+          "Xu J"
         ],
-        "date": "2012-01-01",
-        "first": "Iijima-Ando K",
-        "last": "Iijima KM",
-        "name": "PLoS genetics",
-        "pages": "e1002918",
-        "reference": "22952452",
-        "title": "Loss of axonal mitochondria promotes tau-mediated neurodegeneration and Alzheimer's disease-related tau phosphorylation via PAR-1.",
+        "date": "2008-12-31",
+        "first": "Sato S",
+        "last": "Ikezu T",
+        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
+        "pages": "14511-21",
+        "reference": "19118186",
+        "title": "Spatial learning impairment, enhanced CDK5/p35 activity, and downregulation of NMDA receptor expression in transgenic mice expressing tau-tubulin kinase 1.",
         "type": "PubMed",
-        "volume": "8"
+        "volume": "28"
       },
-      "evidence": "Using transgenic Drosophila expressing human tau, we found that RNAi-mediated knockdown of milton or Miro, an adaptor protein essential for axonal transport of mitochondria, enhanced human tau-induced neurodegeneration. Tau phosphorylation at an AD-related site Ser262 increased with knockdown of milton or Miro; and partitioning defective-1 (PAR-1), the Drosophila homolog of mammalian microtubule affinity-regulating kinase, mediated this increase of tau phosphorylation. Tau phosphorylation at Ser262 has been reported to promote tau detachment from microtubules, and we found that the levels of microtubule-unbound free tau increased by milton knockdown. Blocking tau phosphorylation at Ser262 site by PAR-1 knockdown or by mutating the Ser262 site to unphosphorylatable alanine suppressed the enhancement of tau-induced neurodegeneration caused by milton knockdown. Furthermore, knockdown of milton or Miro increased the levels of active PAR-1.",
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       "relation": "positiveCorrelation",
-      "source": 557,
-      "target": 142
+      "source": 342,
+      "subject": {
+        "modifier": "Activity"
+      },
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     },
     {
       "annotations": {
-        "MeSHDisease": {
-          "Alzheimer Disease": true
+        "Confidence": {
+          "Medium": true
+        },
+        "Species": {
+          "10090": true
         }
       },
       "citation": {
         "authors": [
-          "Babić Leko M",
-          "Bažadona D",
-          "Buée L",
-          "Delalle I",
-          "Di Giovanni G",
-          "Harrington C",
-          "Hof PR",
-          "Jovanov-Milošević N",
-          "Wischik C",
-          "Wray S",
-          "de Silva R",
-          "Šimić G"
+          "Ciborowski P",
+          "Ikezu T",
+          "Jacobsen MT",
+          "Martinez LB",
+          "Okuyama S",
+          "Sato S",
+          "Schlautman JD",
+          "Swan RJ",
+          "Walsh SM",
+          "Xu J"
         ],
-        "date": "2016-01-06",
-        "first": "Šimić G",
-        "last": "Hof PR",
-        "name": "Biomolecules",
-        "pages": "6",
-        "reference": "26751493",
-        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
+        "date": "2008-12-31",
+        "first": "Sato S",
+        "last": "Ikezu T",
+        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
+        "pages": "14511-21",
+        "reference": "19118186",
+        "title": "Spatial learning impairment, enhanced CDK5/p35 activity, and downregulation of NMDA receptor expression in transgenic mice expressing tau-tubulin kinase 1.",
         "type": "PubMed",
-        "volume": "6"
+        "volume": "28"
       },
-      "evidence": "3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain.",
-      "key": "5ba262ecd81609b34de528d8ff5ab8c503e0598ec5893384bcf94eeefe82a93fc77c11ebc1ffa1c49b6399417b2b849866f0dfa6f1b16661f697181b465ff1d3",
-      "line": 1590,
-      "relation": "positiveCorrelation",
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-      "target": 908
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     },
     {
       "annotations": {
-        "MeSHDisease": {
-          "Alzheimer Disease": true
+        "Confidence": {
+          "Medium": true
+        },
+        "Species": {
+          "10090": true
         }
       },
       "citation": {
         "authors": [
-          "Babić Leko M",
-          "Bažadona D",
-          "Buée L",
-          "Delalle I",
-          "Di Giovanni G",
-          "Harrington C",
-          "Hof PR",
-          "Jovanov-Milošević N",
-          "Wischik C",
-          "Wray S",
-          "de Silva R",
-          "Šimić G"
+          "Ikezu S",
+          "Ikezu T"
         ],
-        "date": "2016-01-06",
-        "first": "Šimić G",
-        "last": "Hof PR",
-        "name": "Biomolecules",
-        "pages": "6",
-        "reference": "26751493",
-        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
+        "date": "2014-01-01",
+        "first": "Ikezu S",
+        "last": "Ikezu T",
+        "name": "Frontiers in molecular neuroscience",
+        "pages": "33",
+        "reference": "24808823",
+        "title": "Tau-tubulin kinase.",
         "type": "PubMed",
-        "volume": "6"
+        "volume": "7"
       },
-      "evidence": "3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain.",
-      "key": "e36b4fa72d09609ecaff933f5a3dae911fec47fe95c23b19f850b94886c8741f96fce7ff6d71008101b298e45557b10a3c3e0f73ac4dfc85dee54868f63398b0",
-      "line": 1591,
+      "evidence": "Overexpression of TTBK1 was sufficient in inducing spatial learning impairment in mice, which is associated with enhanced Cdk5 activity and reduction in cell surface level of NR2B. Over-expressionof TTBK1 transgene in JNPL3 mice resulted in accumulation of pre-tangle forms of tau. Inaddition, TTBK1 expression plays a unique role in accelerating motor neuron degeneration and neuroinflammation in JNPL3mice.",
+      "key": "5e3e00a20b35e389790ffd8dcf929415db447cab6e01f11475d6ec340d3df3e0fc98c8b7d334c76798620865700fd57847222675927a384289f9ec6d3c22d028",
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       "relation": "positiveCorrelation",
-      "source": 563,
-      "target": 908
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+            "name": "intracellular",
+            "namespace": "bel"
+          },
+          "toLoc": {
+            "name": "cell surface",
+            "namespace": "bel"
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+        },
+        "modifier": "Translocation"
+      },
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+      "relation": "hasVariant",
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     {
       "annotations": {
-        "Tau_Motif": {
-          "KXGS": true
+        "Confidence": {
+          "Medium": true
+        },
+        "Species": {
+          "10090": true
         }
       },
       "citation": {
         "authors": [
-          "Lu B",
-          "Malenka R",
-          "Polepalli J",
-          "Rajadas J",
-          "Wagh D",
-          "Yu W"
+          "Ciborowski P",
+          "Ikezu T",
+          "Jacobsen MT",
+          "Martinez LB",
+          "Okuyama S",
+          "Sato S",
+          "Schlautman JD",
+          "Swan RJ",
+          "Walsh SM",
+          "Xu J"
         ],
-        "date": "2012-03-15",
-        "first": "Yu W",
-        "last": "Lu B",
-        "name": "Human molecular genetics",
-        "pages": "1384-90",
-        "reference": "22156579",
-        "title": "A critical role for the PAR-1/MARK-tau axis in mediating the toxic effects of Aβ on synapses and dendritic spines.",
+        "date": "2008-12-31",
+        "first": "Sato S",
+        "last": "Ikezu T",
+        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
+        "pages": "14511-21",
+        "reference": "19118186",
+        "title": "Spatial learning impairment, enhanced CDK5/p35 activity, and downregulation of NMDA receptor expression in transgenic mice expressing tau-tubulin kinase 1.",
         "type": "PubMed",
-        "volume": "21"
-      },
-      "evidence": "We first confirmed that expression of an MKI-GFP fusion protein in rat hippocampal neurons effectively attenuated MARK4-mediated phosphorylation of both endogenous tau (Fig. 3A) and transfected human tau at the 12E8 sites (Fig. 3B). Phosphorylation of tau at the PHF-1 site was also reduced by MKI (Fig. 3A). It is possible that the PHF-1 site is also targeted by PAR-1/MARKs in vivo, or that the phosphorylation of tau at the 12E8 sites is a prerequisite for PHF-1 site phosphorylation, as the 12E8 sites were previously shown to be required for tau phosphorylation at other sites",
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-          "name": "kin",
-          "namespace": "bel"
-        },
-        "modifier": "Activity"
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       },
-      "relation": "positiveCorrelation",
-      "source": 563,
-      "target": 759
+      "evidence": "TTBK1-Tg mice show significant age-dependent memory impairment as determined by radial arm water maze test, which is associated with enhancement of tau and neurofilament phosphorylation, increased levels of p25 and p35, both activators of cyclin-dependent protein kinase 5 (CDK5), enhanced calpain I activity, and reduced levels of hippocampal NMDA receptor types 2B (NR2B) and D. Enhanced CDK5/p35 complex formation is strongly correlated with dissociation of F-actin from p35, suggesting the inhibitory mechanism of CDK5/p35 complex formation by F-actin.",
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+      "line": 1647,
+      "relation": "negativeCorrelation",
+      "source": 883,
+      "target": 944
     },
     {
       "annotations": {
-        "Tau_Motif": {
-          "KXGS": true
+        "Confidence": {
+          "Medium": true
+        },
+        "Species": {
+          "10090": true
         }
       },
       "citation": {
         "authors": [
-          "Lu B",
-          "Malenka R",
-          "Polepalli J",
-          "Rajadas J",
-          "Wagh D",
-          "Yu W"
+          "Ciborowski P",
+          "Ikezu T",
+          "Jacobsen MT",
+          "Martinez LB",
+          "Okuyama S",
+          "Sato S",
+          "Schlautman JD",
+          "Swan RJ",
+          "Walsh SM",
+          "Xu J"
         ],
-        "date": "2012-03-15",
-        "first": "Yu W",
-        "last": "Lu B",
-        "name": "Human molecular genetics",
-        "pages": "1384-90",
-        "reference": "22156579",
-        "title": "A critical role for the PAR-1/MARK-tau axis in mediating the toxic effects of Aβ on synapses and dendritic spines.",
+        "date": "2008-12-31",
+        "first": "Sato S",
+        "last": "Ikezu T",
+        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
+        "pages": "14511-21",
+        "reference": "19118186",
+        "title": "Spatial learning impairment, enhanced CDK5/p35 activity, and downregulation of NMDA receptor expression in transgenic mice expressing tau-tubulin kinase 1.",
         "type": "PubMed",
-        "volume": "21"
+        "volume": "28"
       },
-      "evidence": "We first confirmed that expression of an MKI-GFP fusion protein in rat hippocampal neurons effectively attenuated MARK4-mediated phosphorylation of both endogenous tau (Fig. 3A) and transfected human tau at the 12E8 sites (Fig. 3B). Phosphorylation of tau at the PHF-1 site was also reduced by MKI (Fig. 3A). It is possible that the PHF-1 site is also targeted by PAR-1/MARKs in vivo, or that the phosphorylation of tau at the 12E8 sites is a prerequisite for PHF-1 site phosphorylation, as the 12E8 sites were previously shown to be required for tau phosphorylation at other sites",
-      "key": "02db8be044b823652c2745808d0fd1d1e1a6fdd3bdf6908ffd1fda88e3ddad0b00b96a5f6bca434dfc6379f47d39405d0354e1419ee3594d8dd8770a033d52fc",
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-      "relation": "partOf",
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+      "evidence": "TTBK1-Tg mice show significant age-dependent memory impairment as determined by radial arm water maze test, which is associated with enhancement of tau and neurofilament phosphorylation, increased levels of p25 and p35, both activators of cyclin-dependent protein kinase 5 (CDK5), enhanced calpain I activity, and reduced levels of hippocampal NMDA receptor types 2B (NR2B) and D. Enhanced CDK5/p35 complex formation is strongly correlated with dissociation of F-actin from p35, suggesting the inhibitory mechanism of CDK5/p35 complex formation by F-actin.",
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+      "relation": "negativeCorrelation",
+      "source": 219,
+      "target": 893
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
+        "MeSHDisease": {
+          "Alzheimer Disease": true,
+          "Down Syndrome": true
+        },
         "Research_Model": {
-          "rTg4510 mice": true
+          "Ts65Dn mice": true
+        },
+        "Species": {
+          "10090": true
         }
       },
       "citation": {
         "authors": [
-          "Boehm J",
-          "Bourgeois C",
-          "Dudilot A",
-          "Lauzon M",
-          "Leclerc N",
-          "Mondragón-Rodríguez S",
-          "Trillaud-Doppia E"
+          "Chen L",
+          "Sun X",
+          "Wang L",
+          "Wang P"
         ],
-        "date": "2012-09-14",
-        "first": "Mondragón-Rodríguez S",
-        "last": "Boehm J",
-        "name": "The Journal of biological chemistry",
-        "pages": "32040-53",
-        "reference": "22833681",
-        "title": "Interaction of endogenous tau protein with synaptic proteins is regulated by N-methyl-D-aspartate receptor-dependent tau phosphorylation.",
+        "date": "2017-08-03",
+        "first": "Wang P",
+        "last": "Sun X",
+        "name": "Scientific reports",
+        "pages": "7240",
+        "reference": "28775333",
+        "title": "Dual-specificity tyrosine-phosphorylation regulated kinase 1A Gene Transcription is regulated by Myocyte Enhancer Factor 2D.",
         "type": "PubMed",
-        "volume": "287"
+        "volume": "7"
       },
-      "evidence": "Acute treatment of rTg4510 mice with an O-GlcNAcase inhibitor transiently reduced tau phosphorylation at epitopes implicated in tau pathology. More importantly, long-term inhibitor treatment strongly increased tau O-GlcNAcylation, reduced the number of dystrophic neurons, and protected against the formation of pathological tau species without altering the phosphorylation of non-pathological tau.",
-      "key": "8704fdf47e89d1ed04e144341ed955b80affd57d5cf583ed51fe4fe92bb5fb896a93d8e9fe8377963971650a86fb221e97a049a3098989246ca4ffe04d3aa9b1",
-      "line": 2501,
+      "evidence": "Treatment with Dyrk1A inhibitor, green tea flavonol epigallocatechin-gallate (EGCG), from gestation to adulthood suppressed 3R-tau expression and rescued anxiety and memory deficits in Ts65Dn mouse brains.",
+      "key": "a614d9b5e7ef2986842cca916cc2c1b4bd1a0e37c1d2185b3f5784d727db8780787e583f4fd266d554df580bd8ca1cfca39d687a64bad6cb3b820ba1827ebcf7",
+      "line": 2614,
       "relation": "positiveCorrelation",
-      "source": 563,
-      "target": 513
+      "source": 219,
+      "target": 1
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
         "MeSHDisease": {
-          "Alzheimer Disease": true
+          "Alzheimer Disease": true,
+          "Down Syndrome": true
+        },
+        "Research_Model": {
+          "Ts65Dn mice": true
+        },
+        "Species": {
+          "10090": true
         }
       },
       "citation": {
         "authors": [
-          "Babić Leko M",
-          "Bažadona D",
-          "Buée L",
-          "Delalle I",
-          "Di Giovanni G",
-          "Harrington C",
-          "Hof PR",
-          "Jovanov-Milošević N",
-          "Wischik C",
-          "Wray S",
-          "de Silva R",
-          "Šimić G"
+          "Chen L",
+          "Sun X",
+          "Wang L",
+          "Wang P"
         ],
-        "date": "2016-01-06",
-        "first": "Šimić G",
-        "last": "Hof PR",
-        "name": "Biomolecules",
-        "pages": "6",
-        "reference": "26751493",
-        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
+        "date": "2017-08-03",
+        "first": "Wang P",
+        "last": "Sun X",
+        "name": "Scientific reports",
+        "pages": "7240",
+        "reference": "28775333",
+        "title": "Dual-specificity tyrosine-phosphorylation regulated kinase 1A Gene Transcription is regulated by Myocyte Enhancer Factor 2D.",
         "type": "PubMed",
-        "volume": "6"
+        "volume": "7"
       },
-      "evidence": "3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain.",
-      "key": "b0e2748ab9d57bc250d5d7062271916cb710fe577bc441ddbd74a67c5ecb48aad9b9d58b7c567afcd84e7e3fe88322f6b3d625722093b9bde5e64369a509c537",
-      "line": 1592,
-      "relation": "positiveCorrelation",
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+      "evidence": "Treatment with Dyrk1A inhibitor, green tea flavonol epigallocatechin-gallate (EGCG), from gestation to adulthood suppressed 3R-tau expression and rescued anxiety and memory deficits in Ts65Dn mouse brains.",
+      "key": "2f96df75ed8e759ae855af864af6beab653290c365d29e32e5e24c20b94ed8573fd8fbfcd11137cf3e65f3dc9fa34a41e81f0bad8bdb61ebd6ed5c9465269e7d",
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     },
     {
       "annotations": {
-        "MeSHDisease": {
-          "Alzheimer Disease": true
+        "Confidence": {
+          "High": true
+        },
+        "Research_Model": {
+          "SAMP8 mice": true
+        },
+        "Species": {
+          "10090": true
         }
       },
       "citation": {
         "authors": [
-          "Babić Leko M",
-          "Bažadona D",
-          "Buée L",
-          "Delalle I",
-          "Di Giovanni G",
-          "Harrington C",
-          "Hof PR",
-          "Jovanov-Milošević N",
-          "Wischik C",
-          "Wray S",
-          "de Silva R",
-          "Šimić G"
+          "Butterfield DA",
+          "Farr SA",
+          "Kumar V",
+          "Morley JE",
+          "Murphy MP",
+          "Niehoff ML",
+          "Platt TL",
+          "Ripley JL",
+          "Sultana R",
+          "Zhang Z"
         ],
-        "date": "2016-01-06",
-        "first": "Šimić G",
-        "last": "Hof PR",
-        "name": "Biomolecules",
-        "pages": "6",
-        "reference": "26751493",
-        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
+        "date": "2014-02-01",
+        "first": "Farr SA",
+        "last": "Butterfield DA",
+        "name": "Free radical biology &amp; medicine",
+        "pages": "387-95",
+        "reference": "24355211",
+        "title": "Antisense oligonucleotide against GSK-3β in brain of SAMP8 mice improves learning and memory and decreases oxidative stress: Involvement of transcription factor Nrf2 and implications for Alzheimer disease.",
         "type": "PubMed",
-        "volume": "6"
+        "volume": "67"
       },
-      "evidence": "3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain.",
-      "key": "8e5d9d7f608e8219797f3dcb9d7fdf05be13fea764c7d3ce7ce6c7104fdb520ac44baf2a3cc12d02f843842b86889fc41def0c88610ac5b8402756b1263dd681",
-      "line": 1593,
-      "relation": "positiveCorrelation",
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-      "target": 908
+      "evidence": "Nuclear factor erythroid-2-related factor 2 (Nrf2) is a transcription factor known to increase the level of many antioxidants, including glutathione-S transferase (GST), and is negatively regulated by the activity of GSK-3β. Our results indicated the increased nuclear localization of Nrf2 and level of GST, suggesting the increased activity of the transcription factor as a result of GSK-3β suppression, consistent with the decreased oxidative stress observed. Consistent with the improved learning and memory, and consistent with GSK-3b being a tau kinase, we observed decreased tau phosphorylation in brain of GAO-treated SAMP8 mice compared to that of RAO-treated SAMP8 mice.",
+      "key": "72c0c94e075aab79cf1b160cc3f45928e6e2faa35934af5a27cb90254aef64859e77eb9397a5f44f5146988ef6c50462475ad5e0b7904034ade200196a81777e",
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+      "target": 537
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "MeSHDisease": {
           "Alzheimer Disease": true
         }
       },
       "citation": {
         "authors": [
-          "Babić Leko M",
-          "Bažadona D",
-          "Buée L",
-          "Delalle I",
-          "Di Giovanni G",
-          "Harrington C",
-          "Hof PR",
-          "Jovanov-Milošević N",
-          "Wischik C",
-          "Wray S",
-          "de Silva R",
-          "Šimić G"
+          "Cong X",
+          "Ellerby LM",
+          "Gan L",
+          "Huganir RL",
+          "Le D",
+          "Li Y",
+          "Lo I",
+          "Min SW",
+          "Minami SS",
+          "Ponnusamy R",
+          "Schilling B",
+          "Sohn PD",
+          "Tracy TE",
+          "Wang C",
+          "Zhou Y"
         ],
-        "date": "2016-01-06",
-        "first": "Šimić G",
-        "last": "Hof PR",
-        "name": "Biomolecules",
-        "pages": "6",
-        "reference": "26751493",
-        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
+        "date": "2016-04-20",
+        "first": "Tracy TE",
+        "last": "Gan L",
+        "name": "Neuron",
+        "pages": "245-60",
+        "reference": "27041503",
+        "title": "Acetylated Tau Obstructs KIBRA-Mediated Signaling in Synaptic Plasticity and Promotes Tauopathy-Related Memory Loss.",
         "type": "PubMed",
-        "volume": "6"
+        "volume": "90"
       },
-      "evidence": "3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain.",
-      "key": "5bf9e384246c7807dd4f3726275e8982a9c0e7746422a05acb95103b3cc1c3bdf8bab185f3eff1564a8aea177058c2568a24a893e98a94ebcdadb27b7cedab4f",
-      "line": 1594,
-      "relation": "positiveCorrelation",
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+      "evidence": "Here we report abnormal acetylation of K274 and K281 on tau, identified in AD brains, promotes memory loss and disrupts synaptic plasticity by reducing postsynaptic KIdney/BRAin (KIBRA) protein, a memory-associated protein.Transgenic mice expressing human tau with lysine-to-glutamine mutations to mimic K274 and K281 acetylation (tauKQ) exhibit AD-related memory deficits and impaired hippocampal long-term potentiation (LTP). TauKQ reduces synaptic KIBRA levels and disrupts activity-induced postsynaptic actin remodeling and AMPA receptor insertion. The LTP deficit was rescued by promoting actin polymerization or by KIBRA expression. In AD patients with dementia, we found enhanced tau acetylation is linked to loss of KIBRA.",
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     {
       "annotations": {
-        "MeSHDisease": {
-          "Alzheimer Disease": true
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+          "Medium": true
         }
       },
       "citation": {
         "authors": [
-          "Babić Leko M",
-          "Bažadona D",
-          "Buée L",
-          "Delalle I",
-          "Di Giovanni G",
-          "Harrington C",
-          "Hof PR",
-          "Jovanov-Milošević N",
-          "Wischik C",
-          "Wray S",
-          "de Silva R",
-          "Šimić G"
+          "Jin J",
+          "Liu Y",
+          "Wang S",
+          "Xu Y",
+          "Ye X",
+          "Yu L",
+          "Zhu X"
         ],
-        "date": "2016-01-06",
-        "first": "Šimić G",
-        "last": "Hof PR",
-        "name": "Biomolecules",
-        "pages": "6",
-        "reference": "26751493",
-        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
+        "date": "2017-10-01",
+        "first": "Zhu X",
+        "last": "Xu Y",
+        "name": "Aging cell",
+        "pages": "1073-1082",
+        "reference": "28771976",
+        "title": "HDAC3 negatively regulates spatial memory in a mouse model of Alzheimer's disease.",
         "type": "PubMed",
-        "volume": "6"
+        "volume": "16"
       },
-      "evidence": "3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain.",
-      "key": "65c403254636d27e19e7cfdf92aeee359414183d42c81b26bd316086a207881f4f420457769fd5875f2419bc208b3a5f3ecedad7daf033b77cc0b5d22a55fcbd",
-      "line": 1595,
-      "relation": "positiveCorrelation",
-      "source": 571,
-      "target": 908
+      "evidence": "RGFP966, a selective HDAC3 inhibitor, has been shown to affect sensory cortical plasticity and memory formation (Bieszczad et al., 2015).",
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     },
     {
       "annotations": {
-        "MeSHDisease": {
-          "Alzheimer Disease": true
+        "Anatomy": {
+          "hippocampal formation": true
+        },
+        "Confidence": {
+          "High": true
+        },
+        "Species": {
+          "10090": true
         }
       },
       "citation": {
         "authors": [
-          "Babić Leko M",
-          "Bažadona D",
-          "Buée L",
-          "Delalle I",
-          "Di Giovanni G",
-          "Harrington C",
-          "Hof PR",
-          "Jovanov-Milošević N",
-          "Wischik C",
-          "Wray S",
-          "de Silva R",
-          "Šimić G"
+          "Brown JT",
+          "Cimarosti H",
+          "Henley JM",
+          "McMillan LE"
         ],
-        "date": "2016-01-06",
-        "first": "Šimić G",
-        "last": "Hof PR",
-        "name": "Biomolecules",
-        "pages": "6",
-        "reference": "26751493",
-        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
+        "date": "2011-09-20",
+        "first": "McMillan LE",
+        "last": "Cimarosti H",
+        "name": "Neuroscience letters",
+        "pages": "201-8",
+        "reference": "21843595",
+        "title": "Profiles of SUMO and ubiquitin conjugation in an Alzheimer's disease model.",
         "type": "PubMed",
-        "volume": "6"
+        "volume": "502"
       },
-      "evidence": "3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain.",
-      "key": "8e74d4e43b7ea16f1e5b8a9fad175ec232634bfb7fae33678bc9a153b9f1b77066106e3ea3c4abc5d9a2673a2d7ffdbfb89cd203cdc4adc65d443128eec0836c",
-      "line": 1596,
-      "relation": "positiveCorrelation",
-      "source": 586,
-      "target": 908
+      "evidence": "In 25-month-old mice, the number of errors and the latency in the learning phase negatively correlated with the Sumo3 level in the dorsal hippocampus.",
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     },
     {
       "annotations": {
-        "MeSHDisease": {
-          "Alzheimer Disease": true
+        "Confidence": {
+          "Medium": true
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       },
       "citation": {
         "authors": [
-          "Babić Leko M",
-          "Bažadona D",
-          "Buée L",
-          "Delalle I",
-          "Di Giovanni G",
-          "Harrington C",
-          "Hof PR",
-          "Jovanov-Milošević N",
-          "Wischik C",
-          "Wray S",
-          "de Silva R",
-          "Šimić G"
+          "Ciborowski P",
+          "Ikezu T",
+          "Jacobsen MT",
+          "Martinez LB",
+          "Okuyama S",
+          "Sato S",
+          "Schlautman JD",
+          "Swan RJ",
+          "Walsh SM",
+          "Xu J"
         ],
-        "date": "2016-01-06",
-        "first": "Šimić G",
-        "last": "Hof PR",
-        "name": "Biomolecules",
-        "pages": "6",
-        "reference": "26751493",
-        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
+        "date": "2008-12-31",
+        "first": "Sato S",
+        "last": "Ikezu T",
+        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
+        "pages": "14511-21",
+        "reference": "19118186",
+        "title": "Spatial learning impairment, enhanced CDK5/p35 activity, and downregulation of NMDA receptor expression in transgenic mice expressing tau-tubulin kinase 1.",
         "type": "PubMed",
-        "volume": "6"
+        "volume": "28"
       },
-      "evidence": "3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain.",
-      "key": "3771e9a88a0c0980d7101675294841949b34b5b09cb1ec4456cb35bbf9addc81faeb7b5f37865d56d1edab7c0bf0fa6d300a614ed6d26a26c382171384ec3d97",
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+      "evidence": "TTBK1-Tg mice show significant age-dependent memory impairment as determined by radial arm water maze test, which is associated with enhancement of tau and neurofilament phosphorylation, increased levels of p25 and p35, both activators of cyclin-dependent protein kinase 5 (CDK5), enhanced calpain I activity, and reduced levels of hippocampal NMDA receptor types 2B (NR2B) and D. Enhanced CDK5/p35 complex formation is strongly correlated with dissociation of F-actin from p35, suggesting the inhibitory mechanism of CDK5/p35 complex formation by F-actin.",
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     {
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+        "Confidence": {
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+        }
+      },
       "citation": {
         "authors": [
-          "Babić Leko M",
-          "Bažadona D",
-          "Buée L",
-          "Delalle I",
-          "Di Giovanni G",
-          "Harrington C",
-          "Hof PR",
-          "Jovanov-Milošević N",
-          "Wischik C",
-          "Wray S",
-          "de Silva R",
-          "Šimić G"
+          "Ciborowski P",
+          "Ikezu T",
+          "Jacobsen MT",
+          "Martinez LB",
+          "Okuyama S",
+          "Sato S",
+          "Schlautman JD",
+          "Swan RJ",
+          "Walsh SM",
+          "Xu J"
         ],
-        "date": "2016-01-06",
-        "first": "Šimić G",
-        "last": "Hof PR",
-        "name": "Biomolecules",
-        "pages": "6",
-        "reference": "26751493",
-        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
+        "date": "2008-12-31",
+        "first": "Sato S",
+        "last": "Ikezu T",
+        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
+        "pages": "14511-21",
+        "reference": "19118186",
+        "title": "Spatial learning impairment, enhanced CDK5/p35 activity, and downregulation of NMDA receptor expression in transgenic mice expressing tau-tubulin kinase 1.",
         "type": "PubMed",
-        "volume": "6"
+        "volume": "28"
       },
-      "evidence": "Apart from binding to MT, the repeat domains of tau also bind to tubulin deacetylase, histone deacetylase 6 (HDAC6) [68] and apolipoprotein E (apoE) more with the ",
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-        "authors": [
-          "Carlomagno Y",
-          "Cook C",
-          "Petrucelli L",
-          "Stankowski JN",
-          "Stetler C"
-        ],
-        "date": "2014-01-01",
-        "first": "Cook C",
-        "last": "Petrucelli L",
-        "name": "Alzheimer's research &amp; therapy",
-        "pages": "29",
-        "reference": "25031639",
-        "title": "Acetylation: a new key to unlock tau's role in neurodegeneration.",
-        "type": "PubMed",
-        "volume": "6"
-      },
-      "evidence": "We demonstrate that elevated HDAC6 activity increases phosphorylation of tau at the 12E8 epitope (pS262/356), a phospho-epitope present within the KXGS motifs of tau’s microtubule-binding domain. The phosphorylation of KXGS motifs within tau by the kinase Par-1/MARK2 is required for tau proteotoxicity in Drosophila [29], observed at very early stages of NFT formation in AD brain [30], and appears to prime tau for subsequent phosphorylation events",
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-      "subject": {
-        "modifier": "Activity"
-      },
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+      "evidence": "TTBK1-Tg mice show significant age-dependent memory impairment as determined by radial arm water maze test, which is associated with enhancement of tau and neurofilament phosphorylation, increased levels of p25 and p35, both activators of cyclin-dependent protein kinase 5 (CDK5), enhanced calpain I activity, and reduced levels of hippocampal NMDA receptor types 2B (NR2B) and D. Enhanced CDK5/p35 complex formation is strongly correlated with dissociation of F-actin from p35, suggesting the inhibitory mechanism of CDK5/p35 complex formation by F-actin.",
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     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "Species": {
+          "10090": true
+        }
+      },
       "citation": {
         "authors": [
-          "Huang L",
-          "Liu C",
-          "Qin C",
-          "Sheng SL",
-          "Sui XL",
-          "Tao JJ",
-          "Wu J",
-          "Xu YF",
-          "Yao ZG",
-          "Zhang L",
-          "Zhu H"
+          "Ciborowski P",
+          "Ikezu T",
+          "Jacobsen MT",
+          "Martinez LB",
+          "Okuyama S",
+          "Sato S",
+          "Schlautman JD",
+          "Swan RJ",
+          "Walsh SM",
+          "Xu J"
         ],
-        "date": "2014-01-01",
-        "first": "Zhang L",
-        "last": "Qin C",
-        "name": "Journal of Alzheimer's disease : JAD",
-        "pages": "1193-205",
-        "reference": "24844691",
-        "title": "Tubastatin A/ACY-1215 improves cognition in Alzheimer's disease transgenic mice.",
+        "date": "2008-12-31",
+        "first": "Sato S",
+        "last": "Ikezu T",
+        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
+        "pages": "14511-21",
+        "reference": "19118186",
+        "title": "Spatial learning impairment, enhanced CDK5/p35 activity, and downregulation of NMDA receptor expression in transgenic mice expressing tau-tubulin kinase 1.",
         "type": "PubMed",
-        "volume": "41"
+        "volume": "28"
       },
-      "evidence": "In the present study, we tested the potential of two selective HDAC6 inhibitors, tubastatin A and ACY-1215, to rescue cognitive deficits in a mouse model of AD. We found that both tubastatin A and ACY-1215 alleviated behavioral deficits, altered amyloid-β (Aβ) load, and reduced tau hyperphosphorylation in AD mice without obvious adverse effects. Our data suggested that tubastatin A and ACY-1215 not only promoted tubulin acetylation, but also reduced production and facilitated autophagic clearance of Aβ and hyperphosphorylated tau.",
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+      "source": 245,
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+    {
+      "key": "c45fddb37932c3c9064255e9c73172a77807f0cbf74e0caac35e644ddb6eeaa944ffe3ff39f0b81c2c8f2fdda6c88cd5f392adde484f990203e0820ec98554e2",
+      "relation": "hasComponent",
+      "source": 245,
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+    },
+    {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "Species": {
+          "10090": true
+        }
+      },
       "citation": {
         "authors": [
-          "Berkovitch SS",
-          "Chattopadhyay S",
-          "Haggarty SJ",
-          "Huang JH",
-          "Iaconelli J",
-          "Karmacharya R",
-          "Mazitschek R",
-          "Schreiber SL"
+          "Ciborowski P",
+          "Ikezu T",
+          "Jacobsen MT",
+          "Martinez LB",
+          "Okuyama S",
+          "Sato S",
+          "Schlautman JD",
+          "Swan RJ",
+          "Walsh SM",
+          "Xu J"
         ],
-        "date": "2015-03-20",
-        "first": "Iaconelli J",
-        "last": "Karmacharya R",
-        "name": "ACS chemical biology",
-        "pages": "883-90",
-        "reference": "25546293",
-        "title": "HDAC6 inhibitors modulate Lys49 acetylation and membrane localization of β-catenin in human iPSC-derived neuronal cells.",
+        "date": "2008-12-31",
+        "first": "Sato S",
+        "last": "Ikezu T",
+        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
+        "pages": "14511-21",
+        "reference": "19118186",
+        "title": "Spatial learning impairment, enhanced CDK5/p35 activity, and downregulation of NMDA receptor expression in transgenic mice expressing tau-tubulin kinase 1.",
         "type": "PubMed",
-        "volume": "10"
+        "volume": "28"
       },
-      "evidence": "The N-terminus of β-catenin has phosphorylation, ubiquitination, and acetylation sites that regulate its stability and signaling. In the absence of a Wnt signal, Ser33, Ser37, and Thr41 are constitutively phosphorylated by glycogen synthase kinase 3β (GSK3β). β-Catenin phosphorylated at these sites is recognized by β-transducin repeat-containing protein (βTrCP), which results in ubiquitination and degradation by the ubiquitin-proteasome pathway. The N-terminal regulatory domain of β-catenin also includes Ser45, a phosphorylation site for Casein Kinase 1α (CK1α) and Lys49, which is acetylated by the acetyltransferase p300/CBP-associated factor (PCAF). The relevance of Lys49 acetylation and Ser45 phosphorylation to the function of β-catenin is an active area of investigation. We find that HDAC6 inhibitors increase Lys49 acetylation and Ser45 phosphorylation but do not affect Ser33, Ser37, and Thr41 phosphorylation. Lys49 acetylation results in decreased ubiquitination of β-catenin in the presence of proteasome inhibition. While increased Lys49 acetylation does not affect total levels of β-catenin, it results in increased membrane localization of β-catenin.",
-      "key": "03bb5100a720538a02b8a8b874324295c880090b3b79e7a4b1d9fed1b4ffbc16b0f386849e93871c9d5801dbc0b62b94303de8fbf6a57e15918c531f374b5db7",
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+      "evidence": "TTBK1-Tg mice show significant age-dependent memory impairment as determined by radial arm water maze test, which is associated with enhancement of tau and neurofilament phosphorylation, increased levels of p25 and p35, both activators of cyclin-dependent protein kinase 5 (CDK5), enhanced calpain I activity, and reduced levels of hippocampal NMDA receptor types 2B (NR2B) and D. Enhanced CDK5/p35 complex formation is strongly correlated with dissociation of F-actin from p35, suggesting the inhibitory mechanism of CDK5/p35 complex formation by F-actin.",
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       "relation": "negativeCorrelation",
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-      },
-      "target": 421
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+      "target": 304
     },
     {
       "annotations": {
+        "Confidence": {
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+        },
         "Species": {
-          "7227": true
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       },
       "citation": {
         "authors": [
-          "Jin S",
-          "Wu J",
-          "Xiong Y",
-          "Xu Z",
-          "Zhang YQ",
-          "Zhao K"
+          "Ciborowski P",
+          "Ikezu T",
+          "Jacobsen MT",
+          "Martinez LB",
+          "Okuyama S",
+          "Sato S",
+          "Schlautman JD",
+          "Swan RJ",
+          "Walsh SM",
+          "Xu J"
         ],
-        "date": "2013-03-19",
-        "first": "Xiong Y",
-        "last": "Zhang YQ",
-        "name": "Proceedings of the National Academy of Sciences of the United States of America",
-        "pages": "4604-9",
-        "reference": "23487739",
-        "title": "HDAC6 mutations rescue human tau-induced microtubule defects in Drosophila.",
+        "date": "2008-12-31",
+        "first": "Sato S",
+        "last": "Ikezu T",
+        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
+        "pages": "14511-21",
+        "reference": "19118186",
+        "title": "Spatial learning impairment, enhanced CDK5/p35 activity, and downregulation of NMDA receptor expression in transgenic mice expressing tau-tubulin kinase 1.",
         "type": "PubMed",
-        "volume": "110"
+        "volume": "28"
       },
-      "evidence": "Overexpressed tau was hyperphosphorylated and resulted in decreased MT density and greater fragmentation. Using genetic screen, a histone deacetylase 6 (HDAC6) null mutation rescued tau-induced MT defects in both muscles and neurons. Genetic and pharmacological inhibition of the tubulin-specific deacetylase activity of HDAC6 indicates that the rescue effect may be mediated by increased MT acetylation.",
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+      "evidence": "TTBK1-Tg mice show significant age-dependent memory impairment as determined by radial arm water maze test, which is associated with enhancement of tau and neurofilament phosphorylation, increased levels of p25 and p35, both activators of cyclin-dependent protein kinase 5 (CDK5), enhanced calpain I activity, and reduced levels of hippocampal NMDA receptor types 2B (NR2B) and D. Enhanced CDK5/p35 complex formation is strongly correlated with dissociation of F-actin from p35, suggesting the inhibitory mechanism of CDK5/p35 complex formation by F-actin.",
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       "relation": "negativeCorrelation",
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-      "subject": {
-        "modifier": "Activity"
-      },
-      "target": 86
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+      "target": 304
     },
     {
       "annotations": {
-        "Species": {
-          "7227": true
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+          "High": true
         }
       },
       "citation": {
         "authors": [
-          "Jin S",
-          "Wu J",
-          "Xiong Y",
-          "Xu Z",
-          "Zhang YQ",
-          "Zhao K"
+          "Alessi DR",
+          "Campbell DG",
+          "Cousin MA",
+          "Esoof N",
+          "Fritsch MJ",
+          "Gordon SL",
+          "Gourlay R",
+          "Macartney T",
+          "Peggie M",
+          "Velupillai S",
+          "Zhang N",
+          "van Aalten DM"
         ],
-        "date": "2013-03-19",
-        "first": "Xiong Y",
-        "last": "Zhang YQ",
-        "name": "Proceedings of the National Academy of Sciences of the United States of America",
-        "pages": "4604-9",
-        "reference": "23487739",
-        "title": "HDAC6 mutations rescue human tau-induced microtubule defects in Drosophila.",
+        "date": "2015-02-11",
+        "first": "Zhang N",
+        "last": "Alessi DR",
+        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
+        "pages": "2492-507",
+        "reference": "25673844",
+        "title": "Phosphorylation of synaptic vesicle protein 2A at Thr84 by casein kinase 1 family kinases controls the specific retrieval of synaptotagmin-1.",
         "type": "PubMed",
-        "volume": "110"
-      },
-      "evidence": "Overexpressed tau was hyperphosphorylated and resulted in decreased MT density and greater fragmentation. Using genetic screen, a histone deacetylase 6 (HDAC6) null mutation rescued tau-induced MT defects in both muscles and neurons. Genetic and pharmacological inhibition of the tubulin-specific deacetylase activity of HDAC6 indicates that the rescue effect may be mediated by increased MT acetylation.",
-      "key": "f48583a07613cc60a15105ac2ad12a07da64d6050dd11e3a049bb4228085c02949693c8611bf77b57ed9a04a1e20f75d48d65f4a821adb23c164a78469b71321",
-      "line": 3254,
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       },
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+      "evidence": "The CK1 group of eukaryotic protein kinases are composed of seven CK1 isoforms (CK1α, CK1α2, CK1δ, CK1ε, CK1γ1, CK1γ2, and CK1γ3), two Tau–tubulin kinase isoforms (TTBK1 and TTBK2), and three VRK isoforms (VRK1, VRK2, and VRK3)",
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     {
+      "annotations": {
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       "citation": {
         "authors": [
-          "Carlomagno Y",
-          "Castanedes-Casey M",
-          "Chung DC",
-          "Cook C",
-          "DeTure M",
-          "Dickson DW",
-          "Dunmore J",
-          "Madden BJ",
-          "Petrucelli L",
-          "Tong J",
-          "Yue M"
+          "Alessi DR",
+          "Campbell DG",
+          "Cousin MA",
+          "Esoof N",
+          "Fritsch MJ",
+          "Gordon SL",
+          "Gourlay R",
+          "Macartney T",
+          "Peggie M",
+          "Velupillai S",
+          "Zhang N",
+          "van Aalten DM"
         ],
-        "date": "2017-09-15",
-        "first": "Carlomagno Y",
-        "last": "Cook C",
-        "name": "The Journal of biological chemistry",
-        "pages": "15277-15286",
-        "reference": "28760828",
-        "title": "An acetylation-phosphorylation switch that regulates tau aggregation propensity and function.",
+        "date": "2015-02-11",
+        "first": "Zhang N",
+        "last": "Alessi DR",
+        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
+        "pages": "2492-507",
+        "reference": "25673844",
+        "title": "Phosphorylation of synaptic vesicle protein 2A at Thr84 by casein kinase 1 family kinases controls the specific retrieval of synaptotagmin-1.",
         "type": "PubMed",
-        "volume": "292"
+        "volume": "35"
       },
-      "evidence": "HDAC6 inhibition leads to a significant reduction in tau levels as detected by the human tau-specific antibody E1 (Fig. 6 (a and c) and supplemental Fig. S6). We also observed a striking decrease in phosphorylation at Ser-324, which was statistically significant even when normalizing to E1 to control for the reduction in tau levels (Fig. 6 (a and b) and supplemental Fig. S6).",
-      "key": "a125d6df6bfe80e66d1ed9e3ccd39432953ea1f9f43a60c1f692afbe2dd716b2f88a5d0592513f3c3264d8623740c12dabffbe52e59f4de631061f47e2d68e23",
-      "line": 3357,
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+      "evidence": "The CK1 group of eukaryotic protein kinases are composed of seven CK1 isoforms (CK1α, CK1α2, CK1δ, CK1ε, CK1γ1, CK1γ2, and CK1γ3), two Tau–tubulin kinase isoforms (TTBK1 and TTBK2), and three VRK isoforms (VRK1, VRK2, and VRK3)",
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     {
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       "citation": {
         "authors": [
-          "Carlomagno Y",
-          "Castanedes-Casey M",
-          "Chung DC",
-          "Cook C",
-          "DeTure M",
-          "Dickson DW",
-          "Dunmore J",
-          "Madden BJ",
-          "Petrucelli L",
-          "Tong J",
-          "Yue M"
+          "Alessi DR",
+          "Campbell DG",
+          "Cousin MA",
+          "Esoof N",
+          "Fritsch MJ",
+          "Gordon SL",
+          "Gourlay R",
+          "Macartney T",
+          "Peggie M",
+          "Velupillai S",
+          "Zhang N",
+          "van Aalten DM"
         ],
-        "date": "2017-09-15",
-        "first": "Carlomagno Y",
-        "last": "Cook C",
-        "name": "The Journal of biological chemistry",
-        "pages": "15277-15286",
-        "reference": "28760828",
-        "title": "An acetylation-phosphorylation switch that regulates tau aggregation propensity and function.",
+        "date": "2015-02-11",
+        "first": "Zhang N",
+        "last": "Alessi DR",
+        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
+        "pages": "2492-507",
+        "reference": "25673844",
+        "title": "Phosphorylation of synaptic vesicle protein 2A at Thr84 by casein kinase 1 family kinases controls the specific retrieval of synaptotagmin-1.",
         "type": "PubMed",
-        "volume": "292"
+        "volume": "35"
       },
-      "evidence": "HDAC6 inhibition leads to a significant reduction in tau levels as detected by the human tau-specific antibody E1 (Fig. 6 (a and c) and supplemental Fig. S6). We also observed a striking decrease in phosphorylation at Ser-324, which was statistically significant even when normalizing to E1 to control for the reduction in tau levels (Fig. 6 (a and b) and supplemental Fig. S6).",
-      "key": "629987366b04c82a2159841db71a4539954fa36208e90aae8843b13ee3068a302dcc6b4632367f20939448e2658b4db983b970dcbec7f074fa888fb171a08e17",
-      "line": 3358,
-      "relation": "positiveCorrelation",
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-      "target": 561
+      "evidence": "The CK1 group of eukaryotic protein kinases are composed of seven CK1 isoforms (CK1α, CK1α2, CK1δ, CK1ε, CK1γ1, CK1γ2, and CK1γ3), two Tau–tubulin kinase isoforms (TTBK1 and TTBK2), and three VRK isoforms (VRK1, VRK2, and VRK3)",
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     },
     {
       "annotations": {
-        "Cell_Line": {
-          "N2a": true,
-          "SH-SY5Y": true
+        "Confidence": {
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         }
       },
       "citation": {
         "authors": [
-          "Fan SJ",
-          "Huang FI",
-          "Liou JP",
-          "Yang CR"
+          "Alessi DR",
+          "Campbell DG",
+          "Cousin MA",
+          "Esoof N",
+          "Fritsch MJ",
+          "Gordon SL",
+          "Gourlay R",
+          "Macartney T",
+          "Peggie M",
+          "Velupillai S",
+          "Zhang N",
+          "van Aalten DM"
         ],
-        "date": "2018-05-29",
-        "first": "Fan SJ",
-        "last": "Yang CR",
-        "name": "Cell death &amp; disease",
-        "pages": "655",
-        "reference": "29844403",
-        "title": "The novel histone de acetylase 6 inhibitor, MPT0G211, ameliorates tau phosphorylation and cognitive deficits in an Alzheimer's disease model.",
+        "date": "2015-02-11",
+        "first": "Zhang N",
+        "last": "Alessi DR",
+        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
+        "pages": "2492-507",
+        "reference": "25673844",
+        "title": "Phosphorylation of synaptic vesicle protein 2A at Thr84 by casein kinase 1 family kinases controls the specific retrieval of synaptotagmin-1.",
         "type": "PubMed",
-        "volume": "9"
-      },
-      "evidence": "This study aimed to investigate the protective effects and mechanism of the novel HDAC6 inhibitor, MPT0G211, using an AD model. Our results indicated that MPT0G211 significantly reduced tau phosphorylation and aggregation, the processes highly correlated with the formation of NFTs. This HDAC6 inhibitory activity resulted in an increase in acetylated Hsp90, which decreased Hsp90 and HDAC6 binding, causing ubiquitination of phosphorylated tau proteins. In addition, a significant increase of phospho-glycogen synthase kinase-3β (phospho-GSK3β) on Ser9 (the inactive form) through Akt phosphorylation was associated with the inhibition of phospho-tau Ser396 in response to MPT0G211 treatment.",
-      "key": "bcdf8edfc7d3fbec5ab8f31f7e06ed890ed2115cf1884ca57b50e66efd26f12e5af4d1bbfe6072bced8531bce2dd967f48bb3d207931aa334477e2a6e3da18ee",
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-      "relation": "positiveCorrelation",
-      "source": 459,
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       },
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+      "evidence": "The CK1 group of eukaryotic protein kinases are composed of seven CK1 isoforms (CK1α, CK1α2, CK1δ, CK1ε, CK1γ1, CK1γ2, and CK1γ3), two Tau–tubulin kinase isoforms (TTBK1 and TTBK2), and three VRK isoforms (VRK1, VRK2, and VRK3)",
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     {
+      "annotations": {
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+        }
+      },
       "citation": {
         "authors": [
-          "Babić Leko M",
-          "Bažadona D",
-          "Buée L",
-          "Delalle I",
-          "Di Giovanni G",
-          "Harrington C",
-          "Hof PR",
-          "Jovanov-Milošević N",
-          "Wischik C",
-          "Wray S",
-          "de Silva R",
-          "Šimić G"
+          "Alessi DR",
+          "Campbell DG",
+          "Cousin MA",
+          "Esoof N",
+          "Fritsch MJ",
+          "Gordon SL",
+          "Gourlay R",
+          "Macartney T",
+          "Peggie M",
+          "Velupillai S",
+          "Zhang N",
+          "van Aalten DM"
         ],
-        "date": "2016-01-06",
-        "first": "Šimić G",
-        "last": "Hof PR",
-        "name": "Biomolecules",
-        "pages": "6",
-        "reference": "26751493",
-        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
+        "date": "2015-02-11",
+        "first": "Zhang N",
+        "last": "Alessi DR",
+        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
+        "pages": "2492-507",
+        "reference": "25673844",
+        "title": "Phosphorylation of synaptic vesicle protein 2A at Thr84 by casein kinase 1 family kinases controls the specific retrieval of synaptotagmin-1.",
         "type": "PubMed",
-        "volume": "6"
+        "volume": "35"
       },
-      "evidence": "Apart from binding to MT, the repeat domains of tau also bind to tubulin deacetylase, histone deacetylase 6 (HDAC6) [68] and apolipoprotein E (apoE) more with the ",
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-      "line": 1605,
-      "relation": "association",
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+      "evidence": "We demonstrate that Casein kinase 1 family members, including isoforms of Tau-tubulin protein kinases (TTBK1 and TTBK2), phosphorylate human SV2A at two constellations of residues, namely Cluster-1 (Ser42, Ser45, and Ser47) and Cluster-2 (Ser80, Ser81, and Thr84). These residues are also phosphorylated in vivo, and the phosphorylation of Thr84 within Cluster-2 is essential for triggering binding to the C2B domain of human synaptotagmin-1",
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+      "line": 1694,
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     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
-          "Babić Leko M",
-          "Bažadona D",
-          "Buée L",
-          "Delalle I",
-          "Di Giovanni G",
-          "Harrington C",
-          "Hof PR",
-          "Jovanov-Milošević N",
-          "Wischik C",
-          "Wray S",
-          "de Silva R",
-          "Šimić G"
+          "Alessi DR",
+          "Campbell DG",
+          "Cousin MA",
+          "Esoof N",
+          "Fritsch MJ",
+          "Gordon SL",
+          "Gourlay R",
+          "Macartney T",
+          "Peggie M",
+          "Velupillai S",
+          "Zhang N",
+          "van Aalten DM"
         ],
-        "date": "2016-01-06",
-        "first": "Šimić G",
-        "last": "Hof PR",
-        "name": "Biomolecules",
-        "pages": "6",
-        "reference": "26751493",
-        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
+        "date": "2015-02-11",
+        "first": "Zhang N",
+        "last": "Alessi DR",
+        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
+        "pages": "2492-507",
+        "reference": "25673844",
+        "title": "Phosphorylation of synaptic vesicle protein 2A at Thr84 by casein kinase 1 family kinases controls the specific retrieval of synaptotagmin-1.",
         "type": "PubMed",
-        "volume": "6"
+        "volume": "35"
       },
-      "evidence": "The projection domain of tau may be involved in cell signaling that occurs through the interaction with Lck, Fgr and cSrc (Src-family kinases), growth factor receptor-bound protein 2 (Grb2), phospholipase C- [70], phosphatidylinositol and phosphatidylinositol bisphosphate [71,72], peptidyl-prolyl cis/trans isomerase Pin 1, and many others (for review see [73]), making them potential therapeutic targets in tauopathies [74].",
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-          "Jovanov-Milošević N",
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         "authors": [
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+          "Chambraud B",
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-        "first": "Šimić G",
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-        "name": "Biomolecules",
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-          "Feldmann KG",
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-          "Salama M"
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-          "Ueberham E",
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-          "Holzer M",
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-          "Ueberham E",
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         "authors": [
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-          "Zhou XZ"
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-          "Eichner T",
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-          "Labeikovsky W"
+          "Alesutan I",
+          "Dërmaku-Sopjani M",
+          "Lang F",
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-          "Ando K",
-          "Blum D",
-          "Bretteville A",
-          "Buée L",
-          "Bégard S",
-          "Bélarbi K",
-          "Caillet-Boudin ML",
-          "Demey-Thomas E",
-          "Dourlen P",
-          "Drobecq H",
-          "Eddarkaoui S",
-          "Galas MC",
-          "Ghestem A",
-          "Hamdane M",
-          "Landrieu I",
-          "Lippens G",
-          "Maurage CA",
-          "Melnyk P",
-          "Sambo AV",
-          "Sergeant N",
-          "Smet C",
-          "Verdier Y",
-          "Vingtdeux V",
-          "Vinh J"
+          "Chiba S",
+          "Mizuno K",
+          "Nagai T",
+          "Oda T"
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-        "first": "Ando K",
-        "last": "Buée L",
-        "name": "Neurobiology of aging",
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-        "title": "Tau pathology modulates Pin1 post-translational modifications and may be relevant as biomarker.",
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+        "first": "Oda T",
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+        "name": "Genes to cells : devoted to molecular &amp; cellular mechanisms",
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         "type": "PubMed",
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-      "evidence": "Pin1 binds to phosphorylated Thr231 of tau and facilitates the dephosphorylation of phosphoThr231 through isomerization (Galas et al., 2006; Hamdane et al., 2006; Lu et al., 1999a). Phosphorylation at Thr231 on tau is associated with the early events of tau aggregation and NFT (Augustinack et al., 2002). Pin1 binds and isomerizes the proline imidic peptide bond following the phosphothreonine 231",
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         "authors": [
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-          "Hasegawa M",
-          "Hisanaga S",
-          "Ishiguro K",
-          "Kimura T",
-          "Oikawa T",
-          "Saito T",
-          "Uchida C",
-          "Uchida T",
-          "Yotsumoto K"
+          "Chiba S",
+          "Mizuno K",
+          "Nagai T",
+          "Oda T"
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-        "first": "Yotsumoto K",
-        "last": "Hisanaga S",
-        "name": "The Journal of biological chemistry",
-        "pages": "16840-7",
-        "reference": "19401603",
-        "title": "Effect of Pin1 or microtubule binding on dephosphorylation of FTDP-17 mutant Tau.",
+        "date": "2014-12-01",
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+        "name": "Genes to cells : devoted to molecular &amp; cellular mechanisms",
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         "type": "PubMed",
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-          "Ishiguro K",
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-          "Oikawa T",
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       "citation": {
         "authors": [
-          "Babić Leko M",
-          "Bažadona D",
-          "Buée L",
-          "Delalle I",
-          "Di Giovanni G",
-          "Harrington C",
-          "Hof PR",
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-      "evidence": "On the other side, sarkosyl extracts from the filaments of PSP [129], corticobasal degeneration (CBD; [130]), argyrophilic grain disease (AgD; [131]), and some cases of FTDP-17, contain tau protein that separates as doublets of 64 and 69 kDa and are predominantly composed of tau isoforms with 4R (class II tauopathies), whereas sarkosyl extracts from filaments of Pick’s disease are characterized by the presence of pathological tau doublets of 60 and 64 kDa and contain mainly 3R tau isoforms (class III tauopathy).",
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+      "evidence": "TTBK2 bound EB1 and Cep164 through its SxIP motifs and a proline-rich motif, respectively. Using TTBK2 variants that contained mutations in the SxIP or proline-rich motifs, we obtained evidence that Cep164, but not EB1, is essential for centriolar localization of TTBK2. Therefore, Cep164 binding is essential for the function of TTBK2 in promoting CP110 removal and ciliogenesis. We also provide evidence that TTBK2 has the potential to effectively phosphorylate Cep164 and Cep97 and inhibits the interaction between Cep164 and its binding partner Dishevelled-3 (an important regulator of ciliogenesis) in a kinase activity-dependent manner.",
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       "citation": {
         "authors": [
-          "Babić Leko M",
-          "Bažadona D",
-          "Buée L",
-          "Delalle I",
-          "Di Giovanni G",
-          "Harrington C",
-          "Hof PR",
-          "Jovanov-Milošević N",
-          "Wischik C",
-          "Wray S",
-          "de Silva R",
-          "Šimić G"
+          "Chiba S",
+          "Mizuno K",
+          "Nagai T",
+          "Oda T"
         ],
-        "date": "2016-01-06",
-        "first": "Šimić G",
-        "last": "Hof PR",
-        "name": "Biomolecules",
-        "pages": "6",
-        "reference": "26751493",
-        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
+        "date": "2014-12-01",
+        "first": "Oda T",
+        "last": "Mizuno K",
+        "name": "Genes to cells : devoted to molecular &amp; cellular mechanisms",
+        "pages": "927-40",
+        "reference": "25297623",
+        "title": "Binding to Cep164, but not EB1, is essential for centriolar localization of TTBK2 and its function in ciliogenesis.",
         "type": "PubMed",
-        "volume": "6"
+        "volume": "19"
       },
-      "evidence": "On the other side, sarkosyl extracts from the filaments of PSP [129], corticobasal degeneration (CBD; [130]), argyrophilic grain disease (AgD; [131]), and some cases of FTDP-17, contain tau protein that separates as doublets of 64 and 69 kDa and are predominantly composed of tau isoforms with 4R (class II tauopathies), whereas sarkosyl extracts from filaments of Pick’s disease are characterized by the presence of pathological tau doublets of 60 and 64 kDa and contain mainly 3R tau isoforms (class III tauopathy).",
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+      "evidence": "TTBK2 bound EB1 and Cep164 through its SxIP motifs and a proline-rich motif, respectively. Using TTBK2 variants that contained mutations in the SxIP or proline-rich motifs, we obtained evidence that Cep164, but not EB1, is essential for centriolar localization of TTBK2. Therefore, Cep164 binding is essential for the function of TTBK2 in promoting CP110 removal and ciliogenesis. We also provide evidence that TTBK2 has the potential to effectively phosphorylate Cep164 and Cep97 and inhibits the interaction between Cep164 and its binding partner Dishevelled-3 (an important regulator of ciliogenesis) in a kinase activity-dependent manner.",
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     {
       "annotations": {
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-          "Alzheimer Disease": true,
-          "Down Syndrome": true
-        },
-        "Research_Model": {
-          "Ts65Dn mice": true
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           "10090": true
@@ -44167,447 +49755,858 @@
       },
       "citation": {
         "authors": [
-          "Chen L",
-          "Sun X",
-          "Wang L",
-          "Wang P"
+          "Ikezu S",
+          "Ikezu T"
         ],
-        "date": "2017-08-03",
-        "first": "Wang P",
-        "last": "Sun X",
-        "name": "Scientific reports",
-        "pages": "7240",
-        "reference": "28775333",
-        "title": "Dual-specificity tyrosine-phosphorylation regulated kinase 1A Gene Transcription is regulated by Myocyte Enhancer Factor 2D.",
+        "date": "2014-01-01",
+        "first": "Ikezu S",
+        "last": "Ikezu T",
+        "name": "Frontiers in molecular neuroscience",
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         "type": "PubMed",
         "volume": "7"
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-      "evidence": "Inhibition of Dyrk1A enhanced tau exon 10 inclusion, leading to an increase in 4R-tau/3R-tau ratio in differentiated-human neuronal progenitors and in the neonatal rat brains. Accompanied with overexpression of Dyrk1A, 3R-tau was increased and 4R-tau was decreased in the neonatal brains of Ts65Dn mice, a model of Down syndrome.",
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+      "evidence": "Overexpression of TTBK1 was sufficient in inducing spatial learning impairment in mice, which is associated with enhanced Cdk5 activity and reduction in cell surface level of NR2B. Over-expressionof TTBK1 transgene in JNPL3 mice resulted in accumulation of pre-tangle forms of tau. Inaddition, TTBK1 expression plays a unique role in accelerating motor neuron degeneration and neuroinflammation in JNPL3mice.",
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       "citation": {
         "authors": [
-          "Cohen TJ",
-          "Guo JL",
-          "Hurtado DE",
-          "Kwong LK",
-          "Lee VM",
-          "Mills IP",
-          "Trojanowski JQ"
+          "Ikezu S",
+          "Ikezu T"
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-        "date": "2011-01-01",
-        "first": "Cohen TJ",
-        "last": "Lee VM",
-        "name": "Nature communications",
-        "pages": "252",
-        "reference": "21427723",
-        "title": "The acetylation of tau inhibits its function and promotes pathological tau aggregation.",
+        "date": "2014-01-01",
+        "first": "Ikezu S",
+        "last": "Ikezu T",
+        "name": "Frontiers in molecular neuroscience",
+        "pages": "33",
+        "reference": "24808823",
+        "title": "Tau-tubulin kinase.",
         "type": "PubMed",
-        "volume": "2"
+        "volume": "7"
       },
-      "evidence": "Thus, K280 acetylation is a feature found in a variety of human 4R or 3R/4R tauopathies including AD, but not 3R-tauopathies such as PiD.",
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         "authors": [
-          "Abdelmesih B",
-          "Brady ST",
-          "Combs B",
-          "Cox K",
-          "Kanaan NM",
-          "Morfini G"
+          "Ikezu S",
+          "Ikezu T"
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-        "date": "2016-11-01",
-        "first": "Cox K",
-        "last": "Kanaan NM",
-        "name": "Neurobiology of aging",
-        "pages": "113-126",
-        "reference": "27574109",
-        "title": "Analysis of isoform-specific tau aggregates suggests a common toxic mechanism involving similar pathological conformations and axonal transport inhibition.",
+        "date": "2014-01-01",
+        "first": "Ikezu S",
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+        "name": "Frontiers in molecular neuroscience",
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         "type": "PubMed",
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+      "evidence": "Overexpression of TTBK1 was sufficient in inducing spatial learning impairment in mice, which is associated with enhanced Cdk5 activity and reduction in cell surface level of NR2B. Over-expressionof TTBK1 transgene in JNPL3 mice resulted in accumulation of pre-tangle forms of tau. Inaddition, TTBK1 expression plays a unique role in accelerating motor neuron degeneration and neuroinflammation in JNPL3mice.",
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-      "evidence": "Aggregation-induced increases in PAD exposure and oligomerization are common features among all tau isoforms. The extent of PAD exposure and oligomerization was larger for tau aggregates composed of 4-repeat isoforms compared with those made of 3-repeat isoforms.",
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-          "Delalle I",
-          "Di Giovanni G",
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-          "Jovanov-Milošević N",
-          "Wischik C",
-          "Wray S",
-          "de Silva R",
-          "Šimić G"
+          "Buée-Scherrer V",
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-        "first": "Šimić G",
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-        "pages": "6",
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-        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
+        "date": "2002-03-27",
+        "first": "Buée-Scherrer V",
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         "type": "PubMed",
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-      "evidence": "On the other side, sarkosyl extracts from the filaments of PSP [129], corticobasal degeneration (CBD; [130]), argyrophilic grain disease (AgD; [131]), and some cases of FTDP-17, contain tau protein that separates as doublets of 64 and 69 kDa and are predominantly composed of tau isoforms with 4R (class II tauopathies), whereas sarkosyl extracts from filaments of Pick’s disease are characterized by the presence of pathological tau doublets of 60 and 64 kDa and contain mainly 3R tau isoforms (class III tauopathy).",
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-          "Delalle I",
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-          "Jovanov-Milošević N",
-          "Wischik C",
-          "Wray S",
-          "de Silva R",
-          "Šimić G"
+          "Buée-Scherrer V",
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-        "first": "Šimić G",
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         "type": "PubMed",
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       },
-      "evidence": "On the other side, sarkosyl extracts from the filaments of PSP [129], corticobasal degeneration (CBD; [130]), argyrophilic grain disease (AgD; [131]), and some cases of FTDP-17, contain tau protein that separates as doublets of 64 and 69 kDa and are predominantly composed of tau isoforms with 4R (class II tauopathies), whereas sarkosyl extracts from filaments of Pick’s disease are characterized by the presence of pathological tau doublets of 60 and 64 kDa and contain mainly 3R tau isoforms (class III tauopathy).",
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-          "Jovanov-Milošević N",
-          "Wischik C",
-          "Wray S",
-          "de Silva R",
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+          "Buée-Scherrer V",
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-        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
+        "date": "2002-03-27",
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-      "evidence": "A PSEN1 mutation causes a Pick’s disease phenotype including FTD tau pathology without deposition of Abeta [145]; some MAPT single nucleotide polymorphisms have also been linked to sporadic Parkinson’s disease (PD, [146]);",
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-      "evidence": "Poorkaj et al. reported two exonic mutations (P301L and V337M) in two families with FTDP-17 [139], while Hutton et al. reported six different mutations in 10 families: three of these mutations (G272V, P301L and R406W) were missense mutations in exons, while the other three were in the 5' splice site of exon 10 [140].",
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-        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
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+          "NMR Spectroscopy": true,
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+      "citation": {
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+          "Baulieu EE",
+          "Byrne C",
+          "Cantrelle FX",
+          "Chambraud B",
+          "Despres C",
+          "Huvent I",
+          "Jacquot Y",
+          "Landrieu I",
+          "Lippens G",
+          "Qi H",
+          "Smet-Nocca C"
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+        "first": "Despres C",
+        "last": "Smet-Nocca C",
+        "name": "Proceedings of the National Academy of Sciences of the United States of America",
+        "pages": "9080-9085",
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+        "title": "Identification of the Tau phosphorylation pattern that drives its aggregation.",
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+        "name": "Proceedings of the National Academy of Sciences of the United States of America",
+        "pages": "9080-9085",
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+        "title": "Identification of the Tau phosphorylation pattern that drives its aggregation.",
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+      "evidence": "Our finding that the resulting Tau species with phosphorylation at Ser202/Th205, but with a disrupted turn-like structure, forms abundant fibers detectable by thioflavin fluorescence or electron microscopy (Figs. 2 and 4) suggests the initial turn-like structure induced by the phosphorylation of only Ser202 and Thr205 is protective against aggregation.",
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+        "title": "Identification of the Tau phosphorylation pattern that drives its aggregation.",
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+      "evidence": "Indeed, Tau phosphorylation at the three positions, Ser202/Thr205/Ser208, while not at Ser262, is sufficient to induce aggregation without the addition of any exogenous aggregation inducer.",
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+        "name": "Proceedings of the National Academy of Sciences of the United States of America",
+        "pages": "9080-9085",
+        "reference": "28784767",
+        "title": "Identification of the Tau phosphorylation pattern that drives its aggregation.",
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+      "evidence": "When combined with ERK2 catalyzed phosphorylation, the turn-like disrupting G207V mutation in TauF8 hence leads to fast aggregation that already occurs during the phosphorylation reaction.",
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       "citation": {
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           "Babić Leko M",
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       "citation": {
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           "Babić Leko M",
@@ -44666,14 +50676,25 @@
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       "citation": {
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@@ -44699,20 +50720,25 @@
         "type": "PubMed",
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       "citation": {
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           "Babić Leko M",
@@ -44738,14 +50764,25 @@
         "type": "PubMed",
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       "citation": {
         "authors": [
           "Babić Leko M",
@@ -44771,14 +50808,25 @@
         "type": "PubMed",
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       "citation": {
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           "Babić Leko M",
@@ -44804,46 +50852,25 @@
         "type": "PubMed",
         "volume": "6"
       },
-      "evidence": "A PSEN1 mutation causes a Pick’s disease phenotype including FTD tau pathology without deposition of Abeta [145]; some MAPT single nucleotide polymorphisms have also been linked to sporadic Parkinson’s disease (PD, [146]);",
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-          "Dickson DW",
-          "Farrer MJ",
-          "Giasson BI",
-          "Knight J",
-          "Lewis J",
-          "Melrose HL",
-          "Miles S",
-          "Rousseau L",
-          "Watkinson R"
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-        "first": "Bailey RM",
-        "last": "Lewis J",
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-        "title": "LRRK2 phosphorylates novel tau epitopes and promotes tauopathy.",
-        "type": "PubMed",
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-      "evidence": "Using mass spectrometry, we identified multiple sites on recombinant tau that are phosphorylated by LRRK2 in vitro, including pT149 and pT153, which are phospho-epitopes that to date have been largely unexplored. Importantly, we demonstrate that expression of transgenic LRRK2 in a mouse model of tauopathy increased the aggregation of insoluble tau and its phosphorylation at T149, T153, T205, and S199/S202/T205 epitopes.",
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       "citation": {
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           "Babić Leko M",
@@ -44869,14 +50896,25 @@
         "type": "PubMed",
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       "citation": {
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           "Babić Leko M",
@@ -44902,14 +50940,25 @@
         "type": "PubMed",
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       "citation": {
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           "Babić Leko M",
@@ -44935,18 +50984,23 @@
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       "annotations": {
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-          "Stage III": true,
-          "Stage VI": true
+        "Confidence": {
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+        "MeSHAnatomy": {
+          "Brain": true
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@@ -44974,18 +51028,23 @@
         "type": "PubMed",
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         "type": "PubMed",
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-        "name": "The Journal of biological chemistry",
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-          "Jovanov-Milošević N",
-          "Wischik C",
-          "Wray S",
-          "de Silva R",
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-        "last": "Hof PR",
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-        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
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-          "Bažadona D",
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-          "Jovanov-Milošević N",
-          "Wischik C",
-          "Wray S",
-          "de Silva R",
-          "Šimić G"
+          "Chen C",
+          "Dong XP",
+          "Gong HS",
+          "Guo Y",
+          "Liu Y",
+          "Shi Q",
+          "Tian C",
+          "Wang SB",
+          "Xie WL",
+          "Xu Y",
+          "Zhang BY",
+          "Zhang J"
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-        "first": "Šimić G",
-        "last": "Hof PR",
-        "name": "Biomolecules",
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-        "reference": "26751493",
-        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
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       "citation": {
         "authors": [
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-          "Bažadona D",
-          "Buée L",
-          "Delalle I",
-          "Di Giovanni G",
-          "Harrington C",
-          "Hof PR",
-          "Jovanov-Milošević N",
-          "Wischik C",
-          "Wray S",
-          "de Silva R",
-          "Šimić G"
+          "Lu B",
+          "Malenka R",
+          "Polepalli J",
+          "Rajadas J",
+          "Wagh D",
+          "Yu W"
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-        "date": "2016-01-06",
-        "first": "Šimić G",
-        "last": "Hof PR",
-        "name": "Biomolecules",
-        "pages": "6",
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-        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
+        "date": "2012-03-15",
+        "first": "Yu W",
+        "last": "Lu B",
+        "name": "Human molecular genetics",
+        "pages": "1384-90",
+        "reference": "22156579",
+        "title": "A critical role for the PAR-1/MARK-tau axis in mediating the toxic effects of Aβ on synapses and dendritic spines.",
         "type": "PubMed",
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         "authors": [
-          "Adler CH",
-          "Beach TG",
-          "Braithwaite SP",
-          "Lee KW",
-          "Mouradian MM",
-          "Oh S",
-          "Park HJ",
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-          "Voronkov M",
-          "Yan R",
-          "Zhang J"
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-        "first": "Park HJ",
-        "last": "Mouradian MM",
-        "name": "Journal of neuropathology and experimental neurology",
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-        "reference": "29281045",
-        "title": "Protein Phosphatase 2A and Its Methylation Modulating Enzymes LCMT-1 and PME-1 Are Dysregulated in Tauopathies of Progressive Supranuclear Palsy and Alzheimer Disease.",
+          "Chai GS",
+          "Chen NN",
+          "Cheng XS",
+          "Duan DX",
+          "Hu Y",
+          "Liu GP",
+          "Luo Y",
+          "Ni ZF",
+          "Wang JZ"
+        ],
+        "date": "2013-01-01",
+        "first": "Duan DX",
+        "last": "Liu GP",
+        "name": "Journal of Alzheimer's disease : JAD",
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+        "title": "Phosphorylation of tau by death-associated protein kinase 1 antagonizes the kinase-induced cell apoptosis.",
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-      "evidence": "Western blot analyses showed a decrease of methyl-PP2A and an increase of demethyl-PP2A with a concomitant reduction in the methyl/demethyl PP2A ratio in both PSP (74%) and AD (76%) brains, associated with an LCMT-1 decrease and a demethylating enzyme increase, protein phosphatase methylesterase (PME-1), in both diseases.",
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+          "Boehm J",
+          "Bourgeois C",
+          "Dudilot A",
+          "Lauzon M",
+          "Leclerc N",
+          "Mondragón-Rodríguez S",
+          "Trillaud-Doppia E"
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+        "first": "Mondragón-Rodríguez S",
+        "last": "Boehm J",
+        "name": "The Journal of biological chemistry",
+        "pages": "32040-53",
+        "reference": "22833681",
+        "title": "Interaction of endogenous tau protein with synaptic proteins is regulated by N-methyl-D-aspartate receptor-dependent tau phosphorylation.",
+        "type": "PubMed",
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+      "evidence": "Acute treatment of rTg4510 mice with an O-GlcNAcase inhibitor transiently reduced tau phosphorylation at epitopes implicated in tau pathology. More importantly, long-term inhibitor treatment strongly increased tau O-GlcNAcylation, reduced the number of dystrophic neurons, and protected against the formation of pathological tau species without altering the phosphorylation of non-pathological tau.",
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+          "Carlomagno Y",
+          "Cook C",
+          "Petrucelli L",
+          "Stankowski JN",
+          "Stetler C"
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+        "first": "Cook C",
+        "last": "Petrucelli L",
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+        "title": "Acetylation: a new key to unlock tau's role in neurodegeneration.",
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+          "Iijima-Ando K",
+          "Lu B",
+          "Maruko-Otake A",
+          "Ohtake Y",
+          "Sekiya M",
+          "Suzuki E"
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+        "first": "Iijima-Ando K",
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+          "Iijima-Ando K",
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+          "Ohtake Y",
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+        "first": "Iijima-Ando K",
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+        "title": "Loss of axonal mitochondria promotes tau-mediated neurodegeneration and Alzheimer's disease-related tau phosphorylation via PAR-1.",
+        "type": "PubMed",
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+      "evidence": "Using transgenic Drosophila expressing human tau, we found that RNAi-mediated knockdown of milton or Miro, an adaptor protein essential for axonal transport of mitochondria, enhanced human tau-induced neurodegeneration. Tau phosphorylation at an AD-related site Ser262 increased with knockdown of milton or Miro; and partitioning defective-1 (PAR-1), the Drosophila homolog of mammalian microtubule affinity-regulating kinase, mediated this increase of tau phosphorylation. Tau phosphorylation at Ser262 has been reported to promote tau detachment from microtubules, and we found that the levels of microtubule-unbound free tau increased by milton knockdown. Blocking tau phosphorylation at Ser262 site by PAR-1 knockdown or by mutating the Ser262 site to unphosphorylatable alanine suppressed the enhancement of tau-induced neurodegeneration caused by milton knockdown. Furthermore, knockdown of milton or Miro increased the levels of active PAR-1.",
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         "type": "PubMed",
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           "Babić Leko M",
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+        "authors": [
+          "Lu B",
+          "Malenka R",
+          "Polepalli J",
+          "Rajadas J",
+          "Wagh D",
+          "Yu W"
+        ],
+        "date": "2012-03-15",
+        "first": "Yu W",
+        "last": "Lu B",
+        "name": "Human molecular genetics",
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+      "evidence": "We first confirmed that expression of an MKI-GFP fusion protein in rat hippocampal neurons effectively attenuated MARK4-mediated phosphorylation of both endogenous tau (Fig. 3A) and transfected human tau at the 12E8 sites (Fig. 3B). Phosphorylation of tau at the PHF-1 site was also reduced by MKI (Fig. 3A). It is possible that the PHF-1 site is also targeted by PAR-1/MARKs in vivo, or that the phosphorylation of tau at the 12E8 sites is a prerequisite for PHF-1 site phosphorylation, as the 12E8 sites were previously shown to be required for tau phosphorylation at other sites",
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+          "Bourgeois C",
+          "Dudilot A",
+          "Lauzon M",
+          "Leclerc N",
+          "Mondragón-Rodríguez S",
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+        "date": "2012-09-14",
+        "first": "Mondragón-Rodríguez S",
+        "last": "Boehm J",
+        "name": "The Journal of biological chemistry",
+        "pages": "32040-53",
+        "reference": "22833681",
+        "title": "Interaction of endogenous tau protein with synaptic proteins is regulated by N-methyl-D-aspartate receptor-dependent tau phosphorylation.",
+        "type": "PubMed",
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+      "evidence": "Acute treatment of rTg4510 mice with an O-GlcNAcase inhibitor transiently reduced tau phosphorylation at epitopes implicated in tau pathology. More importantly, long-term inhibitor treatment strongly increased tau O-GlcNAcylation, reduced the number of dystrophic neurons, and protected against the formation of pathological tau species without altering the phosphorylation of non-pathological tau.",
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+        "date": "2014-01-01",
+        "first": "Cook C",
+        "last": "Petrucelli L",
+        "name": "Alzheimer's research &amp; therapy",
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           "Babić Leko M",
@@ -45553,14 +51810,25 @@
         "type": "PubMed",
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           "Babić Leko M",
@@ -45586,14 +51854,25 @@
         "type": "PubMed",
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+          "Alzheimer Disease": true
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       "citation": {
         "authors": [
           "Babić Leko M",
@@ -45619,14 +51898,25 @@
         "type": "PubMed",
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@@ -45652,17 +51942,25 @@
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@@ -45688,324 +51986,460 @@
         "type": "PubMed",
         "volume": "6"
       },
-      "evidence": "MB is a phenothiazine that crosses the blood brain barrier and acts as a redox cycler. Moreover, besides its beneficial properties as being able to improve energy metabolism and to act as an antioxidant, it is also able to reduce tau protein aggregation",
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+      "evidence": "3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain.",
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       "annotations": {
-        "Cell_Line": {
-          "HEK293T": true
+        "Confidence": {
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       "citation": {
         "authors": [
-          "Blokzijl A",
-          "Classon C",
-          "Gu GJ",
-          "Kamali-Moghaddam M",
-          "Landegren U",
-          "Lund H",
-          "Sunnemark D",
-          "Wu D",
-          "von Euler G"
+          "Babić Leko M",
+          "Bažadona D",
+          "Buée L",
+          "Delalle I",
+          "Di Giovanni G",
+          "Harrington C",
+          "Hof PR",
+          "Jovanov-Milošević N",
+          "Wischik C",
+          "Wray S",
+          "de Silva R",
+          "Šimić G"
         ],
-        "date": "2013-09-01",
-        "first": "Gu GJ",
-        "last": "Kamali-Moghaddam M",
-        "name": "Neuromolecular medicine",
-        "pages": "458-69",
-        "reference": "23666762",
-        "title": "Role of individual MARK isoforms in phosphorylation of tau at Ser²⁶² in Alzheimer's disease.",
+        "date": "2016-01-06",
+        "first": "Šimić G",
+        "last": "Hof PR",
+        "name": "Biomolecules",
+        "pages": "6",
+        "reference": "26751493",
+        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
         "type": "PubMed",
-        "volume": "15"
-      },
-      "evidence": "In 293T culture, MB decreased MARK4-mediated Tau phosphorylation in a dose dependent manner. MB down-regulates MARK4 protein level through ubiquitin-proteasome pathway and inhibition of MARK4 kinase activity in vitro.",
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+      "evidence": "Apart from binding to MT, the repeat domains of tau also bind to tubulin deacetylase, histone deacetylase 6 (HDAC6) [68] and apolipoprotein E (apoE) more with the ",
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       "annotations": {
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       "citation": {
         "authors": [
-          "Blokzijl A",
-          "Classon C",
-          "Gu GJ",
-          "Kamali-Moghaddam M",
-          "Landegren U",
-          "Lund H",
-          "Sunnemark D",
-          "Wu D",
-          "von Euler G"
+          "Carlomagno Y",
+          "Cook C",
+          "Petrucelli L",
+          "Stankowski JN",
+          "Stetler C"
         ],
-        "date": "2013-09-01",
-        "first": "Gu GJ",
-        "last": "Kamali-Moghaddam M",
-        "name": "Neuromolecular medicine",
-        "pages": "458-69",
-        "reference": "23666762",
-        "title": "Role of individual MARK isoforms in phosphorylation of tau at Ser²⁶² in Alzheimer's disease.",
+        "date": "2014-01-01",
+        "first": "Cook C",
+        "last": "Petrucelli L",
+        "name": "Alzheimer's research &amp; therapy",
+        "pages": "29",
+        "reference": "25031639",
+        "title": "Acetylation: a new key to unlock tau's role in neurodegeneration.",
         "type": "PubMed",
-        "volume": "15"
-      },
-      "evidence": "In 293T culture, MB decreased MARK4-mediated Tau phosphorylation in a dose dependent manner. MB down-regulates MARK4 protein level through ubiquitin-proteasome pathway and inhibition of MARK4 kinase activity in vitro.",
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+      "evidence": "We demonstrate that elevated HDAC6 activity increases phosphorylation of tau at the 12E8 epitope (pS262/356), a phospho-epitope present within the KXGS motifs of tau’s microtubule-binding domain. The phosphorylation of KXGS motifs within tau by the kinase Par-1/MARK2 is required for tau proteotoxicity in Drosophila [29], observed at very early stages of NFT formation in AD brain [30], and appears to prime tau for subsequent phosphorylation events",
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     {
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       "citation": {
         "authors": [
-          "Cohen TJ",
-          "Madden V",
-          "Tripathy A",
-          "Trzeciakiewicz H",
-          "Tseng JH",
-          "Wander CM",
-          "Yuan CX"
+          "Carlomagno Y",
+          "Cook C",
+          "Petrucelli L",
+          "Stankowski JN",
+          "Stetler C"
         ],
-        "date": "2017-03-13",
-        "first": "Trzeciakiewicz H",
-        "last": "Cohen TJ",
-        "name": "Scientific reports",
-        "pages": "44102",
-        "reference": "28287136",
-        "title": "A Dual Pathogenic Mechanism Links Tau Acetylation to Sporadic Tauopathy.",
+        "date": "2014-01-01",
+        "first": "Cook C",
+        "last": "Petrucelli L",
+        "name": "Alzheimer's research &amp; therapy",
+        "pages": "29",
+        "reference": "25031639",
+        "title": "Acetylation: a new key to unlock tau's role in neurodegeneration.",
         "type": "PubMed",
-        "volume": "7"
+        "volume": "6"
       },
-      "evidence": "Thus, K → Q substitutions within the critical PHF6* motif, in the apparent absence of other tau PTMs, appears sufficient to accelerate tau aggregation in vitro.",
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+      "evidence": "We demonstrate that elevated HDAC6 activity increases phosphorylation of tau at the 12E8 epitope (pS262/356), a phospho-epitope present within the KXGS motifs of tau’s microtubule-binding domain. The phosphorylation of KXGS motifs within tau by the kinase Par-1/MARK2 is required for tau proteotoxicity in Drosophila [29], observed at very early stages of NFT formation in AD brain [30], and appears to prime tau for subsequent phosphorylation events",
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+    },
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+          "Medium": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Berkovitch SS",
+          "Chattopadhyay S",
+          "Haggarty SJ",
+          "Huang JH",
+          "Iaconelli J",
+          "Karmacharya R",
+          "Mazitschek R",
+          "Schreiber SL"
+        ],
+        "date": "2015-03-20",
+        "first": "Iaconelli J",
+        "last": "Karmacharya R",
+        "name": "ACS chemical biology",
+        "pages": "883-90",
+        "reference": "25546293",
+        "title": "HDAC6 inhibitors modulate Lys49 acetylation and membrane localization of β-catenin in human iPSC-derived neuronal cells.",
+        "type": "PubMed",
+        "volume": "10"
+      },
+      "evidence": "The N-terminus of β-catenin has phosphorylation, ubiquitination, and acetylation sites that regulate its stability and signaling. In the absence of a Wnt signal, Ser33, Ser37, and Thr41 are constitutively phosphorylated by glycogen synthase kinase 3β (GSK3β). β-Catenin phosphorylated at these sites is recognized by β-transducin repeat-containing protein (βTrCP), which results in ubiquitination and degradation by the ubiquitin-proteasome pathway. The N-terminal regulatory domain of β-catenin also includes Ser45, a phosphorylation site for Casein Kinase 1α (CK1α) and Lys49, which is acetylated by the acetyltransferase p300/CBP-associated factor (PCAF). The relevance of Lys49 acetylation and Ser45 phosphorylation to the function of β-catenin is an active area of investigation. We find that HDAC6 inhibitors increase Lys49 acetylation and Ser45 phosphorylation but do not affect Ser33, Ser37, and Thr41 phosphorylation. Lys49 acetylation results in decreased ubiquitination of β-catenin in the presence of proteasome inhibition. While increased Lys49 acetylation does not affect total levels of β-catenin, it results in increased membrane localization of β-catenin.",
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     {
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       "citation": {
         "authors": [
-          "Hashimoto Y",
-          "Kusakari S",
-          "Matsuoka M",
-          "Nawa M",
-          "Toyama Y"
+          "Berkovitch SS",
+          "Chattopadhyay S",
+          "Haggarty SJ",
+          "Huang JH",
+          "Iaconelli J",
+          "Karmacharya R",
+          "Mazitschek R",
+          "Schreiber SL"
         ],
-        "date": "2016-06-03",
-        "first": "Hashimoto Y",
-        "last": "Matsuoka M",
-        "name": "The Journal of biological chemistry",
-        "pages": "12282-93",
-        "reference": "27068745",
-        "title": "An Alzheimer Disease-linked Rare Mutation Potentiates Netrin Receptor Uncoordinated-5C-induced Signaling That Merges with Amyloid β Precursor Protein Signaling.",
+        "date": "2015-03-20",
+        "first": "Iaconelli J",
+        "last": "Karmacharya R",
+        "name": "ACS chemical biology",
+        "pages": "883-90",
+        "reference": "25546293",
+        "title": "HDAC6 inhibitors modulate Lys49 acetylation and membrane localization of β-catenin in human iPSC-derived neuronal cells.",
         "type": "PubMed",
-        "volume": "291"
+        "volume": "10"
       },
-      "evidence": "Overexpression of wild-type UNC5C causes low-grade death, intensified by an AD-linked mutation T835M inhibited by a AD-linked survival factor, calmodulin-like skin protein (CLSP), and a natural ligand of UNC5C, netrin1. T835M-UNC5C-induced neuronal cell death is mediated by an intracellular death-signaling cascade, consisting of DAPK1/protein kinase D/apoptosis signal-regulating kinase 1 (ASK1)/JNK/NADPH oxidase/caspases, which merges at ASK1 with a death-signaling cascade, mediated by amyloid ß precursor protein (APP).",
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         "modifier": "Activity"
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     {
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+        "Confidence": {
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       "citation": {
         "authors": [
-          "Hashimoto Y",
-          "Kusakari S",
-          "Matsuoka M",
-          "Nawa M",
-          "Toyama Y"
+          "Berkovitch SS",
+          "Chattopadhyay S",
+          "Haggarty SJ",
+          "Huang JH",
+          "Iaconelli J",
+          "Karmacharya R",
+          "Mazitschek R",
+          "Schreiber SL"
         ],
-        "date": "2016-06-03",
-        "first": "Hashimoto Y",
-        "last": "Matsuoka M",
-        "name": "The Journal of biological chemistry",
-        "pages": "12282-93",
-        "reference": "27068745",
-        "title": "An Alzheimer Disease-linked Rare Mutation Potentiates Netrin Receptor Uncoordinated-5C-induced Signaling That Merges with Amyloid β Precursor Protein Signaling.",
+        "date": "2015-03-20",
+        "first": "Iaconelli J",
+        "last": "Karmacharya R",
+        "name": "ACS chemical biology",
+        "pages": "883-90",
+        "reference": "25546293",
+        "title": "HDAC6 inhibitors modulate Lys49 acetylation and membrane localization of β-catenin in human iPSC-derived neuronal cells.",
         "type": "PubMed",
-        "volume": "291"
+        "volume": "10"
       },
-      "evidence": "Overexpression of wild-type UNC5C causes low-grade death, intensified by an AD-linked mutation T835M inhibited by a AD-linked survival factor, calmodulin-like skin protein (CLSP), and a natural ligand of UNC5C, netrin1. T835M-UNC5C-induced neuronal cell death is mediated by an intracellular death-signaling cascade, consisting of DAPK1/protein kinase D/apoptosis signal-regulating kinase 1 (ASK1)/JNK/NADPH oxidase/caspases, which merges at ASK1 with a death-signaling cascade, mediated by amyloid ß precursor protein (APP).",
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       "citation": {
         "authors": [
-          "Hashimoto Y",
-          "Kusakari S",
-          "Matsuoka M",
-          "Nawa M",
-          "Toyama Y"
+          "Berkovitch SS",
+          "Chattopadhyay S",
+          "Haggarty SJ",
+          "Huang JH",
+          "Iaconelli J",
+          "Karmacharya R",
+          "Mazitschek R",
+          "Schreiber SL"
         ],
-        "date": "2016-06-03",
-        "first": "Hashimoto Y",
-        "last": "Matsuoka M",
-        "name": "The Journal of biological chemistry",
-        "pages": "12282-93",
-        "reference": "27068745",
-        "title": "An Alzheimer Disease-linked Rare Mutation Potentiates Netrin Receptor Uncoordinated-5C-induced Signaling That Merges with Amyloid β Precursor Protein Signaling.",
+        "date": "2015-03-20",
+        "first": "Iaconelli J",
+        "last": "Karmacharya R",
+        "name": "ACS chemical biology",
+        "pages": "883-90",
+        "reference": "25546293",
+        "title": "HDAC6 inhibitors modulate Lys49 acetylation and membrane localization of β-catenin in human iPSC-derived neuronal cells.",
         "type": "PubMed",
-        "volume": "291"
+        "volume": "10"
       },
-      "evidence": "Overexpression of wild-type UNC5C causes low-grade death, intensified by an AD-linked mutation T835M inhibited by a AD-linked survival factor, calmodulin-like skin protein (CLSP), and a natural ligand of UNC5C, netrin1. T835M-UNC5C-induced neuronal cell death is mediated by an intracellular death-signaling cascade, consisting of DAPK1/protein kinase D/apoptosis signal-regulating kinase 1 (ASK1)/JNK/NADPH oxidase/caspases, which merges at ASK1 with a death-signaling cascade, mediated by amyloid ß precursor protein (APP).",
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+      "evidence": "The N-terminus of β-catenin has phosphorylation, ubiquitination, and acetylation sites that regulate its stability and signaling. In the absence of a Wnt signal, Ser33, Ser37, and Thr41 are constitutively phosphorylated by glycogen synthase kinase 3β (GSK3β). β-Catenin phosphorylated at these sites is recognized by β-transducin repeat-containing protein (βTrCP), which results in ubiquitination and degradation by the ubiquitin-proteasome pathway. The N-terminal regulatory domain of β-catenin also includes Ser45, a phosphorylation site for Casein Kinase 1α (CK1α) and Lys49, which is acetylated by the acetyltransferase p300/CBP-associated factor (PCAF). The relevance of Lys49 acetylation and Ser45 phosphorylation to the function of β-catenin is an active area of investigation. We find that HDAC6 inhibitors increase Lys49 acetylation and Ser45 phosphorylation but do not affect Ser33, Ser37, and Thr41 phosphorylation. Lys49 acetylation results in decreased ubiquitination of β-catenin in the presence of proteasome inhibition. While increased Lys49 acetylation does not affect total levels of β-catenin, it results in increased membrane localization of β-catenin.",
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     {
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       "citation": {
         "authors": [
-          "Babić Leko M",
-          "Bažadona D",
-          "Buée L",
-          "Delalle I",
-          "Di Giovanni G",
-          "Harrington C",
-          "Hof PR",
-          "Jovanov-Milošević N",
-          "Wischik C",
-          "Wray S",
-          "de Silva R",
-          "Šimić G"
+          "Berkovitch SS",
+          "Chattopadhyay S",
+          "Haggarty SJ",
+          "Huang JH",
+          "Iaconelli J",
+          "Karmacharya R",
+          "Mazitschek R",
+          "Schreiber SL"
         ],
-        "date": "2016-01-06",
-        "first": "Šimić G",
-        "last": "Hof PR",
-        "name": "Biomolecules",
-        "pages": "6",
-        "reference": "26751493",
-        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
+        "date": "2015-03-20",
+        "first": "Iaconelli J",
+        "last": "Karmacharya R",
+        "name": "ACS chemical biology",
+        "pages": "883-90",
+        "reference": "25546293",
+        "title": "HDAC6 inhibitors modulate Lys49 acetylation and membrane localization of β-catenin in human iPSC-derived neuronal cells.",
         "type": "PubMed",
-        "volume": "6"
+        "volume": "10"
       },
-      "evidence": "Recently, it has been proposed that tau protein acetylation may be responsible for tau aggregation in AD. Grinberg and collaborators detected tau acetylation at Lys274 in all tauopathies (both primary and secondary), except in AgD",
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-      "source": 497,
-      "target": 325
+      "evidence": "The N-terminus of β-catenin has phosphorylation, ubiquitination, and acetylation sites that regulate its stability and signaling. In the absence of a Wnt signal, Ser33, Ser37, and Thr41 are constitutively phosphorylated by glycogen synthase kinase 3β (GSK3β). β-Catenin phosphorylated at these sites is recognized by β-transducin repeat-containing protein (βTrCP), which results in ubiquitination and degradation by the ubiquitin-proteasome pathway. The N-terminal regulatory domain of β-catenin also includes Ser45, a phosphorylation site for Casein Kinase 1α (CK1α) and Lys49, which is acetylated by the acetyltransferase p300/CBP-associated factor (PCAF). The relevance of Lys49 acetylation and Ser45 phosphorylation to the function of β-catenin is an active area of investigation. We find that HDAC6 inhibitors increase Lys49 acetylation and Ser45 phosphorylation but do not affect Ser33, Ser37, and Thr41 phosphorylation. Lys49 acetylation results in decreased ubiquitination of β-catenin in the presence of proteasome inhibition. While increased Lys49 acetylation does not affect total levels of β-catenin, it results in increased membrane localization of β-catenin.",
+      "key": "de7f0164b414539ddc6d751133ae55a00d17edce5896815bbd08b05d3027bf4bcb60be6af7e7b3519642c5bf2a97ac90171b39a1c114b21d4502693b7ce94a8d",
+      "line": 3695,
+      "relation": "causesNoChange",
+      "source": 540,
+      "subject": {
+        "modifier": "Activity"
+      },
+      "target": 504
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Muscles": true,
+          "Neurons": true
+        },
         "Species": {
-          "10090": true
+          "7227": true
         }
       },
       "citation": {
         "authors": [
-          "Cong X",
-          "Ellerby LM",
-          "Gan L",
-          "Huganir RL",
-          "Le D",
-          "Li Y",
-          "Lo I",
-          "Min SW",
-          "Minami SS",
-          "Ponnusamy R",
-          "Schilling B",
-          "Sohn PD",
-          "Tracy TE",
-          "Wang C",
-          "Zhou Y"
+          "Jin S",
+          "Wu J",
+          "Xiong Y",
+          "Xu Z",
+          "Zhang YQ",
+          "Zhao K"
         ],
-        "date": "2016-04-20",
-        "first": "Tracy TE",
-        "last": "Gan L",
-        "name": "Neuron",
-        "pages": "245-60",
-        "reference": "27041503",
-        "title": "Acetylated Tau Obstructs KIBRA-Mediated Signaling in Synaptic Plasticity and Promotes Tauopathy-Related Memory Loss.",
+        "date": "2013-03-19",
+        "first": "Xiong Y",
+        "last": "Zhang YQ",
+        "name": "Proceedings of the National Academy of Sciences of the United States of America",
+        "pages": "4604-9",
+        "reference": "23487739",
+        "title": "HDAC6 mutations rescue human tau-induced microtubule defects in Drosophila.",
         "type": "PubMed",
-        "volume": "90"
+        "volume": "110"
       },
-      "evidence": "Here we report abnormal acetylation of K274 and K281 on tau, identified in AD brains, promotes memory loss and disrupts synaptic plasticity by reducing postsynaptic KIdney/BRAin (KIBRA) protein, a memory-associated protein.Transgenic mice expressing human tau with lysine-to-glutamine mutations to mimic K274 and K281 acetylation (tauKQ) exhibit AD-related memory deficits and impaired hippocampal long-term potentiation (LTP). TauKQ reduces synaptic KIBRA levels and disrupts activity-induced postsynaptic actin remodeling and AMPA receptor insertion. The LTP deficit was rescued by promoting actin polymerization or by KIBRA expression. In AD patients with dementia, we found enhanced tau acetylation is linked to loss of KIBRA.",
-      "key": "42730380f09c90c46dc990a50236daf7a9dc46bbffa7b431c4b85f3455a6778713bed406ac998e9791ee508dd169330f6689f76a0990904f65d05ac135b41171",
-      "line": 3165,
+      "evidence": "Overexpressed tau was hyperphosphorylated and resulted in decreased MT density and greater fragmentation. Using genetic screen, a histone deacetylase 6 (HDAC6) null mutation rescued tau-induced MT defects in both muscles and neurons. Genetic and pharmacological inhibition of the tubulin-specific deacetylase activity of HDAC6 indicates that the rescue effect may be mediated by increased MT acetylation.",
+      "key": "f7dfb7d073e40b91003557a5b264d151d5735b8033dc5455de763873d663650260532f211073637c16ecca472215e8ebd915739b43d1b754044be52edfb891be",
+      "line": 4036,
       "relation": "decreases",
-      "source": 497,
-      "target": 752
+      "source": 540,
+      "target": 99
     },
     {
       "annotations": {
-        "Species": {
-          "10090": true
+        "Confidence": {
+          "Medium": true
         }
       },
       "citation": {
         "authors": [
-          "Cong X",
-          "Ellerby LM",
-          "Gan L",
-          "Huganir RL",
-          "Le D",
-          "Li Y",
-          "Lo I",
-          "Min SW",
-          "Minami SS",
-          "Ponnusamy R",
-          "Schilling B",
-          "Sohn PD",
-          "Tracy TE",
-          "Wang C",
-          "Zhou Y"
+          "Carlomagno Y",
+          "Castanedes-Casey M",
+          "Chung DC",
+          "Cook C",
+          "DeTure M",
+          "Dickson DW",
+          "Dunmore J",
+          "Madden BJ",
+          "Petrucelli L",
+          "Tong J",
+          "Yue M"
         ],
-        "date": "2016-04-20",
-        "first": "Tracy TE",
-        "last": "Gan L",
-        "name": "Neuron",
-        "pages": "245-60",
-        "reference": "27041503",
-        "title": "Acetylated Tau Obstructs KIBRA-Mediated Signaling in Synaptic Plasticity and Promotes Tauopathy-Related Memory Loss.",
+        "date": "2017-09-15",
+        "first": "Carlomagno Y",
+        "last": "Cook C",
+        "name": "The Journal of biological chemistry",
+        "pages": "15277-15286",
+        "reference": "28760828",
+        "title": "An acetylation-phosphorylation switch that regulates tau aggregation propensity and function.",
         "type": "PubMed",
-        "volume": "90"
+        "volume": "292"
       },
-      "evidence": "Here we report abnormal acetylation of K274 and K281 on tau, identified in AD brains, promotes memory loss and disrupts synaptic plasticity by reducing postsynaptic KIdney/BRAin (KIBRA) protein, a memory-associated protein.Transgenic mice expressing human tau with lysine-to-glutamine mutations to mimic K274 and K281 acetylation (tauKQ) exhibit AD-related memory deficits and impaired hippocampal long-term potentiation (LTP). TauKQ reduces synaptic KIBRA levels and disrupts activity-induced postsynaptic actin remodeling and AMPA receptor insertion. The LTP deficit was rescued by promoting actin polymerization or by KIBRA expression. In AD patients with dementia, we found enhanced tau acetylation is linked to loss of KIBRA.",
-      "key": "6782ed703270b5e321c277b5b8298a0c5d2ab8a76cf9fd69cc6fde54d038781de5325f432ad670b8335f9ff612ebd237acd7430404eaac1ee0c2d4092ba74791",
-      "line": 3167,
-      "relation": "decreases",
-      "source": 497,
-      "target": 171
+      "evidence": "Our findings indicate that several acetylation sites in tau are responsive to HDAC6 and that acetylation on Lys-321 (within a KCGS motif) is both essential for acetylation-mediated inhibition of tau aggregation in vitro and a molecular tactic for preventing phosphorylation on the downstream Ser-324 residue. Tau phosphorylation of Ser-324 (pSer-324) has not previously been evaluated in the context of tauopathy, and here we observed increased deposition of pSer-324-positive tau both in mouse models of tauopathy and in patients with Alzheimer's disease. These findings uncover a novel acetylation-phosphorylation switch at Lys-321/Ser-324 that coordinately regulates tau polymerization and function.",
+      "key": "a29ba616e5c20e5ed19cccef94f8d8797bf3d8a1645f38bd95b214c9a200d18385bcea5e88d5c58c791ecfb4a0a212e71c62dd3668f3850a308bc909f6a9eac0",
+      "line": 4156,
+      "relation": "increases",
+      "source": 540,
+      "target": 586
+    },
+    {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Carlomagno Y",
+          "Castanedes-Casey M",
+          "Chung DC",
+          "Cook C",
+          "DeTure M",
+          "Dickson DW",
+          "Dunmore J",
+          "Madden BJ",
+          "Petrucelli L",
+          "Tong J",
+          "Yue M"
+        ],
+        "date": "2017-09-15",
+        "first": "Carlomagno Y",
+        "last": "Cook C",
+        "name": "The Journal of biological chemistry",
+        "pages": "15277-15286",
+        "reference": "28760828",
+        "title": "An acetylation-phosphorylation switch that regulates tau aggregation propensity and function.",
+        "type": "PubMed",
+        "volume": "292"
+      },
+      "evidence": "HDAC6 inhibition leads to a significant reduction in tau levels as detected by the human tau-specific antibody E1 (Fig. 6 (a and c) and supplemental Fig. S6). We also observed a striking decrease in phosphorylation at Ser-324, which was statistically significant even when normalizing to E1 to control for the reduction in tau levels (Fig. 6 (a and b) and supplemental Fig. S6).",
+      "key": "a1df6254531792594e0fe11f260a607c52ca6a0a0bd7c21573d08b1f56645f88bb9ce1763f80048079ffe3082c233e7a6f073163f3d355d71a9a5ecde8a2f78f",
+      "line": 4165,
+      "relation": "increases",
+      "source": 540,
+      "target": 567
+    },
+    {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Carlomagno Y",
+          "Castanedes-Casey M",
+          "Chung DC",
+          "Cook C",
+          "DeTure M",
+          "Dickson DW",
+          "Dunmore J",
+          "Madden BJ",
+          "Petrucelli L",
+          "Tong J",
+          "Yue M"
+        ],
+        "date": "2017-09-15",
+        "first": "Carlomagno Y",
+        "last": "Cook C",
+        "name": "The Journal of biological chemistry",
+        "pages": "15277-15286",
+        "reference": "28760828",
+        "title": "An acetylation-phosphorylation switch that regulates tau aggregation propensity and function.",
+        "type": "PubMed",
+        "volume": "292"
+      },
+      "evidence": "HDAC6 inhibition leads to a significant reduction in tau levels as detected by the human tau-specific antibody E1 (Fig. 6 (a and c) and supplemental Fig. S6). We also observed a striking decrease in phosphorylation at Ser-324, which was statistically significant even when normalizing to E1 to control for the reduction in tau levels (Fig. 6 (a and b) and supplemental Fig. S6).",
+      "key": "1c195766dbcdb3f056d9237201db8e657d7b4989925063dbbc7ea9561b8487ec12e00b636787eee418feaf5cd127f5c5c83e61c5ae2dcf3197946b9492c93ce6",
+      "line": 4166,
+      "relation": "increases",
+      "source": 540,
+      "target": 646
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
           "Babić Leko M",
@@ -46031,14 +52465,31 @@
         "type": "PubMed",
         "volume": "6"
       },
-      "evidence": "Other possible inhibitors of tau aggregation are rhodanine-based inhibitors, phenylthiazolyl-hydrazide inhibitors, N-phenylamines, phenothiazines and benzothiazoles, and polyphenols and anthraquinones",
-      "key": "8eba196d2862222f9f3fefc4ee286b89cf06e9e65760228e0cde2a5c0df85ab509acf6ae32075b8d0d332d87c54daefff2c18d3e349c31347a5da0281fd14e5d",
-      "line": 1734,
-      "relation": "decreases",
-      "source": 68,
-      "target": 325
+      "evidence": "Apart from binding to MT, the repeat domains of tau also bind to tubulin deacetylase, histone deacetylase 6 (HDAC6) [68] and apolipoprotein E (apoE) more with the ",
+      "key": "f24725471b33f6a92a1f7b034d744a72160e34229cf0c00a2d55803085476a8d8e46f466eda7876d54a052fba100ac6db81529196d13fb7d8e391b50e761ec99",
+      "line": 1942,
+      "relation": "association",
+      "source": 325,
+      "target": 444
+    },
+    {
+      "key": "57091e14c87eea3ef8db0c04c6688a89400f3246e4e7e2449c4f8385c8065e7febb8acb215fbfbb81a16d8348e253f280366bccc01fb38192d8af82d277cb678",
+      "relation": "hasComponent",
+      "source": 263,
+      "target": 440
+    },
+    {
+      "key": "0345a20e9cc7923d191fb1a8b5ec5269b2d3052aa73c8cd5af7fa6877e5eda96504d378ba295934393a388bd6b3072a8d3bcaceaede7fb864d93da095596fd79",
+      "relation": "hasComponent",
+      "source": 263,
+      "target": 548
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "Babić Leko M",
@@ -46064,14 +52515,19 @@
         "type": "PubMed",
         "volume": "6"
       },
-      "evidence": "Other possible inhibitors of tau aggregation are rhodanine-based inhibitors, phenylthiazolyl-hydrazide inhibitors, N-phenylamines, phenothiazines and benzothiazoles, and polyphenols and anthraquinones",
-      "key": "f6d0e654486dac8b80a5df5df21d0c98f773ab4b561c30b92f048d8c6b855e38028a485b6568c930c2f237b0b199be7ee23c9597330dc2b0d90159a36f5df43d",
-      "line": 1735,
-      "relation": "decreases",
-      "source": 159,
-      "target": 325
+      "evidence": "The projection domain of tau may be involved in cell signaling that occurs through the interaction with Lck, Fgr and cSrc (Src-family kinases), growth factor receptor-bound protein 2 (Grb2), phospholipase C- [70], phosphatidylinositol and phosphatidylinositol bisphosphate [71,72], peptidyl-prolyl cis/trans isomerase Pin 1, and many others (for review see [73]), making them potential therapeutic targets in tauopathies [74].",
+      "key": "cb9f9a19fc52fe0b3cf610cac478b330a317b205aae0db61764fbbb1b9cdb601251f9bdbaca20b7f23a39ee23b2f96b1a5c041dc330868672e055717f1d5738e",
+      "line": 1952,
+      "relation": "association",
+      "source": 263,
+      "target": 179
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "Babić Leko M",
@@ -46097,14 +52553,22 @@
         "type": "PubMed",
         "volume": "6"
       },
-      "evidence": "Other possible inhibitors of tau aggregation are rhodanine-based inhibitors, phenylthiazolyl-hydrazide inhibitors, N-phenylamines, phenothiazines and benzothiazoles, and polyphenols and anthraquinones",
-      "key": "eac5fafd11d15ee91275b849d5b653c93c28606435085e498501a0b6cc9411ba7925cb2e48783cbdc5f6ccf05e218788c7ed212eff585d1eee3a00d6576caf7a",
-      "line": 1736,
-      "relation": "decreases",
-      "source": 156,
-      "target": 325
+      "evidence": "The projection domain of tau may be involved in cell signaling that occurs through the interaction with Lck, Fgr and cSrc (Src-family kinases), growth factor receptor-bound protein 2 (Grb2), phospholipase C- [70], phosphatidylinositol and phosphatidylinositol bisphosphate [71,72], peptidyl-prolyl cis/trans isomerase Pin 1, and many others (for review see [73]), making them potential therapeutic targets in tauopathies [74].",
+      "key": "51f6313d95fe8a386745cfb9f185a31fbea9f5783eace82aa9331146c769b2337cb2cc70533c66f7fcc5b0376055cc79c1c6cd62fc8f76b4eda45987c269568f",
+      "line": 1961,
+      "relation": "partOf",
+      "source": 440,
+      "target": 567
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Synapses": true
+        }
+      },
       "citation": {
         "authors": [
           "Babić Leko M",
@@ -46130,14 +52594,22 @@
         "type": "PubMed",
         "volume": "6"
       },
-      "evidence": "Other possible inhibitors of tau aggregation are rhodanine-based inhibitors, phenylthiazolyl-hydrazide inhibitors, N-phenylamines, phenothiazines and benzothiazoles, and polyphenols and anthraquinones",
-      "key": "2c13499388c2105b40f6e09e04047c0fc54ba0e7b99343138681b5a7f1c36dd261052d2319e955920eb64eb3fd805d0d55fd90ded3446598e751bc447f7dc2b8",
-      "line": 1737,
-      "relation": "decreases",
-      "source": 160,
-      "target": 325
+      "evidence": "In synapses, the projection domain of tau interacts with protein kinase Fyn (plays an important role during myelination [75]), postsynaptic density protein 95 (PSD-95) [76], and N-methyl-D-aspartate receptors (NMDAR).",
+      "key": "43a4424b7d3477007f687dba574b2a30403c8c7c18c194c240f2e9882e6fd88bb942bedc261ee17db096f0f8e1b3be91b024af9defd90d536304413b8bc21bfa",
+      "line": 1968,
+      "relation": "association",
+      "source": 440,
+      "target": 531
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Synapses": true
+        }
+      },
       "citation": {
         "authors": [
           "Babić Leko M",
@@ -46163,14 +52635,22 @@
         "type": "PubMed",
         "volume": "6"
       },
-      "evidence": "Other possible inhibitors of tau aggregation are rhodanine-based inhibitors, phenylthiazolyl-hydrazide inhibitors, N-phenylamines, phenothiazines and benzothiazoles, and polyphenols and anthraquinones",
-      "key": "4fb0e9d949c0eda66d7acb5367a5c0525f2f5aea5724d6b7ec33b37c9e9663e4311f3fcb4318df89eb3b1f809d30faf57722dfbe0353fa5a199c7d1a9198f3e7",
-      "line": 1739,
-      "relation": "decreases",
-      "source": 74,
-      "target": 325
+      "evidence": "In synapses, the projection domain of tau interacts with protein kinase Fyn (plays an important role during myelination [75]), postsynaptic density protein 95 (PSD-95) [76], and N-methyl-D-aspartate receptors (NMDAR).",
+      "key": "dd5a04650c993452204fcd5ac212f3fb383474415781250f194df72cb3c8f3330c4c6d8d9862e23fa8d7fb4eb05cbb4de23434a4da0333bc0dd762fa2b8d7404",
+      "line": 1970,
+      "relation": "association",
+      "source": 440,
+      "target": 518
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Synapses": true
+        }
+      },
       "citation": {
         "authors": [
           "Babić Leko M",
@@ -46196,14 +52676,19 @@
         "type": "PubMed",
         "volume": "6"
       },
-      "evidence": "Other possible inhibitors of tau aggregation are rhodanine-based inhibitors, phenylthiazolyl-hydrazide inhibitors, N-phenylamines, phenothiazines and benzothiazoles, and polyphenols and anthraquinones",
-      "key": "c648c5e92bc8e11576e71c63a33c7104f8d81b6700cdddbe9aa1790cdbe39f16e6525e0cec76ad2df7971801a08f1d42867c7dc811a8cef4f5e308461cdde938",
-      "line": 1740,
-      "relation": "decreases",
-      "source": 158,
-      "target": 325
+      "evidence": "In synapses, the projection domain of tau interacts with protein kinase Fyn (plays an important role during myelination [75]), postsynaptic density protein 95 (PSD-95) [76], and N-methyl-D-aspartate receptors (NMDAR).",
+      "key": "f6d9be7aead1558415d687fb60dfaecf41264444287250efea2dbe6568d288c5b32c1371bfbfe5a6794ab41af1920f38391ccede0ed0e062456e79970c119a85",
+      "line": 1971,
+      "relation": "association",
+      "source": 440,
+      "target": 857
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "Babić Leko M",
@@ -46229,14 +52714,19 @@
         "type": "PubMed",
         "volume": "6"
       },
-      "evidence": "Other possible inhibitors of tau aggregation are rhodanine-based inhibitors, phenylthiazolyl-hydrazide inhibitors, N-phenylamines, phenothiazines and benzothiazoles, and polyphenols and anthraquinones",
-      "key": "9cdf4a190a082aaef14190a4bbb26717a76cccf4bbf0c057069cc41a3d7b256c67224840b40b8016d91887af2458e4892f490a9ac606ed6a817a50ee4b20117b",
-      "line": 1741,
-      "relation": "decreases",
-      "source": 57,
-      "target": 325
+      "evidence": "The projection domain of tau may be involved in cell signaling that occurs through the interaction with Lck, Fgr and cSrc (Src-family kinases), growth factor receptor-bound protein 2 (Grb2), phospholipase C- [70], phosphatidylinositol and phosphatidylinositol bisphosphate [71,72], peptidyl-prolyl cis/trans isomerase Pin 1, and many others (for review see [73]), making them potential therapeutic targets in tauopathies [74].",
+      "key": "050e56227dbae9a2a31b10ad6f1c67f8d8d027a4fb3033044e0ae0840b903e46e02384fded9e5566f09a363582224b5cab302e3ece1767def7d61d34cdc5712c",
+      "line": 1952,
+      "relation": "association",
+      "source": 179,
+      "target": 263
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "Babić Leko M",
@@ -46262,14 +52752,19 @@
         "type": "PubMed",
         "volume": "6"
       },
-      "evidence": "Other possible inhibitors of tau aggregation are rhodanine-based inhibitors, phenylthiazolyl-hydrazide inhibitors, N-phenylamines, phenothiazines and benzothiazoles, and polyphenols and anthraquinones",
-      "key": "54fa723daac53bcdf9c856f5ad4943806282560dad81b24140ff6a8b84ca2a9d3c2b32e9eacb09e0e6963744d4b0717c09129e9f7115f1e39160513bc9696ce6",
-      "line": 1742,
-      "relation": "decreases",
-      "source": 36,
-      "target": 325
+      "evidence": "The projection domain of tau may be involved in cell signaling that occurs through the interaction with Lck, Fgr and cSrc (Src-family kinases), growth factor receptor-bound protein 2 (Grb2), phospholipase C- [70], phosphatidylinositol and phosphatidylinositol bisphosphate [71,72], peptidyl-prolyl cis/trans isomerase Pin 1, and many others (for review see [73]), making them potential therapeutic targets in tauopathies [74].",
+      "key": "5b5efde84a98dd8c82126ddc44264efa709b09b2332b1dc77f84e3d7f845d96d4341e44c0ab22a0149ab31f0ff30f060da127f3df2181751843fb8f4487545f5",
+      "line": 1953,
+      "relation": "association",
+      "source": 179,
+      "target": 261
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
           "Babić Leko M",
@@ -46295,14 +52790,19 @@
         "type": "PubMed",
         "volume": "6"
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-          "Tian C",
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         "authors": [
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-          "Guo Y",
-          "Liu Y",
-          "Shi Q",
-          "Tian C",
-          "Wang SB",
-          "Xie WL",
-          "Xu Y",
-          "Zhang BY",
-          "Zhang J"
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+          "Eichner T",
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         "authors": [
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-          "Malenka R",
-          "Polepalli J",
-          "Rajadas J",
-          "Wagh D",
-          "Yu W"
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+          "Hisanaga S",
+          "Ishiguro K",
+          "Kimura T",
+          "Oikawa T",
+          "Saito T",
+          "Uchida C",
+          "Uchida T",
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-        "title": "A critical role for the PAR-1/MARK-tau axis in mediating the toxic effects of Aβ on synapses and dendritic spines.",
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         "authors": [
-          "Lu B",
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-          "Lu B",
-          "Malenka R",
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-          "Wagh D",
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-          "Malenka R",
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         "authors": [
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-          "Cook C",
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+          "Hof PR",
+          "Jovanov-Milošević N",
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-        "last": "Petrucelli L",
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+        "first": "Šimić G",
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         "authors": [
-          "Carlomagno Y",
-          "Cook C",
-          "Petrucelli L",
-          "Stankowski JN",
-          "Stetler C"
+          "Huang L",
+          "Liu C",
+          "Qin C",
+          "Sheng SL",
+          "Sui XL",
+          "Tao JJ",
+          "Wu J",
+          "Xu YF",
+          "Yao ZG",
+          "Zhang L",
+          "Zhu H"
         ],
         "date": "2014-01-01",
-        "first": "Cook C",
-        "last": "Petrucelli L",
-        "name": "Alzheimer's research &amp; therapy",
-        "pages": "29",
-        "reference": "25031639",
-        "title": "Acetylation: a new key to unlock tau's role in neurodegeneration.",
+        "first": "Zhang L",
+        "last": "Qin C",
+        "name": "Journal of Alzheimer's disease : JAD",
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         "type": "PubMed",
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-      "evidence": "We demonstrate that elevated HDAC6 activity increases phosphorylation of tau at the 12E8 epitope (pS262/356), a phospho-epitope present within the KXGS motifs of tau’s microtubule-binding domain. The phosphorylation of KXGS motifs within tau by the kinase Par-1/MARK2 is required for tau proteotoxicity in Drosophila [29], observed at very early stages of NFT formation in AD brain [30], and appears to prime tau for subsequent phosphorylation events",
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     {
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       "citation": {
         "authors": [
-          "Carlomagno Y",
-          "Cook C",
-          "Petrucelli L",
-          "Stankowski JN",
-          "Stetler C"
+          "Huang L",
+          "Liu C",
+          "Qin C",
+          "Sheng SL",
+          "Sui XL",
+          "Tao JJ",
+          "Wu J",
+          "Xu YF",
+          "Yao ZG",
+          "Zhang L",
+          "Zhu H"
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-        "first": "Cook C",
-        "last": "Petrucelli L",
-        "name": "Alzheimer's research &amp; therapy",
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-        "reference": "25031639",
-        "title": "Acetylation: a new key to unlock tau's role in neurodegeneration.",
+        "first": "Zhang L",
+        "last": "Qin C",
+        "name": "Journal of Alzheimer's disease : JAD",
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+        "reference": "24844691",
+        "title": "Tubastatin A/ACY-1215 improves cognition in Alzheimer's disease transgenic mice.",
         "type": "PubMed",
-        "volume": "6"
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-      "evidence": "In particular, previous studies have demonstrated that the tau ubiquitin ligase, CHIP, is unable to bind and ubiquitinate tau species phosphorylated by Par-1/MARK2 on the 12E8 epitope (S262/356) [33], a p-tau species that is also resistant to degradation upon treatment with Hsp90 inhibitors [32,33]. Tau phosphorylated at the PHF1 epitope (S396/404) is still susceptible to degradation following Hsp90 inhibition and actually exhibits an enhanced interaction with Hsp90",
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       "annotations": {
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       "citation": {
         "authors": [
-          "Beghini A",
-          "Colapietro P",
-          "De Biasi S",
-          "Larizza L",
-          "Moroni RF"
+          "Babić Leko M",
+          "Bažadona D",
+          "Buée L",
+          "Delalle I",
+          "Di Giovanni G",
+          "Harrington C",
+          "Hof PR",
+          "Jovanov-Milošević N",
+          "Wischik C",
+          "Wray S",
+          "de Silva R",
+          "Šimić G"
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-        "first": "Moroni RF",
-        "last": "Beghini A",
-        "name": "Neuroscience",
-        "pages": "83-94",
-        "reference": "16973293",
-        "title": "Distinct expression pattern of microtubule-associated protein/microtubule affinity-regulating kinase 4 in differentiated neurons.",
+        "date": "2016-01-06",
+        "first": "Šimić G",
+        "last": "Hof PR",
+        "name": "Biomolecules",
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+        "reference": "26751493",
+        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
         "type": "PubMed",
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-      "evidence": "Human microtubule affinity-regulating kinase 4S (hMARK4S),undetectable in human neural progenitor cells (HNPCs) and NTera2 (NT2) cells, is up-regulated in both cell systems from the very early stages of neuronal differentiation, suggesting euronal commitment is marked by MARK4S up-regulation.",
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+      "evidence": "An additional “knot” of tau being entangled in epigenetic landscape of neurodegeneration comes from the finding that by acting as a HDAC6 inhibitor, tau is being indirectly involved in both (dys)regulation of transcriptional activity and impairment of autophagic clearance by the ubiquitin proteasome system [81,82].",
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     {
       "annotations": {
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       "citation": {
         "authors": [
-          "Beghini A",
-          "Colapietro P",
-          "De Biasi S",
-          "Larizza L",
-          "Moroni RF"
+          "Choi WH",
+          "Hong C",
+          "Jiang Y",
+          "Kim DE",
+          "Lee JH",
+          "Lee MJ",
+          "Shin SK"
         ],
-        "date": "2006-11-17",
-        "first": "Moroni RF",
-        "last": "Beghini A",
-        "name": "Neuroscience",
-        "pages": "83-94",
-        "reference": "16973293",
-        "title": "Distinct expression pattern of microtubule-associated protein/microtubule affinity-regulating kinase 4 in differentiated neurons.",
+        "date": "2015-06-04",
+        "first": "Lee JH",
+        "last": "Lee MJ",
+        "name": "Scientific reports",
+        "pages": "10757",
+        "reference": "26041011",
+        "title": "Facilitated Tau Degradation by USP14 Aptamers via Enhanced Proteasome Activity.",
         "type": "PubMed",
-        "volume": "143"
+        "volume": "5"
       },
-      "evidence": "Human microtubule affinity-regulating kinase 4S (hMARK4S),undetectable in human neural progenitor cells (HNPCs) and NTera2 (NT2) cells, is up-regulated in both cell systems from the very early stages of neuronal differentiation, suggesting euronal commitment is marked by MARK4S up-regulation.",
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         "authors": [
-          "Beghini A",
-          "Colapietro P",
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-          "Larizza L",
-          "Moroni RF"
+          "Babić Leko M",
+          "Bažadona D",
+          "Buée L",
+          "Delalle I",
+          "Di Giovanni G",
+          "Harrington C",
+          "Hof PR",
+          "Jovanov-Milošević N",
+          "Wischik C",
+          "Wray S",
+          "de Silva R",
+          "Šimić G"
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-        "first": "Moroni RF",
-        "last": "Beghini A",
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-        "pages": "83-94",
-        "reference": "16973293",
-        "title": "Distinct expression pattern of microtubule-associated protein/microtubule affinity-regulating kinase 4 in differentiated neurons.",
+        "date": "2016-01-06",
+        "first": "Šimić G",
+        "last": "Hof PR",
+        "name": "Biomolecules",
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+        "reference": "26751493",
+        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
         "type": "PubMed",
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       },
-      "evidence": "Human microtubule affinity-regulating kinase 4S (hMARK4S),undetectable in human neural progenitor cells (HNPCs) and NTera2 (NT2) cells, is up-regulated in both cell systems from the very early stages of neuronal differentiation, suggesting euronal commitment is marked by MARK4S up-regulation.",
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         "authors": [
-          "Hartman PS",
-          "Ishii N",
-          "Ishii T",
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-          "Onouchi H",
-          "Sugita K",
-          "Takanashi Y",
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-          "Yanagihara R",
-          "Yasuda K"
+          "Babić Leko M",
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+          "Di Giovanni G",
+          "Harrington C",
+          "Hof PR",
+          "Jovanov-Milošević N",
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-        "first": "Ishii T",
-        "last": "Ishii N",
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-        "title": "Endogenous reactive oxygen species cause astrocyte defects and neuronal dysfunctions in the hippocampus: a new model for aging brain.",
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+        "first": "Šimić G",
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         "type": "PubMed",
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+        "date": "2016-01-06",
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         "type": "PubMed",
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-        "reference": "27623715",
-        "title": "Endogenous reactive oxygen species cause astrocyte defects and neuronal dysfunctions in the hippocampus: a new model for aging brain.",
+          "Chen L",
+          "Sun X",
+          "Wang L",
+          "Wang P"
+        ],
+        "date": "2017-08-03",
+        "first": "Wang P",
+        "last": "Sun X",
+        "name": "Scientific reports",
+        "pages": "7240",
+        "reference": "28775333",
+        "title": "Dual-specificity tyrosine-phosphorylation regulated kinase 1A Gene Transcription is regulated by Myocyte Enhancer Factor 2D.",
         "type": "PubMed",
-        "volume": "16"
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-      "evidence": "Only middle-aged Tet-mev-1 mice showed JNK/MARK activation and Ca2+ overload, particularly in astrocytes with decreased hippocampal GFAP and S100ß, but without pathological features such as apoptosis, amyloidosis, and lactic acidosis in neurons and astrocytes. This led to decreasing levels of glial fibrillary acidic protein and S100β in the hippocampal area.",
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-          "Ishii N",
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-          "Onouchi H",
-          "Sugita K",
-          "Takanashi Y",
-          "Yamamoto Y",
-          "Yanagihara R",
-          "Yasuda K"
+          "Cohen TJ",
+          "Guo JL",
+          "Hurtado DE",
+          "Kwong LK",
+          "Lee VM",
+          "Mills IP",
+          "Trojanowski JQ"
         ],
-        "date": "2017-02-01",
-        "first": "Ishii T",
-        "last": "Ishii N",
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+        "date": "2011-01-01",
+        "first": "Cohen TJ",
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+        "title": "The acetylation of tau inhibits its function and promotes pathological tau aggregation.",
         "type": "PubMed",
-        "volume": "16"
+        "volume": "2"
       },
-      "evidence": "Only middle-aged Tet-mev-1 mice showed JNK/MARK activation and Ca2+ overload, particularly in astrocytes with decreased hippocampal GFAP and S100ß, but without pathological features such as apoptosis, amyloidosis, and lactic acidosis in neurons and astrocytes. This led to decreasing levels of glial fibrillary acidic protein and S100β in the hippocampal area.",
-      "key": "063095011cb0dc126b2d2b47c6678a9516c7b0a94633afa5a8efa23240ad3fca561209e95f336fd61aa8e78749b41c8a7da52e4fa11b00fdf6ccbe7b9cbfaf7d",
-      "line": 1823,
-      "relation": "causesNoChange",
-      "source": 205,
-      "target": 174
+      "evidence": "Thus, K280 acetylation is a feature found in a variety of human 4R or 3R/4R tauopathies including AD, but not 3R-tauopathies such as PiD.",
+      "key": "0cf8493f3a80b71053cbd3ef288eb1e5264db2ef586f8bef8fd467a74e1d1a98a6d2d8dad951cfb2df8025e935114413a21340d7b90af1ec95a26737ab073e38",
+      "line": 4060,
+      "relation": "association",
+      "source": 386,
+      "target": 999
     },
     {
       "annotations": {
-        "Anatomy": {
-          "hippocampal formation": true
-        },
-        "Cell": {
-          "astrocyte": true,
-          "neuron": true
-        },
-        "Species": {
-          "10090": true
-        },
-        "Study_Group": {
-          "Tet-mev-1 mice": true
+        "Confidence": {
+          "High": true
         }
       },
       "citation": {
         "authors": [
-          "Hartman PS",
-          "Ishii N",
-          "Ishii T",
-          "Kawabe N",
-          "Miyazawa M",
-          "Nakata M",
-          "Onouchi H",
-          "Sugita K",
-          "Takanashi Y",
-          "Yamamoto Y",
-          "Yanagihara R",
-          "Yasuda K"
+          "Abdelmesih B",
+          "Brady ST",
+          "Combs B",
+          "Cox K",
+          "Kanaan NM",
+          "Morfini G"
         ],
-        "date": "2017-02-01",
-        "first": "Ishii T",
-        "last": "Ishii N",
-        "name": "Aging cell",
-        "pages": "39-51",
-        "reference": "27623715",
-        "title": "Endogenous reactive oxygen species cause astrocyte defects and neuronal dysfunctions in the hippocampus: a new model for aging brain.",
+        "date": "2016-11-01",
+        "first": "Cox K",
+        "last": "Kanaan NM",
+        "name": "Neurobiology of aging",
+        "pages": "113-126",
+        "reference": "27574109",
+        "title": "Analysis of isoform-specific tau aggregates suggests a common toxic mechanism involving similar pathological conformations and axonal transport inhibition.",
         "type": "PubMed",
-        "volume": "16"
+        "volume": "47"
       },
-      "evidence": "Only middle-aged Tet-mev-1 mice showed JNK/MARK activation and Ca2+ overload, particularly in astrocytes with decreased hippocampal GFAP and S100ß, but without pathological features such as apoptosis, amyloidosis, and lactic acidosis in neurons and astrocytes. This led to decreasing levels of glial fibrillary acidic protein and S100β in the hippocampal area.",
-      "key": "4baf24f74ccf487db7a3ded6f2ba6e050b5af65a4db7ec56e2c1206a7a37fe6c61eb8d134c6fecbc7b29100d554f92523d184caeeae8a3f97c5d25c4cc54f96f",
-      "line": 1824,
-      "relation": "causesNoChange",
-      "source": 205,
-      "target": 907
+      "evidence": "Aggregation-induced increases in PAD exposure and oligomerization are common features among all tau isoforms. The extent of PAD exposure and oligomerization was larger for tau aggregates composed of 4-repeat isoforms compared with those made of 3-repeat isoforms.",
+      "key": "7cda66570dc2f9304e6859716c3b999988d651e0dedbbd9ac4ddb9a92f1e4ed70b223556640a86878418bf2aa5ba1d7d05ada2efd1b77e64393bb8ee98144771",
+      "line": 4398,
+      "relation": "positiveCorrelation",
+      "source": 386,
+      "target": 439
     },
     {
       "annotations": {
-        "Anatomy": {
-          "hippocampal formation": true
-        },
-        "Cell": {
-          "astrocyte": true,
-          "neuron": true
-        },
-        "Species": {
-          "10090": true
-        },
-        "Study_Group": {
-          "Tet-mev-1 mice": true
+        "Confidence": {
+          "High": true
         }
       },
       "citation": {
         "authors": [
-          "Hartman PS",
-          "Ishii N",
-          "Ishii T",
-          "Kawabe N",
-          "Miyazawa M",
-          "Nakata M",
-          "Onouchi H",
-          "Sugita K",
-          "Takanashi Y",
-          "Yamamoto Y",
-          "Yanagihara R",
-          "Yasuda K"
+          "Babić Leko M",
+          "Bažadona D",
+          "Buée L",
+          "Delalle I",
+          "Di Giovanni G",
+          "Harrington C",
+          "Hof PR",
+          "Jovanov-Milošević N",
+          "Wischik C",
+          "Wray S",
+          "de Silva R",
+          "Šimić G"
         ],
-        "date": "2017-02-01",
-        "first": "Ishii T",
-        "last": "Ishii N",
-        "name": "Aging cell",
-        "pages": "39-51",
-        "reference": "27623715",
-        "title": "Endogenous reactive oxygen species cause astrocyte defects and neuronal dysfunctions in the hippocampus: a new model for aging brain.",
+        "date": "2016-01-06",
+        "first": "Šimić G",
+        "last": "Hof PR",
+        "name": "Biomolecules",
+        "pages": "6",
+        "reference": "26751493",
+        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
         "type": "PubMed",
-        "volume": "16"
+        "volume": "6"
       },
-      "evidence": "Only middle-aged Tet-mev-1 mice showed JNK/MARK activation and Ca2+ overload, particularly in astrocytes with decreased hippocampal GFAP and S100ß, but without pathological features such as apoptosis, amyloidosis, and lactic acidosis in neurons and astrocytes. This led to decreasing levels of glial fibrillary acidic protein and S100β in the hippocampal area.",
-      "key": "8e22fc3aa6b56897816a93f78865fef6d5b4493ba166870dfd8ec9c41a80163a2a4497b6d8f71393e178485e3da1ac3dc2a9548836473abed6ca5bebbde6dbe7",
-      "line": 1825,
-      "relation": "causesNoChange",
-      "source": 205,
-      "target": 172
+      "evidence": "On the other side, sarkosyl extracts from the filaments of PSP [129], corticobasal degeneration (CBD; [130]), argyrophilic grain disease (AgD; [131]), and some cases of FTDP-17, contain tau protein that separates as doublets of 64 and 69 kDa and are predominantly composed of tau isoforms with 4R (class II tauopathies), whereas sarkosyl extracts from filaments of Pick’s disease are characterized by the presence of pathological tau doublets of 60 and 64 kDa and contain mainly 3R tau isoforms (class III tauopathy).",
+      "key": "66c14057aa5e0d373c90fbe15f9d4d05ab873b9ea1a574507a7c6ead9ebaf9126b5290b7ea7eaa7e8cba86823bcccf3d533f1d0b52cf01b54e048e9198a75db0",
+      "line": 1992,
+      "relation": "positiveCorrelation",
+      "source": 1000,
+      "target": 386
     },
     {
       "annotations": {
-        "Anatomy": {
-          "cerebral cortex": true
-        },
-        "Species": {
-          "10116": true
+        "Confidence": {
+          "High": true
         }
       },
       "citation": {
         "authors": [
-          "Marani L",
-          "Marino S",
-          "Selvatici R",
-          "Siniscalchi A"
+          "Babić Leko M",
+          "Bažadona D",
+          "Buée L",
+          "Delalle I",
+          "Di Giovanni G",
+          "Harrington C",
+          "Hof PR",
+          "Jovanov-Milošević N",
+          "Wischik C",
+          "Wray S",
+          "de Silva R",
+          "Šimić G"
         ],
-        "date": "2013-08-01",
-        "first": "Selvatici R",
-        "last": "Siniscalchi A",
-        "name": "Neurochemistry international",
-        "pages": "112-20",
-        "reference": "23722080",
-        "title": "In vitro mitochondrial failure and oxidative stress mimic biochemical features of Alzheimer disease.",
+        "date": "2016-01-06",
+        "first": "Šimić G",
+        "last": "Hof PR",
+        "name": "Biomolecules",
+        "pages": "6",
+        "reference": "26751493",
+        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
         "type": "PubMed",
-        "volume": "63"
+        "volume": "6"
       },
-      "evidence": "Primary cortical neurons exposed to the mitochondrial toxin NaN3 (0.1-3 mM) were submitted to oxidative stress with H2O2 (30-150 μM), to mimic conditions observed in neurodegenerative disorders. The effects of such treatment on a series of parameters useful in characterizing neuronal damage were investigated: (i) the basal release of glutamate, evaluated as (3)H-d-Aspartate efflux, was sharply, concentration-dependently, increased; (ii) the phosphorylation status of intracellular markers known to be involved in the neurodegenerative processes, in particular in Alzheimer disease: tau and GSK3β were increased, as well as the protein level of β-secretase (BACE1) and p35/25 evaluated by Western blotting, while (iii) the cell metabolic activity, measured with the MTT method, was reduced, in a concentration- and time-dependent manner. The latter effect, as well as tau hyperphosphorylation, was prevented both by a mixture of antioxidant drugs (100 μM ascorbic acid, 10 μM trolox, 100 μM glutathione) and by the anti-Alzheimer drug, memantine, 20 μM.",
-      "key": "8e1a360306277d46ce9f8346b32755e6b1811e47713488d845be3f756507db7fb09417631dd2aba83fd0386ae17c57fd83cad79fff54a2d6023b5a63261ca537",
-      "line": 2717,
-      "relation": "decreases",
-      "source": 205,
-      "target": 87
+      "evidence": "On the other side, sarkosyl extracts from the filaments of PSP [129], corticobasal degeneration (CBD; [130]), argyrophilic grain disease (AgD; [131]), and some cases of FTDP-17, contain tau protein that separates as doublets of 64 and 69 kDa and are predominantly composed of tau isoforms with 4R (class II tauopathies), whereas sarkosyl extracts from filaments of Pick’s disease are characterized by the presence of pathological tau doublets of 60 and 64 kDa and contain mainly 3R tau isoforms (class III tauopathy).",
+      "key": "401007aa644d5c7e9de8f9d45b5476ef911daaf5b852637d8499a4c9c4e4e4c5f9704470b450736c6729a813f033f825de4c4d17605ad199b331e0395e6ba166",
+      "line": 1995,
+      "relation": "positiveCorrelation",
+      "source": 1024,
+      "target": 385
     },
     {
       "annotations": {
-        "Research_Model": {
-          "SAMP8 mice": true
-        },
-        "Species": {
-          "10090": true
+        "Confidence": {
+          "High": true
         }
       },
       "citation": {
         "authors": [
-          "Butterfield DA",
-          "Farr SA",
-          "Kumar V",
-          "Morley JE",
-          "Murphy MP",
-          "Niehoff ML",
-          "Platt TL",
-          "Ripley JL",
-          "Sultana R",
-          "Zhang Z"
+          "Babić Leko M",
+          "Bažadona D",
+          "Buée L",
+          "Delalle I",
+          "Di Giovanni G",
+          "Harrington C",
+          "Hof PR",
+          "Jovanov-Milošević N",
+          "Wischik C",
+          "Wray S",
+          "de Silva R",
+          "Šimić G"
         ],
-        "date": "2014-02-01",
-        "first": "Farr SA",
-        "last": "Butterfield DA",
-        "name": "Free radical biology &amp; medicine",
-        "pages": "387-95",
-        "reference": "24355211",
-        "title": "Antisense oligonucleotide against GSK-3β in brain of SAMP8 mice improves learning and memory and decreases oxidative stress: Involvement of transcription factor Nrf2 and implications for Alzheimer disease.",
+        "date": "2016-01-06",
+        "first": "Šimić G",
+        "last": "Hof PR",
+        "name": "Biomolecules",
+        "pages": "6",
+        "reference": "26751493",
+        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
         "type": "PubMed",
-        "volume": "67"
+        "volume": "6"
       },
-      "evidence": "Nuclear factor erythroid-2-related factor 2 (Nrf2) is a transcription factor known to increase the level of many antioxidants, including glutathione-S transferase (GST), and is negatively regulated by the activity of GSK-3β. Our results indicated the increased nuclear localization of Nrf2 and level of GST, suggesting the increased activity of the transcription factor as a result of GSK-3β suppression, consistent with the decreased oxidative stress observed. Consistent with the improved learning and memory, and consistent with GSK-3b being a tau kinase, we observed decreased tau phosphorylation in brain of GAO-treated SAMP8 mice compared to that of RAO-treated SAMP8 mice.",
-      "key": "6c71c8c05edfc5e2868dec5a122d0c28e74a2320b700b2c38259447ca1ddfef8e8eee31d5210e6a353764d5234ff51d1e968d6d48776a1fc1958e00e484336fd",
-      "line": 2797,
+      "evidence": "A PSEN1 mutation causes a Pick’s disease phenotype including FTD tau pathology without deposition of Abeta [145]; some MAPT single nucleotide polymorphisms have also been linked to sporadic Parkinson’s disease (PD, [146]);",
+      "key": "2151a6707705dd92c3998a05e41e4168906c28038b68faf115488574844eebd05469f7549a6a651f140f3f7c066d8e3803a3f780b762b7c57574f8136a7ad49c",
+      "line": 2014,
       "relation": "positiveCorrelation",
-      "source": 205,
-      "target": 456
+      "source": 1024,
+      "target": 755
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
-          "Alonso AC",
-          "Grundke-Iqbal I",
-          "Iqbal K",
-          "Köpke E",
-          "Shaikh S",
-          "Tung YC"
+          "Babić Leko M",
+          "Bažadona D",
+          "Buée L",
+          "Delalle I",
+          "Di Giovanni G",
+          "Harrington C",
+          "Hof PR",
+          "Jovanov-Milošević N",
+          "Wischik C",
+          "Wray S",
+          "de Silva R",
+          "Šimić G"
         ],
-        "date": "1993-11-15",
-        "first": "Köpke E",
-        "last": "Grundke-Iqbal I",
-        "name": "The Journal of biological chemistry",
-        "pages": "24374-84",
-        "reference": "8226987",
-        "title": "Microtubule-associated protein tau. Abnormal phosphorylation of a non-paired helical filament pool in Alzheimer disease.",
+        "date": "2016-01-06",
+        "first": "Šimić G",
+        "last": "Hof PR",
+        "name": "Biomolecules",
+        "pages": "6",
+        "reference": "26751493",
+        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
         "type": "PubMed",
-        "volume": "268"
+        "volume": "6"
       },
-      "evidence": ">8 phosphates per tau molecules (vs 2 in adult healthy brain); can also be increased during development, hibernation and temperature, heat and oxydative stress These phosphorylated states are detected by specific antibodies and are targets of proline-directed kinases (SP motifs), non-proline kinases (KXGS motif) Weakens tau-MT interaction especially S261 in R1 and S214 in proline-rich domain",
-      "key": "167e5b1ebe4541fddf99975ec66854af9e4eaac7e2afe1e7557990b54a031514325e0c2e0a40f647de2986dc83610c060ba847e7a09cf590f18faf1ddf461f76",
-      "line": 2810,
-      "relation": "increases",
-      "source": 205,
-      "target": 516
+      "evidence": "Poorkaj et al. reported two exonic mutations (P301L and V337M) in two families with FTDP-17 [139], while Hutton et al. reported six different mutations in 10 families: three of these mutations (G272V, P301L and R406W) were missense mutations in exons, while the other three were in the 5' splice site of exon 10 [140].",
+      "key": "8ef3a3419c27dc9a539ed42fb37d87c0928ff620241cf69c40857b3d0206a9a8569c9400f938a16c369b23afff2d7545c4f22177d22ad9424b425e706d0098b8",
+      "line": 2003,
+      "relation": "positiveCorrelation",
+      "source": 1023,
+      "target": 711
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
-          "Biernat J",
-          "Mandelkow E",
-          "Mandelkow EM",
-          "Schweers O"
+          "Dinekov M",
+          "Götz J",
+          "Köhler C"
         ],
-        "date": "1995-08-29",
-        "first": "Schweers O",
-        "last": "Mandelkow E",
-        "name": "Proceedings of the National Academy of Sciences of the United States of America",
-        "pages": "8463-7",
-        "reference": "7667312",
-        "title": "Oxidation of cysteine-322 in the repeat domain of microtubule-associated protein tau controls the in vitro assembly of paired helical filaments.",
+        "date": "2013-05-01",
+        "first": "Köhler C",
+        "last": "Götz J",
+        "name": "Neurobiology of aging",
+        "pages": "1369-79",
+        "reference": "23294633",
+        "title": "Active glycogen synthase kinase-3 and tau pathology-related tyrosine phosphorylation in pR5 human tau transgenic mice.",
         "type": "PubMed",
-        "volume": "92"
+        "volume": "34"
       },
-      "evidence": "Though whole tau assembled poorly, constructs containing three internal repeats (corresponding to the fetal tau isoform) formed PHFs reproducibly. This ability depended on intermolecular disulfide bridges formed by the single Cys-322. Blocking the SH group, mutating Cys for Ala, or keeping T in a reducing environment all inhibited assembly. On the other hand, Cys-322 can be oxidized, and this leads to PHF assembly (ref. 11; this report). In vitro this is achieved most easily by using constructs of the 'fetal' isoform of T (htau23) that has only three repeats. Conversely, reducing agents or the second repeat or T can be viewed as 'antidotes' against PHF assembly.The synthetic PHFs bound the dye thioflavin S used in Alzheimer disease diagnostics.",
-      "key": "0aa12fae18b2be719522350db69aee018742bbaac7d4eb51f6a7d99491687d2b03ccf1435473a00c354d115c333726547e53710fe74066e1f42c896b04d64e72",
-      "line": 2927,
-      "relation": "increases",
-      "source": 205,
-      "target": 131
+      "evidence": "We studied underlying pathomechanisms in tauopathies using pR5 mice that express the P301L tau mutation found in familial forms of frontotemporal dementia. In a longitudinal study we investigated the functional status of glycogen synthase kinase-3 and correlated it with the appearance of distinct tau phospho-epitopes. Neurons displaying increases in activating phosphorylation of glycogen synthase kinase-3α/β at tyrosine 279/216 also showed an intense rather than moderate AT8 (phospho-Ser202/Thr205 tau) immunoreactivity, and immunoreactivity for AT100 (phospho-Ser212/Thr214 tau) and phosphorylated Ser422, phospho-epitopes associated with fibrillar tau pathology.",
+      "key": "80ce1806d06e3bc95477abf8a8558d0f08daa6ecd985ec31e303fab99c023035c62670f6578bd05c550a583247a9b9c18c0746d17afb5d2d2ed1b8112a638da9",
+      "line": 3127,
+      "relation": "positiveCorrelation",
+      "source": 1023,
+      "target": 711
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
-          "Blokzijl A",
-          "Classon C",
-          "Gu GJ",
-          "Kamali-Moghaddam M",
-          "Landegren U",
-          "Lund H",
-          "Sunnemark D",
-          "Wu D",
-          "von Euler G"
+          "Babić Leko M",
+          "Bažadona D",
+          "Buée L",
+          "Delalle I",
+          "Di Giovanni G",
+          "Harrington C",
+          "Hof PR",
+          "Jovanov-Milošević N",
+          "Wischik C",
+          "Wray S",
+          "de Silva R",
+          "Šimić G"
         ],
-        "date": "2013-09-01",
-        "first": "Gu GJ",
-        "last": "Kamali-Moghaddam M",
-        "name": "Neuromolecular medicine",
-        "pages": "458-69",
-        "reference": "23666762",
-        "title": "Role of individual MARK isoforms in phosphorylation of tau at Ser²⁶² in Alzheimer's disease.",
+        "date": "2016-01-06",
+        "first": "Šimić G",
+        "last": "Hof PR",
+        "name": "Biomolecules",
+        "pages": "6",
+        "reference": "26751493",
+        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
         "type": "PubMed",
-        "volume": "15"
+        "volume": "6"
       },
-      "evidence": "In parallel, phosphorylation of tau at Ser262 in MARK-transfected cells was investigated using a rabbit antibody recognizing phosphorylated Ser262 of tau (AGG5759) and a mouse anti-tau antibody (SC-21796) (Fig. S1a3). Tau was shown to interact with each of the transfected MARK isoforms (Fig. 1) and to be phosphorylated at Ser262 (Fig. 2). Staurosporine, a non-selective kinase inhibitor, significantly inhibited interactions between tau and each of the four MARK isoforms after treatment with 20 lM staurosporine for 1 h (Fig. 1; p = 0.02 for MARK1–, MARK2– and MARK3–tau interactions and p = 3 9 10-6 for MARK4–tau interaction). Treatment with staurosporine also significantly reduced PLA signals for tau phosphorylation at Ser262 (Fig. 2; p = 0.04 for MARK1- and p = 0.02 for MARK2- and MARK3- and p = 1 9 10-5 for MARK4-mediated tau phosphorylation)",
-      "key": "c40535811c31665b3e7a7bc11a8b309bef44907728065b1e2fe40f51c869e0708498fd6ae543bd7e4b71bab5ea5499862f5c442185069f2a30958f42dd6fa803",
-      "line": 1840,
-      "relation": "increases",
-      "source": 326,
-      "target": 557
+      "evidence": "Poorkaj et al. reported two exonic mutations (P301L and V337M) in two families with FTDP-17 [139], while Hutton et al. reported six different mutations in 10 families: three of these mutations (G272V, P301L and R406W) were missense mutations in exons, while the other three were in the 5' splice site of exon 10 [140].",
+      "key": "b1431a68c26a9ccc8c701a33e5a893950dfb882a9116d92c5a1be9c6bc32d9911e0b60e4f69f2d826beb87e997fb6baa1288105402a1270b9d523d611d4fb559",
+      "line": 2004,
+      "relation": "positiveCorrelation",
+      "source": 1023,
+      "target": 716
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
-          "Blokzijl A",
-          "Classon C",
-          "Gu GJ",
-          "Kamali-Moghaddam M",
-          "Landegren U",
-          "Lund H",
-          "Sunnemark D",
-          "Wu D",
-          "von Euler G"
+          "Babić Leko M",
+          "Bažadona D",
+          "Buée L",
+          "Delalle I",
+          "Di Giovanni G",
+          "Harrington C",
+          "Hof PR",
+          "Jovanov-Milošević N",
+          "Wischik C",
+          "Wray S",
+          "de Silva R",
+          "Šimić G"
         ],
-        "date": "2013-09-01",
-        "first": "Gu GJ",
-        "last": "Kamali-Moghaddam M",
-        "name": "Neuromolecular medicine",
-        "pages": "458-69",
-        "reference": "23666762",
-        "title": "Role of individual MARK isoforms in phosphorylation of tau at Ser²⁶² in Alzheimer's disease.",
+        "date": "2016-01-06",
+        "first": "Šimić G",
+        "last": "Hof PR",
+        "name": "Biomolecules",
+        "pages": "6",
+        "reference": "26751493",
+        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
         "type": "PubMed",
-        "volume": "15"
+        "volume": "6"
       },
-      "evidence": "In parallel, phosphorylation of tau at Ser262 in MARK-transfected cells was investigated using a rabbit antibody recognizing phosphorylated Ser262 of tau (AGG5759) and a mouse anti-tau antibody (SC-21796) (Fig. S1a3). Tau was shown to interact with each of the transfected MARK isoforms (Fig. 1) and to be phosphorylated at Ser262 (Fig. 2). Staurosporine, a non-selective kinase inhibitor, significantly inhibited interactions between tau and each of the four MARK isoforms after treatment with 20 lM staurosporine for 1 h (Fig. 1; p = 0.02 for MARK1–, MARK2– and MARK3–tau interactions and p = 3 9 10-6 for MARK4–tau interaction). Treatment with staurosporine also significantly reduced PLA signals for tau phosphorylation at Ser262 (Fig. 2; p = 0.04 for MARK1- and p = 0.02 for MARK2- and MARK3- and p = 1 9 10-5 for MARK4-mediated tau phosphorylation)",
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     {
+      "annotations": {
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+          "High": true
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+      },
       "citation": {
         "authors": [
-          "Blokzijl A",
-          "Classon C",
-          "Gu GJ",
-          "Kamali-Moghaddam M",
-          "Landegren U",
-          "Lund H",
-          "Sunnemark D",
-          "Wu D",
-          "von Euler G"
+          "Babić Leko M",
+          "Bažadona D",
+          "Buée L",
+          "Delalle I",
+          "Di Giovanni G",
+          "Harrington C",
+          "Hof PR",
+          "Jovanov-Milošević N",
+          "Wischik C",
+          "Wray S",
+          "de Silva R",
+          "Šimić G"
         ],
-        "date": "2013-09-01",
-        "first": "Gu GJ",
-        "last": "Kamali-Moghaddam M",
-        "name": "Neuromolecular medicine",
-        "pages": "458-69",
-        "reference": "23666762",
-        "title": "Role of individual MARK isoforms in phosphorylation of tau at Ser²⁶² in Alzheimer's disease.",
-        "type": "PubMed",
-        "volume": "15"
-      },
-      "evidence": "In cells, a CagA peptide inhibited tau phosphorylation at Ser²6² mediated by MARK4 but not other MARK isoforms. A strong and significant elevation of MARK4 expression and MARK4-tau interactions in AD brains correlated with the Braak stages of the disease.",
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+        "last": "Hof PR",
+        "name": "Biomolecules",
+        "pages": "6",
+        "reference": "26751493",
+        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
+        "type": "PubMed",
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     {
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       "citation": {
         "authors": [
-          "Chen CH",
-          "Ho Lee T",
-          "Kim BM",
-          "Suh J",
-          "Tanzi RE",
-          "You MH"
+          "Babić Leko M",
+          "Bažadona D",
+          "Buée L",
+          "Delalle I",
+          "Di Giovanni G",
+          "Harrington C",
+          "Hof PR",
+          "Jovanov-Milošević N",
+          "Wischik C",
+          "Wray S",
+          "de Silva R",
+          "Šimić G"
         ],
-        "date": "2016-06-15",
-        "first": "Kim BM",
-        "last": "Ho Lee T",
-        "name": "Human molecular genetics",
-        "pages": "2498-2513",
-        "reference": "27094130",
-        "title": "Inhibition of death-associated protein kinase 1 attenuates the phosphorylation and amyloidogenic processing of amyloid precursor protein.",
+        "date": "2016-01-06",
+        "first": "Šimić G",
+        "last": "Hof PR",
+        "name": "Biomolecules",
+        "pages": "6",
+        "reference": "26751493",
+        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
         "type": "PubMed",
-        "volume": "25"
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-      "evidence": "DAPK1, but not its kinase deficient mutant (K42A), significantly increased human Aβ secretion in neuronal cell culture models. Moreover, knockdown of DAPK1 expression or inhibition of DAPK1 catalytic activity significantly decreased Aβ secretion. Furthermore, DAPK1, but not K42A, triggered Thr668 phosphorylation of APP, which may initiate and facilitate amyloidogenic APP processing leading to the generation of Aβ.",
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+      "evidence": "A PSEN1 mutation causes a Pick’s disease phenotype including FTD tau pathology without deposition of Abeta [145]; some MAPT single nucleotide polymorphisms have also been linked to sporadic Parkinson’s disease (PD, [146]);",
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       "citation": {
         "authors": [
-          "Chen CH",
-          "Ho Lee T",
-          "Kim BM",
-          "Suh J",
-          "Tanzi RE",
-          "You MH"
+          "Babić Leko M",
+          "Bažadona D",
+          "Buée L",
+          "Delalle I",
+          "Di Giovanni G",
+          "Harrington C",
+          "Hof PR",
+          "Jovanov-Milošević N",
+          "Wischik C",
+          "Wray S",
+          "de Silva R",
+          "Šimić G"
         ],
-        "date": "2016-06-15",
-        "first": "Kim BM",
-        "last": "Ho Lee T",
-        "name": "Human molecular genetics",
-        "pages": "2498-2513",
-        "reference": "27094130",
-        "title": "Inhibition of death-associated protein kinase 1 attenuates the phosphorylation and amyloidogenic processing of amyloid precursor protein.",
+        "date": "2016-01-06",
+        "first": "Šimić G",
+        "last": "Hof PR",
+        "name": "Biomolecules",
+        "pages": "6",
+        "reference": "26751493",
+        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
         "type": "PubMed",
-        "volume": "25"
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-      "evidence": "DAPK1, but not its kinase deficient mutant (K42A), significantly increased human Aβ secretion in neuronal cell culture models. Moreover, knockdown of DAPK1 expression or inhibition of DAPK1 catalytic activity significantly decreased Aβ secretion. Furthermore, DAPK1, but not K42A, triggered Thr668 phosphorylation of APP, which may initiate and facilitate amyloidogenic APP processing leading to the generation of Aβ.",
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+      "evidence": "Poorkaj et al. reported two exonic mutations (P301L and V337M) in two families with FTDP-17 [139], while Hutton et al. reported six different mutations in 10 families: three of these mutations (G272V, P301L and R406W) were missense mutations in exons, while the other three were in the 5' splice site of exon 10 [140].",
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       "citation": {
         "authors": [
-          "Chen CH",
-          "Ho Lee T",
-          "Kim BM",
-          "Suh J",
-          "Tanzi RE",
-          "You MH"
+          "Babić Leko M",
+          "Bažadona D",
+          "Buée L",
+          "Delalle I",
+          "Di Giovanni G",
+          "Harrington C",
+          "Hof PR",
+          "Jovanov-Milošević N",
+          "Wischik C",
+          "Wray S",
+          "de Silva R",
+          "Šimić G"
         ],
-        "date": "2016-06-15",
-        "first": "Kim BM",
-        "last": "Ho Lee T",
-        "name": "Human molecular genetics",
-        "pages": "2498-2513",
-        "reference": "27094130",
-        "title": "Inhibition of death-associated protein kinase 1 attenuates the phosphorylation and amyloidogenic processing of amyloid precursor protein.",
+        "date": "2016-01-06",
+        "first": "Šimić G",
+        "last": "Hof PR",
+        "name": "Biomolecules",
+        "pages": "6",
+        "reference": "26751493",
+        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
         "type": "PubMed",
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-      "evidence": "DAPK1, but not its kinase deficient mutant (K42A), significantly increased human Aβ secretion in neuronal cell culture models. Moreover, knockdown of DAPK1 expression or inhibition of DAPK1 catalytic activity significantly decreased Aβ secretion. Furthermore, DAPK1, but not K42A, triggered Thr668 phosphorylation of APP, which may initiate and facilitate amyloidogenic APP processing leading to the generation of Aβ.",
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         "authors": [
-          "Chen CH",
-          "Ho Lee T",
-          "Kim BM",
-          "Suh J",
-          "Tanzi RE",
-          "You MH"
+          "Babić Leko M",
+          "Bažadona D",
+          "Buée L",
+          "Delalle I",
+          "Di Giovanni G",
+          "Harrington C",
+          "Hof PR",
+          "Jovanov-Milošević N",
+          "Wischik C",
+          "Wray S",
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-        "first": "Kim BM",
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+        "date": "2016-01-06",
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         "authors": [
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-          "Ho Lee T",
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-          "You MH"
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+        "date": "2016-01-06",
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-      "evidence": "Furthermore, DAPK1-induced APP phosphorylation was suppressed when DAPK1 ΔDD was introduced (Fig. 4G), indicating that DAPK1 regulates Aβ secretion through APP Thr668 phosphorylation.",
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+          "Hof PR",
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-        "name": "The Journal of biological chemistry",
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-        "title": "An Alzheimer Disease-linked Rare Mutation Potentiates Netrin Receptor Uncoordinated-5C-induced Signaling That Merges with Amyloid β Precursor Protein Signaling.",
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-        "title": "Death Associated Protein Kinase (DAPK) -mediated neurodegenerative mechanisms in nematode excitotoxicity.",
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         "authors": [
-          "Ahmed T",
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-        "title": "JunD/AP-1 Antagonizes the Induction of DAPK1 To Promote the Survival of v-Src-Transformed Cells.",
+          "Babić Leko M",
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         "authors": [
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-        "title": "JunD/AP-1 Antagonizes the Induction of DAPK1 To Promote the Survival of v-Src-Transformed Cells.",
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         "authors": [
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-          "Hong Y",
-          "Kim BM",
-          "Kimchi A",
-          "Lee S",
-          "Lee TH",
-          "You MH",
-          "Zhou XZ"
+          "Bailey RM",
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+          "Farrer MJ",
+          "Giasson BI",
+          "Knight J",
+          "Lewis J",
+          "Melrose HL",
+          "Miles S",
+          "Rousseau L",
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-        "first": "Kim BM",
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+          "Harrington C",
+          "Hof PR",
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-        "title": "Death-associated protein kinase 1 has a critical role in aberrant tau protein regulation and function.",
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-          "Cheng XS",
-          "Duan DX",
-          "Hu Y",
-          "Liu GP",
-          "Luo Y",
-          "Ni ZF",
-          "Wang JZ"
+          "Babić Leko M",
+          "Bažadona D",
+          "Buée L",
+          "Delalle I",
+          "Di Giovanni G",
+          "Harrington C",
+          "Hof PR",
+          "Jovanov-Milošević N",
+          "Wischik C",
+          "Wray S",
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-        "last": "Liu GP",
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-        "reference": "23948915",
-        "title": "Phosphorylation of tau by death-associated protein kinase 1 antagonizes the kinase-induced cell apoptosis.",
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-          "Lee TH",
-          "You MH",
-          "Zhou XZ"
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+          "Buée L",
+          "Delalle I",
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+          "Harrington C",
+          "Hof PR",
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-        "reference": "24853415",
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       "citation": {
         "authors": [
-          "Chai GS",
-          "Chen NN",
-          "Cheng XS",
-          "Duan DX",
-          "Hu Y",
-          "Liu GP",
-          "Luo Y",
-          "Ni ZF",
-          "Wang JZ"
+          "Babić Leko M",
+          "Bažadona D",
+          "Buée L",
+          "Delalle I",
+          "Di Giovanni G",
+          "Harrington C",
+          "Hof PR",
+          "Jovanov-Milošević N",
+          "Wischik C",
+          "Wray S",
+          "de Silva R",
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-        "first": "Duan DX",
-        "last": "Liu GP",
-        "name": "Journal of Alzheimer's disease : JAD",
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-        "reference": "23948915",
-        "title": "Phosphorylation of tau by death-associated protein kinase 1 antagonizes the kinase-induced cell apoptosis.",
+        "date": "2016-01-06",
+        "first": "Šimić G",
+        "last": "Hof PR",
+        "name": "Biomolecules",
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+        "reference": "26751493",
+        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
         "type": "PubMed",
-        "volume": "37"
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       },
-      "evidence": "These data suggest that tau hyperphosphorylation at Thr231, Ser262, and Ser396 by DAPK1 renders the cells more resistant to the kinase-induced apoptotic cell death, providing new insights into the tau-involved apoptotic abortion in the course of chronic neurodegeneration.",
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         "authors": [
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-        "title": "Death-associated protein kinase 1 has a critical role in aberrant tau protein regulation and function.",
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       "citation": {
         "authors": [
-          "Chai GS",
-          "Chen NN",
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-          "Duan DX",
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-          "Liu GP",
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+          "Hof PR",
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-        "first": "Duan DX",
-        "last": "Liu GP",
-        "name": "Journal of Alzheimer's disease : JAD",
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-        "title": "Phosphorylation of tau by death-associated protein kinase 1 antagonizes the kinase-induced cell apoptosis.",
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+        "first": "Šimić G",
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         "authors": [
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-          "Chou HJ",
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-          "Kimchi A",
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-      "evidence": "Furthermore, silencing of both MARK1 and MARK2 blocked DAPK-induced tau S262 phosphorylation (Figure 3e). More importantly, a decrease of pS262 tau, but not total tau, was observed in brain extracts derived from DAPK−/− mice, compared with that from DAPK+/+ mice (Figure 3f). These results strongly suggest a role of endogenous DAPK in stimulating the activity of endogenous MARK, which in turn phosphorylates tau in neurons.",
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       "citation": {
         "authors": [
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-          "Chen RH",
-          "Chen YH",
-          "Chien CT",
-          "Chou HJ",
-          "Huang YP",
-          "Kimchi A",
-          "Lin MY",
-          "Tsai PI",
-          "Wu PR"
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+          "Bažadona D",
+          "Buée L",
+          "Delalle I",
+          "Di Giovanni G",
+          "Harrington C",
+          "Hof PR",
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+          "Wischik C",
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-        "first": "Wu PR",
-        "last": "Chen RH",
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-        "reference": "21311567",
-        "title": "DAPK activates MARK1/2 to regulate microtubule assembly, neuronal differentiation, and tau toxicity.",
+        "date": "2016-01-06",
+        "first": "Šimić G",
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-      "evidence": "Furthermore, silencing of both MARK1 and MARK2 blocked DAPK-induced tau S262 phosphorylation (Figure 3e). More importantly, a decrease of pS262 tau, but not total tau, was observed in brain extracts derived from DAPK−/− mice, compared with that from DAPK+/+ mice (Figure 3f). These results strongly suggest a role of endogenous DAPK in stimulating the activity of endogenous MARK, which in turn phosphorylates tau in neurons.",
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+      "citation": {
+        "authors": [
+          "Akaike T",
+          "Ida T",
+          "Matsushita K",
+          "Soeda Y",
+          "Sumioka A",
+          "Takashima A",
+          "Yoshikawa M",
+          "Yoshitake J"
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+        "date": "2016-10-21",
+        "first": "Yoshitake J",
+        "last": "Takashima A",
+        "name": "The Journal of biological chemistry",
+        "pages": "22714-22720",
+        "reference": "27601475",
+        "title": "Modification of Tau by 8-Nitroguanosine 3',5'-Cyclic Monophosphate (8-Nitro-cGMP): EFFECTS OF NITRIC OXIDE-LINKED CHEMICAL MODIFICATION ON TAU AGGREGATION.",
+        "type": "PubMed",
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+      "evidence": "Tau contains cysteine residues in the microtubule binding region following alternative splicing of exon 10, and formation of intermolecular cysteine disulfide bonds accelerates tau aggregation. 8-Nitro-cGMP (novel second messenger of NO) exposure induced S-guanylation of tau both in vitro and in tau-overexpressed HEK293T cells. S-guanylated tau inhibited heparin-induced tau aggregation (thioflavin T). S-guanylated tau could not form tau granules and fibrils (AFM) inhibited at the step of tau oligomer formation. In P301L tau-expressing Neuro2A cells, 8-nitro-cGMP reduced the amount of sarcosyl-insoluble tau. NO-linked chemical modification on cysteine residues of tau could block tau aggregation",
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     {
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       "citation": {
         "authors": [
-          "Chen GC",
-          "Chen RH",
-          "Chen YH",
-          "Chien CT",
-          "Chou HJ",
-          "Huang YP",
-          "Kimchi A",
-          "Lin MY",
-          "Tsai PI",
-          "Wu PR"
+          "Babić Leko M",
+          "Bažadona D",
+          "Buée L",
+          "Delalle I",
+          "Di Giovanni G",
+          "Harrington C",
+          "Hof PR",
+          "Jovanov-Milošević N",
+          "Wischik C",
+          "Wray S",
+          "de Silva R",
+          "Šimić G"
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-        "first": "Wu PR",
-        "last": "Chen RH",
-        "name": "Cell death and differentiation",
-        "pages": "1507-20",
-        "reference": "21311567",
-        "title": "DAPK activates MARK1/2 to regulate microtubule assembly, neuronal differentiation, and tau toxicity.",
+        "date": "2016-01-06",
+        "first": "Šimić G",
+        "last": "Hof PR",
+        "name": "Biomolecules",
+        "pages": "6",
+        "reference": "26751493",
+        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
         "type": "PubMed",
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+        "volume": "6"
       },
-      "evidence": "Importantly, depletion of MARK1/2 reversed the inhibitory effect of DAPK on MT regrowth (Figure 5c, right panel). These results indicate that the DAPK–MARK signaling axis inhibits MT assembly and stability.",
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+      "evidence": "In the case of soluble monomeric or small oligomeric tau protein, the endocytosis appears to be clathrin-dependent (reviewed in [169]). In contrast, larger aggregates of tau could bind heparin in the extracellular matrix and be internalized through macropinocytosis [170]. As a result of exocytosis and endocytosis, the spreading of tau can occur in various neurodegenerative diseases (tauopathies) including AD. Three plausible mechanisms of tau spreading are shown schematically in Figure 6. Additionally, it appears that microglial cells may facilitate tau propagation by phagocytosis and exocytosis of tau protein [171].",
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       "citation": {
         "authors": [
-          "Chen CH",
-          "Ho Lee T",
-          "Kim BM",
-          "Suh J",
-          "Tanzi RE",
-          "You MH"
+          "Babić Leko M",
+          "Bažadona D",
+          "Buée L",
+          "Delalle I",
+          "Di Giovanni G",
+          "Harrington C",
+          "Hof PR",
+          "Jovanov-Milošević N",
+          "Wischik C",
+          "Wray S",
+          "de Silva R",
+          "Šimić G"
         ],
-        "date": "2016-06-15",
-        "first": "Kim BM",
-        "last": "Ho Lee T",
-        "name": "Human molecular genetics",
-        "pages": "2498-2513",
-        "reference": "27094130",
-        "title": "Inhibition of death-associated protein kinase 1 attenuates the phosphorylation and amyloidogenic processing of amyloid precursor protein.",
+        "date": "2016-01-06",
+        "first": "Šimić G",
+        "last": "Hof PR",
+        "name": "Biomolecules",
+        "pages": "6",
+        "reference": "26751493",
+        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
         "type": "PubMed",
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       },
-      "evidence": "DAPK1, but not its kinase deficient mutant (K42A), significantly increased human Aβ secretion in neuronal cell culture models. Moreover, knockdown of DAPK1 expression or inhibition of DAPK1 catalytic activity significantly decreased Aβ secretion. Furthermore, DAPK1, but not K42A, triggered Thr668 phosphorylation of APP, which may initiate and facilitate amyloidogenic APP processing leading to the generation of Aβ.",
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+      "evidence": "In the case of soluble monomeric or small oligomeric tau protein, the endocytosis appears to be clathrin-dependent (reviewed in [169]). In contrast, larger aggregates of tau could bind heparin in the extracellular matrix and be internalized through macropinocytosis [170]. As a result of exocytosis and endocytosis, the spreading of tau can occur in various neurodegenerative diseases (tauopathies) including AD. Three plausible mechanisms of tau spreading are shown schematically in Figure 6. Additionally, it appears that microglial cells may facilitate tau propagation by phagocytosis and exocytosis of tau protein [171].",
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         "authors": [
-          "Ando K",
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-          "D'Amico E",
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-          "Erneux C",
-          "Jia Y",
-          "Leroy K",
-          "Luo HR",
-          "Pouillon V",
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-          "Stygelbout V"
+          "Babić Leko M",
+          "Bažadona D",
+          "Buée L",
+          "Delalle I",
+          "Di Giovanni G",
+          "Harrington C",
+          "Hof PR",
+          "Jovanov-Milošević N",
+          "Wischik C",
+          "Wray S",
+          "de Silva R",
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-        "name": "Brain : a journal of neurology",
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-        "reference": "24401760",
-        "title": "Inositol trisphosphate 3-kinase B is increased in human Alzheimer brain and exacerbates mouse Alzheimer pathology.",
+        "date": "2016-01-06",
+        "first": "Šimić G",
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-        "last": "Matsuoka M",
-        "name": "The Journal of biological chemistry",
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-        "name": "The Journal of biological chemistry",
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+          "Cohen TJ",
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+          "Tripathy A",
+          "Trzeciakiewicz H",
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-        "first": "Hashimoto Y",
-        "last": "Matsuoka M",
-        "name": "The Journal of biological chemistry",
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-        "title": "An Alzheimer Disease-linked Rare Mutation Potentiates Netrin Receptor Uncoordinated-5C-induced Signaling That Merges with Amyloid β Precursor Protein Signaling.",
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+        "first": "Trzeciakiewicz H",
+        "last": "Cohen TJ",
+        "name": "Scientific reports",
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+        "reference": "28287136",
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         "type": "PubMed",
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       "citation": {
         "authors": [
-          "Hashimoto Y",
-          "Kusakari S",
-          "Matsuoka M",
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+          "Harrington C",
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-        "last": "Matsuoka M",
-        "name": "The Journal of biological chemistry",
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-        "reference": "27068745",
-        "title": "An Alzheimer Disease-linked Rare Mutation Potentiates Netrin Receptor Uncoordinated-5C-induced Signaling That Merges with Amyloid β Precursor Protein Signaling.",
+        "date": "2016-01-06",
+        "first": "Šimić G",
+        "last": "Hof PR",
+        "name": "Biomolecules",
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         "type": "PubMed",
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+      "evidence": "Recently, it has been proposed that tau protein acetylation may be responsible for tau aggregation in AD. Grinberg and collaborators detected tau acetylation at Lys274 in all tauopathies (both primary and secondary), except in AgD",
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       "citation": {
         "authors": [
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-          "Kusakari S",
-          "Matsuoka M",
-          "Nawa M",
-          "Toyama Y"
+          "Cong X",
+          "Ellerby LM",
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+          "Lo I",
+          "Min SW",
+          "Minami SS",
+          "Ponnusamy R",
+          "Schilling B",
+          "Sohn PD",
+          "Tracy TE",
+          "Wang C",
+          "Zhou Y"
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-        "first": "Hashimoto Y",
-        "last": "Matsuoka M",
-        "name": "The Journal of biological chemistry",
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-        "reference": "27068745",
-        "title": "An Alzheimer Disease-linked Rare Mutation Potentiates Netrin Receptor Uncoordinated-5C-induced Signaling That Merges with Amyloid β Precursor Protein Signaling.",
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+        "first": "Tracy TE",
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       "citation": {
         "authors": [
-          "Hashimoto Y",
-          "Kusakari S",
-          "Matsuoka M",
-          "Nawa M",
-          "Toyama Y"
+          "Cong X",
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+          "Lo I",
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+          "Minami SS",
+          "Ponnusamy R",
+          "Schilling B",
+          "Sohn PD",
+          "Tracy TE",
+          "Wang C",
+          "Zhou Y"
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-        "first": "Hashimoto Y",
-        "last": "Matsuoka M",
-        "name": "The Journal of biological chemistry",
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-        "reference": "27068745",
-        "title": "An Alzheimer Disease-linked Rare Mutation Potentiates Netrin Receptor Uncoordinated-5C-induced Signaling That Merges with Amyloid β Precursor Protein Signaling.",
+        "date": "2016-04-20",
+        "first": "Tracy TE",
+        "last": "Gan L",
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+        "title": "Acetylated Tau Obstructs KIBRA-Mediated Signaling in Synaptic Plasticity and Promotes Tauopathy-Related Memory Loss.",
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         "authors": [
-          "Hashimoto Y",
-          "Kusakari S",
-          "Matsuoka M",
-          "Nawa M",
-          "Toyama Y"
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-        "last": "Matsuoka M",
-        "name": "The Journal of biological chemistry",
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-        "reference": "27068745",
-        "title": "An Alzheimer Disease-linked Rare Mutation Potentiates Netrin Receptor Uncoordinated-5C-induced Signaling That Merges with Amyloid β Precursor Protein Signaling.",
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+        "first": "Tracy TE",
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     {
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       "citation": {
         "authors": [
-          "Bi L",
-          "Guo Y",
-          "Jin H",
-          "Li H",
-          "Lu Y",
-          "Pang P",
-          "Pei L",
-          "Shang Y",
-          "Shu S",
-          "Tian Q",
-          "Tian T",
-          "Wang S",
-          "Wei N",
-          "Wu J",
-          "Xu M",
-          "Yan H",
-          "Yang X",
-          "Yao C",
-          "Zhu LQ"
+          "Babić Leko M",
+          "Bažadona D",
+          "Buée L",
+          "Delalle I",
+          "Di Giovanni G",
+          "Harrington C",
+          "Hof PR",
+          "Jovanov-Milošević N",
+          "Wischik C",
+          "Wray S",
+          "de Silva R",
+          "Šimić G"
         ],
-        "date": "2015-11-01",
-        "first": "Pei L",
-        "last": "Lu Y",
-        "name": "Cerebral cortex (New York, N.Y. : 1991)",
-        "pages": "4559-71",
-        "reference": "25995053",
-        "title": "A Novel Mechanism of Spine Damages in Stroke via DAPK1 and Tau.",
+        "date": "2016-01-06",
+        "first": "Šimić G",
+        "last": "Hof PR",
+        "name": "Biomolecules",
+        "pages": "6",
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+        "title": "Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.",
         "type": "PubMed",
-        "volume": "25"
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     {
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         "authors": [
-          "Bi L",
-          "Guo Y",
-          "Jin H",
-          "Li H",
-          "Lu Y",
-          "Pang P",
-          "Pei L",
-          "Shang Y",
-          "Shu S",
-          "Tian Q",
-          "Tian T",
-          "Wang S",
-          "Wei N",
-          "Wu J",
-          "Xu M",
-          "Yan H",
-          "Yang X",
-          "Yao C",
-          "Zhu LQ"
+          "Buée-Scherrer V",
+          "Goedert M"
         ],
-        "date": "2015-11-01",
-        "first": "Pei L",
-        "last": "Lu Y",
-        "name": "Cerebral cortex (New York, N.Y. : 1991)",
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-        "reference": "25995053",
-        "title": "A Novel Mechanism of Spine Damages in Stroke via DAPK1 and Tau.",
+        "date": "2002-03-27",
+        "first": "Buée-Scherrer V",
+        "last": "Goedert M",
+        "name": "FEBS letters",
+        "pages": "151-4",
+        "reference": "11943212",
+        "title": "Phosphorylation of microtubule-associated protein tau by stress-activated protein kinases in intact cells.",
         "type": "PubMed",
-        "volume": "25"
+        "volume": "515"
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-      "evidence": "Direct interaction of DAPK1 with Tau causes spine loss and subsequently neuronal death. DAPK1 phosphorylates Tau protein at Ser262 (pS(262)) in cortical neurons of stroke mice.",
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     {
       "annotations": {
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         "MeSHDisease": {
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-        },
-        "Species": {
-          "10090": true
+          "Creutzfeldt-Jakob Syndrome": true,
+          "Insomnia, Fatal Familial": true
         }
       },
       "citation": {
         "authors": [
-          "Bi L",
+          "Chen C",
+          "Dong XP",
+          "Gong HS",
           "Guo Y",
-          "Jin H",
-          "Li H",
-          "Lu Y",
-          "Pang P",
-          "Pei L",
-          "Shang Y",
-          "Shu S",
-          "Tian Q",
-          "Tian T",
-          "Wang S",
-          "Wei N",
-          "Wu J",
-          "Xu M",
-          "Yan H",
-          "Yang X",
-          "Yao C",
-          "Zhu LQ"
+          "Liu Y",
+          "Shi Q",
+          "Tian C",
+          "Wang SB",
+          "Xie WL",
+          "Xu Y",
+          "Zhang BY",
+          "Zhang J"
         ],
-        "date": "2015-11-01",
-        "first": "Pei L",
-        "last": "Lu Y",
-        "name": "Cerebral cortex (New York, N.Y. : 1991)",
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-        "reference": "25995053",
-        "title": "A Novel Mechanism of Spine Damages in Stroke via DAPK1 and Tau.",
+        "date": "2012-09-01",
+        "first": "Gong HS",
+        "last": "Dong XP",
+        "name": "International journal of molecular medicine",
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+        "reference": "22692785",
+        "title": "Reduction of protein kinase MARK4 in the brains of experimental scrapie rodents and human prion disease correlates with deposits of PrP(Sc).",
         "type": "PubMed",
-        "volume": "25"
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-      "evidence": "Direct interaction of DAPK1 with Tau causes spine loss and subsequently neuronal death. DAPK1 phosphorylates Tau protein at Ser262 (pS(262)) in cortical neurons of stroke mice.",
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+      "evidence": "MARK4 was extremely decreased in the brain regions with a mass of PrPSc in a G114V gCJD patient, but was clearly observable in the regions with a minimum amount of PrPSc or without detectable PrPSc in a D178N FFI patient.",
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-          "Guo Y",
-          "Jin H",
-          "Li H",
-          "Lu Y",
-          "Pang P",
-          "Pei L",
-          "Shang Y",
-          "Shu S",
-          "Tian Q",
-          "Tian T",
-          "Wang S",
-          "Wei N",
-          "Wu J",
-          "Xu M",
-          "Yan H",
-          "Yang X",
-          "Yao C",
-          "Zhu LQ"
+          "Lu B",
+          "Malenka R",
+          "Polepalli J",
+          "Rajadas J",
+          "Wagh D",
+          "Yu W"
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-        "first": "Pei L",
-        "last": "Lu Y",
-        "name": "Cerebral cortex (New York, N.Y. : 1991)",
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-        "reference": "25995053",
-        "title": "A Novel Mechanism of Spine Damages in Stroke via DAPK1 and Tau.",
+        "date": "2012-03-15",
+        "first": "Yu W",
+        "last": "Lu B",
+        "name": "Human molecular genetics",
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         "type": "PubMed",
-        "volume": "25"
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-        "MeSHDisease": {
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         "authors": [
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-          "Guo Y",
-          "Jin H",
-          "Li H",
-          "Lu Y",
-          "Pang P",
-          "Pei L",
-          "Shang Y",
-          "Shu S",
-          "Tian Q",
-          "Tian T",
-          "Wang S",
-          "Wei N",
-          "Wu J",
-          "Xu M",
-          "Yan H",
-          "Yang X",
-          "Yao C",
-          "Zhu LQ"
+          "Blokzijl A",
+          "Classon C",
+          "Gu GJ",
+          "Kamali-Moghaddam M",
+          "Landegren U",
+          "Lund H",
+          "Sunnemark D",
+          "Wu D",
+          "von Euler G"
         ],
-        "date": "2015-11-01",
-        "first": "Pei L",
-        "last": "Lu Y",
-        "name": "Cerebral cortex (New York, N.Y. : 1991)",
-        "pages": "4559-71",
-        "reference": "25995053",
-        "title": "A Novel Mechanism of Spine Damages in Stroke via DAPK1 and Tau.",
+        "date": "2013-09-01",
+        "first": "Gu GJ",
+        "last": "Kamali-Moghaddam M",
+        "name": "Neuromolecular medicine",
+        "pages": "458-69",
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         "type": "PubMed",
-        "volume": "25"
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       },
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     {
       "annotations": {
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       "citation": {
         "authors": [
-          "Campbell SN",
-          "Masliah E",
-          "Monte L",
-          "Rice KC",
-          "Rissman RA",
-          "Roe AD",
-          "Taché Y",
-          "Zhang C"
+          "Ashford JW",
+          "Huang X",
+          "Inayathullah M",
+          "Kim KM",
+          "Lee S",
+          "Liu S",
+          "Rajadas J",
+          "Sun W",
+          "Tang H"
         ],
-        "date": "2015-01-01",
-        "first": "Campbell SN",
-        "last": "Rissman RA",
-        "name": "Journal of Alzheimer's disease : JAD",
-        "pages": "967-76",
-        "reference": "25125464",
-        "title": "Increased tau phosphorylation and aggregation in the hippocampus of mice overexpressing corticotropin-releasing factor.",
+        "date": "2016-10-06",
+        "first": "Sun W",
+        "last": "Rajadas J",
+        "name": "Scientific reports",
+        "pages": "34784",
+        "reference": "27708431",
+        "title": "Attenuation of synaptic toxicity and MARK4/PAR1-mediated Tau phosphorylation by methylene blue for Alzheimer's disease treatment.",
         "type": "PubMed",
-        "volume": "43"
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       },
-      "evidence": "CRF-OE mice had significantly elevated tau-P compared to wild type (WT) mice at the AT8 (S202/T204), PHF-1 (S396/404), S262, and S422 sites. Treating CRF-OE mice with R121919 blocked phosphorylation at the AT8 (S202/T204) and PHF-1 (S396/404) sites, but not at the S262 and S422 sites and reduced phosphorylation of c-Jun N Terminal Kinase (JNK).",
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+      "evidence": "In 293T culture, MB decreased MARK4-mediated Tau phosphorylation in a dose dependent manner. MB down-regulates MARK4 protein level through ubiquitin-proteasome pathway and inhibition of MARK4 kinase activity in vitro.",
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       "citation": {
         "authors": [
-          "Chen CH",
-          "Hong Y",
-          "Kim BM",
-          "Kimchi A",
-          "Lee S",
-          "Lee TH",
-          "You MH",
-          "Zhou XZ"
+          "Lu B",
+          "Malenka R",
+          "Polepalli J",
+          "Rajadas J",
+          "Wagh D",
+          "Yu W"
         ],
-        "date": "2014-05-22",
-        "first": "Kim BM",
-        "last": "Lee TH",
-        "name": "Cell death &amp; disease",
-        "pages": "e1237",
-        "reference": "24853415",
-        "title": "Death-associated protein kinase 1 has a critical role in aberrant tau protein regulation and function.",
+        "date": "2012-03-15",
+        "first": "Yu W",
+        "last": "Lu B",
+        "name": "Human molecular genetics",
+        "pages": "1384-90",
+        "reference": "22156579",
+        "title": "A critical role for the PAR-1/MARK-tau axis in mediating the toxic effects of Aβ on synapses and dendritic spines.",
         "type": "PubMed",
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-      "evidence": "We showed previously that DAPK1 phosphorylates Ser71 in the catalytic active site of Pin1, thereby inhibiting its cellular function.",
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+      "evidence": "We first confirmed that expression of an MKI-GFP fusion protein in rat hippocampal neurons effectively attenuated MARK4-mediated phosphorylation of both endogenous tau (Fig. 3A) and transfected human tau at the 12E8 sites (Fig. 3B). Phosphorylation of tau at the PHF-1 site was also reduced by MKI (Fig. 3A). It is possible that the PHF-1 site is also targeted by PAR-1/MARKs in vivo, or that the phosphorylation of tau at the 12E8 sites is a prerequisite for PHF-1 site phosphorylation, as the 12E8 sites were previously shown to be required for tau phosphorylation at other sites",
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     {
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       "citation": {
         "authors": [
-          "Chen CH",
-          "Hong Y",
-          "Kim BM",
-          "Kimchi A",
-          "Lee S",
-          "Lee TH",
-          "You MH",
-          "Zhou XZ"
+          "Blokzijl A",
+          "Classon C",
+          "Gu GJ",
+          "Kamali-Moghaddam M",
+          "Landegren U",
+          "Lund H",
+          "Sunnemark D",
+          "Wu D",
+          "von Euler G"
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-        "date": "2014-05-22",
-        "first": "Kim BM",
-        "last": "Lee TH",
-        "name": "Cell death &amp; disease",
-        "pages": "e1237",
-        "reference": "24853415",
-        "title": "Death-associated protein kinase 1 has a critical role in aberrant tau protein regulation and function.",
+        "date": "2013-09-01",
+        "first": "Gu GJ",
+        "last": "Kamali-Moghaddam M",
+        "name": "Neuromolecular medicine",
+        "pages": "458-69",
+        "reference": "23666762",
+        "title": "Role of individual MARK isoforms in phosphorylation of tau at Ser²⁶² in Alzheimer's disease.",
         "type": "PubMed",
-        "volume": "5"
+        "volume": "15"
       },
-      "evidence": "DAPK1-mediated increase in tau protein expression and stability were accompanied by increased Pin1 Ser71 phosphorylation.",
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+      "evidence": "In cells, a CagA peptide inhibited tau phosphorylation at Ser²6² mediated by MARK4 but not other MARK isoforms. A strong and significant elevation of MARK4 expression and MARK4-tau interactions in AD brains correlated with the Braak stages of the disease.",
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       "citation": {
         "authors": [
-          "Ando K",
-          "Blum D",
-          "Bretteville A",
-          "Buée L",
-          "Bégard S",
-          "Bélarbi K",
-          "Caillet-Boudin ML",
-          "Demey-Thomas E",
-          "Dourlen P",
-          "Drobecq H",
-          "Eddarkaoui S",
-          "Galas MC",
-          "Ghestem A",
-          "Hamdane M",
-          "Landrieu I",
-          "Lippens G",
-          "Maurage CA",
-          "Melnyk P",
-          "Sambo AV",
-          "Sergeant N",
-          "Smet C",
-          "Verdier Y",
-          "Vingtdeux V",
-          "Vinh J"
+          "Lu B",
+          "Malenka R",
+          "Polepalli J",
+          "Rajadas J",
+          "Wagh D",
+          "Yu W"
         ],
-        "date": "2013-03-01",
-        "first": "Ando K",
-        "last": "Buée L",
-        "name": "Neurobiology of aging",
-        "pages": "757-69",
-        "reference": "22926167",
-        "title": "Tau pathology modulates Pin1 post-translational modifications and may be relevant as biomarker.",
+        "date": "2012-03-15",
+        "first": "Yu W",
+        "last": "Lu B",
+        "name": "Human molecular genetics",
+        "pages": "1384-90",
+        "reference": "22156579",
+        "title": "A critical role for the PAR-1/MARK-tau axis in mediating the toxic effects of Aβ on synapses and dendritic spines.",
         "type": "PubMed",
-        "volume": "34"
+        "volume": "21"
       },
-      "evidence": "Because Pin1 has at least 4 major isovariants in addition to the native polypeptide, this means that Pin1 has 4 (possibly more) posttranslational modifications including phosphorylation at 3 sites (Ser16 and Ser65/Ser71), N-acetylation (amino-terminus and Lys46) and oxidation (Met130 and 146). In all experimental conditions, including tau-overexpressing cells, tau transgenic mice and AD brains, global levels of Pin1 posttranslational modifications were decreased compared with control conditions.",
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       "citation": {
         "authors": [
-          "Chen GC",
-          "Chen RH",
-          "Chen YH",
-          "Chien CT",
-          "Chou HJ",
-          "Huang YP",
-          "Kimchi A",
-          "Lin MY",
-          "Tsai PI",
-          "Wu PR"
+          "Lu B",
+          "Malenka R",
+          "Polepalli J",
+          "Rajadas J",
+          "Wagh D",
+          "Yu W"
         ],
-        "date": "2011-09-01",
-        "first": "Wu PR",
-        "last": "Chen RH",
-        "name": "Cell death and differentiation",
-        "pages": "1507-20",
-        "reference": "21311567",
-        "title": "DAPK activates MARK1/2 to regulate microtubule assembly, neuronal differentiation, and tau toxicity.",
+        "date": "2012-03-15",
+        "first": "Yu W",
+        "last": "Lu B",
+        "name": "Human molecular genetics",
+        "pages": "1384-90",
+        "reference": "22156579",
+        "title": "A critical role for the PAR-1/MARK-tau axis in mediating the toxic effects of Aβ on synapses and dendritic spines.",
         "type": "PubMed",
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+        "volume": "21"
       },
-      "evidence": "Furthermore, silencing of both MARK1 and MARK2 blocked DAPK-induced tau S262 phosphorylation (Figure 3e). More importantly, a decrease of pS262 tau, but not total tau, was observed in brain extracts derived from DAPK−/− mice, compared with that from DAPK+/+ mice (Figure 3f). These results strongly suggest a role of endogenous DAPK in stimulating the activity of endogenous MARK, which in turn phosphorylates tau in neurons.",
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       "citation": {
         "authors": [
-          "Iijima KM",
-          "Iijima-Ando K",
           "Lu B",
-          "Maruko-Otake A",
-          "Ohtake Y",
-          "Sekiya M",
-          "Suzuki E"
+          "Malenka R",
+          "Polepalli J",
+          "Rajadas J",
+          "Wagh D",
+          "Yu W"
         ],
-        "date": "2012-01-01",
-        "first": "Iijima-Ando K",
-        "last": "Iijima KM",
-        "name": "PLoS genetics",
-        "pages": "e1002918",
-        "reference": "22952452",
-        "title": "Loss of axonal mitochondria promotes tau-mediated neurodegeneration and Alzheimer's disease-related tau phosphorylation via PAR-1.",
+        "date": "2012-03-15",
+        "first": "Yu W",
+        "last": "Lu B",
+        "name": "Human molecular genetics",
+        "pages": "1384-90",
+        "reference": "22156579",
+        "title": "A critical role for the PAR-1/MARK-tau axis in mediating the toxic effects of Aβ on synapses and dendritic spines.",
         "type": "PubMed",
-        "volume": "8"
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-      "evidence": "Using transgenic Drosophila expressing human tau, we found that RNAi-mediated knockdown of milton or Miro, an adaptor protein essential for axonal transport of mitochondria, enhanced human tau-induced neurodegeneration. Tau phosphorylation at an AD-related site Ser262 increased with knockdown of milton or Miro; and partitioning defective-1 (PAR-1), the Drosophila homolog of mammalian microtubule affinity-regulating kinase, mediated this increase of tau phosphorylation. Tau phosphorylation at Ser262 has been reported to promote tau detachment from microtubules, and we found that the levels of microtubule-unbound free tau increased by milton knockdown. Blocking tau phosphorylation at Ser262 site by PAR-1 knockdown or by mutating the Ser262 site to unphosphorylatable alanine suppressed the enhancement of tau-induced neurodegeneration caused by milton knockdown. Furthermore, knockdown of milton or Miro increased the levels of active PAR-1.",
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       "citation": {
         "authors": [
-          "Chen GC",
-          "Chen RH",
-          "Chen YH",
-          "Chien CT",
-          "Chou HJ",
-          "Huang YP",
-          "Kimchi A",
-          "Lin MY",
-          "Tsai PI",
-          "Wu PR"
+          "Lu B",
+          "Malenka R",
+          "Polepalli J",
+          "Rajadas J",
+          "Wagh D",
+          "Yu W"
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-        "first": "Wu PR",
-        "last": "Chen RH",
-        "name": "Cell death and differentiation",
-        "pages": "1507-20",
-        "reference": "21311567",
-        "title": "DAPK activates MARK1/2 to regulate microtubule assembly, neuronal differentiation, and tau toxicity.",
+        "date": "2012-03-15",
+        "first": "Yu W",
+        "last": "Lu B",
+        "name": "Human molecular genetics",
+        "pages": "1384-90",
+        "reference": "22156579",
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         "type": "PubMed",
-        "volume": "18"
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-      "evidence": "Importantly, depletion of MARK1/2 reversed the inhibitory effect of DAPK on MT regrowth (Figure 5c, right panel). These results indicate that the DAPK–MARK signaling axis inhibits MT assembly and stability.",
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-          "Iijima-Ando K",
           "Lu B",
-          "Maruko-Otake A",
-          "Ohtake Y",
-          "Sekiya M",
-          "Suzuki E"
+          "Malenka R",
+          "Polepalli J",
+          "Rajadas J",
+          "Wagh D",
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-        "first": "Iijima-Ando K",
-        "last": "Iijima KM",
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-        "reference": "22952452",
-        "title": "Loss of axonal mitochondria promotes tau-mediated neurodegeneration and Alzheimer's disease-related tau phosphorylation via PAR-1.",
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+        "first": "Yu W",
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+        "reference": "22156579",
+        "title": "A critical role for the PAR-1/MARK-tau axis in mediating the toxic effects of Aβ on synapses and dendritic spines.",
         "type": "PubMed",
-        "volume": "8"
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       },
-      "evidence": "Using transgenic Drosophila expressing human tau, we found that RNAi-mediated knockdown of milton or Miro, an adaptor protein essential for axonal transport of mitochondria, enhanced human tau-induced neurodegeneration. Tau phosphorylation at an AD-related site Ser262 increased with knockdown of milton or Miro; and partitioning defective-1 (PAR-1), the Drosophila homolog of mammalian microtubule affinity-regulating kinase, mediated this increase of tau phosphorylation. Tau phosphorylation at Ser262 has been reported to promote tau detachment from microtubules, and we found that the levels of microtubule-unbound free tau increased by milton knockdown. Blocking tau phosphorylation at Ser262 site by PAR-1 knockdown or by mutating the Ser262 site to unphosphorylatable alanine suppressed the enhancement of tau-induced neurodegeneration caused by milton knockdown. Furthermore, knockdown of milton or Miro increased the levels of active PAR-1.",
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       "citation": {
         "authors": [
-          "Iijima KM",
-          "Iijima-Ando K",
-          "Lu B",
-          "Maruko-Otake A",
-          "Ohtake Y",
-          "Sekiya M",
-          "Suzuki E"
+          "Buée-Scherrer V",
+          "Goedert M"
         ],
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-        "first": "Iijima-Ando K",
-        "last": "Iijima KM",
-        "name": "PLoS genetics",
-        "pages": "e1002918",
-        "reference": "22952452",
-        "title": "Loss of axonal mitochondria promotes tau-mediated neurodegeneration and Alzheimer's disease-related tau phosphorylation via PAR-1.",
+        "date": "2002-03-27",
+        "first": "Buée-Scherrer V",
+        "last": "Goedert M",
+        "name": "FEBS letters",
+        "pages": "151-4",
+        "reference": "11943212",
+        "title": "Phosphorylation of microtubule-associated protein tau by stress-activated protein kinases in intact cells.",
         "type": "PubMed",
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-      "evidence": "Using transgenic Drosophila expressing human tau, we found that RNAi-mediated knockdown of milton or Miro, an adaptor protein essential for axonal transport of mitochondria, enhanced human tau-induced neurodegeneration. Tau phosphorylation at an AD-related site Ser262 increased with knockdown of milton or Miro; and partitioning defective-1 (PAR-1), the Drosophila homolog of mammalian microtubule affinity-regulating kinase, mediated this increase of tau phosphorylation. Tau phosphorylation at Ser262 has been reported to promote tau detachment from microtubules, and we found that the levels of microtubule-unbound free tau increased by milton knockdown. Blocking tau phosphorylation at Ser262 site by PAR-1 knockdown or by mutating the Ser262 site to unphosphorylatable alanine suppressed the enhancement of tau-induced neurodegeneration caused by milton knockdown. Furthermore, knockdown of milton or Miro increased the levels of active PAR-1.",
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       "citation": {
         "authors": [
-          "Chen GC",
-          "Chen RH",
-          "Chen YH",
-          "Chien CT",
-          "Chou HJ",
-          "Huang YP",
-          "Kimchi A",
-          "Lin MY",
-          "Tsai PI",
-          "Wu PR"
+          "Buée-Scherrer V",
+          "Goedert M"
         ],
-        "date": "2011-09-01",
-        "first": "Wu PR",
-        "last": "Chen RH",
-        "name": "Cell death and differentiation",
-        "pages": "1507-20",
-        "reference": "21311567",
-        "title": "DAPK activates MARK1/2 to regulate microtubule assembly, neuronal differentiation, and tau toxicity.",
+        "date": "2002-03-27",
+        "first": "Buée-Scherrer V",
+        "last": "Goedert M",
+        "name": "FEBS letters",
+        "pages": "151-4",
+        "reference": "11943212",
+        "title": "Phosphorylation of microtubule-associated protein tau by stress-activated protein kinases in intact cells.",
         "type": "PubMed",
-        "volume": "18"
-      },
-      "evidence": "Furthermore, silencing of both MARK1 and MARK2 blocked DAPK-induced tau S262 phosphorylation (Figure 3e). More importantly, a decrease of pS262 tau, but not total tau, was observed in brain extracts derived from DAPK−/− mice, compared with that from DAPK+/+ mice (Figure 3f). These results strongly suggest a role of endogenous DAPK in stimulating the activity of endogenous MARK, which in turn phosphorylates tau in neurons.",
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       "citation": {
         "authors": [
-          "Bibow S",
-          "Biernat J",
-          "Blackledge M",
-          "Jensen MR",
-          "Kadavath H",
-          "Mandelkow E",
-          "Ozenne V",
-          "Schwalbe M",
-          "Zweckstetter M"
+          "Buée-Scherrer V",
+          "Goedert M"
         ],
-        "date": "2013-12-17",
-        "first": "Schwalbe M",
-        "last": "Zweckstetter M",
-        "name": "Biochemistry",
-        "pages": "9068-79",
-        "reference": "24251416",
-        "title": "Phosphorylation of human Tau protein by microtubule affinity-regulating kinase 2.",
+        "date": "2002-03-27",
+        "first": "Buée-Scherrer V",
+        "last": "Goedert M",
+        "name": "FEBS letters",
+        "pages": "151-4",
+        "reference": "11943212",
+        "title": "Phosphorylation of microtubule-associated protein tau by stress-activated protein kinases in intact cells.",
         "type": "PubMed",
-        "volume": "52"
-      },
-      "evidence": "While residues Ser-262, Ser-324, and Ser-356 were completely phosphorylated, Ser-293 in the second repeat was only 84% phosphorylated (Table 1). Furthermore, four non-KXGS phosphorylation sites were detected, two within the repeat domain (Ser-305 in R2 and Ser-352 in R4) and two more at the C-terminus (Ser-413 and Ser-416) (Figure 1B,C). Of these, Ser-305 was 66% phosphorylated and Ser-352, Ser-413, and Ser-416 were ∼45−58% phosphorylated (Table 1). Using wild-type MARK2cat at 25 °C and pH 6.8, the same phosphorylation sites were observed. The three primary sites, Ser-262, Ser-324, and Ser-356, were still completely phosphorylated.",
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+      "evidence": "Immunohistochemical analyses using isoform-selective antibodies demonstrated that MARK4 in a phosphorylated form colocalizes with p-tau Ser262 in granulovacuolar degeneration bodies (GVDs) that progressively accumulate in AD.",
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+      "line": 2134,
+      "relation": "positiveCorrelation",
+      "source": 1006,
+      "target": 1017
     },
     {
       "annotations": {
-        "Cell_Line": {
-          "NIH/3T3": true
+        "Confidence": {
+          "Medium": true
+        },
+        "Disease": {
+          "Alzheimer's disease": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
         }
       },
       "citation": {
         "authors": [
-          "Agerman K",
-          "Eckersley S",
-          "Gu GJ",
-          "Kamali-Moghaddam M",
-          "Kvist AJ",
-          "Landegren U",
-          "Lund H",
-          "Milner R",
-          "Nilsson LN",
-          "Sunnemark D",
-          "Wu D"
+          "Chen C",
+          "Dong XP",
+          "Gong HS",
+          "Guo Y",
+          "Liu Y",
+          "Shi Q",
+          "Tian C",
+          "Wang SB",
+          "Xie WL",
+          "Xu Y",
+          "Zhang BY",
+          "Zhang J"
         ],
-        "date": "2013-01-01",
-        "first": "Gu GJ",
-        "last": "Kamali-Moghaddam M",
-        "name": "Journal of Alzheimer's disease : JAD",
-        "pages": "699-713",
-        "reference": "23001711",
-        "title": "Elevated MARK2-dependent phosphorylation of Tau in Alzheimer's disease.",
+        "date": "2012-09-01",
+        "first": "Gong HS",
+        "last": "Dong XP",
+        "name": "International journal of molecular medicine",
+        "pages": "569-78",
+        "reference": "22692785",
+        "title": "Reduction of protein kinase MARK4 in the brains of experimental scrapie rodents and human prion disease correlates with deposits of PrP(Sc).",
         "type": "PubMed",
-        "volume": "33"
-      },
-      "evidence": "Several kinases such as microtubule-affinity regulating kinase (MARK), protein kinase A, calcium calmodulin kinase II, and checkpoint kinase 2 are known to phosphorylate tau on Ser(262) in vitro. In this study, we took advantage of the in situ proximity ligation assay to investigate the role of MARK2, one of the four MARK isoforms, in AD. We demonstrate that MARK2 interacts with tau and phosphorylates tau at Ser(262) in stably transfected NIH/3T3 cells expressing human recombinant tau. Staurosporine, a protein kinase inhibitor, significantly reduced the interaction between MARK2 and tau, and also phosphorylation of tau at Ser(262).",
-      "key": "d08804d93f72158abf47d778e49e122ea2233dfbaec9696de12c13549b3067887cc860739a29d368a767a2b078f4508f00d413b389487d305a02d0b42e0f77ca",
-      "line": 2767,
-      "relation": "directlyIncreases",
-      "source": 634,
-      "subject": {
-        "effect": {
-          "name": "kin",
-          "namespace": "bel"
-        },
-        "modifier": "Activity"
+        "volume": "30"
       },
-      "target": 557
+      "evidence": "It has been reported that serine 262 in tau, which is specifically phosphorylated by MARK, is in a hyperphosphorylated form in the neurofibrillary deposits found in Alzheimer’s disease brains (15).",
+      "key": "d491b0d103149caad3e3528eb601c1aa753f668b5e966a74923dc4149101bc534b4d191c05dbb164a4c3ed08e7fabd971e6a94a5ed37cc921f5efd1c110f52aa",
+      "line": 2144,
+      "relation": "increases",
+      "source": 145,
+      "target": 642
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
-          "Chen GC",
-          "Chen RH",
-          "Chen YH",
-          "Chien CT",
-          "Chou HJ",
-          "Huang YP",
-          "Kimchi A",
-          "Lin MY",
-          "Tsai PI",
-          "Wu PR"
+          "Lu B",
+          "Malenka R",
+          "Polepalli J",
+          "Rajadas J",
+          "Wagh D",
+          "Yu W"
         ],
-        "date": "2011-09-01",
-        "first": "Wu PR",
-        "last": "Chen RH",
-        "name": "Cell death and differentiation",
-        "pages": "1507-20",
-        "reference": "21311567",
-        "title": "DAPK activates MARK1/2 to regulate microtubule assembly, neuronal differentiation, and tau toxicity.",
+        "date": "2012-03-15",
+        "first": "Yu W",
+        "last": "Lu B",
+        "name": "Human molecular genetics",
+        "pages": "1384-90",
+        "reference": "22156579",
+        "title": "A critical role for the PAR-1/MARK-tau axis in mediating the toxic effects of Aβ on synapses and dendritic spines.",
         "type": "PubMed",
-        "volume": "18"
+        "volume": "21"
       },
-      "evidence": "Importantly, depletion of MARK1/2 reversed the inhibitory effect of DAPK on MT regrowth (Figure 5c, right panel). These results indicate that the DAPK–MARK signaling axis inhibits MT assembly and stability.",
-      "key": "2c7d91091bdbc72b8b1fb999037d76c6db07100070b602d7f1c861338a19112c83a00be9392eba911fc02365bf386b65bcb2ff42be4b849ae2374e1b66b07dc3",
-      "line": 2009,
-      "relation": "decreases",
-      "source": 634,
-      "subject": {
+      "evidence": "To probe the involvement of endogenous MARK kinases in mediating the synaptic toxicity of Aβ, we employed a peptide inhibitor capable of effectively and specifically inhibiting the activities of all PAR-1/MARK family members. This inhibitor abrogated the toxic effects of Aβ oligomers on dendritic spines and synapses as assayed at the morphological and electrophysiological levels.",
+      "key": "a453ba5a267d2601cf4760f5f97fd6a841db8cd648963b7b100ad6894bef7aff1d3aeddef453e4ee3dc2628febc6ccbad88e30cd3d9e1f95d86a395706c76d32",
+      "line": 2170,
+      "object": {
         "modifier": "Activity"
       },
-      "target": 186
+      "relation": "positiveCorrelation",
+      "source": 145,
+      "target": 123
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        },
+        "MeSHDisease": {
+          "Creutzfeldt-Jakob Syndrome": true,
+          "Insomnia, Fatal Familial": true
+        }
+      },
       "citation": {
         "authors": [
-          "Bibow S",
-          "Biernat J",
-          "Blackledge M",
-          "Jensen MR",
-          "Kadavath H",
-          "Mandelkow E",
-          "Ozenne V",
-          "Schwalbe M",
-          "Zweckstetter M"
+          "Chen C",
+          "Dong XP",
+          "Gong HS",
+          "Guo Y",
+          "Liu Y",
+          "Shi Q",
+          "Tian C",
+          "Wang SB",
+          "Xie WL",
+          "Xu Y",
+          "Zhang BY",
+          "Zhang J"
         ],
-        "date": "2013-12-17",
-        "first": "Schwalbe M",
-        "last": "Zweckstetter M",
-        "name": "Biochemistry",
-        "pages": "9068-79",
-        "reference": "24251416",
-        "title": "Phosphorylation of human Tau protein by microtubule affinity-regulating kinase 2.",
+        "date": "2012-09-01",
+        "first": "Gong HS",
+        "last": "Dong XP",
+        "name": "International journal of molecular medicine",
+        "pages": "569-78",
+        "reference": "22692785",
+        "title": "Reduction of protein kinase MARK4 in the brains of experimental scrapie rodents and human prion disease correlates with deposits of PrP(Sc).",
         "type": "PubMed",
-        "volume": "52"
-      },
-      "evidence": "While residues Ser-262, Ser-324, and Ser-356 were completely phosphorylated, Ser-293 in the second repeat was only 84% phosphorylated (Table 1). Furthermore, four non-KXGS phosphorylation sites were detected, two within the repeat domain (Ser-305 in R2 and Ser-352 in R4) and two more at the C-terminus (Ser-413 and Ser-416) (Figure 1B,C). Of these, Ser-305 was 66% phosphorylated and Ser-352, Ser-413, and Ser-416 were ∼45−58% phosphorylated (Table 1). Using wild-type MARK2cat at 25 °C and pH 6.8, the same phosphorylation sites were observed. The three primary sites, Ser-262, Ser-324, and Ser-356, were still completely phosphorylated.",
-      "key": "959e3f3379bf4f7a4bfddbbede623489e84925651a5c56137030932c755d115b8d14b6d3d8c1dc39d6919cd5f7bdb024927e15b6e076c71dc5f7aa6060eceea1",
-      "line": 2636,
-      "relation": "directlyIncreases",
-      "source": 634,
-      "subject": {
-        "effect": {
-          "name": "kin",
-          "namespace": "bel"
-        },
-        "modifier": "Activity"
+        "volume": "30"
       },
-      "target": 561
+      "evidence": "MARK4 was extremely decreased in the brain regions with a mass of PrPSc in a G114V gCJD patient, but was clearly observable in the regions with a minimum amount of PrPSc or without detectable PrPSc in a D178N FFI patient.",
+      "key": "c75da77d46137b6fe8f550a58aefc96864b4e64524ab5887472a152c03060794f92ec045959f3ed9c494c4891147bc40dbc0fc66d79a49552312dd1c22331e9b",
+      "line": 2153,
+      "relation": "negativeCorrelation",
+      "source": 447,
+      "target": 722
     },
     {
+      "annotations": {
+        "Cell_Line": {
+          "PC12": true,
+          "SK-N-SH": true
+        },
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
-          "Bibow S",
-          "Biernat J",
-          "Blackledge M",
-          "Jensen MR",
-          "Kadavath H",
-          "Mandelkow E",
-          "Ozenne V",
-          "Schwalbe M",
-          "Zweckstetter M"
-        ],
-        "date": "2013-12-17",
-        "first": "Schwalbe M",
-        "last": "Zweckstetter M",
-        "name": "Biochemistry",
-        "pages": "9068-79",
-        "reference": "24251416",
-        "title": "Phosphorylation of human Tau protein by microtubule affinity-regulating kinase 2.",
-        "type": "PubMed",
-        "volume": "52"
-      },
-      "evidence": "While residues Ser-262, Ser-324, and Ser-356 were completely phosphorylated, Ser-293 in the second repeat was only 84% phosphorylated (Table 1). Furthermore, four non-KXGS phosphorylation sites were detected, two within the repeat domain (Ser-305 in R2 and Ser-352 in R4) and two more at the C-terminus (Ser-413 and Ser-416) (Figure 1B,C). Of these, Ser-305 was 66% phosphorylated and Ser-352, Ser-413, and Ser-416 were ∼45−58% phosphorylated (Table 1). Using wild-type MARK2cat at 25 °C and pH 6.8, the same phosphorylation sites were observed. The three primary sites, Ser-262, Ser-324, and Ser-356, were still completely phosphorylated.",
-      "key": "717715808a9a2abeae10cb041263b5fd0f66219a4a9cfe12756c624362133abce5be2d0611aba6af2f79063e847ce93e24e24929adc00b5a36ffeea05dc647f3",
-      "line": 2637,
-      "relation": "directlyIncreases",
-      "source": 634,
-      "subject": {
-        "effect": {
-          "name": "kin",
-          "namespace": "bel"
-        },
-        "modifier": "Activity"
-      },
-      "target": 563
-    },
-    {
-      "citation": {
-        "authors": [
-          "Bibow S",
-          "Biernat J",
-          "Blackledge M",
-          "Jensen MR",
-          "Kadavath H",
-          "Mandelkow E",
-          "Ozenne V",
-          "Schwalbe M",
-          "Zweckstetter M"
+          "Chen C",
+          "Dong XP",
+          "Gong HS",
+          "Guo Y",
+          "Liu Y",
+          "Shi Q",
+          "Tian C",
+          "Wang SB",
+          "Xie WL",
+          "Xu Y",
+          "Zhang BY",
+          "Zhang J"
         ],
-        "date": "2013-12-17",
-        "first": "Schwalbe M",
-        "last": "Zweckstetter M",
-        "name": "Biochemistry",
-        "pages": "9068-79",
-        "reference": "24251416",
-        "title": "Phosphorylation of human Tau protein by microtubule affinity-regulating kinase 2.",
+        "date": "2012-09-01",
+        "first": "Gong HS",
+        "last": "Dong XP",
+        "name": "International journal of molecular medicine",
+        "pages": "569-78",
+        "reference": "22692785",
+        "title": "Reduction of protein kinase MARK4 in the brains of experimental scrapie rodents and human prion disease correlates with deposits of PrP(Sc).",
         "type": "PubMed",
-        "volume": "52"
-      },
-      "evidence": "While residues Ser-262, Ser-324, and Ser-356 were completely phosphorylated, Ser-293 in the second repeat was only 84% phosphorylated (Table 1). Furthermore, four non-KXGS phosphorylation sites were detected, two within the repeat domain (Ser-305 in R2 and Ser-352 in R4) and two more at the C-terminus (Ser-413 and Ser-416) (Figure 1B,C). Of these, Ser-305 was 66% phosphorylated and Ser-352, Ser-413, and Ser-416 were ∼45−58% phosphorylated (Table 1). Using wild-type MARK2cat at 25 °C and pH 6.8, the same phosphorylation sites were observed. The three primary sites, Ser-262, Ser-324, and Ser-356, were still completely phosphorylated.",
-      "key": "2534d690bce73f21e487135b3c9c208a0b816cfc4626af8a82afeb582d74dc6139c93a01fa0d043fc68bc2c6af2d066505153ffe73063752c7a8cd6362eedbe4",
-      "line": 2638,
-      "relation": "directlyIncreases",
-      "source": 634,
-      "subject": {
-        "effect": {
-          "name": "kin",
-          "namespace": "bel"
-        },
-        "modifier": "Activity"
+        "volume": "30"
       },
-      "target": 559
+      "evidence": "These finding highlight that treatment of PrP106-126 in cultured cells does not alter the level of total tau, but induces a reduction of p-tau262.",
+      "key": "4b144f62dc76bf95dca7b02b506102e09089f299ec0a7c61665b7baf056eef6acfce1c67a217c4fe27d12d817ee43a0b5f22a049d6520125cceb3c0765e0b062",
+      "line": 2160,
+      "relation": "decreases",
+      "source": 400,
+      "target": 642
     },
     {
-      "citation": {
-        "authors": [
-          "Bibow S",
-          "Biernat J",
-          "Blackledge M",
-          "Jensen MR",
-          "Kadavath H",
-          "Mandelkow E",
-          "Ozenne V",
-          "Schwalbe M",
-          "Zweckstetter M"
-        ],
-        "date": "2013-12-17",
-        "first": "Schwalbe M",
-        "last": "Zweckstetter M",
-        "name": "Biochemistry",
-        "pages": "9068-79",
-        "reference": "24251416",
-        "title": "Phosphorylation of human Tau protein by microtubule affinity-regulating kinase 2.",
-        "type": "PubMed",
-        "volume": "52"
-      },
-      "evidence": "While residues Ser-262, Ser-324, and Ser-356 were completely phosphorylated, Ser-293 in the second repeat was only 84% phosphorylated (Table 1). Furthermore, four non-KXGS phosphorylation sites were detected, two within the repeat domain (Ser-305 in R2 and Ser-352 in R4) and two more at the C-terminus (Ser-413 and Ser-416) (Figure 1B,C). Of these, Ser-305 was 66% phosphorylated and Ser-352, Ser-413, and Ser-416 were ∼45−58% phosphorylated (Table 1). Using wild-type MARK2cat at 25 °C and pH 6.8, the same phosphorylation sites were observed. The three primary sites, Ser-262, Ser-324, and Ser-356, were still completely phosphorylated.",
-      "key": "afbc0cd779781b3e970d4f1d2c9a6e4b7f7275c56b6592a8171ca641b311f82c729cf6c1fd4cac2d2b6a1233fc560b8a33b2e0def7be8474f67c1e66623b0d8c",
-      "line": 2640,
-      "relation": "directlyIncreases",
-      "source": 634,
-      "subject": {
-        "effect": {
-          "name": "kin",
-          "namespace": "bel"
-        },
-        "modifier": "Activity"
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
       },
-      "target": 560
-    },
-    {
       "citation": {
         "authors": [
-          "Bibow S",
-          "Biernat J",
-          "Blackledge M",
-          "Jensen MR",
-          "Kadavath H",
-          "Mandelkow E",
-          "Ozenne V",
-          "Schwalbe M",
-          "Zweckstetter M"
+          "Lu B",
+          "Malenka R",
+          "Polepalli J",
+          "Rajadas J",
+          "Wagh D",
+          "Yu W"
         ],
-        "date": "2013-12-17",
-        "first": "Schwalbe M",
-        "last": "Zweckstetter M",
-        "name": "Biochemistry",
-        "pages": "9068-79",
-        "reference": "24251416",
-        "title": "Phosphorylation of human Tau protein by microtubule affinity-regulating kinase 2.",
+        "date": "2012-03-15",
+        "first": "Yu W",
+        "last": "Lu B",
+        "name": "Human molecular genetics",
+        "pages": "1384-90",
+        "reference": "22156579",
+        "title": "A critical role for the PAR-1/MARK-tau axis in mediating the toxic effects of Aβ on synapses and dendritic spines.",
         "type": "PubMed",
-        "volume": "52"
+        "volume": "21"
       },
-      "evidence": "While residues Ser-262, Ser-324, and Ser-356 were completely phosphorylated, Ser-293 in the second repeat was only 84% phosphorylated (Table 1). Furthermore, four non-KXGS phosphorylation sites were detected, two within the repeat domain (Ser-305 in R2 and Ser-352 in R4) and two more at the C-terminus (Ser-413 and Ser-416) (Figure 1B,C). Of these, Ser-305 was 66% phosphorylated and Ser-352, Ser-413, and Ser-416 were ∼45−58% phosphorylated (Table 1). Using wild-type MARK2cat at 25 °C and pH 6.8, the same phosphorylation sites were observed. The three primary sites, Ser-262, Ser-324, and Ser-356, were still completely phosphorylated.",
-      "key": "49ae11c4a271fff31a75f67c1bd30cf7857f13ada2e5cb2b18fedbf1419cc942a783ac44f25ecfd99b0edbcfa0f82c4aa6630ba100684164b61e51c0f8d8cead",
-      "line": 2642,
-      "relation": "directlyIncreases",
-      "source": 634,
+      "evidence": "To probe the involvement of endogenous MARK kinases in mediating the synaptic toxicity of Aβ, we employed a peptide inhibitor capable of effectively and specifically inhibiting the activities of all PAR-1/MARK family members. This inhibitor abrogated the toxic effects of Aβ oligomers on dendritic spines and synapses as assayed at the morphological and electrophysiological levels.",
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+      "line": 2170,
+      "relation": "positiveCorrelation",
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       "subject": {
-        "effect": {
-          "name": "kin",
-          "namespace": "bel"
-        },
         "modifier": "Activity"
       },
-      "target": 562
+      "target": 145
     },
     {
-      "citation": {
-        "authors": [
-          "Bibow S",
-          "Biernat J",
-          "Blackledge M",
-          "Jensen MR",
-          "Kadavath H",
-          "Mandelkow E",
-          "Ozenne V",
-          "Schwalbe M",
-          "Zweckstetter M"
-        ],
-        "date": "2013-12-17",
-        "first": "Schwalbe M",
-        "last": "Zweckstetter M",
-        "name": "Biochemistry",
-        "pages": "9068-79",
-        "reference": "24251416",
-        "title": "Phosphorylation of human Tau protein by microtubule affinity-regulating kinase 2.",
-        "type": "PubMed",
-        "volume": "52"
-      },
-      "evidence": "While residues Ser-262, Ser-324, and Ser-356 were completely phosphorylated, Ser-293 in the second repeat was only 84% phosphorylated (Table 1). Furthermore, four non-KXGS phosphorylation sites were detected, two within the repeat domain (Ser-305 in R2 and Ser-352 in R4) and two more at the C-terminus (Ser-413 and Ser-416) (Figure 1B,C). Of these, Ser-305 was 66% phosphorylated and Ser-352, Ser-413, and Ser-416 were ∼45−58% phosphorylated (Table 1). Using wild-type MARK2cat at 25 °C and pH 6.8, the same phosphorylation sites were observed. The three primary sites, Ser-262, Ser-324, and Ser-356, were still completely phosphorylated.",
-      "key": "16644673d63fc779f15ffa63830ffd1393b9755989ffe9f13991dc88c4d560c45b7a061b26a6d195ad551d31c7ab46365c30a20dde538006f59cdfd7471f6649",
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-      "relation": "directlyIncreases",
-      "source": 634,
-      "subject": {
-        "effect": {
-          "name": "kin",
-          "namespace": "bel"
-        },
-        "modifier": "Activity"
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
       },
-      "target": 567
-    },
-    {
       "citation": {
         "authors": [
-          "Bibow S",
-          "Biernat J",
-          "Blackledge M",
-          "Jensen MR",
-          "Kadavath H",
-          "Mandelkow E",
-          "Ozenne V",
-          "Schwalbe M",
-          "Zweckstetter M"
+          "Lu B",
+          "Malenka R",
+          "Polepalli J",
+          "Rajadas J",
+          "Wagh D",
+          "Yu W"
         ],
-        "date": "2013-12-17",
-        "first": "Schwalbe M",
-        "last": "Zweckstetter M",
-        "name": "Biochemistry",
-        "pages": "9068-79",
-        "reference": "24251416",
-        "title": "Phosphorylation of human Tau protein by microtubule affinity-regulating kinase 2.",
+        "date": "2012-03-15",
+        "first": "Yu W",
+        "last": "Lu B",
+        "name": "Human molecular genetics",
+        "pages": "1384-90",
+        "reference": "22156579",
+        "title": "A critical role for the PAR-1/MARK-tau axis in mediating the toxic effects of Aβ on synapses and dendritic spines.",
         "type": "PubMed",
-        "volume": "52"
-      },
-      "evidence": "While residues Ser-262, Ser-324, and Ser-356 were completely phosphorylated, Ser-293 in the second repeat was only 84% phosphorylated (Table 1). Furthermore, four non-KXGS phosphorylation sites were detected, two within the repeat domain (Ser-305 in R2 and Ser-352 in R4) and two more at the C-terminus (Ser-413 and Ser-416) (Figure 1B,C). Of these, Ser-305 was 66% phosphorylated and Ser-352, Ser-413, and Ser-416 were ∼45−58% phosphorylated (Table 1). Using wild-type MARK2cat at 25 °C and pH 6.8, the same phosphorylation sites were observed. The three primary sites, Ser-262, Ser-324, and Ser-356, were still completely phosphorylated.",
-      "key": "4fff548b198ec5f7524dc87112abf42629822e5f0cbcb5e48f31b5b75aeba3bbf16d27e0189ec78927db1083787fc5c397438beb2021f655c240f242abdc1f3e",
-      "line": 2645,
-      "relation": "directlyIncreases",
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-      "subject": {
-        "effect": {
-          "name": "kin",
-          "namespace": "bel"
-        },
-        "modifier": "Activity"
+        "volume": "21"
       },
-      "target": 568
+      "evidence": "We first confirmed that expression of an MKI-GFP fusion protein in rat hippocampal neurons effectively attenuated MARK4-mediated phosphorylation of both endogenous tau (Fig. 3A) and transfected human tau at the 12E8 sites (Fig. 3B). Phosphorylation of tau at the PHF-1 site was also reduced by MKI (Fig. 3A). It is possible that the PHF-1 site is also targeted by PAR-1/MARKs in vivo, or that the phosphorylation of tau at the 12E8 sites is a prerequisite for PHF-1 site phosphorylation, as the 12E8 sites were previously shown to be required for tau phosphorylation at other sites",
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+        "pages": "39-51",
+        "reference": "27623715",
+        "title": "Endogenous reactive oxygen species cause astrocyte defects and neuronal dysfunctions in the hippocampus: a new model for aging brain.",
         "type": "PubMed",
-        "volume": "110"
+        "volume": "16"
       },
-      "evidence": "Normalizing the gene dosage of Dyrk1A in the TS mouse rescued the density of senescent cells in the cingulate cortex, hippocampus and septum, prevented cholinergic neuron degeneration, and reduced App expression in the hippocampus, Aß load in the cortex and hippocampus, the expression of phosphorylated tau at the Ser202 residue in the hippocampus and cerebellum and the levels of total tau in the cortex, hippocampus and cerebellum.",
-      "key": "d5bbf5edc4112f272903538c0629c2a8b2912ba3926cf084656e6034a75b4b6892083c7f4088fc5adc53102fff78f7df0de3f46e93c3ddbf0a439632b2b18866",
-      "line": 2054,
-      "relation": "negativeCorrelation",
-      "source": 786,
-      "target": 803
+      "evidence": "Only middle-aged Tet-mev-1 mice showed JNK/MARK activation and Ca2+ overload, particularly in astrocytes with decreased hippocampal GFAP and S100ß, but without pathological features such as apoptosis, amyloidosis, and lactic acidosis in neurons and astrocytes. This led to decreasing levels of glial fibrillary acidic protein and S100β in the hippocampal area.",
+      "key": "8e22fc3aa6b56897816a93f78865fef6d5b4493ba166870dfd8ec9c41a80163a2a4497b6d8f71393e178485e3da1ac3dc2a9548836473abed6ca5bebbde6dbe7",
+      "line": 2217,
+      "relation": "causesNoChange",
+      "source": 226,
+      "target": 171
     },
     {
       "annotations": {
         "Anatomy": {
-          "dorsal plus ventral thalamus": true,
-          "hippocampal formation": true,
-          "hypothalamus": true,
-          "striatum": true
+          "cerebral cortex": true
+        },
+        "Confidence": {
+          "Medium": true
         },
         "Species": {
-          "10090": true
+          "10116": true
         }
       },
       "citation": {
         "authors": [
-          "Assayag E",
-          "Bui LC",
-          "Dairou J",
-          "Daubigney F",
-          "Delabar JM",
-          "Janel N",
-          "London J",
-          "Luquet S",
-          "Magnan C",
-          "Medjaoui H",
-          "Rouch C",
-          "Souchet B"
+          "Marani L",
+          "Marino S",
+          "Selvatici R",
+          "Siniscalchi A"
         ],
-        "date": "2018-05-01",
-        "first": "London J",
-        "last": "Janel N",
-        "name": "Molecular neurobiology",
-        "pages": "3822-3831",
-        "reference": "28540658",
-        "title": "Overexpression of the DYRK1A Gene (Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 1A) Induces Alterations of the Serotoninergic and Dopaminergic Processing in Murine Brain Tissues.",
+        "date": "2013-08-01",
+        "first": "Selvatici R",
+        "last": "Siniscalchi A",
+        "name": "Neurochemistry international",
+        "pages": "112-20",
+        "reference": "23722080",
+        "title": "In vitro mitochondrial failure and oxidative stress mimic biochemical features of Alzheimer disease.",
         "type": "PubMed",
-        "volume": "55"
+        "volume": "63"
       },
-      "evidence": "DYRK1A overexpression induced dramatic deficits in the serotonin contents of the four brain areas tested and major deficits in dopamine and adrenaline contents especially in the hypothalamus.",
-      "key": "b3e7e4484dffdff880f0d22bd526acdd5a435cda12e50e9cb411feb3696668ee92fa3f60f804c3fc8bef7c0b1c0d99df0b42e7a41f2156b8f3c3ae694e391750",
-      "line": 2086,
+      "evidence": "Primary cortical neurons exposed to the mitochondrial toxin NaN3 (0.1-3 mM) were submitted to oxidative stress with H2O2 (30-150 μM), to mimic conditions observed in neurodegenerative disorders. The effects of such treatment on a series of parameters useful in characterizing neuronal damage were investigated: (i) the basal release of glutamate, evaluated as (3)H-d-Aspartate efflux, was sharply, concentration-dependently, increased; (ii) the phosphorylation status of intracellular markers known to be involved in the neurodegenerative processes, in particular in Alzheimer disease: tau and GSK3β were increased, as well as the protein level of β-secretase (BACE1) and p35/25 evaluated by Western blotting, while (iii) the cell metabolic activity, measured with the MTT method, was reduced, in a concentration- and time-dependent manner. The latter effect, as well as tau hyperphosphorylation, was prevented both by a mixture of antioxidant drugs (100 μM ascorbic acid, 10 μM trolox, 100 μM glutathione) and by the anti-Alzheimer drug, memantine, 20 μM.",
+      "key": "8e1a360306277d46ce9f8346b32755e6b1811e47713488d845be3f756507db7fb09417631dd2aba83fd0386ae17c57fd83cad79fff54a2d6023b5a63261ca537",
+      "line": 3362,
       "relation": "decreases",
-      "source": 786,
-      "target": 71
+      "source": 226,
+      "target": 100
     },
     {
       "annotations": {
-        "Anatomy": {
-          "hypothalamus": true
+        "Confidence": {
+          "High": true
+        },
+        "Research_Model": {
+          "SAMP8 mice": true
         },
         "Species": {
           "10090": true
@@ -51382,858 +58367,892 @@
       },
       "citation": {
         "authors": [
-          "Assayag E",
-          "Bui LC",
-          "Dairou J",
-          "Daubigney F",
-          "Delabar JM",
-          "Janel N",
-          "London J",
-          "Luquet S",
-          "Magnan C",
-          "Medjaoui H",
-          "Rouch C",
-          "Souchet B"
+          "Butterfield DA",
+          "Farr SA",
+          "Kumar V",
+          "Morley JE",
+          "Murphy MP",
+          "Niehoff ML",
+          "Platt TL",
+          "Ripley JL",
+          "Sultana R",
+          "Zhang Z"
         ],
-        "date": "2018-05-01",
-        "first": "London J",
-        "last": "Janel N",
-        "name": "Molecular neurobiology",
-        "pages": "3822-3831",
-        "reference": "28540658",
-        "title": "Overexpression of the DYRK1A Gene (Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 1A) Induces Alterations of the Serotoninergic and Dopaminergic Processing in Murine Brain Tissues.",
+        "date": "2014-02-01",
+        "first": "Farr SA",
+        "last": "Butterfield DA",
+        "name": "Free radical biology &amp; medicine",
+        "pages": "387-95",
+        "reference": "24355211",
+        "title": "Antisense oligonucleotide against GSK-3β in brain of SAMP8 mice improves learning and memory and decreases oxidative stress: Involvement of transcription factor Nrf2 and implications for Alzheimer disease.",
         "type": "PubMed",
-        "volume": "55"
+        "volume": "67"
       },
-      "evidence": "DYRK1A overexpression induced dramatic deficits in the serotonin contents of the four brain areas tested and major deficits in dopamine and adrenaline contents especially in the hypothalamus.",
-      "key": "8e4fa6a1f5928c8fb85519ce28958239d0a711c9ea601131b1b2c564979ff4d6ae261f80a34b2b659a53f9fc9f244720d36c873270d436bef8f2ac06a9203fc1",
-      "line": 2089,
-      "relation": "decreases",
-      "source": 786,
-      "target": 46
+      "evidence": "Nuclear factor erythroid-2-related factor 2 (Nrf2) is a transcription factor known to increase the level of many antioxidants, including glutathione-S transferase (GST), and is negatively regulated by the activity of GSK-3β. Our results indicated the increased nuclear localization of Nrf2 and level of GST, suggesting the increased activity of the transcription factor as a result of GSK-3β suppression, consistent with the decreased oxidative stress observed. Consistent with the improved learning and memory, and consistent with GSK-3b being a tau kinase, we observed decreased tau phosphorylation in brain of GAO-treated SAMP8 mice compared to that of RAO-treated SAMP8 mice.",
+      "key": "6c71c8c05edfc5e2868dec5a122d0c28e74a2320b700b2c38259447ca1ddfef8e8eee31d5210e6a353764d5234ff51d1e968d6d48776a1fc1958e00e484336fd",
+      "line": 3449,
+      "relation": "positiveCorrelation",
+      "source": 226,
+      "target": 537
     },
     {
       "annotations": {
-        "Anatomy": {
-          "hypothalamus": true
-        },
-        "Species": {
-          "10090": true
+        "Confidence": {
+          "Medium": true
         }
       },
       "citation": {
         "authors": [
-          "Assayag E",
-          "Bui LC",
-          "Dairou J",
-          "Daubigney F",
-          "Delabar JM",
-          "Janel N",
-          "London J",
-          "Luquet S",
-          "Magnan C",
-          "Medjaoui H",
-          "Rouch C",
-          "Souchet B"
+          "Alonso AC",
+          "Grundke-Iqbal I",
+          "Iqbal K",
+          "Köpke E",
+          "Shaikh S",
+          "Tung YC"
         ],
-        "date": "2018-05-01",
-        "first": "London J",
-        "last": "Janel N",
-        "name": "Molecular neurobiology",
-        "pages": "3822-3831",
-        "reference": "28540658",
-        "title": "Overexpression of the DYRK1A Gene (Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 1A) Induces Alterations of the Serotoninergic and Dopaminergic Processing in Murine Brain Tissues.",
+        "date": "1993-11-15",
+        "first": "Köpke E",
+        "last": "Grundke-Iqbal I",
+        "name": "The Journal of biological chemistry",
+        "pages": "24374-84",
+        "reference": "8226987",
+        "title": "Microtubule-associated protein tau. Abnormal phosphorylation of a non-paired helical filament pool in Alzheimer disease.",
         "type": "PubMed",
-        "volume": "55"
+        "volume": "268"
       },
-      "evidence": "DYRK1A overexpression induced dramatic deficits in the serotonin contents of the four brain areas tested and major deficits in dopamine and adrenaline contents especially in the hypothalamus.",
-      "key": "6fcdd60f2ff4da99a96b839e9a58c1aac269b5fe28eaac812649b09fb404146e43d8875b35306bec463f21b43547cf2a7a2c5d51683ecad690697c0bfdd82af2",
-      "line": 2090,
-      "relation": "decreases",
-      "source": 786,
-      "target": 41
+      "evidence": ">8 phosphates per tau molecules (vs 2 in adult healthy brain); can also be increased during development, hibernation and temperature, heat and oxydative stress These phosphorylated states are detected by specific antibodies and are targets of proline-directed kinases (SP motifs), non-proline kinases (KXGS motif) Weakens tau-MT interaction especially S261 in R1 and S214 in proline-rich domain",
+      "key": "167e5b1ebe4541fddf99975ec66854af9e4eaac7e2afe1e7557990b54a031514325e0c2e0a40f647de2986dc83610c060ba847e7a09cf590f18faf1ddf461f76",
+      "line": 3464,
+      "relation": "increases",
+      "source": 226,
+      "target": 599
     },
     {
       "annotations": {
-        "MeSHDisease": {
-          "Alzheimer Disease": true,
-          "Down Syndrome": true
-        },
-        "Research_Model": {
-          "Ts65Dn mice": true
-        },
-        "Species": {
-          "10090": true
+        "Confidence": {
+          "High": true
         }
       },
       "citation": {
         "authors": [
-          "Chen L",
-          "Sun X",
-          "Wang L",
-          "Wang P"
+          "Biernat J",
+          "Mandelkow E",
+          "Mandelkow EM",
+          "Schweers O"
         ],
-        "date": "2017-08-03",
-        "first": "Wang P",
-        "last": "Sun X",
-        "name": "Scientific reports",
-        "pages": "7240",
-        "reference": "28775333",
-        "title": "Dual-specificity tyrosine-phosphorylation regulated kinase 1A Gene Transcription is regulated by Myocyte Enhancer Factor 2D.",
+        "date": "1995-08-29",
+        "first": "Schweers O",
+        "last": "Mandelkow E",
+        "name": "Proceedings of the National Academy of Sciences of the United States of America",
+        "pages": "8463-7",
+        "reference": "7667312",
+        "title": "Oxidation of cysteine-322 in the repeat domain of microtubule-associated protein tau controls the in vitro assembly of paired helical filaments.",
         "type": "PubMed",
-        "volume": "7"
+        "volume": "92"
       },
-      "evidence": "Inhibition of Dyrk1A enhanced tau exon 10 inclusion, leading to an increase in 4R-tau/3R-tau ratio in differentiated-human neuronal progenitors and in the neonatal rat brains. Accompanied with overexpression of Dyrk1A, 3R-tau was increased and 4R-tau was decreased in the neonatal brains of Ts65Dn mice, a model of Down syndrome.",
-      "key": "70a6fff1b37515fd08ca1976614f8eae70ae55bda562c64b951e9128b73c0561b0af625a329689917c0c3c4479c23636b87bc158beab1c15d6d3b56d40b30d65",
-      "line": 2123,
-      "relation": "positiveCorrelation",
-      "source": 786,
-      "target": 306
+      "evidence": "Though whole tau assembled poorly, constructs containing three internal repeats (corresponding to the fetal tau isoform) formed PHFs reproducibly. This ability depended on intermolecular disulfide bridges formed by the single Cys-322. Blocking the SH group, mutating Cys for Ala, or keeping T in a reducing environment all inhibited assembly. On the other hand, Cys-322 can be oxidized, and this leads to PHF assembly (ref. 11; this report). In vitro this is achieved most easily by using constructs of the 'fetal' isoform of T (htau23) that has only three repeats. Conversely, reducing agents or the second repeat or T can be viewed as 'antidotes' against PHF assembly.The synthetic PHFs bound the dye thioflavin S used in Alzheimer disease diagnostics.",
+      "key": "0aa12fae18b2be719522350db69aee018742bbaac7d4eb51f6a7d99491687d2b03ccf1435473a00c354d115c333726547e53710fe74066e1f42c896b04d64e72",
+      "line": 3593,
+      "relation": "increases",
+      "source": 226,
+      "target": 127
+    },
+    {
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+      "relation": "hasComponent",
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+      "relation": "hasComponent",
+      "source": 259,
+      "target": 642
+    },
+    {
+      "key": "005c7a20b05ad008d1177aea70cc647f09af292b3271f32a14e0560dd27d0f149bdcf6ac6c4ba97f784c60f263b13028efe1c161d77536afbad189817b21bfb7",
+      "relation": "hasComponent",
+      "source": 260,
+      "target": 407
+    },
+    {
+      "key": "90d8a5b8a3ca2a9fc97bf22142951c48bc5f1814ab69d95f20f93dbf9c57410e91eecf433fb19ce461a996cdb98e5614d727c88e88b57560f966e4ef16b80135",
+      "relation": "hasComponent",
+      "source": 260,
+      "target": 642
+    },
+    {
+      "key": "72fe24635ef02d3492895b1efc3a0c843e438954e13610a3a7c595d44cf96635fb54819c18229ac41061a831a2ddc18d42f9180943746c97fc32d9864d697959",
+      "relation": "hasComponent",
+      "source": 284,
+      "target": 567
+    },
+    {
+      "key": "8ecfa872c0c9b0e3695ae3d8d668e7381178134fd5343950f2a32465ae9f6bdb34d8cb190f88cec50c0be24c1f8e83320932d815c222dba7b36dce8608b41566",
+      "relation": "hasComponent",
+      "source": 284,
+      "target": 719
     },
     {
       "annotations": {
-        "MeSHDisease": {
-          "Alzheimer Disease": true,
-          "Down Syndrome": true
-        },
-        "Research_Model": {
-          "Ts65Dn mice": true
-        },
-        "Species": {
-          "10090": true
+        "Confidence": {
+          "Medium": true
         }
       },
       "citation": {
         "authors": [
-          "Chen L",
-          "Sun X",
-          "Wang L",
-          "Wang P"
+          "Blokzijl A",
+          "Classon C",
+          "Gu GJ",
+          "Kamali-Moghaddam M",
+          "Landegren U",
+          "Lund H",
+          "Sunnemark D",
+          "Wu D",
+          "von Euler G"
         ],
-        "date": "2017-08-03",
-        "first": "Wang P",
-        "last": "Sun X",
-        "name": "Scientific reports",
-        "pages": "7240",
-        "reference": "28775333",
-        "title": "Dual-specificity tyrosine-phosphorylation regulated kinase 1A Gene Transcription is regulated by Myocyte Enhancer Factor 2D.",
+        "date": "2013-09-01",
+        "first": "Gu GJ",
+        "last": "Kamali-Moghaddam M",
+        "name": "Neuromolecular medicine",
+        "pages": "458-69",
+        "reference": "23666762",
+        "title": "Role of individual MARK isoforms in phosphorylation of tau at Ser²⁶² in Alzheimer's disease.",
         "type": "PubMed",
-        "volume": "7"
+        "volume": "15"
       },
-      "evidence": "Inhibition of Dyrk1A enhanced tau exon 10 inclusion, leading to an increase in 4R-tau/3R-tau ratio in differentiated-human neuronal progenitors and in the neonatal rat brains. Accompanied with overexpression of Dyrk1A, 3R-tau was increased and 4R-tau was decreased in the neonatal brains of Ts65Dn mice, a model of Down syndrome.",
-      "key": "8dc752f319b2c4314d3008d831c1ee7792c37089177622537388a2f44d67e0f4ca729fd4e7c81dc3a784bc1d44730763e329bb8edf8d3f5cbafb60fe596eb400",
-      "line": 2124,
-      "relation": "negativeCorrelation",
-      "source": 786,
-      "target": 307
+      "evidence": "In parallel, phosphorylation of tau at Ser262 in MARK-transfected cells was investigated using a rabbit antibody recognizing phosphorylated Ser262 of tau (AGG5759) and a mouse anti-tau antibody (SC-21796) (Fig. S1a3). Tau was shown to interact with each of the transfected MARK isoforms (Fig. 1) and to be phosphorylated at Ser262 (Fig. 2). Staurosporine, a non-selective kinase inhibitor, significantly inhibited interactions between tau and each of the four MARK isoforms after treatment with 20 lM staurosporine for 1 h (Fig. 1; p = 0.02 for MARK1–, MARK2– and MARK3–tau interactions and p = 3 9 10-6 for MARK4–tau interaction). Treatment with staurosporine also significantly reduced PLA signals for tau phosphorylation at Ser262 (Fig. 2; p = 0.04 for MARK1- and p = 0.02 for MARK2- and MARK3- and p = 1 9 10-5 for MARK4-mediated tau phosphorylation)",
+      "key": "79c3868a8fa7ac7c71e14019f023f9c9ca119974c8daecb75fa34e694ff7212ea9fb53dabf56df9f0e41a6b7ffc0f9bc628d970467541e7713897ba08d441d55",
+      "line": 2236,
+      "relation": "increases",
+      "source": 284,
+      "target": 642
     },
     {
       "annotations": {
-        "MeSHDisease": {
-          "Alzheimer Disease": true,
-          "Down Syndrome": true
-        },
-        "Research_Model": {
-          "Ts65Dn mice": true
+        "Confidence": {
+          "Medium": true
         },
-        "Species": {
-          "10090": true
+        "MeSHAnatomy": {
+          "Neurons": true
         }
       },
       "citation": {
         "authors": [
-          "Chen L",
-          "Sun X",
-          "Wang L",
-          "Wang P"
+          "Chen GC",
+          "Chen RH",
+          "Chen YH",
+          "Chien CT",
+          "Chou HJ",
+          "Huang YP",
+          "Kimchi A",
+          "Lin MY",
+          "Tsai PI",
+          "Wu PR"
         ],
-        "date": "2017-08-03",
-        "first": "Wang P",
-        "last": "Sun X",
-        "name": "Scientific reports",
-        "pages": "7240",
-        "reference": "28775333",
-        "title": "Dual-specificity tyrosine-phosphorylation regulated kinase 1A Gene Transcription is regulated by Myocyte Enhancer Factor 2D.",
+        "date": "2011-09-01",
+        "first": "Wu PR",
+        "last": "Chen RH",
+        "name": "Cell death and differentiation",
+        "pages": "1507-20",
+        "reference": "21311567",
+        "title": "DAPK activates MARK1/2 to regulate microtubule assembly, neuronal differentiation, and tau toxicity.",
         "type": "PubMed",
-        "volume": "7"
+        "volume": "18"
       },
-      "evidence": "Treatment with Dyrk1A inhibitor, green tea flavonol epigallocatechin-gallate (EGCG), from gestation to adulthood suppressed 3R-tau expression and rescued anxiety and memory deficits in Ts65Dn mouse brains.",
-      "key": "a3de8bb4703315e780c0572fc516897d5f3952a75e3a1d99f31325ebf901f4a738500ded9c2c581b423a1c247990fb668d161025f7abb07e520e25dcd55eca96",
-      "line": 2132,
-      "relation": "positiveCorrelation",
-      "source": 786,
-      "target": 919
+      "evidence": "Furthermore, silencing of both MARK1 and MARK2 blocked DAPK-induced tau S262 phosphorylation (Figure 3e). More importantly, a decrease of pS262 tau, but not total tau, was observed in brain extracts derived from DAPK−/− mice, compared with that from DAPK+/+ mice (Figure 3f). These results strongly suggest a role of endogenous DAPK in stimulating the activity of endogenous MARK, which in turn phosphorylates tau in neurons.",
+      "key": "bca6870a443c4b7fd69b0cbd5375b3ade8a4070bd4d1416ae3c7e0e7e0acde289be710aa0b57a7d1323f32e9975afeda909499ad64c321dbef88d067acbee084",
+      "line": 2454,
+      "relation": "increases",
+      "source": 719,
+      "subject": {
+        "modifier": "Activity"
+      },
+      "target": 642
     },
     {
       "annotations": {
-        "MeSHDisease": {
-          "Alzheimer Disease": true,
-          "Down Syndrome": true
-        },
-        "Research_Model": {
-          "Ts65Dn mice": true
+        "Confidence": {
+          "Medium": true
         },
         "Species": {
-          "10090": true
+          "7227": true
         }
       },
       "citation": {
         "authors": [
-          "Chen L",
-          "Sun X",
-          "Wang L",
-          "Wang P"
+          "Iijima KM",
+          "Iijima-Ando K",
+          "Lu B",
+          "Maruko-Otake A",
+          "Ohtake Y",
+          "Sekiya M",
+          "Suzuki E"
         ],
-        "date": "2017-08-03",
-        "first": "Wang P",
-        "last": "Sun X",
-        "name": "Scientific reports",
-        "pages": "7240",
-        "reference": "28775333",
-        "title": "Dual-specificity tyrosine-phosphorylation regulated kinase 1A Gene Transcription is regulated by Myocyte Enhancer Factor 2D.",
+        "date": "2012-01-01",
+        "first": "Iijima-Ando K",
+        "last": "Iijima KM",
+        "name": "PLoS genetics",
+        "pages": "e1002918",
+        "reference": "22952452",
+        "title": "Loss of axonal mitochondria promotes tau-mediated neurodegeneration and Alzheimer's disease-related tau phosphorylation via PAR-1.",
         "type": "PubMed",
-        "volume": "7"
+        "volume": "8"
       },
-      "evidence": "Treatment with Dyrk1A inhibitor, green tea flavonol epigallocatechin-gallate (EGCG), from gestation to adulthood suppressed 3R-tau expression and rescued anxiety and memory deficits in Ts65Dn mouse brains.",
-      "key": "dd63d83b25e5ea6ea70c3fe38baec4924de295bf10512af22d7f699a3609307bf59af14efe970ded3526d51c34b21c7944d38f6de3f3348568140e6866d4135b",
-      "line": 2133,
-      "relation": "negativeCorrelation",
-      "source": 786,
-      "target": 200
-    },
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+      "evidence": "Using transgenic Drosophila expressing human tau, we found that RNAi-mediated knockdown of milton or Miro, an adaptor protein essential for axonal transport of mitochondria, enhanced human tau-induced neurodegeneration. Tau phosphorylation at an AD-related site Ser262 increased with knockdown of milton or Miro; and partitioning defective-1 (PAR-1), the Drosophila homolog of mammalian microtubule affinity-regulating kinase, mediated this increase of tau phosphorylation. Tau phosphorylation at Ser262 has been reported to promote tau detachment from microtubules, and we found that the levels of microtubule-unbound free tau increased by milton knockdown. Blocking tau phosphorylation at Ser262 site by PAR-1 knockdown or by mutating the Ser262 site to unphosphorylatable alanine suppressed the enhancement of tau-induced neurodegeneration caused by milton knockdown. Furthermore, knockdown of milton or Miro increased the levels of active PAR-1.",
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+      "line": 3394,
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+      "subject": {
+        "effect": {
+          "name": "kin",
+          "namespace": "bel"
+        },
+        "modifier": "Activity"
+      },
+      "target": 642
     },
     {
       "annotations": {
-        "Species": {
-          "10090": true
+        "Confidence": {
+          "Medium": true
         }
       },
       "citation": {
         "authors": [
-          "Gaertig MA",
-          "Li S",
-          "Li XJ",
-          "Reeves RH",
-          "Xiang J",
-          "Xin N",
-          "Yang S"
+          "Agerman K",
+          "Eckersley S",
+          "Gu GJ",
+          "Kamali-Moghaddam M",
+          "Kvist AJ",
+          "Landegren U",
+          "Lund H",
+          "Milner R",
+          "Nilsson LN",
+          "Sunnemark D",
+          "Wu D"
         ],
-        "date": "2017-02-14",
-        "first": "Xiang J",
-        "last": "Li XJ",
-        "name": "Proceedings of the National Academy of Sciences of the United States of America",
-        "pages": "E1224-E1233",
-        "reference": "28137862",
-        "title": "DYRK1A regulates Hap1-Dcaf7/WDR68 binding with implication for delayed growth in Down syndrome.",
+        "date": "2013-01-01",
+        "first": "Gu GJ",
+        "last": "Kamali-Moghaddam M",
+        "name": "Journal of Alzheimer's disease : JAD",
+        "pages": "699-713",
+        "reference": "23001711",
+        "title": "Elevated MARK2-dependent phosphorylation of Tau in Alzheimer's disease.",
         "type": "PubMed",
-        "volume": "114"
+        "volume": "33"
       },
-      "evidence": "Moreover, we found that Hap1 bound Dcaf7 competitively in cytoplasm with dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), a protein implicated in Down syndrome (DS). Depleting Hap1 promoted the DYRK1A-Dcaf7 interaction and increased the DYRK1A protein level.",
-      "key": "4c8df606d482cc437cde002014e35a91aaf090ec50f61e6017b6bdbb4c4a26da1f0723a490f73adb1e57ba1bda23e3304284d2f08571d4fed48c73b53e7e8924",
-      "line": 2022,
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-      "target": 797
+      "evidence": "Several kinases such as microtubule-affinity regulating kinase (MARK), protein kinase A, calcium calmodulin kinase II, and checkpoint kinase 2 are known to phosphorylate tau on Ser(262) in vitro. In this study, we took advantage of the in situ proximity ligation assay to investigate the role of MARK2, one of the four MARK isoforms, in AD. We demonstrate that MARK2 interacts with tau and phosphorylates tau at Ser(262) in stably transfected NIH/3T3 cells expressing human recombinant tau. Staurosporine, a protein kinase inhibitor, significantly reduced the interaction between MARK2 and tau, and also phosphorylation of tau at Ser(262).",
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     },
     {
       "annotations": {
-        "Species": {
-          "10090": true
+        "Confidence": {
+          "High": true
         }
       },
       "citation": {
         "authors": [
-          "Gaertig MA",
-          "Li S",
-          "Li XJ",
-          "Reeves RH",
-          "Xiang J",
-          "Xin N",
-          "Yang S"
+          "Chen GC",
+          "Chen RH",
+          "Chen YH",
+          "Chien CT",
+          "Chou HJ",
+          "Huang YP",
+          "Kimchi A",
+          "Lin MY",
+          "Tsai PI",
+          "Wu PR"
         ],
-        "date": "2017-02-14",
-        "first": "Xiang J",
-        "last": "Li XJ",
-        "name": "Proceedings of the National Academy of Sciences of the United States of America",
-        "pages": "E1224-E1233",
-        "reference": "28137862",
-        "title": "DYRK1A regulates Hap1-Dcaf7/WDR68 binding with implication for delayed growth in Down syndrome.",
+        "date": "2011-09-01",
+        "first": "Wu PR",
+        "last": "Chen RH",
+        "name": "Cell death and differentiation",
+        "pages": "1507-20",
+        "reference": "21311567",
+        "title": "DAPK activates MARK1/2 to regulate microtubule assembly, neuronal differentiation, and tau toxicity.",
         "type": "PubMed",
-        "volume": "114"
+        "volume": "18"
       },
-      "evidence": "Moreover, we found that Hap1 bound Dcaf7 competitively in cytoplasm with dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), a protein implicated in Down syndrome (DS). Depleting Hap1 promoted the DYRK1A-Dcaf7 interaction and increased the DYRK1A protein level.",
-      "key": "815621a1ea2d9ed8282379d58d92749f41340383dd1da9bef75583adb84ab7d95edcf80d43a1cb313a6d950be6c7ad80aa90ca98de9dbf4ecba91299ffca16df",
-      "line": 2020,
-      "relation": "association",
-      "source": 797,
-      "target": 782
+      "evidence": "Importantly, depletion of MARK1/2 reversed the inhibitory effect of DAPK on MT regrowth (Figure 5c, right panel). These results indicate that the DAPK–MARK signaling axis inhibits MT assembly and stability.",
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+      "line": 2464,
+      "relation": "decreases",
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+      "relation": "hasComponent",
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     },
     {
       "annotations": {
-        "Species": {
-          "10090": true
+        "Confidence": {
+          "Medium": true
         }
       },
       "citation": {
         "authors": [
-          "Gaertig MA",
-          "Li S",
-          "Li XJ",
-          "Reeves RH",
-          "Xiang J",
-          "Xin N",
-          "Yang S"
+          "Blokzijl A",
+          "Classon C",
+          "Gu GJ",
+          "Kamali-Moghaddam M",
+          "Landegren U",
+          "Lund H",
+          "Sunnemark D",
+          "Wu D",
+          "von Euler G"
         ],
-        "date": "2017-02-14",
-        "first": "Xiang J",
-        "last": "Li XJ",
-        "name": "Proceedings of the National Academy of Sciences of the United States of America",
-        "pages": "E1224-E1233",
-        "reference": "28137862",
-        "title": "DYRK1A regulates Hap1-Dcaf7/WDR68 binding with implication for delayed growth in Down syndrome.",
+        "date": "2013-09-01",
+        "first": "Gu GJ",
+        "last": "Kamali-Moghaddam M",
+        "name": "Neuromolecular medicine",
+        "pages": "458-69",
+        "reference": "23666762",
+        "title": "Role of individual MARK isoforms in phosphorylation of tau at Ser²⁶² in Alzheimer's disease.",
         "type": "PubMed",
-        "volume": "114"
+        "volume": "15"
       },
-      "evidence": "Moreover, we found that Hap1 bound Dcaf7 competitively in cytoplasm with dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), a protein implicated in Down syndrome (DS). Depleting Hap1 promoted the DYRK1A-Dcaf7 interaction and increased the DYRK1A protein level.",
-      "key": "4e3df1c3bd7c00b38ba11945a42625833a69fbd4ee407cfa2bfd56139b3bbf3d634ed3a3a8a6b8c60bced7edc6a6542fc2ed7d66b5997dffc15a97cb13d4785a",
-      "line": 2021,
-      "relation": "negativeCorrelation",
-      "source": 797,
-      "target": 786
+      "evidence": "In parallel, phosphorylation of tau at Ser262 in MARK-transfected cells was investigated using a rabbit antibody recognizing phosphorylated Ser262 of tau (AGG5759) and a mouse anti-tau antibody (SC-21796) (Fig. S1a3). Tau was shown to interact with each of the transfected MARK isoforms (Fig. 1) and to be phosphorylated at Ser262 (Fig. 2). Staurosporine, a non-selective kinase inhibitor, significantly inhibited interactions between tau and each of the four MARK isoforms after treatment with 20 lM staurosporine for 1 h (Fig. 1; p = 0.02 for MARK1–, MARK2– and MARK3–tau interactions and p = 3 9 10-6 for MARK4–tau interaction). Treatment with staurosporine also significantly reduced PLA signals for tau phosphorylation at Ser262 (Fig. 2; p = 0.04 for MARK1- and p = 0.02 for MARK2- and MARK3- and p = 1 9 10-5 for MARK4-mediated tau phosphorylation)",
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+      "line": 2237,
+      "relation": "increases",
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+      "target": 642
     },
     {
       "annotations": {
-        "Species": {
-          "10090": true
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Neurons": true
         }
       },
       "citation": {
         "authors": [
-          "Gaertig MA",
-          "Li S",
-          "Li XJ",
-          "Reeves RH",
-          "Xiang J",
-          "Xin N",
-          "Yang S"
+          "Chen GC",
+          "Chen RH",
+          "Chen YH",
+          "Chien CT",
+          "Chou HJ",
+          "Huang YP",
+          "Kimchi A",
+          "Lin MY",
+          "Tsai PI",
+          "Wu PR"
         ],
-        "date": "2017-02-14",
-        "first": "Xiang J",
-        "last": "Li XJ",
-        "name": "Proceedings of the National Academy of Sciences of the United States of America",
-        "pages": "E1224-E1233",
-        "reference": "28137862",
-        "title": "DYRK1A regulates Hap1-Dcaf7/WDR68 binding with implication for delayed growth in Down syndrome.",
+        "date": "2011-09-01",
+        "first": "Wu PR",
+        "last": "Chen RH",
+        "name": "Cell death and differentiation",
+        "pages": "1507-20",
+        "reference": "21311567",
+        "title": "DAPK activates MARK1/2 to regulate microtubule assembly, neuronal differentiation, and tau toxicity.",
         "type": "PubMed",
-        "volume": "114"
+        "volume": "18"
       },
-      "evidence": "Moreover, we found that Hap1 bound Dcaf7 competitively in cytoplasm with dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), a protein implicated in Down syndrome (DS). Depleting Hap1 promoted the DYRK1A-Dcaf7 interaction and increased the DYRK1A protein level.",
-      "key": "3105e2aff819e460040407b7fa470d8490aa19940b53c98e536666d943635d8d1ede042da30c8c73cb192852b9218ffd9c235a4b38aa8cdd1b7583a7ed1d2cf0",
-      "line": 2022,
-      "relation": "negativeCorrelation",
-      "source": 797,
-      "target": 242
+      "evidence": "Furthermore, silencing of both MARK1 and MARK2 blocked DAPK-induced tau S262 phosphorylation (Figure 3e). More importantly, a decrease of pS262 tau, but not total tau, was observed in brain extracts derived from DAPK−/− mice, compared with that from DAPK+/+ mice (Figure 3f). These results strongly suggest a role of endogenous DAPK in stimulating the activity of endogenous MARK, which in turn phosphorylates tau in neurons.",
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+      "line": 2453,
+      "relation": "increases",
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+      "subject": {
+        "modifier": "Activity"
+      },
+      "target": 642
     },
     {
       "annotations": {
-        "MeSHDisease": {
-          "Alzheimer Disease": true,
-          "Down Syndrome": true
-        },
-        "Research_Model": {
-          "Ts65Dn mice": true
-        },
-        "Species": {
-          "10090": true
+        "Confidence": {
+          "High": true
         }
       },
       "citation": {
         "authors": [
-          "Berciano MT",
-          "García-Cerro S",
-          "Lafarga M",
-          "Lantigua S",
-          "Martínez-Cué C",
-          "Padro D",
-          "Ramos-Cabrer P",
-          "Rueda N",
-          "Vidal V"
+          "Bibow S",
+          "Biernat J",
+          "Blackledge M",
+          "Jensen MR",
+          "Kadavath H",
+          "Mandelkow E",
+          "Ozenne V",
+          "Schwalbe M",
+          "Zweckstetter M"
         ],
-        "date": "2018-02-01",
-        "first": "García-Cerro S",
-        "last": "Martínez-Cué C",
-        "name": "Neurobiology of disease",
-        "pages": "206-217",
-        "reference": "29221819",
-        "title": "Cerebellar alterations in a model of Down syndrome: The role of the Dyrk1A gene.",
+        "date": "2013-12-17",
+        "first": "Schwalbe M",
+        "last": "Zweckstetter M",
+        "name": "Biochemistry",
+        "pages": "9068-79",
+        "reference": "24251416",
+        "title": "Phosphorylation of human Tau protein by microtubule affinity-regulating kinase 2.",
         "type": "PubMed",
-        "volume": "110"
+        "volume": "52"
       },
-      "evidence": "The normalization of the Dyrk1A gene dosage did not rescue the reduced cerebellar volume but increased the size of the granular and molecular layers, the densities of granular and Purkinje cells, and dendritic arborization.",
-      "key": "263981772f65947c09fcbb0d3f1e6bf28d679a29b7c33331bd3c12d406b59279be6e92e1a397cb2d54eeeb1e5ecfa5187f9e8659c9600de3d6899b04257bdfc4",
-      "line": 2032,
-      "relation": "positiveCorrelation",
-      "source": 127,
-      "target": 786
+      "evidence": "While residues Ser-262, Ser-324, and Ser-356 were completely phosphorylated, Ser-293 in the second repeat was only 84% phosphorylated (Table 1). Furthermore, four non-KXGS phosphorylation sites were detected, two within the repeat domain (Ser-305 in R2 and Ser-352 in R4) and two more at the C-terminus (Ser-413 and Ser-416) (Figure 1B,C). Of these, Ser-305 was 66% phosphorylated and Ser-352, Ser-413, and Ser-416 were ∼45−58% phosphorylated (Table 1). Using wild-type MARK2cat at 25 °C and pH 6.8, the same phosphorylation sites were observed. The three primary sites, Ser-262, Ser-324, and Ser-356, were still completely phosphorylated.",
+      "key": "469028357db820a1612d3ad7d3a522a0c6fa7f952dc2353d78c13e68fd5025ceeb3406cd6a43a5d75ea154845f358851b3294877061f18a5f7a5850cf7a51c5c",
+      "line": 3258,
+      "relation": "directlyIncreases",
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+      "subject": {
+        "effect": {
+          "name": "kin",
+          "namespace": "bel"
+        },
+        "modifier": "Activity"
+      },
+      "target": 642
     },
     {
       "annotations": {
-        "MeSHDisease": {
-          "Alzheimer Disease": true,
-          "Down Syndrome": true
-        },
-        "Research_Model": {
-          "Ts65Dn mice": true
-        },
-        "Species": {
-          "10090": true
+        "Confidence": {
+          "Medium": true
         }
       },
       "citation": {
         "authors": [
-          "Berciano MT",
-          "García-Cerro S",
-          "Lafarga M",
-          "Lantigua S",
-          "Martínez-Cué C",
-          "Padro D",
-          "Ramos-Cabrer P",
-          "Rueda N",
-          "Vidal V"
+          "Carlomagno Y",
+          "Cook C",
+          "Petrucelli L",
+          "Stankowski JN",
+          "Stetler C"
         ],
-        "date": "2018-02-01",
-        "first": "García-Cerro S",
-        "last": "Martínez-Cué C",
-        "name": "Neurobiology of disease",
-        "pages": "206-217",
-        "reference": "29221819",
-        "title": "Cerebellar alterations in a model of Down syndrome: The role of the Dyrk1A gene.",
+        "date": "2014-01-01",
+        "first": "Cook C",
+        "last": "Petrucelli L",
+        "name": "Alzheimer's research &amp; therapy",
+        "pages": "29",
+        "reference": "25031639",
+        "title": "Acetylation: a new key to unlock tau's role in neurodegeneration.",
         "type": "PubMed",
-        "volume": "110"
+        "volume": "6"
       },
-      "evidence": "The normalization of the Dyrk1A gene dosage did not rescue the reduced cerebellar volume but increased the size of the granular and molecular layers, the densities of granular and Purkinje cells, and dendritic arborization.",
-      "key": "5b1b956bdc61564761fea79b6a980bc9d8f207f736feddaabbd2efe43214e6455ffa932f954215f5e38f039b63ae93eb2c7bd41d0d2e4a0c3382f640e70f8322",
-      "line": 2033,
-      "relation": "positiveCorrelation",
-      "source": 130,
-      "target": 786
+      "evidence": "In particular, previous studies have demonstrated that the tau ubiquitin ligase, CHIP, is unable to bind and ubiquitinate tau species phosphorylated by Par-1/MARK2 on the 12E8 epitope (S262/356) [33], a p-tau species that is also resistant to degradation upon treatment with Hsp90 inhibitors [32,33]. Tau phosphorylated at the PHF1 epitope (S396/404) is still susceptible to degradation following Hsp90 inhibition and actually exhibits an enhanced interaction with Hsp90",
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+      "line": 3289,
+      "relation": "increases",
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     },
     {
       "annotations": {
-        "MeSHDisease": {
-          "Alzheimer Disease": true,
-          "Down Syndrome": true
-        },
-        "Research_Model": {
-          "Ts65Dn mice": true
+        "Cell_Line": {
+          "NIH/3T3": true
         },
-        "Species": {
-          "10090": true
+        "Confidence": {
+          "Medium": true
         }
       },
       "citation": {
         "authors": [
-          "Berciano MT",
-          "García-Cerro S",
-          "Lafarga M",
-          "Lantigua S",
-          "Martínez-Cué C",
-          "Padro D",
-          "Ramos-Cabrer P",
-          "Rueda N",
-          "Vidal V"
+          "Agerman K",
+          "Eckersley S",
+          "Gu GJ",
+          "Kamali-Moghaddam M",
+          "Kvist AJ",
+          "Landegren U",
+          "Lund H",
+          "Milner R",
+          "Nilsson LN",
+          "Sunnemark D",
+          "Wu D"
         ],
-        "date": "2018-02-01",
-        "first": "García-Cerro S",
-        "last": "Martínez-Cué C",
-        "name": "Neurobiology of disease",
-        "pages": "206-217",
-        "reference": "29221819",
-        "title": "Cerebellar alterations in a model of Down syndrome: The role of the Dyrk1A gene.",
+        "date": "2013-01-01",
+        "first": "Gu GJ",
+        "last": "Kamali-Moghaddam M",
+        "name": "Journal of Alzheimer's disease : JAD",
+        "pages": "699-713",
+        "reference": "23001711",
+        "title": "Elevated MARK2-dependent phosphorylation of Tau in Alzheimer's disease.",
         "type": "PubMed",
-        "volume": "110"
+        "volume": "33"
       },
-      "evidence": "The normalization of the Dyrk1A gene dosage did not rescue the reduced cerebellar volume but increased the size of the granular and molecular layers, the densities of granular and Purkinje cells, and dendritic arborization.",
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-      "line": 2034,
-      "relation": "positiveCorrelation",
-      "source": 108,
-      "target": 786
+      "evidence": "Several kinases such as microtubule-affinity regulating kinase (MARK), protein kinase A, calcium calmodulin kinase II, and checkpoint kinase 2 are known to phosphorylate tau on Ser(262) in vitro. In this study, we took advantage of the in situ proximity ligation assay to investigate the role of MARK2, one of the four MARK isoforms, in AD. We demonstrate that MARK2 interacts with tau and phosphorylates tau at Ser(262) in stably transfected NIH/3T3 cells expressing human recombinant tau. Staurosporine, a protein kinase inhibitor, significantly reduced the interaction between MARK2 and tau, and also phosphorylation of tau at Ser(262).",
+      "key": "d08804d93f72158abf47d778e49e122ea2233dfbaec9696de12c13549b3067887cc860739a29d368a767a2b078f4508f00d413b389487d305a02d0b42e0f77ca",
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+      "relation": "directlyIncreases",
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+      "subject": {
+        "effect": {
+          "name": "kin",
+          "namespace": "bel"
+        },
+        "modifier": "Activity"
+      },
+      "target": 642
     },
     {
       "annotations": {
-        "MeSHDisease": {
-          "Alzheimer Disease": true,
-          "Down Syndrome": true
-        },
-        "Research_Model": {
-          "Ts65Dn mice": true
-        },
-        "Species": {
-          "10090": true
+        "Confidence": {
+          "High": true
         }
       },
       "citation": {
         "authors": [
-          "Berciano MT",
-          "García-Cerro S",
-          "Lafarga M",
-          "Lantigua S",
-          "Martínez-Cué C",
-          "Padro D",
-          "Ramos-Cabrer P",
-          "Rueda N",
-          "Vidal V"
+          "Chen GC",
+          "Chen RH",
+          "Chen YH",
+          "Chien CT",
+          "Chou HJ",
+          "Huang YP",
+          "Kimchi A",
+          "Lin MY",
+          "Tsai PI",
+          "Wu PR"
         ],
-        "date": "2018-02-01",
-        "first": "García-Cerro S",
-        "last": "Martínez-Cué C",
-        "name": "Neurobiology of disease",
-        "pages": "206-217",
-        "reference": "29221819",
-        "title": "Cerebellar alterations in a model of Down syndrome: The role of the Dyrk1A gene.",
+        "date": "2011-09-01",
+        "first": "Wu PR",
+        "last": "Chen RH",
+        "name": "Cell death and differentiation",
+        "pages": "1507-20",
+        "reference": "21311567",
+        "title": "DAPK activates MARK1/2 to regulate microtubule assembly, neuronal differentiation, and tau toxicity.",
         "type": "PubMed",
-        "volume": "110"
+        "volume": "18"
       },
-      "evidence": "The normalization of the Dyrk1A gene dosage did not rescue the reduced cerebellar volume but increased the size of the granular and molecular layers, the densities of granular and Purkinje cells, and dendritic arborization.",
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-      "relation": "positiveCorrelation",
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+      "evidence": "Importantly, depletion of MARK1/2 reversed the inhibitory effect of DAPK on MT regrowth (Figure 5c, right panel). These results indicate that the DAPK–MARK signaling axis inhibits MT assembly and stability.",
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     {
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-          "Down Syndrome": true
-        },
-        "Research_Model": {
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-        "Species": {
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       },
       "citation": {
         "authors": [
-          "Berciano MT",
-          "García-Cerro S",
-          "Lafarga M",
-          "Lantigua S",
-          "Martínez-Cué C",
-          "Padro D",
-          "Ramos-Cabrer P",
-          "Rueda N",
-          "Vidal V"
+          "Bibow S",
+          "Biernat J",
+          "Blackledge M",
+          "Jensen MR",
+          "Kadavath H",
+          "Mandelkow E",
+          "Ozenne V",
+          "Schwalbe M",
+          "Zweckstetter M"
         ],
-        "date": "2018-02-01",
-        "first": "García-Cerro S",
-        "last": "Martínez-Cué C",
-        "name": "Neurobiology of disease",
-        "pages": "206-217",
-        "reference": "29221819",
-        "title": "Cerebellar alterations in a model of Down syndrome: The role of the Dyrk1A gene.",
+        "date": "2013-12-17",
+        "first": "Schwalbe M",
+        "last": "Zweckstetter M",
+        "name": "Biochemistry",
+        "pages": "9068-79",
+        "reference": "24251416",
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         "type": "PubMed",
-        "volume": "110"
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       },
-      "evidence": "Normalizing the gene dosage of Dyrk1A in the TS mouse rescued the density of senescent cells in the cingulate cortex, hippocampus and septum, prevented cholinergic neuron degeneration, and reduced App expression in the hippocampus, Aß load in the cortex and hippocampus, the expression of phosphorylated tau at the Ser202 residue in the hippocampus and cerebellum and the levels of total tau in the cortex, hippocampus and cerebellum.",
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     {
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       "citation": {
         "authors": [
-          "Berciano MT",
-          "García-Cerro S",
-          "Lafarga M",
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-          "Martínez-Cué C",
-          "Padro D",
-          "Ramos-Cabrer P",
-          "Rueda N",
-          "Vidal V"
+          "Bibow S",
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+          "Blackledge M",
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+          "Kadavath H",
+          "Mandelkow E",
+          "Ozenne V",
+          "Schwalbe M",
+          "Zweckstetter M"
         ],
-        "date": "2018-02-01",
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-        "last": "Martínez-Cué C",
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-        "pages": "206-217",
-        "reference": "29221819",
-        "title": "Cerebellar alterations in a model of Down syndrome: The role of the Dyrk1A gene.",
+        "date": "2013-12-17",
+        "first": "Schwalbe M",
+        "last": "Zweckstetter M",
+        "name": "Biochemistry",
+        "pages": "9068-79",
+        "reference": "24251416",
+        "title": "Phosphorylation of human Tau protein by microtubule affinity-regulating kinase 2.",
         "type": "PubMed",
-        "volume": "110"
+        "volume": "52"
       },
-      "evidence": "Normalizing the gene dosage of Dyrk1A in the TS mouse rescued the density of senescent cells in the cingulate cortex, hippocampus and septum, prevented cholinergic neuron degeneration, and reduced App expression in the hippocampus, Aß load in the cortex and hippocampus, the expression of phosphorylated tau at the Ser202 residue in the hippocampus and cerebellum and the levels of total tau in the cortex, hippocampus and cerebellum.",
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+      "evidence": "While residues Ser-262, Ser-324, and Ser-356 were completely phosphorylated, Ser-293 in the second repeat was only 84% phosphorylated (Table 1). Furthermore, four non-KXGS phosphorylation sites were detected, two within the repeat domain (Ser-305 in R2 and Ser-352 in R4) and two more at the C-terminus (Ser-413 and Ser-416) (Figure 1B,C). Of these, Ser-305 was 66% phosphorylated and Ser-352, Ser-413, and Ser-416 were ∼45−58% phosphorylated (Table 1). Using wild-type MARK2cat at 25 °C and pH 6.8, the same phosphorylation sites were observed. The three primary sites, Ser-262, Ser-324, and Ser-356, were still completely phosphorylated.",
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     {
       "annotations": {
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-          "Down Syndrome": true
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       "citation": {
         "authors": [
-          "Berciano MT",
-          "García-Cerro S",
-          "Lafarga M",
-          "Lantigua S",
-          "Martínez-Cué C",
-          "Padro D",
-          "Ramos-Cabrer P",
-          "Rueda N",
-          "Vidal V"
-        ],
-        "date": "2018-02-01",
-        "first": "García-Cerro S",
-        "last": "Martínez-Cué C",
-        "name": "Neurobiology of disease",
-        "pages": "206-217",
-        "reference": "29221819",
-        "title": "Cerebellar alterations in a model of Down syndrome: The role of the Dyrk1A gene.",
+          "Carlomagno Y",
+          "Cook C",
+          "Petrucelli L",
+          "Stankowski JN",
+          "Stetler C"
+        ],
+        "date": "2014-01-01",
+        "first": "Cook C",
+        "last": "Petrucelli L",
+        "name": "Alzheimer's research &amp; therapy",
+        "pages": "29",
+        "reference": "25031639",
+        "title": "Acetylation: a new key to unlock tau's role in neurodegeneration.",
         "type": "PubMed",
-        "volume": "110"
+        "volume": "6"
       },
-      "evidence": "Normalizing the gene dosage of Dyrk1A in the TS mouse rescued the density of senescent cells in the cingulate cortex, hippocampus and septum, prevented cholinergic neuron degeneration, and reduced App expression in the hippocampus, Aß load in the cortex and hippocampus, the expression of phosphorylated tau at the Ser202 residue in the hippocampus and cerebellum and the levels of total tau in the cortex, hippocampus and cerebellum.",
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+      "evidence": "In particular, previous studies have demonstrated that the tau ubiquitin ligase, CHIP, is unable to bind and ubiquitinate tau species phosphorylated by Par-1/MARK2 on the 12E8 epitope (S262/356) [33], a p-tau species that is also resistant to degradation upon treatment with Hsp90 inhibitors [32,33]. Tau phosphorylated at the PHF1 epitope (S396/404) is still susceptible to degradation following Hsp90 inhibition and actually exhibits an enhanced interaction with Hsp90",
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       "annotations": {
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       "citation": {
         "authors": [
-          "Bellmaine SF",
-          "Cuddy CE",
-          "Elefanty AG",
-          "Manallack DT",
-          "Ovchinnikov DA",
-          "Pera M",
-          "Stanley EG",
-          "Williams SJ",
-          "Wolvetang EJ"
+          "Bibow S",
+          "Biernat J",
+          "Blackledge M",
+          "Jensen MR",
+          "Kadavath H",
+          "Mandelkow E",
+          "Ozenne V",
+          "Schwalbe M",
+          "Zweckstetter M"
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-        "date": "2017-09-08",
-        "first": "Bellmaine SF",
-        "last": "Pera M",
-        "name": "eLife",
-        "reference": "28884684",
-        "title": "Inhibition of DYRK1A disrupts neural lineage specificationin human pluripotent stem cells.",
+        "date": "2013-12-17",
+        "first": "Schwalbe M",
+        "last": "Zweckstetter M",
+        "name": "Biochemistry",
+        "pages": "9068-79",
+        "reference": "24251416",
+        "title": "Phosphorylation of human Tau protein by microtubule affinity-regulating kinase 2.",
         "type": "PubMed",
-        "volume": "6"
+        "volume": "52"
       },
-      "evidence": "ID-8 indeed showed selectivity against the CMGC kinase family, with DYRK1B, GSK3B and DYRK1A being the top three kinase targets. Although a biotinylated derivative of ID-8 bound DYRK2 and DYRK4 in affinity chromatography pull down assays (Hasegawa et al., 2012), ID-8 itself showed little activity against these kinases, or against DYRK3. Next we determined IC50 values for a subset of these kinase targets, using the same 33P incorporation assay (Table 1).",
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     {
       "annotations": {
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       "citation": {
         "authors": [
-          "Bellmaine SF",
-          "Cuddy CE",
-          "Elefanty AG",
-          "Manallack DT",
-          "Ovchinnikov DA",
-          "Pera M",
-          "Stanley EG",
-          "Williams SJ",
-          "Wolvetang EJ"
+          "Bibow S",
+          "Biernat J",
+          "Blackledge M",
+          "Jensen MR",
+          "Kadavath H",
+          "Mandelkow E",
+          "Ozenne V",
+          "Schwalbe M",
+          "Zweckstetter M"
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-        "date": "2017-09-08",
-        "first": "Bellmaine SF",
-        "last": "Pera M",
-        "name": "eLife",
-        "reference": "28884684",
-        "title": "Inhibition of DYRK1A disrupts neural lineage specificationin human pluripotent stem cells.",
+        "date": "2013-12-17",
+        "first": "Schwalbe M",
+        "last": "Zweckstetter M",
+        "name": "Biochemistry",
+        "pages": "9068-79",
+        "reference": "24251416",
+        "title": "Phosphorylation of human Tau protein by microtubule affinity-regulating kinase 2.",
         "type": "PubMed",
-        "volume": "6"
+        "volume": "52"
       },
-      "evidence": "ID-8 indeed showed selectivity against the CMGC kinase family, with DYRK1B, GSK3B and DYRK1A being the top three kinase targets. Although a biotinylated derivative of ID-8 bound DYRK2 and DYRK4 in affinity chromatography pull down assays (Hasegawa et al., 2012), ID-8 itself showed little activity against these kinases, or against DYRK3. Next we determined IC50 values for a subset of these kinase targets, using the same 33P incorporation assay (Table 1).",
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       "annotations": {
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       "citation": {
         "authors": [
-          "Bellmaine SF",
-          "Cuddy CE",
-          "Elefanty AG",
-          "Manallack DT",
-          "Ovchinnikov DA",
-          "Pera M",
-          "Stanley EG",
-          "Williams SJ",
-          "Wolvetang EJ"
+          "Bibow S",
+          "Biernat J",
+          "Blackledge M",
+          "Jensen MR",
+          "Kadavath H",
+          "Mandelkow E",
+          "Ozenne V",
+          "Schwalbe M",
+          "Zweckstetter M"
         ],
-        "date": "2017-09-08",
-        "first": "Bellmaine SF",
-        "last": "Pera M",
-        "name": "eLife",
-        "reference": "28884684",
-        "title": "Inhibition of DYRK1A disrupts neural lineage specificationin human pluripotent stem cells.",
+        "date": "2013-12-17",
+        "first": "Schwalbe M",
+        "last": "Zweckstetter M",
+        "name": "Biochemistry",
+        "pages": "9068-79",
+        "reference": "24251416",
+        "title": "Phosphorylation of human Tau protein by microtubule affinity-regulating kinase 2.",
         "type": "PubMed",
-        "volume": "6"
+        "volume": "52"
       },
-      "evidence": "ID-8 indeed showed selectivity against the CMGC kinase family, with DYRK1B, GSK3B and DYRK1A being the top three kinase targets. Although a biotinylated derivative of ID-8 bound DYRK2 and DYRK4 in affinity chromatography pull down assays (Hasegawa et al., 2012), ID-8 itself showed little activity against these kinases, or against DYRK3. Next we determined IC50 values for a subset of these kinase targets, using the same 33P incorporation assay (Table 1).",
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     {
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+      },
       "citation": {
         "authors": [
-          "Bellmaine SF",
-          "Cuddy CE",
-          "Elefanty AG",
-          "Manallack DT",
-          "Ovchinnikov DA",
-          "Pera M",
-          "Stanley EG",
-          "Williams SJ",
-          "Wolvetang EJ"
+          "Bibow S",
+          "Biernat J",
+          "Blackledge M",
+          "Jensen MR",
+          "Kadavath H",
+          "Mandelkow E",
+          "Ozenne V",
+          "Schwalbe M",
+          "Zweckstetter M"
         ],
-        "date": "2017-09-08",
-        "first": "Bellmaine SF",
-        "last": "Pera M",
-        "name": "eLife",
-        "reference": "28884684",
-        "title": "Inhibition of DYRK1A disrupts neural lineage specificationin human pluripotent stem cells.",
+        "date": "2013-12-17",
+        "first": "Schwalbe M",
+        "last": "Zweckstetter M",
+        "name": "Biochemistry",
+        "pages": "9068-79",
+        "reference": "24251416",
+        "title": "Phosphorylation of human Tau protein by microtubule affinity-regulating kinase 2.",
         "type": "PubMed",
-        "volume": "6"
+        "volume": "52"
       },
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-          "Cuddy CE",
-          "Elefanty AG",
-          "Manallack DT",
-          "Ovchinnikov DA",
-          "Pera M",
-          "Stanley EG",
-          "Williams SJ",
-          "Wolvetang EJ"
+          "Bibow S",
+          "Biernat J",
+          "Blackledge M",
+          "Jensen MR",
+          "Kadavath H",
+          "Mandelkow E",
+          "Ozenne V",
+          "Schwalbe M",
+          "Zweckstetter M"
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-        "first": "Bellmaine SF",
-        "last": "Pera M",
-        "name": "eLife",
-        "reference": "28884684",
-        "title": "Inhibition of DYRK1A disrupts neural lineage specificationin human pluripotent stem cells.",
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+        "name": "Biochemistry",
+        "pages": "9068-79",
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         "type": "PubMed",
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+      "evidence": "While residues Ser-262, Ser-324, and Ser-356 were completely phosphorylated, Ser-293 in the second repeat was only 84% phosphorylated (Table 1). Furthermore, four non-KXGS phosphorylation sites were detected, two within the repeat domain (Ser-305 in R2 and Ser-352 in R4) and two more at the C-terminus (Ser-413 and Ser-416) (Figure 1B,C). Of these, Ser-305 was 66% phosphorylated and Ser-352, Ser-413, and Ser-416 were ∼45−58% phosphorylated (Table 1). Using wild-type MARK2cat at 25 °C and pH 6.8, the same phosphorylation sites were observed. The three primary sites, Ser-262, Ser-324, and Ser-356, were still completely phosphorylated.",
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@@ -52241,1246 +59260,1289 @@
         },
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       "annotations": {
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-          "Human fibroblasts": true
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-        "MeSHDisease": {
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       "citation": {
         "authors": [
-          "Asai M",
-          "Iwata N",
-          "Kawakubo T",
-          "Mori R",
-          "Shirotani K"
+          "Blokzijl A",
+          "Classon C",
+          "Gu GJ",
+          "Kamali-Moghaddam M",
+          "Landegren U",
+          "Lund H",
+          "Sunnemark D",
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-        "first": "Kawakubo T",
-        "last": "Asai M",
-        "name": "Biological &amp; pharmaceutical bulletin",
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-        "reference": "28250274",
-        "title": "Neprilysin Is Suppressed by Dual-Specificity Tyrosine-Phosphorylation Regulated Kinase 1A (DYRK1A) in Down-Syndrome-Derived Fibroblasts.",
+        "date": "2013-09-01",
+        "first": "Gu GJ",
+        "last": "Kamali-Moghaddam M",
+        "name": "Neuromolecular medicine",
+        "pages": "458-69",
+        "reference": "23666762",
+        "title": "Role of individual MARK isoforms in phosphorylation of tau at Ser²⁶² in Alzheimer's disease.",
         "type": "PubMed",
-        "volume": "40"
+        "volume": "15"
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-      "evidence": "Neprilysin, a major Aß-degrading enzyme, was downregulated in DS patient-derived fibroblasts. Treatment with harmine, a DYRK1A inhibitor and gene knockdown of DYRK1A, upregulated neprilysin in fibroblasts.",
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-          "Alexopoulos P",
-          "Arbones M",
-          "Badel A",
-          "Camproux AC",
-          "Delabar JM",
-          "Dubois B",
-          "Feraudet-Tarisse C",
-          "Janel N",
-          "Lagarde J",
-          "Lamari F",
-          "Lamourette P",
-          "Paul JL",
-          "Potier MC",
-          "Sarazin M",
-          "Simon S"
+          "Blokzijl A",
+          "Classon C",
+          "Gu GJ",
+          "Kamali-Moghaddam M",
+          "Landegren U",
+          "Lund H",
+          "Sunnemark D",
+          "Wu D",
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-        "date": "2017-06-20",
-        "first": "Janel N",
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-        "name": "Translational psychiatry",
-        "pages": "e1154",
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-        "title": "Combined assessment of DYRK1A, BDNF and homocysteine levels as diagnostic marker for Alzheimer's disease.",
+        "date": "2013-09-01",
+        "first": "Gu GJ",
+        "last": "Kamali-Moghaddam M",
+        "name": "Neuromolecular medicine",
+        "pages": "458-69",
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         "type": "PubMed",
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-      "evidence": "Receiver-operating characteristic curves and logistic regression analyses showed that combined assessment of DYRK1A, BDNF and homocysteine has a sensitivity of 0.952, a specificity of 0.889 and an accuracy of 0.933 in testing for AD. The blood levels of these markers provide a diagnosis assessment profile. Combined assessment of these three markers outperforms most of the previous markers and could become a useful substitute to the current panel of AD biomarkers.",
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-          "Cheng C",
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-          "Wu M",
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-          "Ye K",
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-          "Zhang WX",
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+          "Landegren U",
+          "Lund H",
+          "Sunnemark D",
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-        "date": "2018-03-01",
-        "first": "Dang T",
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-        "title": "Autism-associated Dyrk1a truncation mutants impair neuronal dendritic and spine growth and interfere with postnatal cortical development.",
+        "date": "2013-09-01",
+        "first": "Gu GJ",
+        "last": "Kamali-Moghaddam M",
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         "type": "PubMed",
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+          "Sunnemark D",
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       "annotations": {
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         "authors": [
-          "Asai M",
-          "Iwata N",
-          "Kawakubo T",
-          "Mori R",
-          "Shirotani K"
+          "Blokzijl A",
+          "Classon C",
+          "Gu GJ",
+          "Kamali-Moghaddam M",
+          "Landegren U",
+          "Lund H",
+          "Sunnemark D",
+          "Wu D",
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-        "date": "2017-01-01",
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-        "title": "Neprilysin Is Suppressed by Dual-Specificity Tyrosine-Phosphorylation Regulated Kinase 1A (DYRK1A) in Down-Syndrome-Derived Fibroblasts.",
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         "authors": [
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-          "Iwata N",
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-          "Mori R",
-          "Shirotani K"
+          "Ashford JW",
+          "Huang X",
+          "Inayathullah M",
+          "Kim KM",
+          "Lee S",
+          "Liu S",
+          "Rajadas J",
+          "Sun W",
+          "Tang H"
         ],
-        "date": "2017-01-01",
-        "first": "Kawakubo T",
-        "last": "Asai M",
-        "name": "Biological &amp; pharmaceutical bulletin",
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-        "title": "Neprilysin Is Suppressed by Dual-Specificity Tyrosine-Phosphorylation Regulated Kinase 1A (DYRK1A) in Down-Syndrome-Derived Fibroblasts.",
+        "date": "2016-10-06",
+        "first": "Sun W",
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+        "name": "Scientific reports",
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+        "reference": "27708431",
+        "title": "Attenuation of synaptic toxicity and MARK4/PAR1-mediated Tau phosphorylation by methylene blue for Alzheimer's disease treatment.",
         "type": "PubMed",
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-        "title": "Binding of Harmine Derivatives to DNA: A Spectroscopic Investigation.",
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+          "Tian Q",
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     {
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-          "Down Syndrome": true
-        },
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-        },
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         }
       },
       "citation": {
         "authors": [
-          "Chen L",
-          "Sun X",
-          "Wang L",
-          "Wang P"
+          "Hashimoto Y",
+          "Kusakari S",
+          "Matsuoka M",
+          "Nawa M",
+          "Toyama Y"
         ],
-        "date": "2017-08-03",
-        "first": "Wang P",
-        "last": "Sun X",
-        "name": "Scientific reports",
-        "pages": "7240",
-        "reference": "28775333",
-        "title": "Dual-specificity tyrosine-phosphorylation regulated kinase 1A Gene Transcription is regulated by Myocyte Enhancer Factor 2D.",
+        "date": "2016-06-03",
+        "first": "Hashimoto Y",
+        "last": "Matsuoka M",
+        "name": "The Journal of biological chemistry",
+        "pages": "12282-93",
+        "reference": "27068745",
+        "title": "An Alzheimer Disease-linked Rare Mutation Potentiates Netrin Receptor Uncoordinated-5C-induced Signaling That Merges with Amyloid β Precursor Protein Signaling.",
         "type": "PubMed",
-        "volume": "7"
+        "volume": "291"
       },
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+      "evidence": "Overexpression of UNC5B induces neuronal death by activating death-associated protein kinase (DAPK1) (19) via protein phosphatase 2A-mediated dephosphorylation of DAPK1 (20).",
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     {
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       "citation": {
         "authors": [
-          "Chen L",
-          "Sun X",
+          "Bédard PA",
+          "Fielding B",
+          "Maślikowski BM",
           "Wang L",
-          "Wang P"
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-        "first": "Wang P",
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-        "name": "Scientific reports",
-        "pages": "7240",
-        "reference": "28775333",
-        "title": "Dual-specificity tyrosine-phosphorylation regulated kinase 1A Gene Transcription is regulated by Myocyte Enhancer Factor 2D.",
+        "date": "2017-01-01",
+        "first": "Maślikowski BM",
+        "last": "Bédard PA",
+        "name": "Journal of virology",
+        "reference": "27795443",
+        "title": "JunD/AP-1 Antagonizes the Induction of DAPK1 To Promote the Survival of v-Src-Transformed Cells.",
         "type": "PubMed",
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       "citation": {
         "authors": [
-          "Chen L",
-          "Sun X",
+          "Bédard PA",
+          "Fielding B",
+          "Maślikowski BM",
           "Wang L",
-          "Wang P"
+          "Wu Y"
         ],
-        "date": "2017-08-03",
-        "first": "Wang P",
-        "last": "Sun X",
-        "name": "Scientific reports",
-        "pages": "7240",
-        "reference": "28775333",
-        "title": "Dual-specificity tyrosine-phosphorylation regulated kinase 1A Gene Transcription is regulated by Myocyte Enhancer Factor 2D.",
+        "date": "2017-01-01",
+        "first": "Maślikowski BM",
+        "last": "Bédard PA",
+        "name": "Journal of virology",
+        "reference": "27795443",
+        "title": "JunD/AP-1 Antagonizes the Induction of DAPK1 To Promote the Survival of v-Src-Transformed Cells.",
         "type": "PubMed",
-        "volume": "7"
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       },
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     {
       "annotations": {
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       },
       "citation": {
         "authors": [
-          "Butterfield DA",
-          "Farr SA",
-          "Kumar V",
-          "Morley JE",
-          "Murphy MP",
-          "Niehoff ML",
-          "Platt TL",
-          "Ripley JL",
-          "Sultana R",
-          "Zhang Z"
+          "Chen CH",
+          "Hong Y",
+          "Kim BM",
+          "Kimchi A",
+          "Lee S",
+          "Lee TH",
+          "You MH",
+          "Zhou XZ"
         ],
-        "date": "2014-02-01",
-        "first": "Farr SA",
-        "last": "Butterfield DA",
-        "name": "Free radical biology &amp; medicine",
-        "pages": "387-95",
-        "reference": "24355211",
-        "title": "Antisense oligonucleotide against GSK-3β in brain of SAMP8 mice improves learning and memory and decreases oxidative stress: Involvement of transcription factor Nrf2 and implications for Alzheimer disease.",
+        "date": "2014-05-22",
+        "first": "Kim BM",
+        "last": "Lee TH",
+        "name": "Cell death &amp; disease",
+        "pages": "e1237",
+        "reference": "24853415",
+        "title": "Death-associated protein kinase 1 has a critical role in aberrant tau protein regulation and function.",
         "type": "PubMed",
-        "volume": "67"
+        "volume": "5"
       },
-      "evidence": "Nuclear factor erythroid-2-related factor 2 (Nrf2) is a transcription factor known to increase the level of many antioxidants, including glutathione-S transferase (GST), and is negatively regulated by the activity of GSK-3β. Our results indicated the increased nuclear localization of Nrf2 and level of GST, suggesting the increased activity of the transcription factor as a result of GSK-3β suppression, consistent with the decreased oxidative stress observed. Consistent with the improved learning and memory, and consistent with GSK-3b being a tau kinase, we observed decreased tau phosphorylation in brain of GAO-treated SAMP8 mice compared to that of RAO-treated SAMP8 mice.",
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+      "evidence": "We showed previously that DAPK1 phosphorylates Ser71 in the catalytic active site of Pin1, thereby inhibiting its cellular function.",
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     {
       "annotations": {
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       "citation": {
         "authors": [
-          "Cong X",
-          "Ellerby LM",
-          "Gan L",
-          "Huganir RL",
-          "Le D",
-          "Li Y",
-          "Lo I",
-          "Min SW",
-          "Minami SS",
-          "Ponnusamy R",
-          "Schilling B",
-          "Sohn PD",
-          "Tracy TE",
-          "Wang C",
-          "Zhou Y"
+          "Chen CH",
+          "Hong Y",
+          "Kim BM",
+          "Kimchi A",
+          "Lee S",
+          "Lee TH",
+          "You MH",
+          "Zhou XZ"
         ],
-        "date": "2016-04-20",
-        "first": "Tracy TE",
-        "last": "Gan L",
-        "name": "Neuron",
-        "pages": "245-60",
-        "reference": "27041503",
-        "title": "Acetylated Tau Obstructs KIBRA-Mediated Signaling in Synaptic Plasticity and Promotes Tauopathy-Related Memory Loss.",
+        "date": "2014-05-22",
+        "first": "Kim BM",
+        "last": "Lee TH",
+        "name": "Cell death &amp; disease",
+        "pages": "e1237",
+        "reference": "24853415",
+        "title": "Death-associated protein kinase 1 has a critical role in aberrant tau protein regulation and function.",
         "type": "PubMed",
-        "volume": "90"
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       },
-      "evidence": "Here we report abnormal acetylation of K274 and K281 on tau, identified in AD brains, promotes memory loss and disrupts synaptic plasticity by reducing postsynaptic KIdney/BRAin (KIBRA) protein, a memory-associated protein.Transgenic mice expressing human tau with lysine-to-glutamine mutations to mimic K274 and K281 acetylation (tauKQ) exhibit AD-related memory deficits and impaired hippocampal long-term potentiation (LTP). TauKQ reduces synaptic KIBRA levels and disrupts activity-induced postsynaptic actin remodeling and AMPA receptor insertion. The LTP deficit was rescued by promoting actin polymerization or by KIBRA expression. In AD patients with dementia, we found enhanced tau acetylation is linked to loss of KIBRA.",
-      "key": "fd4dbc842dd89629f261d4cc80d56069305e4775079bb60d380d2d604d65aa97dc131d25ddfe5974e20216a7eb9dff56902b49990da758e05da60a68d047d427",
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+      "evidence": "As shown in Figure 7a, compared with the vector control, DAPK1, but not DAPK1K42A, increased the phosphorylation of exogenous tau protein in HeLa cells, as detected by Thr231-specific (AT180), Ser262-specific, and Ser396-specific (PHF-13) antibodies that recognize specific tau phosphoepitopes and/or abnormal conformations specific to AD NFT.",
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     {
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-          "Devidze N",
-          "Gan L",
-          "Gestwicki JE",
-          "Johnson JR",
-          "Krogan NJ",
-          "Li Y",
-          "Masliah E",
-          "Min SW",
-          "Mok SA",
-          "Sohn PD"
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-        "date": "2018-04-11",
-        "first": "Min SW",
-        "last": "Gan L",
-        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
-        "pages": "3680-3688",
-        "reference": "29540553",
-        "title": "SIRT1 Deacetylates Tau and Reduces Pathogenic Tau Spread in a Mouse Model of Tauopathy.",
-        "type": "PubMed",
-        "volume": "38"
+      "annotations": {
+        "Confidence": {
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       },
-      "evidence": "SIRT1 activation or elevation ameliorates pathology and neurodegeneration in AD (Qin et al., 2006; Kim et al., 2007). Loss of SIRT1 induces impairment of learning and memory (Gao et al., 2010; Michán et al., 2010).",
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-      "line": 3334,
-      "relation": "positiveCorrelation",
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-    {
       "citation": {
         "authors": [
-          "Jin J",
-          "Liu Y",
-          "Wang S",
-          "Xu Y",
-          "Ye X",
-          "Yu L",
-          "Zhu X"
+          "Chai GS",
+          "Chen NN",
+          "Cheng XS",
+          "Duan DX",
+          "Hu Y",
+          "Liu GP",
+          "Luo Y",
+          "Ni ZF",
+          "Wang JZ"
         ],
-        "date": "2017-10-01",
-        "first": "Zhu X",
-        "last": "Xu Y",
-        "name": "Aging cell",
-        "pages": "1073-1082",
-        "reference": "28771976",
-        "title": "HDAC3 negatively regulates spatial memory in a mouse model of Alzheimer's disease.",
+        "date": "2013-01-01",
+        "first": "Duan DX",
+        "last": "Liu GP",
+        "name": "Journal of Alzheimer's disease : JAD",
+        "pages": "795-808",
+        "reference": "23948915",
+        "title": "Phosphorylation of tau by death-associated protein kinase 1 antagonizes the kinase-induced cell apoptosis.",
         "type": "PubMed",
-        "volume": "16"
+        "volume": "37"
       },
-      "evidence": "RGFP966, a selective HDAC3 inhibitor, has been shown to affect sensory cortical plasticity and memory formation (Bieszczad et al., 2015).",
-      "key": "a465c44f1f694ba1e89740e57cd2fa7ea5329ee2b7d288c63ad299b1e9bbd5c55a13facca0d7e9fee91bc3e0341c64a85667463c81ebe42f0927d0e61c59fb37",
-      "line": 3375,
-      "relation": "association",
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-      "target": 143
+      "evidence": "These data suggest that tau hyperphosphorylation at Thr231, Ser262, and Ser396 by DAPK1 renders the cells more resistant to the kinase-induced apoptotic cell death, providing new insights into the tau-involved apoptotic abortion in the course of chronic neurodegeneration.",
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     },
     {
       "annotations": {
-        "Anatomy": {
-          "hippocampal formation": true
+        "Confidence": {
+          "Medium": true
         },
-        "Species": {
-          "10090": true
+        "MeSHAnatomy": {
+          "Neurons": true
         }
       },
       "citation": {
         "authors": [
-          "Brown JT",
-          "Cimarosti H",
-          "Henley JM",
-          "McMillan LE"
+          "Chen GC",
+          "Chen RH",
+          "Chen YH",
+          "Chien CT",
+          "Chou HJ",
+          "Huang YP",
+          "Kimchi A",
+          "Lin MY",
+          "Tsai PI",
+          "Wu PR"
         ],
-        "date": "2011-09-20",
-        "first": "McMillan LE",
-        "last": "Cimarosti H",
-        "name": "Neuroscience letters",
-        "pages": "201-8",
-        "reference": "21843595",
-        "title": "Profiles of SUMO and ubiquitin conjugation in an Alzheimer's disease model.",
+        "date": "2011-09-01",
+        "first": "Wu PR",
+        "last": "Chen RH",
+        "name": "Cell death and differentiation",
+        "pages": "1507-20",
+        "reference": "21311567",
+        "title": "DAPK activates MARK1/2 to regulate microtubule assembly, neuronal differentiation, and tau toxicity.",
         "type": "PubMed",
-        "volume": "502"
+        "volume": "18"
       },
-      "evidence": "In 25-month-old mice, the number of errors and the latency in the learning phase negatively correlated with the Sumo3 level in the dorsal hippocampus.",
-      "key": "64a59aaf859ea7076abd9ba0a98bbbfc133ba63d7e4e9e133bad2ac48197ed868f50efe3b57c857f7e373c74d37a6b9c55fc2f43ba9442da14da6e4f3e302b0e",
-      "line": 3642,
-      "relation": "negativeCorrelation",
-      "source": 200,
-      "target": 850
+      "evidence": "Furthermore, silencing of both MARK1 and MARK2 blocked DAPK-induced tau S262 phosphorylation (Figure 3e). More importantly, a decrease of pS262 tau, but not total tau, was observed in brain extracts derived from DAPK−/− mice, compared with that from DAPK+/+ mice (Figure 3f). These results strongly suggest a role of endogenous DAPK in stimulating the activity of endogenous MARK, which in turn phosphorylates tau in neurons.",
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+      "relation": "directlyIncreases",
+      "source": 510,
+      "subject": {
+        "effect": {
+          "name": "kin",
+          "namespace": "bel"
+        },
+        "modifier": "Activity"
+      },
+      "target": 642
     },
     {
       "annotations": {
-        "Anatomy": {
-          "blood plasma": true
+        "Cell_Line": {
+          "HeLa": true
         },
-        "MeSHDisease": {
-          "Alzheimer Disease": true
+        "Confidence": {
+          "High": true
         }
       },
       "citation": {
         "authors": [
-          "Alexopoulos P",
-          "Arbones M",
-          "Badel A",
-          "Camproux AC",
-          "Delabar JM",
-          "Dubois B",
-          "Feraudet-Tarisse C",
-          "Janel N",
-          "Lagarde J",
-          "Lamari F",
-          "Lamourette P",
-          "Paul JL",
-          "Potier MC",
-          "Sarazin M",
-          "Simon S"
+          "Chen CH",
+          "Hong Y",
+          "Kim BM",
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@@ -53488,45 +60550,41 @@
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-          "Mullan M",
-          "Paris D",
-          "Schweig JE",
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+          "Gan L",
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+          "Johnson JR",
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+          "Li Y",
+          "Masliah E",
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@@ -53534,372 +60592,442 @@
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-          "Mullan M",
-          "Paris D",
-          "Schweig JE",
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+          "Ando K",
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+          "D'Amico E",
+          "Duyckaerts C",
+          "Erneux C",
+          "Jia Y",
+          "Leroy K",
+          "Luo HR",
+          "Pouillon V",
+          "Schurmans S",
+          "Stygelbout V"
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-        "title": "Alzheimer's disease pathological lesions activate the spleen tyrosine kinase.",
+        "date": "2014-02-01",
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+        "name": "Brain : a journal of neurology",
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+        "title": "Inositol trisphosphate 3-kinase B is increased in human Alzheimer brain and exacerbates mouse Alzheimer pathology.",
         "type": "PubMed",
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-      "evidence": "We further validated Syk as a target-regulating Aβ by showing that pharmacological inhibition of Syk or down-regulation of Syk expression reduces Aβ production and increases the clearance of Aβ across the BBB mimicking (-)-nilvadipine effects. Moreover, treatment of transgenic mice overexpressing Aβ and transgenic Tau P301S mice with a selective Syk inhibitor respectively decreased brain Aβ accumulation and Tau hyperphosphorylation at multiple AD relevant epitopes.",
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     {
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       "citation": {
         "authors": [
-          "Ait-Ghezala G",
-          "Beaulieu-Abdelahad D",
-          "Crawford F",
-          "Mouzon B",
-          "Mullan M",
-          "Paris D",
-          "Schweig JE",
-          "Yao H"
+          "Hashimoto Y",
+          "Kusakari S",
+          "Matsuoka M",
+          "Nawa M",
+          "Toyama Y"
         ],
-        "date": "2017-09-06",
-        "first": "Schweig JE",
-        "last": "Paris D",
-        "name": "Acta neuropathologica communications",
-        "pages": "69",
-        "reference": "28877763",
-        "title": "Alzheimer's disease pathological lesions activate the spleen tyrosine kinase.",
+        "date": "2016-06-03",
+        "first": "Hashimoto Y",
+        "last": "Matsuoka M",
+        "name": "The Journal of biological chemistry",
+        "pages": "12282-93",
+        "reference": "27068745",
+        "title": "An Alzheimer Disease-linked Rare Mutation Potentiates Netrin Receptor Uncoordinated-5C-induced Signaling That Merges with Amyloid β Precursor Protein Signaling.",
         "type": "PubMed",
-        "volume": "5"
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-      "evidence": "We found an increase in Syk activation in DNs surrounding Aβ deposits as well as in neurons displaying an accumulation of phosphorylated Tau at Y18 and elevated levels of MC1 pathogenic tau conformers in AD brain sections whereas only weak immunoreactivity for pSyk was observed in brain sections from a non-demented control",
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     {
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       "citation": {
         "authors": [
-          "Ait-Ghezala G",
-          "Beaulieu-Abdelahad D",
-          "Crawford F",
-          "Mouzon B",
-          "Mullan M",
-          "Paris D",
-          "Schweig JE",
-          "Yao H"
+          "Hashimoto Y",
+          "Kusakari S",
+          "Matsuoka M",
+          "Nawa M",
+          "Toyama Y"
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-        "first": "Schweig JE",
-        "last": "Paris D",
-        "name": "Acta neuropathologica communications",
-        "pages": "69",
-        "reference": "28877763",
-        "title": "Alzheimer's disease pathological lesions activate the spleen tyrosine kinase.",
+        "date": "2016-06-03",
+        "first": "Hashimoto Y",
+        "last": "Matsuoka M",
+        "name": "The Journal of biological chemistry",
+        "pages": "12282-93",
+        "reference": "27068745",
+        "title": "An Alzheimer Disease-linked Rare Mutation Potentiates Netrin Receptor Uncoordinated-5C-induced Signaling That Merges with Amyloid β Precursor Protein Signaling.",
         "type": "PubMed",
-        "volume": "5"
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-      "evidence": "We found an increase in Syk activation in DNs surrounding Aβ deposits as well as in neurons displaying an accumulation of phosphorylated Tau at Y18 and elevated levels of MC1 pathogenic tau conformers in AD brain sections whereas only weak immunoreactivity for pSyk was observed in brain sections from a non-demented control",
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       "citation": {
         "authors": [
-          "Hosomi N",
-          "Izumi Y",
-          "Maruyama H",
-          "Matsumoto M",
-          "Miyazaki Y",
-          "Nakamori M",
-          "Nishikawa T",
-          "Takahashi T"
+          "Hashimoto Y",
+          "Kusakari S",
+          "Matsuoka M",
+          "Nawa M",
+          "Toyama Y"
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-        "date": "2016-12-01",
-        "first": "Nishikawa T",
-        "last": "Matsumoto M",
-        "name": "Neuropathology and applied neurobiology",
-        "pages": "639-653",
-        "reference": "26501932",
-        "title": "The identification of raft-derived tau-associated vesicles that are incorporated into immature tangles and paired helical filaments.",
+        "date": "2016-06-03",
+        "first": "Hashimoto Y",
+        "last": "Matsuoka M",
+        "name": "The Journal of biological chemistry",
+        "pages": "12282-93",
+        "reference": "27068745",
+        "title": "An Alzheimer Disease-linked Rare Mutation Potentiates Netrin Receptor Uncoordinated-5C-induced Signaling That Merges with Amyloid β Precursor Protein Signaling.",
         "type": "PubMed",
-        "volume": "42"
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       },
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     {
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       "citation": {
         "authors": [
-          "Hosomi N",
-          "Izumi Y",
-          "Maruyama H",
-          "Matsumoto M",
-          "Miyazaki Y",
-          "Nakamori M",
-          "Nishikawa T",
-          "Takahashi T"
+          "Hashimoto Y",
+          "Kusakari S",
+          "Matsuoka M",
+          "Nawa M",
+          "Toyama Y"
         ],
-        "date": "2016-12-01",
-        "first": "Nishikawa T",
-        "last": "Matsumoto M",
-        "name": "Neuropathology and applied neurobiology",
-        "pages": "639-653",
-        "reference": "26501932",
-        "title": "The identification of raft-derived tau-associated vesicles that are incorporated into immature tangles and paired helical filaments.",
+        "date": "2016-06-03",
+        "first": "Hashimoto Y",
+        "last": "Matsuoka M",
+        "name": "The Journal of biological chemistry",
+        "pages": "12282-93",
+        "reference": "27068745",
+        "title": "An Alzheimer Disease-linked Rare Mutation Potentiates Netrin Receptor Uncoordinated-5C-induced Signaling That Merges with Amyloid β Precursor Protein Signaling.",
         "type": "PubMed",
-        "volume": "42"
+        "volume": "291"
       },
-      "evidence": "Pretangles contained either paired helical filaments (PHFs) or PtdIns(4,5)P2-immunopositive small vesicles (approximately 1 µm in diameter) with nearly identical topology to granulovacuolar degeneration (GVD) bodies. Various combinations of these vesicles and GVD bodies, the latter of which are pathological hallmarks observed within the neurons of AD patients, were found concurrently in neurons.These vesicles and GVD bodies were both immunopositive not only for PtdIns(4,5)P2, but also for several tau kinases such as glycogen synthase kinase-3ß and spleen tyrosine kinase.",
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     {
       "annotations": {
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       "citation": {
         "authors": [
-          "Ait-Ghezala G",
-          "Bachmeier C",
-          "Beaulieu-Abdelahad D",
-          "Crawford F",
-          "Jin C",
-          "Laco G",
-          "Lin Y",
-          "Mullan M",
-          "Paris D"
+          "Hashimoto Y",
+          "Kusakari S",
+          "Matsuoka M",
+          "Nawa M",
+          "Toyama Y"
         ],
-        "date": "2014-12-05",
-        "first": "Paris D",
-        "last": "Mullan M",
+        "date": "2016-06-03",
+        "first": "Hashimoto Y",
+        "last": "Matsuoka M",
         "name": "The Journal of biological chemistry",
-        "pages": "33927-44",
-        "reference": "25331948",
-        "title": "The spleen tyrosine kinase (Syk) regulates Alzheimer amyloid-β production and Tau hyperphosphorylation.",
+        "pages": "12282-93",
+        "reference": "27068745",
+        "title": "An Alzheimer Disease-linked Rare Mutation Potentiates Netrin Receptor Uncoordinated-5C-induced Signaling That Merges with Amyloid β Precursor Protein Signaling.",
         "type": "PubMed",
-        "volume": "289"
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-      "evidence": "We observed that pharmacological inhibition of Syk with BAY61-3606 stimulates Ser-9 phosphorylation of GSK3β in SH-SY5Y cells (Fig. 9, A and B) suggesting that blocking Syk activity results in GSK3β inhibition.",
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     {
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         "authors": [
-          "Ait-Ghezala G",
-          "Bachmeier C",
-          "Beaulieu-Abdelahad D",
-          "Crawford F",
-          "Jin C",
-          "Laco G",
-          "Lin Y",
-          "Mullan M",
-          "Paris D"
+          "Hashimoto Y",
+          "Kusakari S",
+          "Matsuoka M",
+          "Nawa M",
+          "Toyama Y"
         ],
-        "date": "2014-12-05",
-        "first": "Paris D",
-        "last": "Mullan M",
+        "date": "2016-06-03",
+        "first": "Hashimoto Y",
+        "last": "Matsuoka M",
         "name": "The Journal of biological chemistry",
-        "pages": "33927-44",
-        "reference": "25331948",
-        "title": "The spleen tyrosine kinase (Syk) regulates Alzheimer amyloid-β production and Tau hyperphosphorylation.",
+        "pages": "12282-93",
+        "reference": "27068745",
+        "title": "An Alzheimer Disease-linked Rare Mutation Potentiates Netrin Receptor Uncoordinated-5C-induced Signaling That Merges with Amyloid β Precursor Protein Signaling.",
         "type": "PubMed",
-        "volume": "289"
+        "volume": "291"
       },
-      "evidence": "We observed that pharmacological inhibition of Syk with BAY61-3606 stimulates Ser-9 phosphorylation of GSK3β in SH-SY5Y cells (Fig. 9, A and B) suggesting that blocking Syk activity results in GSK3β inhibition.",
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+          "Hashimoto Y",
+          "Kusakari S",
+          "Matsuoka M",
+          "Nawa M",
+          "Toyama Y"
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+        "date": "2016-06-03",
+        "first": "Hashimoto Y",
+        "last": "Matsuoka M",
+        "name": "The Journal of biological chemistry",
+        "pages": "12282-93",
+        "reference": "27068745",
+        "title": "An Alzheimer Disease-linked Rare Mutation Potentiates Netrin Receptor Uncoordinated-5C-induced Signaling That Merges with Amyloid β Precursor Protein Signaling.",
+        "type": "PubMed",
+        "volume": "291"
       },
+      "evidence": "Overexpression of wild-type UNC5C causes low-grade death, intensified by an AD-linked mutation T835M inhibited by a AD-linked survival factor, calmodulin-like skin protein (CLSP), and a natural ligand of UNC5C, netrin1. T835M-UNC5C-induced neuronal cell death is mediated by an intracellular death-signaling cascade, consisting of DAPK1/protein kinase D/apoptosis signal-regulating kinase 1 (ASK1)/JNK/NADPH oxidase/caspases, which merges at ASK1 with a death-signaling cascade, mediated by amyloid ß precursor protein (APP).",
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     {
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       "citation": {
         "authors": [
-          "Anderton BH",
-          "Derkinderen P",
-          "Geahlen RL",
-          "Hanger DP",
-          "Lardeux B",
-          "Lebouvier T",
-          "Reynolds CH",
-          "Scales TM"
+          "Hashimoto Y",
+          "Kusakari S",
+          "Matsuoka M",
+          "Nawa M",
+          "Toyama Y"
         ],
-        "date": "2008-02-01",
-        "first": "Lebouvier T",
-        "last": "Derkinderen P",
-        "name": "Biochimica et biophysica acta",
-        "pages": "188-92",
-        "reference": "18070606",
-        "title": "The microtubule-associated protein tau is phosphorylated by Syk.",
+        "date": "2016-06-03",
+        "first": "Hashimoto Y",
+        "last": "Matsuoka M",
+        "name": "The Journal of biological chemistry",
+        "pages": "12282-93",
+        "reference": "27068745",
+        "title": "An Alzheimer Disease-linked Rare Mutation Potentiates Netrin Receptor Uncoordinated-5C-induced Signaling That Merges with Amyloid β Precursor Protein Signaling.",
         "type": "PubMed",
-        "volume": "1783"
+        "volume": "291"
       },
-      "evidence": "We report herein that Syk is also a tau kinase, phosphorylating tau in vitro and in CHO cells when both proteins are expressed exogenously. In CHO cells, we have also demonstrated by co-immunoprecipitation that Syk binds to tau. Finally, by site-directed mutagenesis substituting the tyrosine residues of tau with phenylalanine, we established that tyrosine 18 was the primary residue in tau phosphorylated by Syk.",
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-          "Hosomi N",
-          "Izumi Y",
-          "Maruyama H",
-          "Matsumoto M",
-          "Miyazaki Y",
-          "Nakamori M",
-          "Nishikawa T",
-          "Takahashi T"
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-        "date": "2016-12-01",
-        "first": "Nishikawa T",
-        "last": "Matsumoto M",
-        "name": "Neuropathology and applied neurobiology",
-        "pages": "639-653",
-        "reference": "26501932",
-        "title": "The identification of raft-derived tau-associated vesicles that are incorporated into immature tangles and paired helical filaments.",
-        "type": "PubMed",
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@@ -55167,1232 +62291,1270 @@
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-          "Wei Z",
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-          "York J",
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     {
       "annotations": {
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       "citation": {
         "authors": [
-          "Cruz JC",
-          "Goldman JA",
-          "Shih H",
-          "Tsai LH",
-          "Tseng HC"
+          "Chen CH",
+          "Hong Y",
+          "Kim BM",
+          "Kimchi A",
+          "Lee S",
+          "Lee TH",
+          "You MH",
+          "Zhou XZ"
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         "type": "PubMed",
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       "citation": {
         "authors": [
-          "Cruz JC",
-          "Goldman JA",
-          "Shih H",
-          "Tsai LH",
-          "Tseng HC"
+          "Ando K",
+          "Blum D",
+          "Bretteville A",
+          "Buée L",
+          "Bégard S",
+          "Bélarbi K",
+          "Caillet-Boudin ML",
+          "Demey-Thomas E",
+          "Dourlen P",
+          "Drobecq H",
+          "Eddarkaoui S",
+          "Galas MC",
+          "Ghestem A",
+          "Hamdane M",
+          "Landrieu I",
+          "Lippens G",
+          "Maurage CA",
+          "Melnyk P",
+          "Sambo AV",
+          "Sergeant N",
+          "Smet C",
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+          "Vingtdeux V",
+          "Vinh J"
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-        "first": "Cruz JC",
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-        "name": "Neuron",
-        "pages": "471-83",
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         "type": "PubMed",
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-          "Ban T",
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-          "Jiang XM",
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-          "Su XL",
-          "Sun LH",
-          "Sun LL",
-          "Wang X",
-          "Yan ML",
-          "Zhao LJ",
-          "Zong DK"
+          "Chen CH",
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-        "last": "Ai J",
-        "name": "Journal of neurochemistry",
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-        "title": "Activation of Cdk5/p25 and tau phosphorylation following chronic brain hypoperfusion in rats involves microRNA-195 down-regulation.",
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-        "title": "Activation of Cdk5/p25 and tau phosphorylation following chronic brain hypoperfusion in rats involves microRNA-195 down-regulation.",
+          "Gaertig MA",
+          "Li S",
+          "Li XJ",
+          "Reeves RH",
+          "Xiang J",
+          "Xin N",
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-          "Pei SC",
-          "Su XL",
-          "Sun LH",
-          "Sun LL",
-          "Wang X",
-          "Yan ML",
-          "Zhao LJ",
-          "Zong DK"
+          "Gaertig MA",
+          "Li S",
+          "Li XJ",
+          "Reeves RH",
+          "Xiang J",
+          "Xin N",
+          "Yang S"
         ],
-        "date": "2015-09-01",
-        "first": "Sun LH",
-        "last": "Ai J",
-        "name": "Journal of neurochemistry",
-        "pages": "1139-51",
-        "reference": "26118667",
-        "title": "Activation of Cdk5/p25 and tau phosphorylation following chronic brain hypoperfusion in rats involves microRNA-195 down-regulation.",
+        "date": "2017-02-14",
+        "first": "Xiang J",
+        "last": "Li XJ",
+        "name": "Proceedings of the National Academy of Sciences of the United States of America",
+        "pages": "E1224-E1233",
+        "reference": "28137862",
+        "title": "DYRK1A regulates Hap1-Dcaf7/WDR68 binding with implication for delayed growth in Down syndrome.",
         "type": "PubMed",
-        "volume": "134"
+        "volume": "114"
       },
-      "evidence": "We observed that 2VO leads to tau hyperphosphorylation at Ser202/Thr205, Ser262, Thr231, and Ser422 and to the conversion from cyclin-dependent kinase 5 (Cdk5)/p35 to Cdk5/p25 in rat hippocampi. ",
-      "key": "6f651a06fdef1af85e35ea58f27a3d293e7d71d581205ae7fa6db2bbf3c3dd9fc59681a71fe22319d00cc42cfc24b8ad5736bda23ee7473e71b14d20968eef95",
-      "line": 2317,
-      "relation": "increases",
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+      "evidence": "Moreover, we found that Hap1 bound Dcaf7 competitively in cytoplasm with dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), a protein implicated in Down syndrome (DS). Depleting Hap1 promoted the DYRK1A-Dcaf7 interaction and increased the DYRK1A protein level.",
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     },
     {
       "annotations": {
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+        },
+        "MeSHDisease": {
+          "Alzheimer Disease": true,
+          "Down Syndrome": true
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         "Species": {
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         }
       },
       "citation": {
         "authors": [
-          "Ai J",
-          "Ban T",
-          "Bao YN",
-          "Chen QX",
-          "Hu XL",
-          "Jiang XM",
-          "Liu CD",
-          "Pei SC",
-          "Su XL",
-          "Sun LH",
-          "Sun LL",
-          "Wang X",
-          "Yan ML",
-          "Zhao LJ",
-          "Zong DK"
+          "Berciano MT",
+          "García-Cerro S",
+          "Lafarga M",
+          "Lantigua S",
+          "Martínez-Cué C",
+          "Padro D",
+          "Ramos-Cabrer P",
+          "Rueda N",
+          "Vidal V"
         ],
-        "date": "2015-09-01",
-        "first": "Sun LH",
-        "last": "Ai J",
-        "name": "Journal of neurochemistry",
-        "pages": "1139-51",
-        "reference": "26118667",
-        "title": "Activation of Cdk5/p25 and tau phosphorylation following chronic brain hypoperfusion in rats involves microRNA-195 down-regulation.",
+        "date": "2018-02-01",
+        "first": "García-Cerro S",
+        "last": "Martínez-Cué C",
+        "name": "Neurobiology of disease",
+        "pages": "206-217",
+        "reference": "29221819",
+        "title": "Cerebellar alterations in a model of Down syndrome: The role of the Dyrk1A gene.",
         "type": "PubMed",
-        "volume": "134"
+        "volume": "110"
       },
-      "evidence": "Chronic Brain hypoperfusion (CBH) elevates nuclear factor-kB (NF-kB), which binds with the promoter sequences of miR-195 and negatively regulates its expression. Down-regulated miR-195 up-regulates APP and BACE1 and increases Aß levels. Some Aß then enter the intracellular space and activate calpain, promoting the conversion of Cdk5/p35 to Cdk5/p25 and catalyzes the degradation of IkB (inhibitor of NF-?B)and directly phosphorylates Tau. Down-regulated miR-195 up-regulates p35, which provides the active substrates of p25",
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+      "evidence": "The normalization of the Dyrk1A gene dosage did not rescue the reduced cerebellar volume but increased the size of the granular and molecular layers, the densities of granular and Purkinje cells, and dendritic arborization.",
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     {
       "annotations": {
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+        },
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+          "Down Syndrome": true
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         "Species": {
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       },
       "citation": {
         "authors": [
-          "Ai J",
-          "Ban T",
-          "Bao YN",
-          "Chen QX",
-          "Hu XL",
-          "Jiang XM",
-          "Liu CD",
-          "Pei SC",
-          "Su XL",
-          "Sun LH",
-          "Sun LL",
-          "Wang X",
-          "Yan ML",
-          "Zhao LJ",
-          "Zong DK"
+          "Berciano MT",
+          "García-Cerro S",
+          "Lafarga M",
+          "Lantigua S",
+          "Martínez-Cué C",
+          "Padro D",
+          "Ramos-Cabrer P",
+          "Rueda N",
+          "Vidal V"
         ],
-        "date": "2015-09-01",
-        "first": "Sun LH",
-        "last": "Ai J",
-        "name": "Journal of neurochemistry",
-        "pages": "1139-51",
-        "reference": "26118667",
-        "title": "Activation of Cdk5/p25 and tau phosphorylation following chronic brain hypoperfusion in rats involves microRNA-195 down-regulation.",
+        "date": "2018-02-01",
+        "first": "García-Cerro S",
+        "last": "Martínez-Cué C",
+        "name": "Neurobiology of disease",
+        "pages": "206-217",
+        "reference": "29221819",
+        "title": "Cerebellar alterations in a model of Down syndrome: The role of the Dyrk1A gene.",
         "type": "PubMed",
-        "volume": "134"
+        "volume": "110"
       },
-      "evidence": "Endogenous miR-195 was knocked down using over-expression of its antisense molecule (pre-AMO-miR-195) via a lentivirus (lenti-pre-AMO-miR-195); this knockdown increased the tau phosphorylation at Ser202/Thr205, Ser262, Thr231, Ser422, and the Cdk5/p25 activation, but over-expression of miR-195 using lenti-pre-miR-195 decreased the tau phosphorylation and Cdk5/p25 activation.",
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+      "evidence": "The normalization of the Dyrk1A gene dosage did not rescue the reduced cerebellar volume but increased the size of the granular and molecular layers, the densities of granular and Purkinje cells, and dendritic arborization.",
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     },
     {
       "annotations": {
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         "Species": {
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       "citation": {
         "authors": [
-          "Ai J",
-          "Ban T",
-          "Bao YN",
-          "Chen QX",
-          "Hu XL",
-          "Jiang XM",
-          "Liu CD",
-          "Pei SC",
-          "Su XL",
-          "Sun LH",
-          "Sun LL",
-          "Wang X",
-          "Yan ML",
-          "Zhao LJ",
-          "Zong DK"
+          "Berciano MT",
+          "García-Cerro S",
+          "Lafarga M",
+          "Lantigua S",
+          "Martínez-Cué C",
+          "Padro D",
+          "Ramos-Cabrer P",
+          "Rueda N",
+          "Vidal V"
         ],
-        "date": "2015-09-01",
-        "first": "Sun LH",
-        "last": "Ai J",
-        "name": "Journal of neurochemistry",
-        "pages": "1139-51",
-        "reference": "26118667",
-        "title": "Activation of Cdk5/p25 and tau phosphorylation following chronic brain hypoperfusion in rats involves microRNA-195 down-regulation.",
+        "date": "2018-02-01",
+        "first": "García-Cerro S",
+        "last": "Martínez-Cué C",
+        "name": "Neurobiology of disease",
+        "pages": "206-217",
+        "reference": "29221819",
+        "title": "Cerebellar alterations in a model of Down syndrome: The role of the Dyrk1A gene.",
         "type": "PubMed",
-        "volume": "134"
+        "volume": "110"
       },
-      "evidence": "Endogenous miR-195 was knocked down using over-expression of its antisense molecule (pre-AMO-miR-195) via a lentivirus (lenti-pre-AMO-miR-195); this knockdown increased the tau phosphorylation at Ser202/Thr205, Ser262, Thr231, Ser422, and the Cdk5/p25 activation, but over-expression of miR-195 using lenti-pre-miR-195 decreased the tau phosphorylation and Cdk5/p25 activation.",
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     },
     {
       "annotations": {
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+          "Medium": true
+        },
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+          "Alzheimer Disease": true,
+          "Down Syndrome": true
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+          "Ts65Dn mice": true
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         "Species": {
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       "citation": {
         "authors": [
-          "Ai J",
-          "Ban T",
-          "Bao YN",
-          "Chen QX",
-          "Hu XL",
-          "Jiang XM",
-          "Liu CD",
-          "Pei SC",
-          "Su XL",
-          "Sun LH",
-          "Sun LL",
-          "Wang X",
-          "Yan ML",
-          "Zhao LJ",
-          "Zong DK"
+          "Berciano MT",
+          "García-Cerro S",
+          "Lafarga M",
+          "Lantigua S",
+          "Martínez-Cué C",
+          "Padro D",
+          "Ramos-Cabrer P",
+          "Rueda N",
+          "Vidal V"
         ],
-        "date": "2015-09-01",
-        "first": "Sun LH",
-        "last": "Ai J",
-        "name": "Journal of neurochemistry",
-        "pages": "1139-51",
-        "reference": "26118667",
-        "title": "Activation of Cdk5/p25 and tau phosphorylation following chronic brain hypoperfusion in rats involves microRNA-195 down-regulation.",
+        "date": "2018-02-01",
+        "first": "García-Cerro S",
+        "last": "Martínez-Cué C",
+        "name": "Neurobiology of disease",
+        "pages": "206-217",
+        "reference": "29221819",
+        "title": "Cerebellar alterations in a model of Down syndrome: The role of the Dyrk1A gene.",
         "type": "PubMed",
-        "volume": "134"
+        "volume": "110"
       },
-      "evidence": "Endogenous miR-195 was knocked down using over-expression of its antisense molecule (pre-AMO-miR-195) via a lentivirus (lenti-pre-AMO-miR-195); this knockdown increased the tau phosphorylation at Ser202/Thr205, Ser262, Thr231, Ser422, and the Cdk5/p25 activation, but over-expression of miR-195 using lenti-pre-miR-195 decreased the tau phosphorylation and Cdk5/p25 activation.",
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     {
       "annotations": {
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+          "hippocampal formation": true,
+          "septum": true
+        },
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHDisease": {
+          "Alzheimer Disease": true,
+          "Down Syndrome": true
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       "citation": {
         "authors": [
-          "Ai J",
-          "Ban T",
-          "Bao YN",
-          "Chen QX",
-          "Hu XL",
-          "Jiang XM",
-          "Liu CD",
-          "Pei SC",
-          "Su XL",
-          "Sun LH",
-          "Sun LL",
-          "Wang X",
-          "Yan ML",
-          "Zhao LJ",
-          "Zong DK"
+          "Berciano MT",
+          "García-Cerro S",
+          "Lafarga M",
+          "Lantigua S",
+          "Martínez-Cué C",
+          "Padro D",
+          "Ramos-Cabrer P",
+          "Rueda N",
+          "Vidal V"
         ],
-        "date": "2015-09-01",
-        "first": "Sun LH",
-        "last": "Ai J",
-        "name": "Journal of neurochemistry",
-        "pages": "1139-51",
-        "reference": "26118667",
-        "title": "Activation of Cdk5/p25 and tau phosphorylation following chronic brain hypoperfusion in rats involves microRNA-195 down-regulation.",
+        "date": "2018-02-01",
+        "first": "García-Cerro S",
+        "last": "Martínez-Cué C",
+        "name": "Neurobiology of disease",
+        "pages": "206-217",
+        "reference": "29221819",
+        "title": "Cerebellar alterations in a model of Down syndrome: The role of the Dyrk1A gene.",
         "type": "PubMed",
-        "volume": "134"
+        "volume": "110"
       },
-      "evidence": "Endogenous miR-195 was knocked down using over-expression of its antisense molecule (pre-AMO-miR-195) via a lentivirus (lenti-pre-AMO-miR-195); this knockdown increased the tau phosphorylation at Ser202/Thr205, Ser262, Thr231, Ser422, and the Cdk5/p25 activation, but over-expression of miR-195 using lenti-pre-miR-195 decreased the tau phosphorylation and Cdk5/p25 activation.",
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+      "evidence": "Normalizing the gene dosage of Dyrk1A in the TS mouse rescued the density of senescent cells in the cingulate cortex, hippocampus and septum, prevented cholinergic neuron degeneration, and reduced App expression in the hippocampus, Aß load in the cortex and hippocampus, the expression of phosphorylated tau at the Ser202 residue in the hippocampus and cerebellum and the levels of total tau in the cortex, hippocampus and cerebellum.",
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     {
       "annotations": {
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         "Species": {
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       "citation": {
         "authors": [
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-          "Ban T",
-          "Bao YN",
-          "Chen QX",
-          "Hu XL",
-          "Jiang XM",
-          "Liu CD",
-          "Pei SC",
-          "Su XL",
-          "Sun LH",
-          "Sun LL",
-          "Wang X",
-          "Yan ML",
-          "Zhao LJ",
-          "Zong DK"
+          "Berciano MT",
+          "García-Cerro S",
+          "Lafarga M",
+          "Lantigua S",
+          "Martínez-Cué C",
+          "Padro D",
+          "Ramos-Cabrer P",
+          "Rueda N",
+          "Vidal V"
         ],
-        "date": "2015-09-01",
-        "first": "Sun LH",
-        "last": "Ai J",
-        "name": "Journal of neurochemistry",
-        "pages": "1139-51",
-        "reference": "26118667",
-        "title": "Activation of Cdk5/p25 and tau phosphorylation following chronic brain hypoperfusion in rats involves microRNA-195 down-regulation.",
+        "date": "2018-02-01",
+        "first": "García-Cerro S",
+        "last": "Martínez-Cué C",
+        "name": "Neurobiology of disease",
+        "pages": "206-217",
+        "reference": "29221819",
+        "title": "Cerebellar alterations in a model of Down syndrome: The role of the Dyrk1A gene.",
         "type": "PubMed",
-        "volume": "134"
+        "volume": "110"
       },
-      "evidence": "Endogenous miR-195 was knocked down using over-expression of its antisense molecule (pre-AMO-miR-195) via a lentivirus (lenti-pre-AMO-miR-195); this knockdown increased the tau phosphorylation at Ser202/Thr205, Ser262, Thr231, Ser422, and the Cdk5/p25 activation, but over-expression of miR-195 using lenti-pre-miR-195 decreased the tau phosphorylation and Cdk5/p25 activation.",
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     {
       "annotations": {
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         "Species": {
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       "citation": {
         "authors": [
-          "Ai J",
-          "Ban T",
-          "Bao YN",
-          "Chen QX",
-          "Hu XL",
-          "Jiang XM",
-          "Liu CD",
-          "Pei SC",
-          "Su XL",
-          "Sun LH",
-          "Sun LL",
-          "Wang X",
-          "Yan ML",
-          "Zhao LJ",
-          "Zong DK"
+          "Berciano MT",
+          "García-Cerro S",
+          "Lafarga M",
+          "Lantigua S",
+          "Martínez-Cué C",
+          "Padro D",
+          "Ramos-Cabrer P",
+          "Rueda N",
+          "Vidal V"
         ],
-        "date": "2015-09-01",
-        "first": "Sun LH",
-        "last": "Ai J",
-        "name": "Journal of neurochemistry",
-        "pages": "1139-51",
-        "reference": "26118667",
-        "title": "Activation of Cdk5/p25 and tau phosphorylation following chronic brain hypoperfusion in rats involves microRNA-195 down-regulation.",
+        "date": "2018-02-01",
+        "first": "García-Cerro S",
+        "last": "Martínez-Cué C",
+        "name": "Neurobiology of disease",
+        "pages": "206-217",
+        "reference": "29221819",
+        "title": "Cerebellar alterations in a model of Down syndrome: The role of the Dyrk1A gene.",
         "type": "PubMed",
-        "volume": "134"
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-      "evidence": "A dual luciferase reporter assay showed that miR-195 bound to the Cdk5r1 gene, which encodes p35 protein, in the 3'UTR and inhibited p35 expression.",
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+        "reference": "28775333",
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         "type": "PubMed",
-        "volume": "134"
+        "volume": "7"
       },
-      "evidence": "Chronic Brain hypoperfusion (CBH) elevates nuclear factor-kB (NF-kB), which binds with the promoter sequences of miR-195 and negatively regulates its expression. Down-regulated miR-195 up-regulates APP and BACE1 and increases Aß levels. Some Aß then enter the intracellular space and activate calpain, promoting the conversion of Cdk5/p35 to Cdk5/p25 and catalyzes the degradation of IkB (inhibitor of NF-?B)and directly phosphorylates Tau. Down-regulated miR-195 up-regulates p35, which provides the active substrates of p25",
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     {
       "annotations": {
+        "Confidence": {
+          "High": true
+        },
+        "MeSHDisease": {
+          "Alzheimer Disease": true,
+          "Down Syndrome": true
+        },
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+          "Ts65Dn mice": true
+        },
         "Species": {
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       "citation": {
         "authors": [
-          "Ai J",
-          "Ban T",
-          "Bao YN",
-          "Chen QX",
-          "Hu XL",
-          "Jiang XM",
-          "Liu CD",
-          "Pei SC",
-          "Su XL",
-          "Sun LH",
-          "Sun LL",
-          "Wang X",
-          "Yan ML",
-          "Zhao LJ",
-          "Zong DK"
+          "Chen L",
+          "Sun X",
+          "Wang L",
+          "Wang P"
         ],
-        "date": "2015-09-01",
-        "first": "Sun LH",
-        "last": "Ai J",
-        "name": "Journal of neurochemistry",
-        "pages": "1139-51",
-        "reference": "26118667",
-        "title": "Activation of Cdk5/p25 and tau phosphorylation following chronic brain hypoperfusion in rats involves microRNA-195 down-regulation.",
+        "date": "2017-08-03",
+        "first": "Wang P",
+        "last": "Sun X",
+        "name": "Scientific reports",
+        "pages": "7240",
+        "reference": "28775333",
+        "title": "Dual-specificity tyrosine-phosphorylation regulated kinase 1A Gene Transcription is regulated by Myocyte Enhancer Factor 2D.",
         "type": "PubMed",
-        "volume": "134"
+        "volume": "7"
       },
-      "evidence": "Chronic Brain hypoperfusion (CBH) elevates nuclear factor-kB (NF-kB), which binds with the promoter sequences of miR-195 and negatively regulates its expression. Down-regulated miR-195 up-regulates APP and BACE1 and increases Aß levels. Some Aß then enter the intracellular space and activate calpain, promoting the conversion of Cdk5/p35 to Cdk5/p25 and catalyzes the degradation of IkB (inhibitor of NF-?B)and directly phosphorylates Tau. Down-regulated miR-195 up-regulates p35, which provides the active substrates of p25",
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+      "evidence": "Inhibition of Dyrk1A enhanced tau exon 10 inclusion, leading to an increase in 4R-tau/3R-tau ratio in differentiated-human neuronal progenitors and in the neonatal rat brains. Accompanied with overexpression of Dyrk1A, 3R-tau was increased and 4R-tau was decreased in the neonatal brains of Ts65Dn mice, a model of Down syndrome.",
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+      "target": 386
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     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
+        "MeSHDisease": {
+          "Alzheimer Disease": true,
+          "Down Syndrome": true
+        },
+        "Research_Model": {
+          "Ts65Dn mice": true
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         "Species": {
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       "citation": {
         "authors": [
-          "Ai J",
-          "Ban T",
-          "Bao YN",
-          "Chen QX",
-          "Hu XL",
-          "Jiang XM",
-          "Liu CD",
-          "Pei SC",
-          "Su XL",
-          "Sun LH",
-          "Sun LL",
-          "Wang X",
-          "Yan ML",
-          "Zhao LJ",
-          "Zong DK"
+          "Chen L",
+          "Sun X",
+          "Wang L",
+          "Wang P"
         ],
-        "date": "2015-09-01",
-        "first": "Sun LH",
-        "last": "Ai J",
-        "name": "Journal of neurochemistry",
-        "pages": "1139-51",
-        "reference": "26118667",
-        "title": "Activation of Cdk5/p25 and tau phosphorylation following chronic brain hypoperfusion in rats involves microRNA-195 down-regulation.",
+        "date": "2017-08-03",
+        "first": "Wang P",
+        "last": "Sun X",
+        "name": "Scientific reports",
+        "pages": "7240",
+        "reference": "28775333",
+        "title": "Dual-specificity tyrosine-phosphorylation regulated kinase 1A Gene Transcription is regulated by Myocyte Enhancer Factor 2D.",
         "type": "PubMed",
-        "volume": "134"
+        "volume": "7"
       },
-      "evidence": "Chronic Brain hypoperfusion (CBH) elevates nuclear factor-kB (NF-kB), which binds with the promoter sequences of miR-195 and negatively regulates its expression. Down-regulated miR-195 up-regulates APP and BACE1 and increases Aß levels. Some Aß then enter the intracellular space and activate calpain, promoting the conversion of Cdk5/p35 to Cdk5/p25 and catalyzes the degradation of IkB (inhibitor of NF-?B)and directly phosphorylates Tau. Down-regulated miR-195 up-regulates p35, which provides the active substrates of p25",
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-      "relation": "negativeCorrelation",
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+      "evidence": "Treatment with Dyrk1A inhibitor, green tea flavonol epigallocatechin-gallate (EGCG), from gestation to adulthood suppressed 3R-tau expression and rescued anxiety and memory deficits in Ts65Dn mouse brains.",
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     {
       "annotations": {
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+          "Medium": true
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+        "MeSHAnatomy": {
+          "Brain": true
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+        "MeSHDisease": {
+          "Alzheimer Disease": true,
+          "Down Syndrome": true
+        },
+        "Research_Model": {
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         "Species": {
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       "citation": {
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-          "Ai J",
-          "Ban T",
-          "Bao YN",
-          "Chen QX",
-          "Hu XL",
-          "Jiang XM",
-          "Liu CD",
-          "Pei SC",
-          "Su XL",
-          "Sun LH",
-          "Sun LL",
-          "Wang X",
-          "Yan ML",
-          "Zhao LJ",
-          "Zong DK"
+          "Chen L",
+          "Sun X",
+          "Wang L",
+          "Wang P"
         ],
-        "date": "2015-09-01",
-        "first": "Sun LH",
-        "last": "Ai J",
-        "name": "Journal of neurochemistry",
-        "pages": "1139-51",
-        "reference": "26118667",
-        "title": "Activation of Cdk5/p25 and tau phosphorylation following chronic brain hypoperfusion in rats involves microRNA-195 down-regulation.",
+        "date": "2017-08-03",
+        "first": "Wang P",
+        "last": "Sun X",
+        "name": "Scientific reports",
+        "pages": "7240",
+        "reference": "28775333",
+        "title": "Dual-specificity tyrosine-phosphorylation regulated kinase 1A Gene Transcription is regulated by Myocyte Enhancer Factor 2D.",
         "type": "PubMed",
-        "volume": "134"
-      },
-      "evidence": "Chronic Brain hypoperfusion (CBH) elevates nuclear factor-kB (NF-kB), which binds with the promoter sequences of miR-195 and negatively regulates its expression. Down-regulated miR-195 up-regulates APP and BACE1 and increases Aß levels. Some Aß then enter the intracellular space and activate calpain, promoting the conversion of Cdk5/p35 to Cdk5/p25 and catalyzes the degradation of IkB (inhibitor of NF-?B)and directly phosphorylates Tau. Down-regulated miR-195 up-regulates p35, which provides the active substrates of p25",
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-      "relation": "positiveCorrelation",
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+      "evidence": "Treatment with Dyrk1A inhibitor, green tea flavonol epigallocatechin-gallate (EGCG), from gestation to adulthood suppressed 3R-tau expression and rescued anxiety and memory deficits in Ts65Dn mouse brains.",
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     {
       "annotations": {
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         "Species": {
-          "10116": true
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       "citation": {
         "authors": [
-          "Ai J",
-          "Ban T",
-          "Bao YN",
-          "Chen QX",
-          "Hu XL",
-          "Jiang XM",
-          "Liu CD",
-          "Pei SC",
-          "Su XL",
-          "Sun LH",
-          "Sun LL",
-          "Wang X",
-          "Yan ML",
-          "Zhao LJ",
-          "Zong DK"
+          "Gaertig MA",
+          "Li S",
+          "Li XJ",
+          "Reeves RH",
+          "Xiang J",
+          "Xin N",
+          "Yang S"
         ],
-        "date": "2015-09-01",
-        "first": "Sun LH",
-        "last": "Ai J",
-        "name": "Journal of neurochemistry",
-        "pages": "1139-51",
-        "reference": "26118667",
-        "title": "Activation of Cdk5/p25 and tau phosphorylation following chronic brain hypoperfusion in rats involves microRNA-195 down-regulation.",
+        "date": "2017-02-14",
+        "first": "Xiang J",
+        "last": "Li XJ",
+        "name": "Proceedings of the National Academy of Sciences of the United States of America",
+        "pages": "E1224-E1233",
+        "reference": "28137862",
+        "title": "DYRK1A regulates Hap1-Dcaf7/WDR68 binding with implication for delayed growth in Down syndrome.",
         "type": "PubMed",
-        "volume": "134"
-      },
-      "evidence": "Chronic Brain hypoperfusion (CBH) elevates nuclear factor-kB (NF-kB), which binds with the promoter sequences of miR-195 and negatively regulates its expression. Down-regulated miR-195 up-regulates APP and BACE1 and increases Aß levels. Some Aß then enter the intracellular space and activate calpain, promoting the conversion of Cdk5/p35 to Cdk5/p25 and catalyzes the degradation of IkB (inhibitor of NF-?B)and directly phosphorylates Tau. Down-regulated miR-195 up-regulates p35, which provides the active substrates of p25",
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+      "evidence": "Moreover, we found that Hap1 bound Dcaf7 competitively in cytoplasm with dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), a protein implicated in Down syndrome (DS). Depleting Hap1 promoted the DYRK1A-Dcaf7 interaction and increased the DYRK1A protein level.",
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     {
       "annotations": {
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         "Species": {
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       "citation": {
         "authors": [
-          "Ai J",
-          "Ban T",
-          "Bao YN",
-          "Chen QX",
-          "Hu XL",
-          "Jiang XM",
-          "Liu CD",
-          "Pei SC",
-          "Su XL",
-          "Sun LH",
-          "Sun LL",
-          "Wang X",
-          "Yan ML",
-          "Zhao LJ",
-          "Zong DK"
+          "Gaertig MA",
+          "Li S",
+          "Li XJ",
+          "Reeves RH",
+          "Xiang J",
+          "Xin N",
+          "Yang S"
         ],
-        "date": "2015-09-01",
-        "first": "Sun LH",
-        "last": "Ai J",
-        "name": "Journal of neurochemistry",
-        "pages": "1139-51",
-        "reference": "26118667",
-        "title": "Activation of Cdk5/p25 and tau phosphorylation following chronic brain hypoperfusion in rats involves microRNA-195 down-regulation.",
+        "date": "2017-02-14",
+        "first": "Xiang J",
+        "last": "Li XJ",
+        "name": "Proceedings of the National Academy of Sciences of the United States of America",
+        "pages": "E1224-E1233",
+        "reference": "28137862",
+        "title": "DYRK1A regulates Hap1-Dcaf7/WDR68 binding with implication for delayed growth in Down syndrome.",
         "type": "PubMed",
-        "volume": "134"
+        "volume": "114"
       },
-      "evidence": "Chronic Brain hypoperfusion (CBH) elevates nuclear factor-kB (NF-kB), which binds with the promoter sequences of miR-195 and negatively regulates its expression. Down-regulated miR-195 up-regulates APP and BACE1 and increases Aß levels. Some Aß then enter the intracellular space and activate calpain, promoting the conversion of Cdk5/p35 to Cdk5/p25 and catalyzes the degradation of IkB (inhibitor of NF-?B)and directly phosphorylates Tau. Down-regulated miR-195 up-regulates p35, which provides the active substrates of p25",
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-      "target": 264
+      "evidence": "Moreover, we found that Hap1 bound Dcaf7 competitively in cytoplasm with dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), a protein implicated in Down syndrome (DS). Depleting Hap1 promoted the DYRK1A-Dcaf7 interaction and increased the DYRK1A protein level.",
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     {
       "annotations": {
-        "Research_Model": {
-          "E4FAD mice": true
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Cytosol": true
         },
         "Species": {
           "10090": true
@@ -56400,42 +63562,38 @@
       },
       "citation": {
         "authors": [
-          "Chen X",
-          "Collins N",
-          "Dai X",
-          "Huang T",
-          "LaDu MJ",
-          "Lin L",
-          "Shen H",
-          "Wei Z",
-          "Wu X",
-          "Xiao N",
-          "York J",
-          "Zhang J",
-          "Zhou M",
-          "Zhu Y"
+          "Gaertig MA",
+          "Li S",
+          "Li XJ",
+          "Reeves RH",
+          "Xiang J",
+          "Xin N",
+          "Yang S"
         ],
-        "date": "2016-01-01",
-        "first": "Zhou M",
-        "last": "Chen X",
-        "name": "Current Alzheimer research",
-        "pages": "1048-55",
-        "reference": "27087442",
-        "title": "APOE4 Induces Site-Specific Tau Phosphorylation Through Calpain-CDK5 Signaling Pathway in EFAD-Tg Mice.",
+        "date": "2017-02-14",
+        "first": "Xiang J",
+        "last": "Li XJ",
+        "name": "Proceedings of the National Academy of Sciences of the United States of America",
+        "pages": "E1224-E1233",
+        "reference": "28137862",
+        "title": "DYRK1A regulates Hap1-Dcaf7/WDR68 binding with implication for delayed growth in Down syndrome.",
         "type": "PubMed",
-        "volume": "13"
+        "volume": "114"
       },
-      "evidence": "The levels of CDK5, its regulatory subunits (p35 and p25) and calpain (including calpain1 and calpain2), but not GSK3ß, were significantly increased in E4FAD mice compared to E3FAD mice.",
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-      "line": 2353,
-      "relation": "increases",
-      "source": 309,
-      "target": 777
+      "evidence": "Moreover, we found that Hap1 bound Dcaf7 competitively in cytoplasm with dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), a protein implicated in Down syndrome (DS). Depleting Hap1 promoted the DYRK1A-Dcaf7 interaction and increased the DYRK1A protein level.",
+      "key": "4e3df1c3bd7c00b38ba11945a42625833a69fbd4ee407cfa2bfd56139b3bbf3d634ed3a3a8a6b8c60bced7edc6a6542fc2ed7d66b5997dffc15a97cb13d4785a",
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+      "relation": "negativeCorrelation",
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     },
     {
       "annotations": {
-        "Research_Model": {
-          "E4FAD mice": true
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Cytosol": true
         },
         "Species": {
           "10090": true
@@ -56443,474 +63601,506 @@
       },
       "citation": {
         "authors": [
-          "Chen X",
-          "Collins N",
-          "Dai X",
-          "Huang T",
-          "LaDu MJ",
-          "Lin L",
-          "Shen H",
-          "Wei Z",
-          "Wu X",
-          "Xiao N",
-          "York J",
-          "Zhang J",
-          "Zhou M",
-          "Zhu Y"
+          "Gaertig MA",
+          "Li S",
+          "Li XJ",
+          "Reeves RH",
+          "Xiang J",
+          "Xin N",
+          "Yang S"
         ],
-        "date": "2016-01-01",
-        "first": "Zhou M",
-        "last": "Chen X",
-        "name": "Current Alzheimer research",
-        "pages": "1048-55",
-        "reference": "27087442",
-        "title": "APOE4 Induces Site-Specific Tau Phosphorylation Through Calpain-CDK5 Signaling Pathway in EFAD-Tg Mice.",
+        "date": "2017-02-14",
+        "first": "Xiang J",
+        "last": "Li XJ",
+        "name": "Proceedings of the National Academy of Sciences of the United States of America",
+        "pages": "E1224-E1233",
+        "reference": "28137862",
+        "title": "DYRK1A regulates Hap1-Dcaf7/WDR68 binding with implication for delayed growth in Down syndrome.",
         "type": "PubMed",
-        "volume": "13"
+        "volume": "114"
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-      "evidence": "The levels of CDK5, its regulatory subunits (p35 and p25) and calpain (including calpain1 and calpain2), but not GSK3ß, were significantly increased in E4FAD mice compared to E3FAD mice.",
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-      "line": 2354,
-      "relation": "increases",
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-      "target": 311
+      "evidence": "Moreover, we found that Hap1 bound Dcaf7 competitively in cytoplasm with dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), a protein implicated in Down syndrome (DS). Depleting Hap1 promoted the DYRK1A-Dcaf7 interaction and increased the DYRK1A protein level.",
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     {
       "annotations": {
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-          "E4FAD mice": true
-        },
-        "Species": {
-          "10090": true
+        "Confidence": {
+          "Medium": true
         }
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       "citation": {
         "authors": [
-          "Chen X",
-          "Collins N",
-          "Dai X",
-          "Huang T",
-          "LaDu MJ",
-          "Lin L",
-          "Shen H",
-          "Wei Z",
-          "Wu X",
-          "Xiao N",
-          "York J",
-          "Zhang J",
-          "Zhou M",
-          "Zhu Y"
+          "Gaertig MA",
+          "Li S",
+          "Li XJ",
+          "Reeves RH",
+          "Xiang J",
+          "Xin N",
+          "Yang S"
         ],
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-        "first": "Zhou M",
-        "last": "Chen X",
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-        "title": "APOE4 Induces Site-Specific Tau Phosphorylation Through Calpain-CDK5 Signaling Pathway in EFAD-Tg Mice.",
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-          "LaDu MJ",
-          "Lin L",
-          "Shen H",
-          "Wei Z",
-          "Wu X",
-          "Xiao N",
-          "York J",
-          "Zhang J",
-          "Zhou M",
-          "Zhu Y"
+          "Bellmaine SF",
+          "Cuddy CE",
+          "Elefanty AG",
+          "Manallack DT",
+          "Ovchinnikov DA",
+          "Pera M",
+          "Stanley EG",
+          "Williams SJ",
+          "Wolvetang EJ"
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-        "first": "Zhou M",
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-        "title": "APOE4 Induces Site-Specific Tau Phosphorylation Through Calpain-CDK5 Signaling Pathway in EFAD-Tg Mice.",
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-          "Dai X",
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-          "Shen H",
-          "Wei Z",
-          "Wu X",
-          "Xiao N",
-          "York J",
-          "Zhang J",
-          "Zhou M",
-          "Zhu Y"
+          "Asai M",
+          "Iwata N",
+          "Kawakubo T",
+          "Mori R",
+          "Shirotani K"
         ],
-        "date": "2016-01-01",
-        "first": "Zhou M",
-        "last": "Chen X",
-        "name": "Current Alzheimer research",
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-        "reference": "27087442",
-        "title": "APOE4 Induces Site-Specific Tau Phosphorylation Through Calpain-CDK5 Signaling Pathway in EFAD-Tg Mice.",
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+        "last": "Asai M",
+        "name": "Biological &amp; pharmaceutical bulletin",
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+        "reference": "28250274",
+        "title": "Neprilysin Is Suppressed by Dual-Specificity Tyrosine-Phosphorylation Regulated Kinase 1A (DYRK1A) in Down-Syndrome-Derived Fibroblasts.",
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-          "Chen X",
-          "Collins N",
-          "Dai X",
-          "Huang T",
-          "LaDu MJ",
-          "Lin L",
-          "Shen H",
-          "Wei Z",
-          "Wu X",
-          "Xiao N",
-          "York J",
-          "Zhang J",
-          "Zhou M",
-          "Zhu Y"
+          "Alexopoulos P",
+          "Arbones M",
+          "Badel A",
+          "Camproux AC",
+          "Delabar JM",
+          "Dubois B",
+          "Feraudet-Tarisse C",
+          "Janel N",
+          "Lagarde J",
+          "Lamari F",
+          "Lamourette P",
+          "Paul JL",
+          "Potier MC",
+          "Sarazin M",
+          "Simon S"
         ],
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-        "first": "Zhou M",
-        "last": "Chen X",
-        "name": "Current Alzheimer research",
-        "pages": "1048-55",
-        "reference": "27087442",
-        "title": "APOE4 Induces Site-Specific Tau Phosphorylation Through Calpain-CDK5 Signaling Pathway in EFAD-Tg Mice.",
+        "date": "2017-06-20",
+        "first": "Janel N",
+        "last": "Delabar JM",
+        "name": "Translational psychiatry",
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+        "title": "Combined assessment of DYRK1A, BDNF and homocysteine levels as diagnostic marker for Alzheimer's disease.",
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-          "Bredesen DE",
-          "Rao RV",
-          "Theendakara V"
+          "An Y",
+          "Cheng C",
+          "Dang T",
+          "Duan WY",
+          "Qiu ZL",
+          "Tong DL",
+          "Wu BB",
+          "Wu BL",
+          "Wu M",
+          "Wu W",
+          "Ye K",
+          "Yu B",
+          "Zhang WX",
+          "Zhang YF"
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-        "last": "Rao RV",
-        "name": "Molecular and cellular neurosciences",
-        "pages": "83-91",
-        "reference": "28720530",
-        "title": "Downregulation of protein phosphatase 2A by apolipoprotein E: Implications for Alzheimer's disease.",
+        "date": "2018-03-01",
+        "first": "Dang T",
+        "last": "Wu BL",
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+        "title": "Autism-associated Dyrk1a truncation mutants impair neuronal dendritic and spine growth and interfere with postnatal cortical development.",
         "type": "PubMed",
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         "authors": [
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-          "Rao RV",
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+          "Duan WY",
+          "Qiu ZL",
+          "Tong DL",
+          "Wu BB",
+          "Wu BL",
+          "Wu M",
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-        "title": "Downregulation of protein phosphatase 2A by apolipoprotein E: Implications for Alzheimer's disease.",
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+        "title": "Autism-associated Dyrk1a truncation mutants impair neuronal dendritic and spine growth and interfere with postnatal cortical development.",
         "type": "PubMed",
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-          "Wei Z",
-          "Wu X",
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-          "York J",
-          "Zhang J",
-          "Zhou M",
-          "Zhu Y"
+          "Gaertig MA",
+          "Li S",
+          "Li XJ",
+          "Reeves RH",
+          "Xiang J",
+          "Xin N",
+          "Yang S"
         ],
-        "date": "2016-01-01",
-        "first": "Zhou M",
-        "last": "Chen X",
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-        "pages": "1048-55",
-        "reference": "27087442",
-        "title": "APOE4 Induces Site-Specific Tau Phosphorylation Through Calpain-CDK5 Signaling Pathway in EFAD-Tg Mice.",
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+        "last": "Li XJ",
+        "name": "Proceedings of the National Academy of Sciences of the United States of America",
+        "pages": "E1224-E1233",
+        "reference": "28137862",
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         "type": "PubMed",
-        "volume": "13"
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-          "Wei Z",
-          "Wu X",
-          "Xiao N",
-          "York J",
-          "Zhang J",
-          "Zhou M",
-          "Zhu Y"
+          "Asai M",
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-        "first": "Zhou M",
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-        "title": "APOE4 Induces Site-Specific Tau Phosphorylation Through Calpain-CDK5 Signaling Pathway in EFAD-Tg Mice.",
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+        "name": "Biological &amp; pharmaceutical bulletin",
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+        "reference": "28250274",
+        "title": "Neprilysin Is Suppressed by Dual-Specificity Tyrosine-Phosphorylation Regulated Kinase 1A (DYRK1A) in Down-Syndrome-Derived Fibroblasts.",
         "type": "PubMed",
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       "citation": {
         "authors": [
-          "Chen X",
-          "Collins N",
-          "Dai X",
-          "Huang T",
-          "LaDu MJ",
-          "Lin L",
-          "Shen H",
-          "Wei Z",
-          "Wu X",
-          "Xiao N",
-          "York J",
-          "Zhang J",
-          "Zhou M",
-          "Zhu Y"
-        ],
-        "date": "2016-01-01",
-        "first": "Zhou M",
-        "last": "Chen X",
-        "name": "Current Alzheimer research",
-        "pages": "1048-55",
-        "reference": "27087442",
-        "title": "APOE4 Induces Site-Specific Tau Phosphorylation Through Calpain-CDK5 Signaling Pathway in EFAD-Tg Mice.",
+          "Berciano MT",
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-          "Wei Z",
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-          "Zhang J",
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-          "Zhu Y"
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@@ -56918,322 +64108,300 @@
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-          "Wei Z",
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-      "evidence": "We demonstrated that the treatment of cultured hippocampal neurons with 125 µM glutamate for 20 min induced the cleavage of p35 to produce the p25 fragment 6 h after glutamate treatment, and the maximal levels of p25 were detected at 12 h (Fig. 1A), which is consistent with a peak in tau hyperphosphorylation (AT8).",
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-          "Chen S",
-          "Gao XD",
-          "Liu AR",
-          "Wang Y",
-          "Xu Z",
-          "Yao WB",
-          "Yin L"
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-        "title": "Glucagon-like peptide-1 regulates mitochondrial biogenesis and tau phosphorylation against advanced glycation end product-induced neuronal insult: Studies in vivo and in vitro.",
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-          "Lu B",
-          "Maruko-Otake A",
-          "Ohtake Y",
-          "Sekiya M",
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-        "title": "Loss of axonal mitochondria promotes tau-mediated neurodegeneration and Alzheimer's disease-related tau phosphorylation via PAR-1.",
+        "date": "2018-02-01",
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         "authors": [
-          "Ando K",
-          "Brion JP",
-          "D'Amico E",
-          "Duyckaerts C",
-          "Erneux C",
-          "Jia Y",
-          "Leroy K",
-          "Luo HR",
-          "Pouillon V",
-          "Schurmans S",
-          "Stygelbout V"
+          "Bellmaine SF",
+          "Cuddy CE",
+          "Elefanty AG",
+          "Manallack DT",
+          "Ovchinnikov DA",
+          "Pera M",
+          "Stanley EG",
+          "Williams SJ",
+          "Wolvetang EJ"
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-        "first": "Stygelbout V",
-        "last": "Brion JP",
-        "name": "Brain : a journal of neurology",
-        "pages": "537-52",
-        "reference": "24401760",
-        "title": "Inositol trisphosphate 3-kinase B is increased in human Alzheimer brain and exacerbates mouse Alzheimer pathology.",
+        "date": "2017-09-08",
+        "first": "Bellmaine SF",
+        "last": "Pera M",
+        "name": "eLife",
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+        "title": "Inhibition of DYRK1A disrupts neural lineage specificationin human pluripotent stem cells.",
         "type": "PubMed",
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-      "evidence": "We show here that ITPKB protein level was increased 3-fold in the cerebral cortex of most patients with Alzheimer's disease compared with control subjects, and accumulated in dystrophic neurites associated to amyloid plaques. In mouse Neuro-2a neuroblastoma cells, Itpkb overexpression was associated with increased cell apoptosis and increased β-secretase 1 activity leading to overproduction of amyloid-β peptides. In this cellular model, an inhibitor of mitogen-activated kinase kinases 1/2 completely prevented overproduction of amyloid-β peptides. Transgenic overexpression of ITPKB in mouse forebrain neurons was not sufficient to induce amyloid plaque formation or tau hyperphosphorylation. However, in the 5X familial Alzheimer's disease mouse model, neuronal ITPKB overexpression significantly increased extracellular signal-regulated kinases 1/2 activation and β-secretase 1 activity, resulting in exacerbated Alzheimer's disease pathology as shown by increased astrogliosis, amyloid-β40 peptide production and tau hyperphosphorylation.",
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         "authors": [
-          "Jin S",
-          "Wu J",
-          "Xiong Y",
-          "Xu Z",
-          "Zhang YQ",
-          "Zhao K"
+          "Bellmaine SF",
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+          "Manallack DT",
+          "Ovchinnikov DA",
+          "Pera M",
+          "Stanley EG",
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-        "last": "Zhang YQ",
-        "name": "Proceedings of the National Academy of Sciences of the United States of America",
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-        "reference": "23487739",
-        "title": "HDAC6 mutations rescue human tau-induced microtubule defects in Drosophila.",
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+        "last": "Pera M",
+        "name": "eLife",
+        "reference": "28884684",
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-          "Xu Z",
-          "Yao WB",
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-          "Xu Z",
-          "Yao WB",
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+        "reference": "28250274",
+        "title": "Neprilysin Is Suppressed by Dual-Specificity Tyrosine-Phosphorylation Regulated Kinase 1A (DYRK1A) in Down-Syndrome-Derived Fibroblasts.",
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-          "Gerhardt E",
-          "Herrera F",
-          "Mendes T",
-          "Obriot H",
-          "Outeiro TF",
-          "Sergeant N"
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-        "reference": "25143394",
-        "title": "Mutant huntingtin alters Tau phosphorylation and subcellular distribution.",
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+        "first": "Kawakubo T",
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         "type": "PubMed",
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-          "Gerhardt E",
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-          "Outeiro TF",
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+      "evidence": "Neprilysin, a major Aß-degrading enzyme, was downregulated in DS patient-derived fibroblasts. Treatment with harmine, a DYRK1A inhibitor and gene knockdown of DYRK1A, upregulated neprilysin in fibroblasts.",
+      "key": "fb7a928abb75122d3b220c7859970d9b78d7494aabf1f8b92124bb5df7337f33648fcf4b81e54b61732b63b026ab88cae08857dd7ab1052d68c591d39193e9e4",
+      "line": 2576,
+      "relation": "decreases",
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+      "target": 521
     },
     {
       "annotations": {
-        "Research_Model": {
-          "HD murine model": true
+        "Cell_Line": {
+          "Human fibroblasts": true
         },
-        "Species": {
-          "10090": true
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHDisease": {
+          "Down Syndrome": true
         }
       },
       "citation": {
         "authors": [
-          "Basquin M",
-          "Blum D",
-          "Brouillet E",
-          "Buée L",
-          "Demeyer D",
-          "Francelle L",
-          "Gerhardt E",
-          "Herrera F",
-          "Mendes T",
-          "Obriot H",
-          "Outeiro TF",
-          "Sergeant N"
+          "Asai M",
+          "Iwata N",
+          "Kawakubo T",
+          "Mori R",
+          "Shirotani K"
         ],
-        "date": "2015-01-01",
-        "first": "Blum D",
-        "last": "Outeiro TF",
-        "name": "Human molecular genetics",
-        "pages": "76-85",
-        "reference": "25143394",
-        "title": "Mutant huntingtin alters Tau phosphorylation and subcellular distribution.",
+        "date": "2017-01-01",
+        "first": "Kawakubo T",
+        "last": "Asai M",
+        "name": "Biological &amp; pharmaceutical bulletin",
+        "pages": "327-333",
+        "reference": "28250274",
+        "title": "Neprilysin Is Suppressed by Dual-Specificity Tyrosine-Phosphorylation Regulated Kinase 1A (DYRK1A) in Down-Syndrome-Derived Fibroblasts.",
         "type": "PubMed",
-        "volume": "24"
+        "volume": "40"
       },
-      "evidence": "We found strong Tau hyperphosphorylation in brain samples from R6/2 and 140CAG Tg knock-in, associated with a significant reduction in the levels of Tau phosphatases (PP1, PP2A and PP2B), with no apparent involvement of major Tau kinases.",
-      "key": "517b4ddc1d0b542945b2a142942614b6cd8259a25286824d6ef5bb1e25b116e46bfe3ccd41dc450b541e43dd41b0dda0e6734ffb2749c1bdbd092c26eefb39c9",
-      "line": 3815,
-      "relation": "negativeCorrelation",
-      "source": 808,
-      "target": 841
+      "evidence": "Neprilysin, a major Aß-degrading enzyme, was downregulated in DS patient-derived fibroblasts. Treatment with harmine, a DYRK1A inhibitor and gene knockdown of DYRK1A, upregulated neprilysin in fibroblasts.",
+      "key": "75f2b19762a9b473a3627b994af1e7def929294b68ff316aa6b9d186ac532ebb2ed28e3c99220dc4204be0cc6e37faac5e7608c1b55032dd937ab5742352a700",
+      "line": 2578,
+      "relation": "increases",
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+      "target": 727
     },
     {
       "annotations": {
-        "Species": {
-          "10116": true
+        "Confidence": {
+          "Low": true
         }
       },
       "citation": {
         "authors": [
-          "Al-Khaledi G",
-          "Attur S",
-          "Khan I",
-          "Khan KM",
-          "Rahman A"
+          "Caterino M",
+          "Filosa R",
+          "Giancola C",
+          "Pagano B"
         ],
-        "date": "2012-12-01",
-        "first": "Rahman A",
-        "last": "Attur S",
-        "name": "Acta biologica Hungarica",
-        "pages": "411-25",
-        "reference": "23134599",
-        "title": "Early postnatal lead exposure induces tau phosphorylation in the brain of young rats.",
+        "date": "2017-10-27",
+        "first": "Pagano B",
+        "last": "Giancola C",
+        "name": "Molecules (Basel, Switzerland)",
+        "reference": "29077046",
+        "title": "Binding of Harmine Derivatives to DNA: A Spectroscopic Investigation.",
         "type": "PubMed",
-        "volume": "63"
+        "volume": "22"
       },
-      "evidence": "PP2A expression decreased, whereas, PP1 and PP5 expression increased in lead-exposed rats. These results demonstrate that early postnatal exposure to lead decrease PP2A expression and induce tau hyperphosphorylation at several serine and threonine residues.",
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-      "line": 3827,
-      "relation": "negativeCorrelation",
-      "source": 808,
-      "target": 897
+      "evidence": "DNA binding and stabilising",
+      "key": "3a2f7bcee614b39cf5993b82f346e0cb4f0dcb85c7ba1409fe9b8c38b2ddcede2dbbb55df295df7052ff12a91b102e94f1589dbfea8f021ddf30de8dd1a09567",
+      "line": 2657,
+      "relation": "increases",
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+      "target": 242
     },
     {
       "annotations": {
-        "Anatomy": {
-          "hippocampal formation": true
+        "Confidence": {
+          "High": true
         },
         "Species": {
           "10090": true
@@ -57530,36 +64666,32 @@
       },
       "citation": {
         "authors": [
-          "Campbell SN",
-          "Masliah E",
-          "Monte L",
-          "Rice KC",
-          "Rissman RA",
-          "Roe AD",
-          "Taché Y",
-          "Zhang C"
+          "Chen L",
+          "Sun X",
+          "Wang L",
+          "Wang P"
         ],
-        "date": "2015-01-01",
-        "first": "Campbell SN",
-        "last": "Rissman RA",
-        "name": "Journal of Alzheimer's disease : JAD",
-        "pages": "967-76",
-        "reference": "25125464",
-        "title": "Increased tau phosphorylation and aggregation in the hippocampus of mice overexpressing corticotropin-releasing factor.",
+        "date": "2017-08-03",
+        "first": "Wang P",
+        "last": "Sun X",
+        "name": "Scientific reports",
+        "pages": "7240",
+        "reference": "28775333",
+        "title": "Dual-specificity tyrosine-phosphorylation regulated kinase 1A Gene Transcription is regulated by Myocyte Enhancer Factor 2D.",
         "type": "PubMed",
-        "volume": "43"
+        "volume": "7"
       },
-      "evidence": "CRF-OE mice had significantly elevated tau-P compared to wild type (WT) mice at the AT8 (S202/T204), PHF-1 (S396/404), S262, and S422 sites. Treating CRF-OE mice with R121919 blocked phosphorylation at the AT8 (S202/T204) and PHF-1 (S396/404) sites, but not at the S262 and S422 sites and reduced phosphorylation of c-Jun N Terminal Kinase (JNK).",
-      "key": "b46d5584eb2a0335d67c08be19ac54a3a74b53b68a1c102791a8c395b17f5480d189f18dd716891424e94b3f592695a6221477e45a1b8fe7cd05a4de7860931b",
-      "line": 2414,
+      "evidence": "Here we demonstrated that MEF2D could upregulate DYRK1A gene expression through specific activation of DYRK1A isoform 5 gene transcription. The coordinated expression of DYRK1A and MEF2D in mouse brain development indicated a possibility of the cross-interaction of these two genes during neurodevelopment. The DYRK1A kinase activity was also affected by MEF2D's transcriptional regulation of DYRK1A.",
+      "key": "3b9215d40c3c581cd918c613638576284a495da7bed19882f51fc4947b6517575bdd9d344faf145f200e72b243fc9729ec990e9698b3f1ae6ec80b267f9a8ee2",
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       "relation": "increases",
-      "source": 779,
-      "target": 336
+      "source": 927,
+      "target": 1050
     },
     {
       "annotations": {
-        "Anatomy": {
-          "hippocampal formation": true
+        "Confidence": {
+          "High": true
         },
         "Species": {
           "10090": true
@@ -57567,73 +64699,49 @@
       },
       "citation": {
         "authors": [
-          "Campbell SN",
-          "Masliah E",
-          "Monte L",
-          "Rice KC",
-          "Rissman RA",
-          "Roe AD",
-          "Taché Y",
-          "Zhang C"
+          "Chen L",
+          "Sun X",
+          "Wang L",
+          "Wang P"
         ],
-        "date": "2015-01-01",
-        "first": "Campbell SN",
-        "last": "Rissman RA",
-        "name": "Journal of Alzheimer's disease : JAD",
-        "pages": "967-76",
-        "reference": "25125464",
-        "title": "Increased tau phosphorylation and aggregation in the hippocampus of mice overexpressing corticotropin-releasing factor.",
+        "date": "2017-08-03",
+        "first": "Wang P",
+        "last": "Sun X",
+        "name": "Scientific reports",
+        "pages": "7240",
+        "reference": "28775333",
+        "title": "Dual-specificity tyrosine-phosphorylation regulated kinase 1A Gene Transcription is regulated by Myocyte Enhancer Factor 2D.",
         "type": "PubMed",
-        "volume": "43"
+        "volume": "7"
       },
-      "evidence": "CRF-OE mice had significantly elevated tau-P compared to wild type (WT) mice at the AT8 (S202/T204), PHF-1 (S396/404), S262, and S422 sites. Treating CRF-OE mice with R121919 blocked phosphorylation at the AT8 (S202/T204) and PHF-1 (S396/404) sites, but not at the S262 and S422 sites and reduced phosphorylation of c-Jun N Terminal Kinase (JNK).",
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-      "line": 2415,
-      "relation": "increases",
-      "source": 779,
-      "target": 116
-    },
-    {
-      "annotations": {
-        "Anatomy": {
-          "hippocampal formation": true
+      "evidence": "Here we demonstrated that MEF2D could upregulate DYRK1A gene expression through specific activation of DYRK1A isoform 5 gene transcription. The coordinated expression of DYRK1A and MEF2D in mouse brain development indicated a possibility of the cross-interaction of these two genes during neurodevelopment. The DYRK1A kinase activity was also affected by MEF2D's transcriptional regulation of DYRK1A.",
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-        "Species": {
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-      },
-      "citation": {
-        "authors": [
-          "Campbell SN",
-          "Masliah E",
-          "Monte L",
-          "Rice KC",
-          "Rissman RA",
-          "Roe AD",
-          "Taché Y",
-          "Zhang C"
-        ],
-        "date": "2015-01-01",
-        "first": "Campbell SN",
-        "last": "Rissman RA",
-        "name": "Journal of Alzheimer's disease : JAD",
-        "pages": "967-76",
-        "reference": "25125464",
-        "title": "Increased tau phosphorylation and aggregation in the hippocampus of mice overexpressing corticotropin-releasing factor.",
-        "type": "PubMed",
-        "volume": "43"
+        "modifier": "Activity"
       },
-      "evidence": "CRF-OE mice had significantly elevated tau-P compared to wild type (WT) mice at the AT8 (S202/T204), PHF-1 (S396/404), S262, and S422 sites. Treating CRF-OE mice with R121919 blocked phosphorylation at the AT8 (S202/T204) and PHF-1 (S396/404) sites, but not at the S262 and S422 sites and reduced phosphorylation of c-Jun N Terminal Kinase (JNK).",
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-      "line": 2418,
-      "relation": "positiveCorrelation",
-      "source": 779,
-      "target": 821
+      "relation": "increases",
+      "source": 927,
+      "target": 874
     },
     {
       "annotations": {
-        "Anatomy": {
-          "hippocampal formation": true
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
+        "MeSHDisease": {
+          "Alzheimer Disease": true,
+          "Down Syndrome": true
+        },
+        "Research_Model": {
+          "Ts65Dn mice": true
         },
         "Species": {
           "10090": true
@@ -57641,36 +64749,42 @@
       },
       "citation": {
         "authors": [
-          "Campbell SN",
-          "Masliah E",
-          "Monte L",
-          "Rice KC",
-          "Rissman RA",
-          "Roe AD",
-          "Taché Y",
-          "Zhang C"
+          "Chen L",
+          "Sun X",
+          "Wang L",
+          "Wang P"
         ],
-        "date": "2015-01-01",
-        "first": "Campbell SN",
-        "last": "Rissman RA",
-        "name": "Journal of Alzheimer's disease : JAD",
-        "pages": "967-76",
-        "reference": "25125464",
-        "title": "Increased tau phosphorylation and aggregation in the hippocampus of mice overexpressing corticotropin-releasing factor.",
+        "date": "2017-08-03",
+        "first": "Wang P",
+        "last": "Sun X",
+        "name": "Scientific reports",
+        "pages": "7240",
+        "reference": "28775333",
+        "title": "Dual-specificity tyrosine-phosphorylation regulated kinase 1A Gene Transcription is regulated by Myocyte Enhancer Factor 2D.",
         "type": "PubMed",
-        "volume": "43"
+        "volume": "7"
       },
-      "evidence": "CRF-OE mice had significantly elevated tau-P compared to wild type (WT) mice at the AT8 (S202/T204), PHF-1 (S396/404), S262, and S422 sites. Treating CRF-OE mice with R121919 blocked phosphorylation at the AT8 (S202/T204) and PHF-1 (S396/404) sites, but not at the S262 and S422 sites and reduced phosphorylation of c-Jun N Terminal Kinase (JNK).",
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-      "line": 2419,
-      "relation": "positiveCorrelation",
-      "source": 779,
-      "target": 826
+      "evidence": "Treatment with Dyrk1A inhibitor, green tea flavonol epigallocatechin-gallate (EGCG), from gestation to adulthood suppressed 3R-tau expression and rescued anxiety and memory deficits in Ts65Dn mouse brains.",
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+      "line": 2611,
+      "relation": "decreases",
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+      "target": 874
     },
     {
       "annotations": {
-        "Anatomy": {
-          "hippocampal formation": true
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
+        "MeSHDisease": {
+          "Alzheimer Disease": true,
+          "Down Syndrome": true
+        },
+        "Research_Model": {
+          "Ts65Dn mice": true
         },
         "Species": {
           "10090": true
@@ -57678,36 +64792,42 @@
       },
       "citation": {
         "authors": [
-          "Campbell SN",
-          "Masliah E",
-          "Monte L",
-          "Rice KC",
-          "Rissman RA",
-          "Roe AD",
-          "Taché Y",
-          "Zhang C"
+          "Chen L",
+          "Sun X",
+          "Wang L",
+          "Wang P"
         ],
-        "date": "2015-01-01",
-        "first": "Campbell SN",
-        "last": "Rissman RA",
-        "name": "Journal of Alzheimer's disease : JAD",
-        "pages": "967-76",
-        "reference": "25125464",
-        "title": "Increased tau phosphorylation and aggregation in the hippocampus of mice overexpressing corticotropin-releasing factor.",
+        "date": "2017-08-03",
+        "first": "Wang P",
+        "last": "Sun X",
+        "name": "Scientific reports",
+        "pages": "7240",
+        "reference": "28775333",
+        "title": "Dual-specificity tyrosine-phosphorylation regulated kinase 1A Gene Transcription is regulated by Myocyte Enhancer Factor 2D.",
         "type": "PubMed",
-        "volume": "43"
+        "volume": "7"
       },
-      "evidence": "CRF-OE mice had significantly elevated tau-P compared to wild type (WT) mice at the AT8 (S202/T204), PHF-1 (S396/404), S262, and S422 sites. Treating CRF-OE mice with R121919 blocked phosphorylation at the AT8 (S202/T204) and PHF-1 (S396/404) sites, but not at the S262 and S422 sites and reduced phosphorylation of c-Jun N Terminal Kinase (JNK).",
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-      "line": 2416,
-      "relation": "positiveCorrelation",
-      "source": 780,
-      "target": 336
+      "evidence": "Treatment with Dyrk1A inhibitor, green tea flavonol epigallocatechin-gallate (EGCG), from gestation to adulthood suppressed 3R-tau expression and rescued anxiety and memory deficits in Ts65Dn mouse brains.",
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+      "relation": "decreases",
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+      "target": 385
     },
     {
       "annotations": {
-        "Anatomy": {
-          "hippocampal formation": true
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
+        "MeSHDisease": {
+          "Alzheimer Disease": true,
+          "Down Syndrome": true
+        },
+        "Research_Model": {
+          "Ts65Dn mice": true
         },
         "Species": {
           "10090": true
@@ -57715,36 +64835,42 @@
       },
       "citation": {
         "authors": [
-          "Campbell SN",
-          "Masliah E",
-          "Monte L",
-          "Rice KC",
-          "Rissman RA",
-          "Roe AD",
-          "Taché Y",
-          "Zhang C"
+          "Chen L",
+          "Sun X",
+          "Wang L",
+          "Wang P"
         ],
-        "date": "2015-01-01",
-        "first": "Campbell SN",
-        "last": "Rissman RA",
-        "name": "Journal of Alzheimer's disease : JAD",
-        "pages": "967-76",
-        "reference": "25125464",
-        "title": "Increased tau phosphorylation and aggregation in the hippocampus of mice overexpressing corticotropin-releasing factor.",
+        "date": "2017-08-03",
+        "first": "Wang P",
+        "last": "Sun X",
+        "name": "Scientific reports",
+        "pages": "7240",
+        "reference": "28775333",
+        "title": "Dual-specificity tyrosine-phosphorylation regulated kinase 1A Gene Transcription is regulated by Myocyte Enhancer Factor 2D.",
         "type": "PubMed",
-        "volume": "43"
+        "volume": "7"
       },
-      "evidence": "CRF-OE mice had significantly elevated tau-P compared to wild type (WT) mice at the AT8 (S202/T204), PHF-1 (S396/404), S262, and S422 sites. Treating CRF-OE mice with R121919 blocked phosphorylation at the AT8 (S202/T204) and PHF-1 (S396/404) sites, but not at the S262 and S422 sites and reduced phosphorylation of c-Jun N Terminal Kinase (JNK).",
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-      "line": 2417,
-      "relation": "positiveCorrelation",
-      "source": 780,
-      "target": 116
+      "evidence": "Treatment with Dyrk1A inhibitor, green tea flavonol epigallocatechin-gallate (EGCG), from gestation to adulthood suppressed 3R-tau expression and rescued anxiety and memory deficits in Ts65Dn mouse brains.",
+      "key": "67101e8ff519d17aacf4f78314e3a56172c506b043f0a727ae029ca609bc5c81d5e7ee5f272396e480596d3d175f3493af9e44676e3b742e5d1dc783ea8e75ad",
+      "line": 2613,
+      "relation": "decreases",
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+      "target": 1030
     },
     {
       "annotations": {
-        "Anatomy": {
-          "hippocampal formation": true
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
+        "MeSHDisease": {
+          "Alzheimer Disease": true,
+          "Down Syndrome": true
+        },
+        "Research_Model": {
+          "Ts65Dn mice": true
         },
         "Species": {
           "10090": true
@@ -57752,36 +64878,42 @@
       },
       "citation": {
         "authors": [
-          "Campbell SN",
-          "Masliah E",
-          "Monte L",
-          "Rice KC",
-          "Rissman RA",
-          "Roe AD",
-          "Taché Y",
-          "Zhang C"
+          "Chen L",
+          "Sun X",
+          "Wang L",
+          "Wang P"
         ],
-        "date": "2015-01-01",
-        "first": "Campbell SN",
-        "last": "Rissman RA",
-        "name": "Journal of Alzheimer's disease : JAD",
-        "pages": "967-76",
-        "reference": "25125464",
-        "title": "Increased tau phosphorylation and aggregation in the hippocampus of mice overexpressing corticotropin-releasing factor.",
+        "date": "2017-08-03",
+        "first": "Wang P",
+        "last": "Sun X",
+        "name": "Scientific reports",
+        "pages": "7240",
+        "reference": "28775333",
+        "title": "Dual-specificity tyrosine-phosphorylation regulated kinase 1A Gene Transcription is regulated by Myocyte Enhancer Factor 2D.",
         "type": "PubMed",
-        "volume": "43"
+        "volume": "7"
       },
-      "evidence": "CRF-OE mice had significantly elevated tau-P compared to wild type (WT) mice at the AT8 (S202/T204), PHF-1 (S396/404), S262, and S422 sites. Treating CRF-OE mice with R121919 blocked phosphorylation at the AT8 (S202/T204) and PHF-1 (S396/404) sites, but not at the S262 and S422 sites and reduced phosphorylation of c-Jun N Terminal Kinase (JNK).",
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+      "evidence": "Treatment with Dyrk1A inhibitor, green tea flavonol epigallocatechin-gallate (EGCG), from gestation to adulthood suppressed 3R-tau expression and rescued anxiety and memory deficits in Ts65Dn mouse brains.",
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@@ -57789,594 +64921,692 @@
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         "name": "The Journal of biological chemistry",
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-        "reference": "22833681",
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+        "title": "Alzheimer's disease pathological lesions activate the spleen tyrosine kinase.",
         "type": "PubMed",
-        "volume": "34"
-      },
-      "evidence": "We studied underlying pathomechanisms in tauopathies using pR5 mice that express the P301L tau mutation found in familial forms of frontotemporal dementia. In a longitudinal study we investigated the functional status of glycogen synthase kinase-3 and correlated it with the appearance of distinct tau phospho-epitopes. Neurons displaying increases in activating phosphorylation of glycogen synthase kinase-3α/β at tyrosine 279/216 also showed an intense rather than moderate AT8 (phospho-Ser202/Thr205 tau) immunoreactivity, and immunoreactivity for AT100 (phospho-Ser212/Thr214 tau) and phosphorylated Ser422, phospho-epitopes associated with fibrillar tau pathology.",
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+      "evidence": "Interestingly, Syk upregulation in SH-SY5Y cells leads to a significant increase (1.7-fold) in phosphorylated tau at Y18 (Fig. 14c, p < 0.01) and at S396/404 (Fig. 14d, 3-fold, p < 0.0001) compared to control cells. Total tau levels are also significantly increased following Syk overexpression (Fig. 14e, 4.2-fold, p < 0.0001).",
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     {
       "annotations": {
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-          "CA3 field of hippocampus": true,
-          "cerebral cortex": true,
-          "dentate gyrus granule cell layer": true
-        },
-        "Research_Model": {
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           "10090": true
@@ -58680,1518 +65918,1467 @@
       },
       "citation": {
         "authors": [
-          "Kraemer BC",
-          "Leverenz JB",
-          "McMillan PJ",
-          "Raskind M",
-          "Robinson L",
-          "Schellenberg G"
+          "Ait-Ghezala G",
+          "Bachmeier C",
+          "Beaulieu-Abdelahad D",
+          "Crawford F",
+          "Jin C",
+          "Laco G",
+          "Lin Y",
+          "Mullan M",
+          "Paris D"
         ],
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-        "first": "McMillan PJ",
-        "last": "Schellenberg G",
-        "name": "Journal of neuropathology and experimental neurology",
-        "pages": "1006-19",
-        "reference": "22002427",
-        "title": "Truncation of tau at E391 promotes early pathologic changes in transgenic mice.",
+        "date": "2014-12-05",
+        "first": "Paris D",
+        "last": "Mullan M",
+        "name": "The Journal of biological chemistry",
+        "pages": "33927-44",
+        "reference": "25331948",
+        "title": "The spleen tyrosine kinase (Syk) regulates Alzheimer amyloid-β production and Tau hyperphosphorylation.",
         "type": "PubMed",
-        "volume": "70"
+        "volume": "289"
       },
-      "evidence": "E391-3610 mice (higher expressers) exhibit robust somatodendritic distribution of phospho- Ser 202/Thr 205 tau throughout the cortex, in hippocampal CA3 pyramidal neurons, CA1 apical dendrites and cell bodies and dentate granule cells.",
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+      "evidence": "We further validated Syk as a target-regulating Aβ by showing that pharmacological inhibition of Syk or down-regulation of Syk expression reduces Aβ production and increases the clearance of Aβ across the BBB mimicking (-)-nilvadipine effects. Moreover, treatment of transgenic mice overexpressing Aβ and transgenic Tau P301S mice with a selective Syk inhibitor respectively decreased brain Aβ accumulation and Tau hyperphosphorylation at multiple AD relevant epitopes.",
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       "citation": {
         "authors": [
-          "Kraemer BC",
-          "Leverenz JB",
-          "McMillan PJ",
-          "Raskind M",
-          "Robinson L",
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-        "first": "McMillan PJ",
-        "last": "Schellenberg G",
-        "name": "Journal of neuropathology and experimental neurology",
-        "pages": "1006-19",
-        "reference": "22002427",
-        "title": "Truncation of tau at E391 promotes early pathologic changes in transgenic mice.",
+          "Ait-Ghezala G",
+          "Beaulieu-Abdelahad D",
+          "Crawford F",
+          "Mouzon B",
+          "Mullan M",
+          "Paris D",
+          "Schweig JE",
+          "Yao H"
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+        "date": "2017-09-06",
+        "first": "Schweig JE",
+        "last": "Paris D",
+        "name": "Acta neuropathologica communications",
+        "pages": "69",
+        "reference": "28877763",
+        "title": "Alzheimer's disease pathological lesions activate the spleen tyrosine kinase.",
         "type": "PubMed",
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       },
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+      "evidence": "We found an increase in Syk activation in DNs surrounding Aβ deposits as well as in neurons displaying an accumulation of phosphorylated Tau at Y18 and elevated levels of MC1 pathogenic tau conformers in AD brain sections whereas only weak immunoreactivity for pSyk was observed in brain sections from a non-demented control",
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       "citation": {
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-          "Giasson BI",
-          "Knight J",
-          "Lewis J",
-          "Melrose HL",
-          "Miles S",
-          "Rousseau L",
-          "Watkinson R"
+          "Ait-Ghezala G",
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+          "Crawford F",
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+          "Mullan M",
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-        "first": "Bailey RM",
-        "last": "Lewis J",
-        "name": "Acta neuropathologica",
-        "pages": "809-27",
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-        "title": "LRRK2 phosphorylates novel tau epitopes and promotes tauopathy.",
+        "date": "2017-09-06",
+        "first": "Schweig JE",
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+        "name": "Acta neuropathologica communications",
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         "type": "PubMed",
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       },
-      "evidence": "Using mass spectrometry, we identified multiple sites on recombinant tau that are phosphorylated by LRRK2 in vitro, including pT149 and pT153, which are phospho-epitopes that to date have been largely unexplored. Importantly, we demonstrate that expression of transgenic LRRK2 in a mouse model of tauopathy increased the aggregation of insoluble tau and its phosphorylation at T149, T153, T205, and S199/S202/T205 epitopes.",
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-          "Melrose HL",
-          "Miles S",
-          "Rousseau L",
-          "Watkinson R"
+          "Anderton BH",
+          "Derkinderen P",
+          "Geahlen RL",
+          "Hanger DP",
+          "Lardeux B",
+          "Lebouvier T",
+          "Reynolds CH",
+          "Scales TM"
         ],
-        "date": "2013-12-01",
-        "first": "Bailey RM",
-        "last": "Lewis J",
-        "name": "Acta neuropathologica",
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-        "title": "LRRK2 phosphorylates novel tau epitopes and promotes tauopathy.",
+        "date": "2008-02-01",
+        "first": "Lebouvier T",
+        "last": "Derkinderen P",
+        "name": "Biochimica et biophysica acta",
+        "pages": "188-92",
+        "reference": "18070606",
+        "title": "The microtubule-associated protein tau is phosphorylated by Syk.",
         "type": "PubMed",
-        "volume": "126"
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-      "evidence": "Using mass spectrometry, we identified multiple sites on recombinant tau that are phosphorylated by LRRK2 in vitro, including pT149 and pT153, which are phospho-epitopes that to date have been largely unexplored. Importantly, we demonstrate that expression of transgenic LRRK2 in a mouse model of tauopathy increased the aggregation of insoluble tau and its phosphorylation at T149, T153, T205, and S199/S202/T205 epitopes.",
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+          "Matsumoto M",
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+          "Nakamori M",
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         "type": "PubMed",
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-          "Giasson BI",
-          "Knight J",
-          "Lewis J",
-          "Melrose HL",
-          "Miles S",
-          "Rousseau L",
-          "Watkinson R"
+          "Hosomi N",
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+          "Maruyama H",
+          "Matsumoto M",
+          "Miyazaki Y",
+          "Nakamori M",
+          "Nishikawa T",
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-        "last": "Lewis J",
-        "name": "Acta neuropathologica",
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-        "title": "LRRK2 phosphorylates novel tau epitopes and promotes tauopathy.",
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         "type": "PubMed",
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-          "Knight J",
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-          "Melrose HL",
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-          "Watkinson R"
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+          "Matsumoto M",
+          "Miyazaki Y",
+          "Nakamori M",
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-        "name": "Acta neuropathologica",
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         "type": "PubMed",
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       "citation": {
         "authors": [
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-          "Covy JP",
-          "Dickson DW",
-          "Farrer MJ",
-          "Giasson BI",
-          "Knight J",
-          "Lewis J",
-          "Melrose HL",
-          "Miles S",
-          "Rousseau L",
-          "Watkinson R"
+          "Ait-Ghezala G",
+          "Bachmeier C",
+          "Beaulieu-Abdelahad D",
+          "Crawford F",
+          "Jin C",
+          "Laco G",
+          "Lin Y",
+          "Mullan M",
+          "Paris D"
         ],
-        "date": "2013-12-01",
-        "first": "Bailey RM",
-        "last": "Lewis J",
-        "name": "Acta neuropathologica",
-        "pages": "809-27",
-        "reference": "24113872",
-        "title": "LRRK2 phosphorylates novel tau epitopes and promotes tauopathy.",
+        "date": "2014-12-05",
+        "first": "Paris D",
+        "last": "Mullan M",
+        "name": "The Journal of biological chemistry",
+        "pages": "33927-44",
+        "reference": "25331948",
+        "title": "The spleen tyrosine kinase (Syk) regulates Alzheimer amyloid-β production and Tau hyperphosphorylation.",
         "type": "PubMed",
-        "volume": "126"
-      },
-      "evidence": "Using mass spectrometry, we identified multiple sites on recombinant tau that are phosphorylated by LRRK2 in vitro, including pT149 and pT153, which are phospho-epitopes that to date have been largely unexplored. Importantly, we demonstrate that expression of transgenic LRRK2 in a mouse model of tauopathy increased the aggregation of insoluble tau and its phosphorylation at T149, T153, T205, and S199/S202/T205 epitopes.",
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     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        }
+      },
       "citation": {
         "authors": [
-          "Acevedo-Aquino MC",
-          "Luna-Muñoz J",
-          "Mondragón-Rodríguez S",
-          "Perry G",
-          "Williams S"
+          "Ait-Ghezala G",
+          "Bachmeier C",
+          "Beaulieu-Abdelahad D",
+          "Crawford F",
+          "Jin C",
+          "Laco G",
+          "Lin Y",
+          "Mullan M",
+          "Paris D"
         ],
-        "date": "2014-02-01",
-        "first": "Mondragón-Rodríguez S",
-        "last": "Williams S",
-        "name": "Neuropathology and applied neurobiology",
-        "pages": "121-35",
-        "reference": "24033439",
-        "title": "Phosphorylation of tau protein at sites Ser(396-404) is one of the earliest events in Alzheimer's disease and Down syndrome.",
+        "date": "2014-12-05",
+        "first": "Paris D",
+        "last": "Mullan M",
+        "name": "The Journal of biological chemistry",
+        "pages": "33927-44",
+        "reference": "25331948",
+        "title": "The spleen tyrosine kinase (Syk) regulates Alzheimer amyloid-β production and Tau hyperphosphorylation.",
         "type": "PubMed",
-        "volume": "40"
+        "volume": "289"
       },
-      "evidence": "Finally, these data validate PHF-1 as an efficient marker for AD cytopathology following the progression of tau aggregation into NFT.",
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     {
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       "citation": {
         "authors": [
-          "Acevedo-Aquino MC",
-          "Luna-Muñoz J",
-          "Mondragón-Rodríguez S",
-          "Perry G",
-          "Williams S"
+          "Ait-Ghezala G",
+          "Bachmeier C",
+          "Beaulieu-Abdelahad D",
+          "Crawford F",
+          "Jin C",
+          "Laco G",
+          "Lin Y",
+          "Mullan M",
+          "Paris D"
         ],
-        "date": "2014-02-01",
-        "first": "Mondragón-Rodríguez S",
-        "last": "Williams S",
-        "name": "Neuropathology and applied neurobiology",
-        "pages": "121-35",
-        "reference": "24033439",
-        "title": "Phosphorylation of tau protein at sites Ser(396-404) is one of the earliest events in Alzheimer's disease and Down syndrome.",
+        "date": "2014-12-05",
+        "first": "Paris D",
+        "last": "Mullan M",
+        "name": "The Journal of biological chemistry",
+        "pages": "33927-44",
+        "reference": "25331948",
+        "title": "The spleen tyrosine kinase (Syk) regulates Alzheimer amyloid-β production and Tau hyperphosphorylation.",
         "type": "PubMed",
-        "volume": "40"
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-      "evidence": "Finally, these data validate PHF-1 as an efficient marker for AD cytopathology following the progression of tau aggregation into NFT.",
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-      "line": 2600,
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     {
       "annotations": {
-        "Disease_Progression": {
-          "Late Stage": true
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         },
-        "MeSHDisease": {
-          "Alzheimer Disease": true
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         }
       },
       "citation": {
         "authors": [
-          "Castillo-Carranza DL",
-          "Jackson GR",
-          "Kayed R",
-          "Lasagna-Reeves CA",
-          "Sarmiento J",
-          "Sengupta U",
-          "Troncoso J"
+          "Ait-Ghezala G",
+          "Bachmeier C",
+          "Beaulieu-Abdelahad D",
+          "Crawford F",
+          "Jin C",
+          "Laco G",
+          "Lin Y",
+          "Mullan M",
+          "Paris D"
         ],
-        "date": "2012-05-01",
-        "first": "Lasagna-Reeves CA",
-        "last": "Kayed R",
-        "name": "FASEB journal : official publication of the Federation of American Societies for Experimental Biology",
-        "pages": "1946-59",
-        "reference": "22253473",
-        "title": "Identification of oligomers at early stages of tau aggregation in Alzheimer's disease.",
+        "date": "2014-12-05",
+        "first": "Paris D",
+        "last": "Mullan M",
+        "name": "The Journal of biological chemistry",
+        "pages": "33927-44",
+        "reference": "25331948",
+        "title": "The spleen tyrosine kinase (Syk) regulates Alzheimer amyloid-β production and Tau hyperphosphorylation.",
         "type": "PubMed",
-        "volume": "26"
+        "volume": "289"
       },
-      "evidence": "Phosphorylation at the epitope Ser202/Thr205 is regarded as a good marker for late-stage NFTs (5, 72). Hyman and colleagues (5) demonstrated that AT8 immunoreactivity is present primarily in eNFTs and in certain cases in iNFTs. These investigators also found that AT8 revealed dense neuropil thread staining.",
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-          "Carlomagno Y",
-          "Castanedes-Casey M",
-          "Chung DC",
-          "Cook C",
-          "DeTure M",
-          "Dickson DW",
-          "Dunmore J",
-          "Madden BJ",
-          "Petrucelli L",
-          "Tong J",
-          "Yue M"
-        ],
-        "date": "2017-09-15",
-        "first": "Carlomagno Y",
-        "last": "Cook C",
-        "name": "The Journal of biological chemistry",
-        "pages": "15277-15286",
-        "reference": "28760828",
-        "title": "An acetylation-phosphorylation switch that regulates tau aggregation propensity and function.",
-        "type": "PubMed",
-        "volume": "292"
+      "evidence": "We have previously shown that the L-type calcium channel (LCC) antagonist nilvadipine reduces brain amyloid-β (Aβ) accumulation by affecting both Aβ production and Aβ clearance across the blood-brain barrier (BBB).",
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       },
-      "evidence": "Our findings indicate that several acetylation sites in tau are responsive to HDAC6 and that acetylation on Lys-321 (within a KCGS motif) is both essential for acetylation-mediated inhibition of tau aggregation in vitro and a molecular tactic for preventing phosphorylation on the downstream Ser-324 residue. Tau phosphorylation of Ser-324 (pSer-324) has not previously been evaluated in the context of tauopathy, and here we observed increased deposition of pSer-324-positive tau both in mouse models of tauopathy and in patients with Alzheimer's disease. These findings uncover a novel acetylation-phosphorylation switch at Lys-321/Ser-324 that coordinately regulates tau polymerization and function.",
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     },
     {
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       "citation": {
         "authors": [
-          "Carlomagno Y",
-          "Castanedes-Casey M",
-          "Chung DC",
-          "Cook C",
-          "DeTure M",
-          "Dickson DW",
-          "Dunmore J",
-          "Madden BJ",
-          "Petrucelli L",
-          "Tong J",
-          "Yue M"
+          "Ait-Ghezala G",
+          "Bachmeier C",
+          "Beaulieu-Abdelahad D",
+          "Crawford F",
+          "Jin C",
+          "Laco G",
+          "Lin Y",
+          "Mullan M",
+          "Paris D"
         ],
-        "date": "2017-09-15",
-        "first": "Carlomagno Y",
-        "last": "Cook C",
+        "date": "2014-12-05",
+        "first": "Paris D",
+        "last": "Mullan M",
         "name": "The Journal of biological chemistry",
-        "pages": "15277-15286",
-        "reference": "28760828",
-        "title": "An acetylation-phosphorylation switch that regulates tau aggregation propensity and function.",
+        "pages": "33927-44",
+        "reference": "25331948",
+        "title": "The spleen tyrosine kinase (Syk) regulates Alzheimer amyloid-β production and Tau hyperphosphorylation.",
         "type": "PubMed",
-        "volume": "292"
+        "volume": "289"
       },
-      "evidence": "HDAC6 inhibition leads to a significant reduction in tau levels as detected by the human tau-specific antibody E1 (Fig. 6 (a and c) and supplemental Fig. S6). We also observed a striking decrease in phosphorylation at Ser-324, which was statistically significant even when normalizing to E1 to control for the reduction in tau levels (Fig. 6 (a and b) and supplemental Fig. S6).",
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-      "line": 3358,
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+      "evidence": "Western blot analyses of brain homogenates show that (−)-nilvadipine significantly reduces Tau phosphorylation in AT8 (phosphorylated Ser-199/Ser-202/Thr-205) and PHF-1 (phosphorylated Ser-396/Ser-404) epitopes",
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     {
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-        "authors": [
-          "Bibow S",
-          "Biernat J",
-          "Blackledge M",
-          "Jensen MR",
-          "Kadavath H",
-          "Mandelkow E",
-          "Ozenne V",
-          "Schwalbe M",
-          "Zweckstetter M"
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-        "date": "2013-12-17",
-        "first": "Schwalbe M",
-        "last": "Zweckstetter M",
-        "name": "Biochemistry",
-        "pages": "9068-79",
-        "reference": "24251416",
-        "title": "Phosphorylation of human Tau protein by microtubule affinity-regulating kinase 2.",
-        "type": "PubMed",
-        "volume": "52"
+      "annotations": {
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       },
-      "evidence": "While residues Ser-262, Ser-324, and Ser-356 were completely phosphorylated, Ser-293 in the second repeat was only 84% phosphorylated (Table 1). Furthermore, four non-KXGS phosphorylation sites were detected, two within the repeat domain (Ser-305 in R2 and Ser-352 in R4) and two more at the C-terminus (Ser-413 and Ser-416) (Figure 1B,C). Of these, Ser-305 was 66% phosphorylated and Ser-352, Ser-413, and Ser-416 were ∼45−58% phosphorylated (Table 1). Using wild-type MARK2cat at 25 °C and pH 6.8, the same phosphorylation sites were observed. The three primary sites, Ser-262, Ser-324, and Ser-356, were still completely phosphorylated.",
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-          "Kadavath H",
-          "Mandelkow E",
-          "Ozenne V",
-          "Schwalbe M",
-          "Zweckstetter M"
+          "Ait-Ghezala G",
+          "Bachmeier C",
+          "Beaulieu-Abdelahad D",
+          "Crawford F",
+          "Jin C",
+          "Laco G",
+          "Lin Y",
+          "Mullan M",
+          "Paris D"
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-        "date": "2013-12-17",
-        "first": "Schwalbe M",
-        "last": "Zweckstetter M",
-        "name": "Biochemistry",
-        "pages": "9068-79",
-        "reference": "24251416",
-        "title": "Phosphorylation of human Tau protein by microtubule affinity-regulating kinase 2.",
+        "date": "2014-12-05",
+        "first": "Paris D",
+        "last": "Mullan M",
+        "name": "The Journal of biological chemistry",
+        "pages": "33927-44",
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+        "title": "The spleen tyrosine kinase (Syk) regulates Alzheimer amyloid-β production and Tau hyperphosphorylation.",
         "type": "PubMed",
-        "volume": "52"
+        "volume": "289"
       },
-      "evidence": "While residues Ser-262, Ser-324, and Ser-356 were completely phosphorylated, Ser-293 in the second repeat was only 84% phosphorylated (Table 1). Furthermore, four non-KXGS phosphorylation sites were detected, two within the repeat domain (Ser-305 in R2 and Ser-352 in R4) and two more at the C-terminus (Ser-413 and Ser-416) (Figure 1B,C). Of these, Ser-305 was 66% phosphorylated and Ser-352, Ser-413, and Ser-416 were ∼45−58% phosphorylated (Table 1). Using wild-type MARK2cat at 25 °C and pH 6.8, the same phosphorylation sites were observed. The three primary sites, Ser-262, Ser-324, and Ser-356, were still completely phosphorylated.",
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-          "Kadavath H",
-          "Mandelkow E",
-          "Ozenne V",
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-          "Zweckstetter M"
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-        "date": "2013-12-17",
-        "first": "Schwalbe M",
-        "last": "Zweckstetter M",
-        "name": "Biochemistry",
-        "pages": "9068-79",
-        "reference": "24251416",
-        "title": "Phosphorylation of human Tau protein by microtubule affinity-regulating kinase 2.",
-        "type": "PubMed",
-        "volume": "52"
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
       },
-      "evidence": "While residues Ser-262, Ser-324, and Ser-356 were completely phosphorylated, Ser-293 in the second repeat was only 84% phosphorylated (Table 1). Furthermore, four non-KXGS phosphorylation sites were detected, two within the repeat domain (Ser-305 in R2 and Ser-352 in R4) and two more at the C-terminus (Ser-413 and Ser-416) (Figure 1B,C). Of these, Ser-305 was 66% phosphorylated and Ser-352, Ser-413, and Ser-416 were ∼45−58% phosphorylated (Table 1). Using wild-type MARK2cat at 25 °C and pH 6.8, the same phosphorylation sites were observed. The three primary sites, Ser-262, Ser-324, and Ser-356, were still completely phosphorylated.",
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         "authors": [
-          "Carlomagno Y",
-          "Cook C",
-          "Petrucelli L",
-          "Stankowski JN",
-          "Stetler C"
+          "Ait-Ghezala G",
+          "Bachmeier C",
+          "Beaulieu-Abdelahad D",
+          "Crawford F",
+          "Jin C",
+          "Laco G",
+          "Lin Y",
+          "Mullan M",
+          "Paris D"
         ],
-        "date": "2014-01-01",
-        "first": "Cook C",
-        "last": "Petrucelli L",
-        "name": "Alzheimer's research &amp; therapy",
-        "pages": "29",
-        "reference": "25031639",
-        "title": "Acetylation: a new key to unlock tau's role in neurodegeneration.",
+        "date": "2014-12-05",
+        "first": "Paris D",
+        "last": "Mullan M",
+        "name": "The Journal of biological chemistry",
+        "pages": "33927-44",
+        "reference": "25331948",
+        "title": "The spleen tyrosine kinase (Syk) regulates Alzheimer amyloid-β production and Tau hyperphosphorylation.",
         "type": "PubMed",
-        "volume": "6"
-      },
-      "evidence": "In particular, previous studies have demonstrated that the tau ubiquitin ligase, CHIP, is unable to bind and ubiquitinate tau species phosphorylated by Par-1/MARK2 on the 12E8 epitope (S262/356) [33], a p-tau species that is also resistant to degradation upon treatment with Hsp90 inhibitors [32,33]. Tau phosphorylated at the PHF1 epitope (S396/404) is still susceptible to degradation following Hsp90 inhibition and actually exhibits an enhanced interaction with Hsp90",
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-      "subject": {
-        "modifier": "Activity"
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       },
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+      "evidence": "Western blot analyses of brain homogenates show that (−)-nilvadipine significantly reduces Tau phosphorylation in AT8 (phosphorylated Ser-199/Ser-202/Thr-205) and PHF-1 (phosphorylated Ser-396/Ser-404) epitopes",
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     {
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-          "Cook C",
-          "Petrucelli L",
-          "Stankowski JN",
-          "Stetler C"
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-        "date": "2014-01-01",
-        "first": "Cook C",
-        "last": "Petrucelli L",
-        "name": "Alzheimer's research &amp; therapy",
-        "pages": "29",
-        "reference": "25031639",
-        "title": "Acetylation: a new key to unlock tau's role in neurodegeneration.",
-        "type": "PubMed",
-        "volume": "6"
-      },
-      "evidence": "In particular, previous studies have demonstrated that the tau ubiquitin ligase, CHIP, is unable to bind and ubiquitinate tau species phosphorylated by Par-1/MARK2 on the 12E8 epitope (S262/356) [33], a p-tau species that is also resistant to degradation upon treatment with Hsp90 inhibitors [32,33]. Tau phosphorylated at the PHF1 epitope (S396/404) is still susceptible to degradation following Hsp90 inhibition and actually exhibits an enhanced interaction with Hsp90",
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         "authors": [
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-        "name": "Neurochemistry international",
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-        "reference": "23722080",
-        "title": "In vitro mitochondrial failure and oxidative stress mimic biochemical features of Alzheimer disease.",
+        "date": "2015-09-01",
+        "first": "Sun LH",
+        "last": "Ai J",
+        "name": "Journal of neurochemistry",
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@@ -60199,32 +67386,46 @@
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       "citation": {
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-          "Marino S",
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-        "name": "Neurochemistry international",
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-        "reference": "23722080",
-        "title": "In vitro mitochondrial failure and oxidative stress mimic biochemical features of Alzheimer disease.",
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@@ -60232,898 +67433,1130 @@
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       "citation": {
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-        "title": "In vitro mitochondrial failure and oxidative stress mimic biochemical features of Alzheimer disease.",
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-          "Lu B",
-          "Maruko-Otake A",
-          "Ohtake Y",
-          "Sekiya M",
-          "Suzuki E"
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-        "first": "Iijima-Ando K",
-        "last": "Iijima KM",
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-        "title": "Loss of axonal mitochondria promotes tau-mediated neurodegeneration and Alzheimer's disease-related tau phosphorylation via PAR-1.",
+        "date": "2015-09-01",
+        "first": "Sun LH",
+        "last": "Ai J",
+        "name": "Journal of neurochemistry",
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-      "evidence": "Using transgenic Drosophila expressing human tau, we found that RNAi-mediated knockdown of milton or Miro, an adaptor protein essential for axonal transport of mitochondria, enhanced human tau-induced neurodegeneration. Tau phosphorylation at an AD-related site Ser262 increased with knockdown of milton or Miro; and partitioning defective-1 (PAR-1), the Drosophila homolog of mammalian microtubule affinity-regulating kinase, mediated this increase of tau phosphorylation. Tau phosphorylation at Ser262 has been reported to promote tau detachment from microtubules, and we found that the levels of microtubule-unbound free tau increased by milton knockdown. Blocking tau phosphorylation at Ser262 site by PAR-1 knockdown or by mutating the Ser262 site to unphosphorylatable alanine suppressed the enhancement of tau-induced neurodegeneration caused by milton knockdown. Furthermore, knockdown of milton or Miro increased the levels of active PAR-1.",
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-          "Maruko-Otake A",
-          "Ohtake Y",
-          "Sekiya M",
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-          "Lu B",
-          "Maruko-Otake A",
-          "Ohtake Y",
-          "Sekiya M",
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+          "Sun LH",
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-        "title": "Loss of axonal mitochondria promotes tau-mediated neurodegeneration and Alzheimer's disease-related tau phosphorylation via PAR-1.",
+        "date": "2015-09-01",
+        "first": "Sun LH",
+        "last": "Ai J",
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         "type": "PubMed",
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     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "Species": {
-          "7227": true
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       },
       "citation": {
         "authors": [
-          "Iijima KM",
-          "Iijima-Ando K",
-          "Lu B",
-          "Maruko-Otake A",
-          "Ohtake Y",
-          "Sekiya M",
-          "Suzuki E"
+          "Ai J",
+          "Ban T",
+          "Bao YN",
+          "Chen QX",
+          "Hu XL",
+          "Jiang XM",
+          "Liu CD",
+          "Pei SC",
+          "Su XL",
+          "Sun LH",
+          "Sun LL",
+          "Wang X",
+          "Yan ML",
+          "Zhao LJ",
+          "Zong DK"
         ],
-        "date": "2012-01-01",
-        "first": "Iijima-Ando K",
-        "last": "Iijima KM",
-        "name": "PLoS genetics",
-        "pages": "e1002918",
-        "reference": "22952452",
-        "title": "Loss of axonal mitochondria promotes tau-mediated neurodegeneration and Alzheimer's disease-related tau phosphorylation via PAR-1.",
+        "date": "2015-09-01",
+        "first": "Sun LH",
+        "last": "Ai J",
+        "name": "Journal of neurochemistry",
+        "pages": "1139-51",
+        "reference": "26118667",
+        "title": "Activation of Cdk5/p25 and tau phosphorylation following chronic brain hypoperfusion in rats involves microRNA-195 down-regulation.",
         "type": "PubMed",
-        "volume": "8"
-      },
-      "evidence": "Using transgenic Drosophila expressing human tau, we found that RNAi-mediated knockdown of milton or Miro, an adaptor protein essential for axonal transport of mitochondria, enhanced human tau-induced neurodegeneration. Tau phosphorylation at an AD-related site Ser262 increased with knockdown of milton or Miro; and partitioning defective-1 (PAR-1), the Drosophila homolog of mammalian microtubule affinity-regulating kinase, mediated this increase of tau phosphorylation. Tau phosphorylation at Ser262 has been reported to promote tau detachment from microtubules, and we found that the levels of microtubule-unbound free tau increased by milton knockdown. Blocking tau phosphorylation at Ser262 site by PAR-1 knockdown or by mutating the Ser262 site to unphosphorylatable alanine suppressed the enhancement of tau-induced neurodegeneration caused by milton knockdown. Furthermore, knockdown of milton or Miro increased the levels of active PAR-1.",
-      "key": "448a9c844d16be0f2c6f2a23be5cd3345e689b8e47e9a0d19622131204cfbe7f1d646aec6238522a855a1ef36d31e9e36ff3a2a7ab86a79c3dccf04930d5e242",
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       },
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+      "evidence": "Chronic Brain hypoperfusion (CBH) elevates nuclear factor-kB (NF-kB), which binds with the promoter sequences of miR-195 and negatively regulates its expression. Down-regulated miR-195 up-regulates APP and BACE1 and increases Aß levels. Some Aß then enter the intracellular space and activate calpain, promoting the conversion of Cdk5/p35 to Cdk5/p25 and catalyzes the degradation of IkB (inhibitor of NF-?B)and directly phosphorylates Tau. Down-regulated miR-195 up-regulates p35, which provides the active substrates of p25",
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+      "relation": "increases",
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     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "Species": {
-          "7227": true
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         }
       },
       "citation": {
         "authors": [
-          "Iijima KM",
-          "Iijima-Ando K",
-          "Lu B",
-          "Maruko-Otake A",
-          "Ohtake Y",
-          "Sekiya M",
-          "Suzuki E"
+          "Ai J",
+          "Ban T",
+          "Bao YN",
+          "Chen QX",
+          "Hu XL",
+          "Jiang XM",
+          "Liu CD",
+          "Pei SC",
+          "Su XL",
+          "Sun LH",
+          "Sun LL",
+          "Wang X",
+          "Yan ML",
+          "Zhao LJ",
+          "Zong DK"
         ],
-        "date": "2012-01-01",
-        "first": "Iijima-Ando K",
-        "last": "Iijima KM",
-        "name": "PLoS genetics",
-        "pages": "e1002918",
-        "reference": "22952452",
-        "title": "Loss of axonal mitochondria promotes tau-mediated neurodegeneration and Alzheimer's disease-related tau phosphorylation via PAR-1.",
+        "date": "2015-09-01",
+        "first": "Sun LH",
+        "last": "Ai J",
+        "name": "Journal of neurochemistry",
+        "pages": "1139-51",
+        "reference": "26118667",
+        "title": "Activation of Cdk5/p25 and tau phosphorylation following chronic brain hypoperfusion in rats involves microRNA-195 down-regulation.",
         "type": "PubMed",
-        "volume": "8"
+        "volume": "134"
       },
-      "evidence": "Using transgenic Drosophila expressing human tau, we found that RNAi-mediated knockdown of milton or Miro, an adaptor protein essential for axonal transport of mitochondria, enhanced human tau-induced neurodegeneration. Tau phosphorylation at an AD-related site Ser262 increased with knockdown of milton or Miro; and partitioning defective-1 (PAR-1), the Drosophila homolog of mammalian microtubule affinity-regulating kinase, mediated this increase of tau phosphorylation. Tau phosphorylation at Ser262 has been reported to promote tau detachment from microtubules, and we found that the levels of microtubule-unbound free tau increased by milton knockdown. Blocking tau phosphorylation at Ser262 site by PAR-1 knockdown or by mutating the Ser262 site to unphosphorylatable alanine suppressed the enhancement of tau-induced neurodegeneration caused by milton knockdown. Furthermore, knockdown of milton or Miro increased the levels of active PAR-1.",
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+      "evidence": "Endogenous miR-195 was knocked down using over-expression of its antisense molecule (pre-AMO-miR-195) via a lentivirus (lenti-pre-AMO-miR-195); this knockdown increased the tau phosphorylation at Ser202/Thr205, Ser262, Thr231, Ser422, and the Cdk5/p25 activation, but over-expression of miR-195 using lenti-pre-miR-195 decreased the tau phosphorylation and Cdk5/p25 activation.",
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+      "target": 629
     },
     {
       "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
         "Species": {
-          "7227": true
+          "10116": true
         }
       },
       "citation": {
         "authors": [
-          "Iijima KM",
-          "Iijima-Ando K",
-          "Lu B",
-          "Maruko-Otake A",
-          "Ohtake Y",
-          "Sekiya M",
-          "Suzuki E"
+          "Ai J",
+          "Ban T",
+          "Bao YN",
+          "Chen QX",
+          "Hu XL",
+          "Jiang XM",
+          "Liu CD",
+          "Pei SC",
+          "Su XL",
+          "Sun LH",
+          "Sun LL",
+          "Wang X",
+          "Yan ML",
+          "Zhao LJ",
+          "Zong DK"
         ],
-        "date": "2012-01-01",
-        "first": "Iijima-Ando K",
-        "last": "Iijima KM",
-        "name": "PLoS genetics",
-        "pages": "e1002918",
-        "reference": "22952452",
-        "title": "Loss of axonal mitochondria promotes tau-mediated neurodegeneration and Alzheimer's disease-related tau phosphorylation via PAR-1.",
+        "date": "2015-09-01",
+        "first": "Sun LH",
+        "last": "Ai J",
+        "name": "Journal of neurochemistry",
+        "pages": "1139-51",
+        "reference": "26118667",
+        "title": "Activation of Cdk5/p25 and tau phosphorylation following chronic brain hypoperfusion in rats involves microRNA-195 down-regulation.",
         "type": "PubMed",
-        "volume": "8"
+        "volume": "134"
       },
-      "evidence": "Using transgenic Drosophila expressing human tau, we found that RNAi-mediated knockdown of milton or Miro, an adaptor protein essential for axonal transport of mitochondria, enhanced human tau-induced neurodegeneration. Tau phosphorylation at an AD-related site Ser262 increased with knockdown of milton or Miro; and partitioning defective-1 (PAR-1), the Drosophila homolog of mammalian microtubule affinity-regulating kinase, mediated this increase of tau phosphorylation. Tau phosphorylation at Ser262 has been reported to promote tau detachment from microtubules, and we found that the levels of microtubule-unbound free tau increased by milton knockdown. Blocking tau phosphorylation at Ser262 site by PAR-1 knockdown or by mutating the Ser262 site to unphosphorylatable alanine suppressed the enhancement of tau-induced neurodegeneration caused by milton knockdown. Furthermore, knockdown of milton or Miro increased the levels of active PAR-1.",
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+      "evidence": "Endogenous miR-195 was knocked down using over-expression of its antisense molecule (pre-AMO-miR-195) via a lentivirus (lenti-pre-AMO-miR-195); this knockdown increased the tau phosphorylation at Ser202/Thr205, Ser262, Thr231, Ser422, and the Cdk5/p25 activation, but over-expression of miR-195 using lenti-pre-miR-195 decreased the tau phosphorylation and Cdk5/p25 activation.",
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     {
-      "citation": {
-        "authors": [
-          "Agerman K",
-          "Eckersley S",
-          "Gu GJ",
-          "Kamali-Moghaddam M",
-          "Kvist AJ",
-          "Landegren U",
-          "Lund H",
-          "Milner R",
-          "Nilsson LN",
-          "Sunnemark D",
-          "Wu D"
-        ],
-        "date": "2013-01-01",
-        "first": "Gu GJ",
-        "last": "Kamali-Moghaddam M",
-        "name": "Journal of Alzheimer's disease : JAD",
-        "pages": "699-713",
-        "reference": "23001711",
-        "title": "Elevated MARK2-dependent phosphorylation of Tau in Alzheimer's disease.",
-        "type": "PubMed",
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+        }
       },
-      "evidence": "Several kinases such as microtubule-affinity regulating kinase (MARK), protein kinase A, calcium calmodulin kinase II, and checkpoint kinase 2 are known to phosphorylate tau on Ser(262) in vitro. In this study, we took advantage of the in situ proximity ligation assay to investigate the role of MARK2, one of the four MARK isoforms, in AD. We demonstrate that MARK2 interacts with tau and phosphorylates tau at Ser(262) in stably transfected NIH/3T3 cells expressing human recombinant tau. Staurosporine, a protein kinase inhibitor, significantly reduced the interaction between MARK2 and tau, and also phosphorylation of tau at Ser(262).",
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       "citation": {
         "authors": [
-          "Agerman K",
-          "Eckersley S",
-          "Gu GJ",
-          "Kamali-Moghaddam M",
-          "Kvist AJ",
-          "Landegren U",
-          "Lund H",
-          "Milner R",
-          "Nilsson LN",
-          "Sunnemark D",
-          "Wu D"
+          "Ai J",
+          "Ban T",
+          "Bao YN",
+          "Chen QX",
+          "Hu XL",
+          "Jiang XM",
+          "Liu CD",
+          "Pei SC",
+          "Su XL",
+          "Sun LH",
+          "Sun LL",
+          "Wang X",
+          "Yan ML",
+          "Zhao LJ",
+          "Zong DK"
         ],
-        "date": "2013-01-01",
-        "first": "Gu GJ",
-        "last": "Kamali-Moghaddam M",
-        "name": "Journal of Alzheimer's disease : JAD",
-        "pages": "699-713",
-        "reference": "23001711",
-        "title": "Elevated MARK2-dependent phosphorylation of Tau in Alzheimer's disease.",
+        "date": "2015-09-01",
+        "first": "Sun LH",
+        "last": "Ai J",
+        "name": "Journal of neurochemistry",
+        "pages": "1139-51",
+        "reference": "26118667",
+        "title": "Activation of Cdk5/p25 and tau phosphorylation following chronic brain hypoperfusion in rats involves microRNA-195 down-regulation.",
         "type": "PubMed",
-        "volume": "33"
+        "volume": "134"
       },
-      "evidence": "Several kinases such as microtubule-affinity regulating kinase (MARK), protein kinase A, calcium calmodulin kinase II, and checkpoint kinase 2 are known to phosphorylate tau on Ser(262) in vitro. In this study, we took advantage of the in situ proximity ligation assay to investigate the role of MARK2, one of the four MARK isoforms, in AD. We demonstrate that MARK2 interacts with tau and phosphorylates tau at Ser(262) in stably transfected NIH/3T3 cells expressing human recombinant tau. Staurosporine, a protein kinase inhibitor, significantly reduced the interaction between MARK2 and tau, and also phosphorylation of tau at Ser(262).",
-      "key": "508ce9704b93864de6c4bd6bc1c2ab3b78123ac619dacf0fb4f86ba1f1a4491e80a5ed9f4251163fabb1ccc351ea5ac8ef85845634b6c0fbdc4fe811dba28312",
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     {
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+          "10116": true
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       "citation": {
         "authors": [
-          "Amniai L",
-          "Fauquant C",
-          "Huvent I",
-          "Landrieu I",
-          "Leroy A",
-          "Lippens G",
-          "Sibille N",
-          "Verdegem D",
-          "Wieruszeski JM"
+          "Ai J",
+          "Ban T",
+          "Bao YN",
+          "Chen QX",
+          "Hu XL",
+          "Jiang XM",
+          "Liu CD",
+          "Pei SC",
+          "Su XL",
+          "Sun LH",
+          "Sun LL",
+          "Wang X",
+          "Yan ML",
+          "Zhao LJ",
+          "Zong DK"
         ],
-        "date": "2012-02-01",
-        "first": "Sibille N",
-        "last": "Landrieu I",
-        "name": "Proteins",
-        "pages": "454-62",
-        "reference": "22072628",
-        "title": "Structural characterization by nuclear magnetic resonance of the impact of phosphorylation in the proline-rich region of the disordered Tau protein.",
+        "date": "2015-09-01",
+        "first": "Sun LH",
+        "last": "Ai J",
+        "name": "Journal of neurochemistry",
+        "pages": "1139-51",
+        "reference": "26118667",
+        "title": "Activation of Cdk5/p25 and tau phosphorylation following chronic brain hypoperfusion in rats involves microRNA-195 down-regulation.",
         "type": "PubMed",
-        "volume": "80"
+        "volume": "134"
       },
-      "evidence": "In this study, we address the structural impact of phosphorylation of the Tau protein by Nuclear Magnetic Resonance (NMR) spectroscopy on a functional fragment of Tau (Tau[Ser208-Ser324] = TauF4). TauF4 was phosphorylated by the proline-directed CDK2/CycA3 kinase on Thr231 (generating the AT180 epitope), Ser235, and equally on Thr212 and Thr217 in the Proline-rich region (Tau[Ser208-Gln244] or PRR). These modifications strongly decrease the capacity of TauF4 to polymerize tubulin into microtubules. While all the NMR parameters are consistent with a globally disordered Tau protein fragment, local clusters of structuration can be defined. The most salient result of our NMR analysis is that phosphorylation in the PRR stabilizes a short α-helix that runs from pSer235 till the very beginning of the microtubule-binding region (Tau[Thr245-Ser324] or MTBR of TauF4).",
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     {
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-        "authors": [
-          "Amniai L",
-          "Fauquant C",
-          "Huvent I",
-          "Landrieu I",
-          "Leroy A",
-          "Lippens G",
-          "Sibille N",
-          "Verdegem D",
-          "Wieruszeski JM"
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-        "date": "2012-02-01",
-        "first": "Sibille N",
-        "last": "Landrieu I",
-        "name": "Proteins",
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-        "reference": "22072628",
-        "title": "Structural characterization by nuclear magnetic resonance of the impact of phosphorylation in the proline-rich region of the disordered Tau protein.",
-        "type": "PubMed",
-        "volume": "80"
-      },
-      "evidence": "In this study, we address the structural impact of phosphorylation of the Tau protein by Nuclear Magnetic Resonance (NMR) spectroscopy on a functional fragment of Tau (Tau[Ser208-Ser324] = TauF4). TauF4 was phosphorylated by the proline-directed CDK2/CycA3 kinase on Thr231 (generating the AT180 epitope), Ser235, and equally on Thr212 and Thr217 in the Proline-rich region (Tau[Ser208-Gln244] or PRR). These modifications strongly decrease the capacity of TauF4 to polymerize tubulin into microtubules. While all the NMR parameters are consistent with a globally disordered Tau protein fragment, local clusters of structuration can be defined. The most salient result of our NMR analysis is that phosphorylation in the PRR stabilizes a short α-helix that runs from pSer235 till the very beginning of the microtubule-binding region (Tau[Thr245-Ser324] or MTBR of TauF4).",
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-        "modifier": "Activity"
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       "citation": {
         "authors": [
-          "Amniai L",
-          "Fauquant C",
-          "Huvent I",
-          "Landrieu I",
-          "Leroy A",
-          "Lippens G",
-          "Sibille N",
-          "Verdegem D",
-          "Wieruszeski JM"
+          "Ai J",
+          "Ban T",
+          "Bao YN",
+          "Chen QX",
+          "Hu XL",
+          "Jiang XM",
+          "Liu CD",
+          "Pei SC",
+          "Su XL",
+          "Sun LH",
+          "Sun LL",
+          "Wang X",
+          "Yan ML",
+          "Zhao LJ",
+          "Zong DK"
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-        "date": "2012-02-01",
-        "first": "Sibille N",
-        "last": "Landrieu I",
-        "name": "Proteins",
-        "pages": "454-62",
-        "reference": "22072628",
-        "title": "Structural characterization by nuclear magnetic resonance of the impact of phosphorylation in the proline-rich region of the disordered Tau protein.",
+        "date": "2015-09-01",
+        "first": "Sun LH",
+        "last": "Ai J",
+        "name": "Journal of neurochemistry",
+        "pages": "1139-51",
+        "reference": "26118667",
+        "title": "Activation of Cdk5/p25 and tau phosphorylation following chronic brain hypoperfusion in rats involves microRNA-195 down-regulation.",
         "type": "PubMed",
-        "volume": "80"
-      },
-      "evidence": "In this study, we address the structural impact of phosphorylation of the Tau protein by Nuclear Magnetic Resonance (NMR) spectroscopy on a functional fragment of Tau (Tau[Ser208-Ser324] = TauF4). TauF4 was phosphorylated by the proline-directed CDK2/CycA3 kinase on Thr231 (generating the AT180 epitope), Ser235, and equally on Thr212 and Thr217 in the Proline-rich region (Tau[Ser208-Gln244] or PRR). These modifications strongly decrease the capacity of TauF4 to polymerize tubulin into microtubules. While all the NMR parameters are consistent with a globally disordered Tau protein fragment, local clusters of structuration can be defined. The most salient result of our NMR analysis is that phosphorylation in the PRR stabilizes a short α-helix that runs from pSer235 till the very beginning of the microtubule-binding region (Tau[Thr245-Ser324] or MTBR of TauF4).",
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     {
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       "citation": {
         "authors": [
-          "Amniai L",
-          "Fauquant C",
-          "Huvent I",
-          "Landrieu I",
-          "Leroy A",
-          "Lippens G",
-          "Sibille N",
-          "Verdegem D",
-          "Wieruszeski JM"
+          "Ai J",
+          "Ban T",
+          "Bao YN",
+          "Chen QX",
+          "Hu XL",
+          "Jiang XM",
+          "Liu CD",
+          "Pei SC",
+          "Su XL",
+          "Sun LH",
+          "Sun LL",
+          "Wang X",
+          "Yan ML",
+          "Zhao LJ",
+          "Zong DK"
         ],
-        "date": "2012-02-01",
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-        "reference": "22072628",
-        "title": "Structural characterization by nuclear magnetic resonance of the impact of phosphorylation in the proline-rich region of the disordered Tau protein.",
+        "date": "2015-09-01",
+        "first": "Sun LH",
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+        "name": "Journal of neurochemistry",
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+        "reference": "26118667",
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         "type": "PubMed",
-        "volume": "80"
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       },
-      "evidence": "In this study, we address the structural impact of phosphorylation of the Tau protein by Nuclear Magnetic Resonance (NMR) spectroscopy on a functional fragment of Tau (Tau[Ser208-Ser324] = TauF4). TauF4 was phosphorylated by the proline-directed CDK2/CycA3 kinase on Thr231 (generating the AT180 epitope), Ser235, and equally on Thr212 and Thr217 in the Proline-rich region (Tau[Ser208-Gln244] or PRR). These modifications strongly decrease the capacity of TauF4 to polymerize tubulin into microtubules. While all the NMR parameters are consistent with a globally disordered Tau protein fragment, local clusters of structuration can be defined. The most salient result of our NMR analysis is that phosphorylation in the PRR stabilizes a short α-helix that runs from pSer235 till the very beginning of the microtubule-binding region (Tau[Thr245-Ser324] or MTBR of TauF4).",
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       "citation": {
         "authors": [
-          "Amniai L",
-          "Fauquant C",
-          "Huvent I",
-          "Landrieu I",
-          "Leroy A",
-          "Lippens G",
-          "Sibille N",
-          "Verdegem D",
-          "Wieruszeski JM"
+          "Ai J",
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+          "Hu XL",
+          "Jiang XM",
+          "Liu CD",
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+          "Su XL",
+          "Sun LH",
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+          "Wang X",
+          "Yan ML",
+          "Zhao LJ",
+          "Zong DK"
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-        "reference": "22072628",
-        "title": "Structural characterization by nuclear magnetic resonance of the impact of phosphorylation in the proline-rich region of the disordered Tau protein.",
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+        "first": "Sun LH",
+        "last": "Ai J",
+        "name": "Journal of neurochemistry",
+        "pages": "1139-51",
+        "reference": "26118667",
+        "title": "Activation of Cdk5/p25 and tau phosphorylation following chronic brain hypoperfusion in rats involves microRNA-195 down-regulation.",
         "type": "PubMed",
-        "volume": "80"
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       },
-      "evidence": "In this study, we address the structural impact of phosphorylation of the Tau protein by Nuclear Magnetic Resonance (NMR) spectroscopy on a functional fragment of Tau (Tau[Ser208-Ser324] = TauF4). TauF4 was phosphorylated by the proline-directed CDK2/CycA3 kinase on Thr231 (generating the AT180 epitope), Ser235, and equally on Thr212 and Thr217 in the Proline-rich region (Tau[Ser208-Gln244] or PRR). These modifications strongly decrease the capacity of TauF4 to polymerize tubulin into microtubules. While all the NMR parameters are consistent with a globally disordered Tau protein fragment, local clusters of structuration can be defined. The most salient result of our NMR analysis is that phosphorylation in the PRR stabilizes a short α-helix that runs from pSer235 till the very beginning of the microtubule-binding region (Tau[Thr245-Ser324] or MTBR of TauF4).",
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       "citation": {
         "authors": [
-          "Buosi V",
-          "Eichner T",
-          "Kern D",
-          "Kutter S",
-          "Labeikovsky W"
+          "Ai J",
+          "Ban T",
+          "Bao YN",
+          "Chen QX",
+          "Hu XL",
+          "Jiang XM",
+          "Liu CD",
+          "Pei SC",
+          "Su XL",
+          "Sun LH",
+          "Sun LL",
+          "Wang X",
+          "Yan ML",
+          "Zhao LJ",
+          "Zong DK"
         ],
-        "date": "2016-05-08",
-        "first": "Eichner T",
-        "last": "Kern D",
-        "name": "Journal of molecular biology",
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-        "reference": "26996941",
-        "title": "Molecular Mechanism of Pin1-Tau Recognition and Catalysis.",
+        "date": "2015-09-01",
+        "first": "Sun LH",
+        "last": "Ai J",
+        "name": "Journal of neurochemistry",
+        "pages": "1139-51",
+        "reference": "26118667",
+        "title": "Activation of Cdk5/p25 and tau phosphorylation following chronic brain hypoperfusion in rats involves microRNA-195 down-regulation.",
         "type": "PubMed",
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         "authors": [
-          "Amniai L",
-          "Fauquant C",
-          "Huvent I",
-          "Landrieu I",
-          "Leroy A",
-          "Lippens G",
-          "Sibille N",
-          "Verdegem D",
-          "Wieruszeski JM"
+          "Ai J",
+          "Ban T",
+          "Bao YN",
+          "Chen QX",
+          "Hu XL",
+          "Jiang XM",
+          "Liu CD",
+          "Pei SC",
+          "Su XL",
+          "Sun LH",
+          "Sun LL",
+          "Wang X",
+          "Yan ML",
+          "Zhao LJ",
+          "Zong DK"
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-        "first": "Sibille N",
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-        "title": "Structural characterization by nuclear magnetic resonance of the impact of phosphorylation in the proline-rich region of the disordered Tau protein.",
+        "date": "2015-09-01",
+        "first": "Sun LH",
+        "last": "Ai J",
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+        "reference": "26118667",
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         "type": "PubMed",
-        "volume": "80"
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-      "evidence": "In this study, we address the structural impact of phosphorylation of the Tau protein by Nuclear Magnetic Resonance (NMR) spectroscopy on a functional fragment of Tau (Tau[Ser208-Ser324] = TauF4). TauF4 was phosphorylated by the proline-directed CDK2/CycA3 kinase on Thr231 (generating the AT180 epitope), Ser235, and equally on Thr212 and Thr217 in the Proline-rich region (Tau[Ser208-Gln244] or PRR). These modifications strongly decrease the capacity of TauF4 to polymerize tubulin into microtubules. While all the NMR parameters are consistent with a globally disordered Tau protein fragment, local clusters of structuration can be defined. The most salient result of our NMR analysis is that phosphorylation in the PRR stabilizes a short α-helix that runs from pSer235 till the very beginning of the microtubule-binding region (Tau[Thr245-Ser324] or MTBR of TauF4).",
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       "citation": {
         "authors": [
-          "Amniai L",
-          "Fauquant C",
-          "Huvent I",
-          "Landrieu I",
-          "Leroy A",
-          "Lippens G",
-          "Sibille N",
-          "Verdegem D",
-          "Wieruszeski JM"
+          "Ai J",
+          "Ban T",
+          "Bao YN",
+          "Chen QX",
+          "Hu XL",
+          "Jiang XM",
+          "Liu CD",
+          "Pei SC",
+          "Su XL",
+          "Sun LH",
+          "Sun LL",
+          "Wang X",
+          "Yan ML",
+          "Zhao LJ",
+          "Zong DK"
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-        "first": "Sibille N",
-        "last": "Landrieu I",
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-        "reference": "22072628",
-        "title": "Structural characterization by nuclear magnetic resonance of the impact of phosphorylation in the proline-rich region of the disordered Tau protein.",
+        "date": "2015-09-01",
+        "first": "Sun LH",
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+        "name": "Journal of neurochemistry",
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+        "reference": "26118667",
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         "type": "PubMed",
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-      "evidence": "In this study, we address the structural impact of phosphorylation of the Tau protein by Nuclear Magnetic Resonance (NMR) spectroscopy on a functional fragment of Tau (Tau[Ser208-Ser324] = TauF4). TauF4 was phosphorylated by the proline-directed CDK2/CycA3 kinase on Thr231 (generating the AT180 epitope), Ser235, and equally on Thr212 and Thr217 in the Proline-rich region (Tau[Ser208-Gln244] or PRR). These modifications strongly decrease the capacity of TauF4 to polymerize tubulin into microtubules. While all the NMR parameters are consistent with a globally disordered Tau protein fragment, local clusters of structuration can be defined. The most salient result of our NMR analysis is that phosphorylation in the PRR stabilizes a short α-helix that runs from pSer235 till the very beginning of the microtubule-binding region (Tau[Thr245-Ser324] or MTBR of TauF4).",
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         "authors": [
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+          "Zhao LJ",
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+        "date": "2015-09-01",
+        "first": "Sun LH",
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         "type": "PubMed",
-        "volume": "80"
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-      "evidence": "In this study, we address the structural impact of phosphorylation of the Tau protein by Nuclear Magnetic Resonance (NMR) spectroscopy on a functional fragment of Tau (Tau[Ser208-Ser324] = TauF4). TauF4 was phosphorylated by the proline-directed CDK2/CycA3 kinase on Thr231 (generating the AT180 epitope), Ser235, and equally on Thr212 and Thr217 in the Proline-rich region (Tau[Ser208-Gln244] or PRR). These modifications strongly decrease the capacity of TauF4 to polymerize tubulin into microtubules. While all the NMR parameters are consistent with a globally disordered Tau protein fragment, local clusters of structuration can be defined. The most salient result of our NMR analysis is that phosphorylation in the PRR stabilizes a short α-helix that runs from pSer235 till the very beginning of the microtubule-binding region (Tau[Thr245-Ser324] or MTBR of TauF4).",
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       "citation": {
         "authors": [
-          "Amniai L",
-          "Fauquant C",
-          "Huvent I",
-          "Landrieu I",
-          "Leroy A",
-          "Lippens G",
-          "Sibille N",
-          "Verdegem D",
-          "Wieruszeski JM"
+          "Ai J",
+          "Ban T",
+          "Bao YN",
+          "Chen QX",
+          "Hu XL",
+          "Jiang XM",
+          "Liu CD",
+          "Pei SC",
+          "Su XL",
+          "Sun LH",
+          "Sun LL",
+          "Wang X",
+          "Yan ML",
+          "Zhao LJ",
+          "Zong DK"
         ],
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-        "first": "Sibille N",
-        "last": "Landrieu I",
-        "name": "Proteins",
-        "pages": "454-62",
-        "reference": "22072628",
-        "title": "Structural characterization by nuclear magnetic resonance of the impact of phosphorylation in the proline-rich region of the disordered Tau protein.",
+        "date": "2015-09-01",
+        "first": "Sun LH",
+        "last": "Ai J",
+        "name": "Journal of neurochemistry",
+        "pages": "1139-51",
+        "reference": "26118667",
+        "title": "Activation of Cdk5/p25 and tau phosphorylation following chronic brain hypoperfusion in rats involves microRNA-195 down-regulation.",
         "type": "PubMed",
-        "volume": "80"
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-      "evidence": "In this study, we address the structural impact of phosphorylation of the Tau protein by Nuclear Magnetic Resonance (NMR) spectroscopy on a functional fragment of Tau (Tau[Ser208-Ser324] = TauF4). TauF4 was phosphorylated by the proline-directed CDK2/CycA3 kinase on Thr231 (generating the AT180 epitope), Ser235, and equally on Thr212 and Thr217 in the Proline-rich region (Tau[Ser208-Gln244] or PRR). These modifications strongly decrease the capacity of TauF4 to polymerize tubulin into microtubules. While all the NMR parameters are consistent with a globally disordered Tau protein fragment, local clusters of structuration can be defined. The most salient result of our NMR analysis is that phosphorylation in the PRR stabilizes a short α-helix that runs from pSer235 till the very beginning of the microtubule-binding region (Tau[Thr245-Ser324] or MTBR of TauF4).",
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@@ -61131,42 +68564,45 @@
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       "citation": {
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-          "Brion JP",
-          "D'Amico E",
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-          "Jia Y",
-          "Leroy K",
-          "Luo HR",
-          "Pouillon V",
-          "Schurmans S",
-          "Stygelbout V"
+          "Chen X",
+          "Collins N",
+          "Dai X",
+          "Huang T",
+          "LaDu MJ",
+          "Lin L",
+          "Shen H",
+          "Wei Z",
+          "Wu X",
+          "Xiao N",
+          "York J",
+          "Zhang J",
+          "Zhou M",
+          "Zhu Y"
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-        "date": "2014-02-01",
-        "first": "Stygelbout V",
-        "last": "Brion JP",
-        "name": "Brain : a journal of neurology",
-        "pages": "537-52",
-        "reference": "24401760",
-        "title": "Inositol trisphosphate 3-kinase B is increased in human Alzheimer brain and exacerbates mouse Alzheimer pathology.",
+        "date": "2016-01-01",
+        "first": "Zhou M",
+        "last": "Chen X",
+        "name": "Current Alzheimer research",
+        "pages": "1048-55",
+        "reference": "27087442",
+        "title": "APOE4 Induces Site-Specific Tau Phosphorylation Through Calpain-CDK5 Signaling Pathway in EFAD-Tg Mice.",
         "type": "PubMed",
-        "volume": "137"
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-      "evidence": "We show here that ITPKB protein level was increased 3-fold in the cerebral cortex of most patients with Alzheimer's disease compared with control subjects, and accumulated in dystrophic neurites associated to amyloid plaques. In mouse Neuro-2a neuroblastoma cells, Itpkb overexpression was associated with increased cell apoptosis and increased β-secretase 1 activity leading to overproduction of amyloid-β peptides. In this cellular model, an inhibitor of mitogen-activated kinase kinases 1/2 completely prevented overproduction of amyloid-β peptides. Transgenic overexpression of ITPKB in mouse forebrain neurons was not sufficient to induce amyloid plaque formation or tau hyperphosphorylation. However, in the 5X familial Alzheimer's disease mouse model, neuronal ITPKB overexpression significantly increased extracellular signal-regulated kinases 1/2 activation and β-secretase 1 activity, resulting in exacerbated Alzheimer's disease pathology as shown by increased astrogliosis, amyloid-β40 peptide production and tau hyperphosphorylation.",
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     {
       "annotations": {
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@@ -61174,42 +68610,45 @@
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       "citation": {
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-          "Jia Y",
-          "Leroy K",
-          "Luo HR",
-          "Pouillon V",
-          "Schurmans S",
-          "Stygelbout V"
+          "Chen X",
+          "Collins N",
+          "Dai X",
+          "Huang T",
+          "LaDu MJ",
+          "Lin L",
+          "Shen H",
+          "Wei Z",
+          "Wu X",
+          "Xiao N",
+          "York J",
+          "Zhang J",
+          "Zhou M",
+          "Zhu Y"
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-        "first": "Stygelbout V",
-        "last": "Brion JP",
-        "name": "Brain : a journal of neurology",
-        "pages": "537-52",
-        "reference": "24401760",
-        "title": "Inositol trisphosphate 3-kinase B is increased in human Alzheimer brain and exacerbates mouse Alzheimer pathology.",
+        "date": "2016-01-01",
+        "first": "Zhou M",
+        "last": "Chen X",
+        "name": "Current Alzheimer research",
+        "pages": "1048-55",
+        "reference": "27087442",
+        "title": "APOE4 Induces Site-Specific Tau Phosphorylation Through Calpain-CDK5 Signaling Pathway in EFAD-Tg Mice.",
         "type": "PubMed",
-        "volume": "137"
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-      "evidence": "We show here that ITPKB protein level was increased 3-fold in the cerebral cortex of most patients with Alzheimer's disease compared with control subjects, and accumulated in dystrophic neurites associated to amyloid plaques. In mouse Neuro-2a neuroblastoma cells, Itpkb overexpression was associated with increased cell apoptosis and increased β-secretase 1 activity leading to overproduction of amyloid-β peptides. In this cellular model, an inhibitor of mitogen-activated kinase kinases 1/2 completely prevented overproduction of amyloid-β peptides. Transgenic overexpression of ITPKB in mouse forebrain neurons was not sufficient to induce amyloid plaque formation or tau hyperphosphorylation. However, in the 5X familial Alzheimer's disease mouse model, neuronal ITPKB overexpression significantly increased extracellular signal-regulated kinases 1/2 activation and β-secretase 1 activity, resulting in exacerbated Alzheimer's disease pathology as shown by increased astrogliosis, amyloid-β40 peptide production and tau hyperphosphorylation.",
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     {
       "annotations": {
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@@ -61217,42 +68656,45 @@
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-          "Leroy K",
-          "Luo HR",
-          "Pouillon V",
-          "Schurmans S",
-          "Stygelbout V"
+          "Chen X",
+          "Collins N",
+          "Dai X",
+          "Huang T",
+          "LaDu MJ",
+          "Lin L",
+          "Shen H",
+          "Wei Z",
+          "Wu X",
+          "Xiao N",
+          "York J",
+          "Zhang J",
+          "Zhou M",
+          "Zhu Y"
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-        "date": "2014-02-01",
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-        "last": "Brion JP",
-        "name": "Brain : a journal of neurology",
-        "pages": "537-52",
-        "reference": "24401760",
-        "title": "Inositol trisphosphate 3-kinase B is increased in human Alzheimer brain and exacerbates mouse Alzheimer pathology.",
+        "date": "2016-01-01",
+        "first": "Zhou M",
+        "last": "Chen X",
+        "name": "Current Alzheimer research",
+        "pages": "1048-55",
+        "reference": "27087442",
+        "title": "APOE4 Induces Site-Specific Tau Phosphorylation Through Calpain-CDK5 Signaling Pathway in EFAD-Tg Mice.",
         "type": "PubMed",
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-      "evidence": "We show here that ITPKB protein level was increased 3-fold in the cerebral cortex of most patients with Alzheimer's disease compared with control subjects, and accumulated in dystrophic neurites associated to amyloid plaques. In mouse Neuro-2a neuroblastoma cells, Itpkb overexpression was associated with increased cell apoptosis and increased β-secretase 1 activity leading to overproduction of amyloid-β peptides. In this cellular model, an inhibitor of mitogen-activated kinase kinases 1/2 completely prevented overproduction of amyloid-β peptides. Transgenic overexpression of ITPKB in mouse forebrain neurons was not sufficient to induce amyloid plaque formation or tau hyperphosphorylation. However, in the 5X familial Alzheimer's disease mouse model, neuronal ITPKB overexpression significantly increased extracellular signal-regulated kinases 1/2 activation and β-secretase 1 activity, resulting in exacerbated Alzheimer's disease pathology as shown by increased astrogliosis, amyloid-β40 peptide production and tau hyperphosphorylation.",
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     {
       "annotations": {
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@@ -61260,39 +68702,45 @@
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       "citation": {
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-          "Jia Y",
-          "Leroy K",
-          "Luo HR",
-          "Pouillon V",
-          "Schurmans S",
-          "Stygelbout V"
+          "Chen X",
+          "Collins N",
+          "Dai X",
+          "Huang T",
+          "LaDu MJ",
+          "Lin L",
+          "Shen H",
+          "Wei Z",
+          "Wu X",
+          "Xiao N",
+          "York J",
+          "Zhang J",
+          "Zhou M",
+          "Zhu Y"
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-        "first": "Stygelbout V",
-        "last": "Brion JP",
-        "name": "Brain : a journal of neurology",
-        "pages": "537-52",
-        "reference": "24401760",
-        "title": "Inositol trisphosphate 3-kinase B is increased in human Alzheimer brain and exacerbates mouse Alzheimer pathology.",
+        "date": "2016-01-01",
+        "first": "Zhou M",
+        "last": "Chen X",
+        "name": "Current Alzheimer research",
+        "pages": "1048-55",
+        "reference": "27087442",
+        "title": "APOE4 Induces Site-Specific Tau Phosphorylation Through Calpain-CDK5 Signaling Pathway in EFAD-Tg Mice.",
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     {
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@@ -61300,39 +68748,45 @@
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       "citation": {
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-          "Jia Y",
-          "Leroy K",
-          "Luo HR",
-          "Pouillon V",
-          "Schurmans S",
-          "Stygelbout V"
+          "Chen X",
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+          "Dai X",
+          "Huang T",
+          "LaDu MJ",
+          "Lin L",
+          "Shen H",
+          "Wei Z",
+          "Wu X",
+          "Xiao N",
+          "York J",
+          "Zhang J",
+          "Zhou M",
+          "Zhu Y"
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-        "date": "2014-02-01",
-        "first": "Stygelbout V",
-        "last": "Brion JP",
-        "name": "Brain : a journal of neurology",
-        "pages": "537-52",
-        "reference": "24401760",
-        "title": "Inositol trisphosphate 3-kinase B is increased in human Alzheimer brain and exacerbates mouse Alzheimer pathology.",
+        "date": "2016-01-01",
+        "first": "Zhou M",
+        "last": "Chen X",
+        "name": "Current Alzheimer research",
+        "pages": "1048-55",
+        "reference": "27087442",
+        "title": "APOE4 Induces Site-Specific Tau Phosphorylation Through Calpain-CDK5 Signaling Pathway in EFAD-Tg Mice.",
         "type": "PubMed",
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     {
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@@ -61340,119 +68794,106 @@
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-          "D'Amico E",
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-          "Jia Y",
-          "Leroy K",
-          "Luo HR",
-          "Pouillon V",
-          "Schurmans S",
-          "Stygelbout V"
+          "Chen X",
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+          "Dai X",
+          "Huang T",
+          "LaDu MJ",
+          "Lin L",
+          "Shen H",
+          "Wei Z",
+          "Wu X",
+          "Xiao N",
+          "York J",
+          "Zhang J",
+          "Zhou M",
+          "Zhu Y"
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-        "date": "2014-02-01",
-        "first": "Stygelbout V",
-        "last": "Brion JP",
-        "name": "Brain : a journal of neurology",
-        "pages": "537-52",
-        "reference": "24401760",
-        "title": "Inositol trisphosphate 3-kinase B is increased in human Alzheimer brain and exacerbates mouse Alzheimer pathology.",
+        "date": "2016-01-01",
+        "first": "Zhou M",
+        "last": "Chen X",
+        "name": "Current Alzheimer research",
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+        "reference": "27087442",
+        "title": "APOE4 Induces Site-Specific Tau Phosphorylation Through Calpain-CDK5 Signaling Pathway in EFAD-Tg Mice.",
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-          "Jia Y",
-          "Leroy K",
-          "Luo HR",
-          "Pouillon V",
-          "Schurmans S",
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+          "Bredesen DE",
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-        "first": "Stygelbout V",
-        "last": "Brion JP",
-        "name": "Brain : a journal of neurology",
-        "pages": "537-52",
-        "reference": "24401760",
-        "title": "Inositol trisphosphate 3-kinase B is increased in human Alzheimer brain and exacerbates mouse Alzheimer pathology.",
+        "date": "2017-09-01",
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+        "name": "Molecular and cellular neurosciences",
+        "pages": "83-91",
+        "reference": "28720530",
+        "title": "Downregulation of protein phosphatase 2A by apolipoprotein E: Implications for Alzheimer's disease.",
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-          "Brion JP",
-          "D'Amico E",
-          "Duyckaerts C",
-          "Erneux C",
-          "Jia Y",
-          "Leroy K",
-          "Luo HR",
-          "Pouillon V",
-          "Schurmans S",
-          "Stygelbout V"
+          "Bredesen DE",
+          "Rao RV",
+          "Theendakara V"
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-        "first": "Stygelbout V",
-        "last": "Brion JP",
-        "name": "Brain : a journal of neurology",
-        "pages": "537-52",
-        "reference": "24401760",
-        "title": "Inositol trisphosphate 3-kinase B is increased in human Alzheimer brain and exacerbates mouse Alzheimer pathology.",
+        "date": "2017-09-01",
+        "first": "Theendakara V",
+        "last": "Rao RV",
+        "name": "Molecular and cellular neurosciences",
+        "pages": "83-91",
+        "reference": "28720530",
+        "title": "Downregulation of protein phosphatase 2A by apolipoprotein E: Implications for Alzheimer's disease.",
         "type": "PubMed",
-        "volume": "137"
+        "volume": "83"
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-      "evidence": "We show here that ITPKB protein level was increased 3-fold in the cerebral cortex of most patients with Alzheimer's disease compared with control subjects, and accumulated in dystrophic neurites associated to amyloid plaques. In mouse Neuro-2a neuroblastoma cells, Itpkb overexpression was associated with increased cell apoptosis and increased β-secretase 1 activity leading to overproduction of amyloid-β peptides. In this cellular model, an inhibitor of mitogen-activated kinase kinases 1/2 completely prevented overproduction of amyloid-β peptides. Transgenic overexpression of ITPKB in mouse forebrain neurons was not sufficient to induce amyloid plaque formation or tau hyperphosphorylation. However, in the 5X familial Alzheimer's disease mouse model, neuronal ITPKB overexpression significantly increased extracellular signal-regulated kinases 1/2 activation and β-secretase 1 activity, resulting in exacerbated Alzheimer's disease pathology as shown by increased astrogliosis, amyloid-β40 peptide production and tau hyperphosphorylation.",
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+      "evidence": "Our results indicated a significant down-regulation of PPP2R5E gene expression and reduction in PP2A activity by ApoE4 compared with ApoE3. This may also explain an elevated Tau phosphorylation in AD human brains that featured at least one ApoE4 allele.",
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     {
       "annotations": {
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@@ -61460,39 +68901,51 @@
       },
       "citation": {
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-          "Jia Y",
-          "Leroy K",
-          "Luo HR",
-          "Pouillon V",
-          "Schurmans S",
-          "Stygelbout V"
+          "Chen X",
+          "Collins N",
+          "Dai X",
+          "Huang T",
+          "LaDu MJ",
+          "Lin L",
+          "Shen H",
+          "Wei Z",
+          "Wu X",
+          "Xiao N",
+          "York J",
+          "Zhang J",
+          "Zhou M",
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-        "reference": "24401760",
-        "title": "Inositol trisphosphate 3-kinase B is increased in human Alzheimer brain and exacerbates mouse Alzheimer pathology.",
+        "date": "2016-01-01",
+        "first": "Zhou M",
+        "last": "Chen X",
+        "name": "Current Alzheimer research",
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+        "reference": "27087442",
+        "title": "APOE4 Induces Site-Specific Tau Phosphorylation Through Calpain-CDK5 Signaling Pathway in EFAD-Tg Mice.",
         "type": "PubMed",
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-      "evidence": "We show here that ITPKB protein level was increased 3-fold in the cerebral cortex of most patients with Alzheimer's disease compared with control subjects, and accumulated in dystrophic neurites associated to amyloid plaques. In mouse Neuro-2a neuroblastoma cells, Itpkb overexpression was associated with increased cell apoptosis and increased β-secretase 1 activity leading to overproduction of amyloid-β peptides. In this cellular model, an inhibitor of mitogen-activated kinase kinases 1/2 completely prevented overproduction of amyloid-β peptides. Transgenic overexpression of ITPKB in mouse forebrain neurons was not sufficient to induce amyloid plaque formation or tau hyperphosphorylation. However, in the 5X familial Alzheimer's disease mouse model, neuronal ITPKB overexpression significantly increased extracellular signal-regulated kinases 1/2 activation and β-secretase 1 activity, resulting in exacerbated Alzheimer's disease pathology as shown by increased astrogliosis, amyloid-β40 peptide production and tau hyperphosphorylation.",
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@@ -61500,2703 +68953,2866 @@
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-        "reference": "24401760",
-        "title": "Inositol trisphosphate 3-kinase B is increased in human Alzheimer brain and exacerbates mouse Alzheimer pathology.",
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+        "name": "Current Alzheimer research",
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+        "title": "APOE4 Induces Site-Specific Tau Phosphorylation Through Calpain-CDK5 Signaling Pathway in EFAD-Tg Mice.",
         "type": "PubMed",
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-      "evidence": "We show here that ITPKB protein level was increased 3-fold in the cerebral cortex of most patients with Alzheimer's disease compared with control subjects, and accumulated in dystrophic neurites associated to amyloid plaques. In mouse Neuro-2a neuroblastoma cells, Itpkb overexpression was associated with increased cell apoptosis and increased β-secretase 1 activity leading to overproduction of amyloid-β peptides. In this cellular model, an inhibitor of mitogen-activated kinase kinases 1/2 completely prevented overproduction of amyloid-β peptides. Transgenic overexpression of ITPKB in mouse forebrain neurons was not sufficient to induce amyloid plaque formation or tau hyperphosphorylation. However, in the 5X familial Alzheimer's disease mouse model, neuronal ITPKB overexpression significantly increased extracellular signal-regulated kinases 1/2 activation and β-secretase 1 activity, resulting in exacerbated Alzheimer's disease pathology as shown by increased astrogliosis, amyloid-β40 peptide production and tau hyperphosphorylation.",
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-        "title": "Diaminothiazoles modify Tau phosphorylation and improve the tauopathy in mouse models.",
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-        "title": "Diaminothiazoles modify Tau phosphorylation and improve the tauopathy in mouse models.",
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+        "first": "An FM",
+        "last": "Gao XD",
+        "name": "Neuroscience",
+        "pages": "75-84",
+        "reference": "25987199",
+        "title": "Glucagon-like peptide-1 regulates mitochondrial biogenesis and tau phosphorylation against advanced glycation end product-induced neuronal insult: Studies in vivo and in vitro.",
         "type": "PubMed",
-        "volume": "288"
+        "volume": "300"
       },
-      "evidence": "Small molecules in the diaminothiazole class are potent Tau kinase inhibitors that target CDK5 and GSK3β. Lead compounds from the series have IC50 values toward CDK5/p25 and GSK3β in the low nanomolar range and no observed toxicity in the therapeutic dose range. Neuronal protective effects and decreased PHF-1 immunoreactivity were observed in two animal models, 3×Tg-AD and CK-p25. Treatment nearly eliminated Sarkosyl-insoluble Tau with the most prominent effect on the phosphorylation at Ser-404. Treatment also induced the recovery of memory in a fear conditioning assay.",
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       "citation": {
         "authors": [
-          "Cornwell ME",
-          "Cuny GD",
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-          "Kosik KS",
-          "Laha JK",
-          "Mair W",
-          "Rei D",
-          "Steen JA",
-          "Tsai LH",
-          "Zhang X"
+          "Campbell SN",
+          "Masliah E",
+          "Monte L",
+          "Rice KC",
+          "Rissman RA",
+          "Roe AD",
+          "Taché Y",
+          "Zhang C"
         ],
-        "date": "2013-07-26",
-        "first": "Zhang X",
-        "last": "Kosik KS",
-        "name": "The Journal of biological chemistry",
-        "pages": "22042-56",
-        "reference": "23737518",
-        "title": "Diaminothiazoles modify Tau phosphorylation and improve the tauopathy in mouse models.",
+        "date": "2015-01-01",
+        "first": "Campbell SN",
+        "last": "Rissman RA",
+        "name": "Journal of Alzheimer's disease : JAD",
+        "pages": "967-76",
+        "reference": "25125464",
+        "title": "Increased tau phosphorylation and aggregation in the hippocampus of mice overexpressing corticotropin-releasing factor.",
         "type": "PubMed",
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-      "evidence": "Small molecules in the diaminothiazole class are potent Tau kinase inhibitors that target CDK5 and GSK3β. Lead compounds from the series have IC50 values toward CDK5/p25 and GSK3β in the low nanomolar range and no observed toxicity in the therapeutic dose range. Neuronal protective effects and decreased PHF-1 immunoreactivity were observed in two animal models, 3×Tg-AD and CK-p25. Treatment nearly eliminated Sarkosyl-insoluble Tau with the most prominent effect on the phosphorylation at Ser-404. Treatment also induced the recovery of memory in a fear conditioning assay.",
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         "authors": [
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-          "Hernandez I",
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-          "Laha JK",
-          "Mair W",
-          "Rei D",
-          "Steen JA",
-          "Tsai LH",
-          "Zhang X"
+          "Campbell SN",
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+          "Monte L",
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+          "Taché Y",
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         ],
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-        "first": "Zhang X",
-        "last": "Kosik KS",
-        "name": "The Journal of biological chemistry",
-        "pages": "22042-56",
-        "reference": "23737518",
-        "title": "Diaminothiazoles modify Tau phosphorylation and improve the tauopathy in mouse models.",
+        "date": "2015-01-01",
+        "first": "Campbell SN",
+        "last": "Rissman RA",
+        "name": "Journal of Alzheimer's disease : JAD",
+        "pages": "967-76",
+        "reference": "25125464",
+        "title": "Increased tau phosphorylation and aggregation in the hippocampus of mice overexpressing corticotropin-releasing factor.",
         "type": "PubMed",
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-      "evidence": "Small molecules in the diaminothiazole class are potent Tau kinase inhibitors that target CDK5 and GSK3β. Lead compounds from the series have IC50 values toward CDK5/p25 and GSK3β in the low nanomolar range and no observed toxicity in the therapeutic dose range. Neuronal protective effects and decreased PHF-1 immunoreactivity were observed in two animal models, 3×Tg-AD and CK-p25. Treatment nearly eliminated Sarkosyl-insoluble Tau with the most prominent effect on the phosphorylation at Ser-404. Treatment also induced the recovery of memory in a fear conditioning assay.",
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         "authors": [
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-          "Laha JK",
-          "Mair W",
-          "Rei D",
-          "Steen JA",
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-          "Zhang X"
+          "Campbell SN",
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+          "Monte L",
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+          "Rissman RA",
+          "Roe AD",
+          "Taché Y",
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         ],
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-        "first": "Zhang X",
-        "last": "Kosik KS",
-        "name": "The Journal of biological chemistry",
-        "pages": "22042-56",
-        "reference": "23737518",
-        "title": "Diaminothiazoles modify Tau phosphorylation and improve the tauopathy in mouse models.",
+        "date": "2015-01-01",
+        "first": "Campbell SN",
+        "last": "Rissman RA",
+        "name": "Journal of Alzheimer's disease : JAD",
+        "pages": "967-76",
+        "reference": "25125464",
+        "title": "Increased tau phosphorylation and aggregation in the hippocampus of mice overexpressing corticotropin-releasing factor.",
         "type": "PubMed",
-        "volume": "288"
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-      "evidence": "Small molecules in the diaminothiazole class are potent Tau kinase inhibitors that target CDK5 and GSK3β. Lead compounds from the series have IC50 values toward CDK5/p25 and GSK3β in the low nanomolar range and no observed toxicity in the therapeutic dose range. Neuronal protective effects and decreased PHF-1 immunoreactivity were observed in two animal models, 3×Tg-AD and CK-p25. Treatment nearly eliminated Sarkosyl-insoluble Tau with the most prominent effect on the phosphorylation at Ser-404. Treatment also induced the recovery of memory in a fear conditioning assay.",
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       "citation": {
         "authors": [
-          "Cornwell ME",
-          "Cuny GD",
-          "Hernandez I",
-          "Kosik KS",
-          "Laha JK",
-          "Mair W",
-          "Rei D",
-          "Steen JA",
-          "Tsai LH",
-          "Zhang X"
+          "Campbell SN",
+          "Masliah E",
+          "Monte L",
+          "Rice KC",
+          "Rissman RA",
+          "Roe AD",
+          "Taché Y",
+          "Zhang C"
         ],
-        "date": "2013-07-26",
-        "first": "Zhang X",
-        "last": "Kosik KS",
-        "name": "The Journal of biological chemistry",
-        "pages": "22042-56",
-        "reference": "23737518",
-        "title": "Diaminothiazoles modify Tau phosphorylation and improve the tauopathy in mouse models.",
+        "date": "2015-01-01",
+        "first": "Campbell SN",
+        "last": "Rissman RA",
+        "name": "Journal of Alzheimer's disease : JAD",
+        "pages": "967-76",
+        "reference": "25125464",
+        "title": "Increased tau phosphorylation and aggregation in the hippocampus of mice overexpressing corticotropin-releasing factor.",
         "type": "PubMed",
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+        "volume": "43"
       },
-      "evidence": "Small molecules in the diaminothiazole class are potent Tau kinase inhibitors that target CDK5 and GSK3β. Lead compounds from the series have IC50 values toward CDK5/p25 and GSK3β in the low nanomolar range and no observed toxicity in the therapeutic dose range. Neuronal protective effects and decreased PHF-1 immunoreactivity were observed in two animal models, 3×Tg-AD and CK-p25. Treatment nearly eliminated Sarkosyl-insoluble Tau with the most prominent effect on the phosphorylation at Ser-404. Treatment also induced the recovery of memory in a fear conditioning assay.",
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       "annotations": {
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         "authors": [
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-          "Laha JK",
-          "Mair W",
-          "Rei D",
-          "Steen JA",
-          "Tsai LH",
-          "Zhang X"
+          "Campbell SN",
+          "Masliah E",
+          "Monte L",
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+          "Rissman RA",
+          "Roe AD",
+          "Taché Y",
+          "Zhang C"
         ],
-        "date": "2013-07-26",
-        "first": "Zhang X",
-        "last": "Kosik KS",
-        "name": "The Journal of biological chemistry",
-        "pages": "22042-56",
-        "reference": "23737518",
-        "title": "Diaminothiazoles modify Tau phosphorylation and improve the tauopathy in mouse models.",
+        "date": "2015-01-01",
+        "first": "Campbell SN",
+        "last": "Rissman RA",
+        "name": "Journal of Alzheimer's disease : JAD",
+        "pages": "967-76",
+        "reference": "25125464",
+        "title": "Increased tau phosphorylation and aggregation in the hippocampus of mice overexpressing corticotropin-releasing factor.",
         "type": "PubMed",
-        "volume": "288"
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-      "evidence": "Small molecules in the diaminothiazole class are potent Tau kinase inhibitors that target CDK5 and GSK3β. Lead compounds from the series have IC50 values toward CDK5/p25 and GSK3β in the low nanomolar range and no observed toxicity in the therapeutic dose range. Neuronal protective effects and decreased PHF-1 immunoreactivity were observed in two animal models, 3×Tg-AD and CK-p25. Treatment nearly eliminated Sarkosyl-insoluble Tau with the most prominent effect on the phosphorylation at Ser-404. Treatment also induced the recovery of memory in a fear conditioning assay.",
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     {
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         },
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       "citation": {
         "authors": [
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-          "Cuny GD",
-          "Hernandez I",
-          "Kosik KS",
-          "Laha JK",
-          "Mair W",
-          "Rei D",
-          "Steen JA",
-          "Tsai LH",
-          "Zhang X"
+          "Campbell SN",
+          "Masliah E",
+          "Monte L",
+          "Rice KC",
+          "Rissman RA",
+          "Roe AD",
+          "Taché Y",
+          "Zhang C"
         ],
-        "date": "2013-07-26",
-        "first": "Zhang X",
-        "last": "Kosik KS",
-        "name": "The Journal of biological chemistry",
-        "pages": "22042-56",
-        "reference": "23737518",
-        "title": "Diaminothiazoles modify Tau phosphorylation and improve the tauopathy in mouse models.",
+        "date": "2015-01-01",
+        "first": "Campbell SN",
+        "last": "Rissman RA",
+        "name": "Journal of Alzheimer's disease : JAD",
+        "pages": "967-76",
+        "reference": "25125464",
+        "title": "Increased tau phosphorylation and aggregation in the hippocampus of mice overexpressing corticotropin-releasing factor.",
         "type": "PubMed",
-        "volume": "288"
-      },
-      "evidence": "Small molecules in the diaminothiazole class are potent Tau kinase inhibitors that target CDK5 and GSK3β. Lead compounds from the series have IC50 values toward CDK5/p25 and GSK3β in the low nanomolar range and no observed toxicity in the therapeutic dose range. Neuronal protective effects and decreased PHF-1 immunoreactivity were observed in two animal models, 3×Tg-AD and CK-p25. Treatment nearly eliminated Sarkosyl-insoluble Tau with the most prominent effect on the phosphorylation at Ser-404. Treatment also induced the recovery of memory in a fear conditioning assay.",
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     {
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-          "Biernat J",
-          "Mandelkow E",
-          "Mandelkow EM",
-          "Schweers O"
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-        "date": "1995-08-29",
-        "first": "Schweers O",
-        "last": "Mandelkow E",
-        "name": "Proceedings of the National Academy of Sciences of the United States of America",
-        "pages": "8463-7",
-        "reference": "7667312",
-        "title": "Oxidation of cysteine-322 in the repeat domain of microtubule-associated protein tau controls the in vitro assembly of paired helical filaments.",
-        "type": "PubMed",
-        "volume": "92"
+      "annotations": {
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+        }
       },
-      "evidence": "Though whole tau assembled poorly, constructs containing three internal repeats (corresponding to the fetal tau isoform) formed PHFs reproducibly. This ability depended on intermolecular disulfide bridges formed by the single Cys-322. Blocking the SH group, mutating Cys for Ala, or keeping T in a reducing environment all inhibited assembly. On the other hand, Cys-322 can be oxidized, and this leads to PHF assembly (ref. 11; this report). In vitro this is achieved most easily by using constructs of the 'fetal' isoform of T (htau23) that has only three repeats. Conversely, reducing agents or the second repeat or T can be viewed as 'antidotes' against PHF assembly.The synthetic PHFs bound the dye thioflavin S used in Alzheimer disease diagnostics.",
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       "citation": {
         "authors": [
-          "Biernat J",
-          "Mandelkow E",
-          "Mandelkow EM",
-          "Schweers O"
+          "Campbell SN",
+          "Masliah E",
+          "Monte L",
+          "Rice KC",
+          "Rissman RA",
+          "Roe AD",
+          "Taché Y",
+          "Zhang C"
         ],
-        "date": "1995-08-29",
-        "first": "Schweers O",
-        "last": "Mandelkow E",
-        "name": "Proceedings of the National Academy of Sciences of the United States of America",
-        "pages": "8463-7",
-        "reference": "7667312",
-        "title": "Oxidation of cysteine-322 in the repeat domain of microtubule-associated protein tau controls the in vitro assembly of paired helical filaments.",
+        "date": "2015-01-01",
+        "first": "Campbell SN",
+        "last": "Rissman RA",
+        "name": "Journal of Alzheimer's disease : JAD",
+        "pages": "967-76",
+        "reference": "25125464",
+        "title": "Increased tau phosphorylation and aggregation in the hippocampus of mice overexpressing corticotropin-releasing factor.",
         "type": "PubMed",
-        "volume": "92"
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       },
-      "evidence": "Though whole tau assembled poorly, constructs containing three internal repeats (corresponding to the fetal tau isoform) formed PHFs reproducibly. This ability depended on intermolecular disulfide bridges formed by the single Cys-322. Blocking the SH group, mutating Cys for Ala, or keeping T in a reducing environment all inhibited assembly. On the other hand, Cys-322 can be oxidized, and this leads to PHF assembly (ref. 11; this report). In vitro this is achieved most easily by using constructs of the 'fetal' isoform of T (htau23) that has only three repeats. Conversely, reducing agents or the second repeat or T can be viewed as 'antidotes' against PHF assembly.The synthetic PHFs bound the dye thioflavin S used in Alzheimer disease diagnostics.",
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     {
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       },
       "citation": {
         "authors": [
-          "Bae D",
-          "Kim MJ",
-          "Kim S",
-          "Kim YJ",
-          "Lee YH",
-          "Na Y",
-          "Park SY",
-          "Yoon HG"
+          "Campbell SN",
+          "Masliah E",
+          "Monte L",
+          "Rice KC",
+          "Rissman RA",
+          "Roe AD",
+          "Taché Y",
+          "Zhang C"
         ],
-        "date": "2015-04-01",
-        "first": "Park SY",
-        "last": "Yoon HG",
-        "name": "International journal of molecular medicine",
-        "pages": "1109-18",
-        "reference": "25672970",
-        "title": "Selective PCAF inhibitor ameliorates cognitive and behavioral deficits by suppressing NF-κB-mediated neuroinflammation induced by Aβ in a model of Alzheimer's disease.",
+        "date": "2015-01-01",
+        "first": "Campbell SN",
+        "last": "Rissman RA",
+        "name": "Journal of Alzheimer's disease : JAD",
+        "pages": "967-76",
+        "reference": "25125464",
+        "title": "Increased tau phosphorylation and aggregation in the hippocampus of mice overexpressing corticotropin-releasing factor.",
         "type": "PubMed",
-        "volume": "35"
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-      "evidence": "In this study, we modified the PCAF inhibitor by chemical derivatization and selected compound C-30-27 as the most potent PCAF inhibitor. We demonstrated that C-30-27 selectively inhibited acetylation-dependent nuclear factor-κB (NF-κB) at Lys-122 and suppressed the NF-κB-mediated inflammatory response induced by lipopolysaccharide (LPS) or Aβ in both BV2 and Neuro-2A (N2A) cells. Finally, we demonstrated that C-30-27 improved cognitive deficits, as well as the capacity for locomotion and the damaged cholinergic system in the Aβ-treated rats.",
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       "annotations": {
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         "Species": {
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       "citation": {
         "authors": [
-          "Bae D",
-          "Kim MJ",
-          "Kim S",
-          "Kim YJ",
-          "Lee YH",
-          "Na Y",
-          "Park SY",
-          "Yoon HG"
+          "Campbell SN",
+          "Masliah E",
+          "Monte L",
+          "Rice KC",
+          "Rissman RA",
+          "Roe AD",
+          "Taché Y",
+          "Zhang C"
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-        "date": "2015-04-01",
-        "first": "Park SY",
-        "last": "Yoon HG",
-        "name": "International journal of molecular medicine",
-        "pages": "1109-18",
-        "reference": "25672970",
-        "title": "Selective PCAF inhibitor ameliorates cognitive and behavioral deficits by suppressing NF-κB-mediated neuroinflammation induced by Aβ in a model of Alzheimer's disease.",
+        "date": "2015-01-01",
+        "first": "Campbell SN",
+        "last": "Rissman RA",
+        "name": "Journal of Alzheimer's disease : JAD",
+        "pages": "967-76",
+        "reference": "25125464",
+        "title": "Increased tau phosphorylation and aggregation in the hippocampus of mice overexpressing corticotropin-releasing factor.",
         "type": "PubMed",
-        "volume": "35"
+        "volume": "43"
       },
-      "evidence": "In this study, we modified the PCAF inhibitor by chemical derivatization and selected compound C-30-27 as the most potent PCAF inhibitor. We demonstrated that C-30-27 selectively inhibited acetylation-dependent nuclear factor-κB (NF-κB) at Lys-122 and suppressed the NF-κB-mediated inflammatory response induced by lipopolysaccharide (LPS) or Aβ in both BV2 and Neuro-2A (N2A) cells. Finally, we demonstrated that C-30-27 improved cognitive deficits, as well as the capacity for locomotion and the damaged cholinergic system in the Aβ-treated rats.",
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       "annotations": {
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       "citation": {
         "authors": [
-          "Bae D",
-          "Kim MJ",
-          "Kim S",
-          "Kim YJ",
-          "Lee YH",
-          "Na Y",
-          "Park SY",
-          "Yoon HG"
+          "Campbell SN",
+          "Masliah E",
+          "Monte L",
+          "Rice KC",
+          "Rissman RA",
+          "Roe AD",
+          "Taché Y",
+          "Zhang C"
         ],
-        "date": "2015-04-01",
-        "first": "Park SY",
-        "last": "Yoon HG",
-        "name": "International journal of molecular medicine",
-        "pages": "1109-18",
-        "reference": "25672970",
-        "title": "Selective PCAF inhibitor ameliorates cognitive and behavioral deficits by suppressing NF-κB-mediated neuroinflammation induced by Aβ in a model of Alzheimer's disease.",
+        "date": "2015-01-01",
+        "first": "Campbell SN",
+        "last": "Rissman RA",
+        "name": "Journal of Alzheimer's disease : JAD",
+        "pages": "967-76",
+        "reference": "25125464",
+        "title": "Increased tau phosphorylation and aggregation in the hippocampus of mice overexpressing corticotropin-releasing factor.",
         "type": "PubMed",
-        "volume": "35"
-      },
-      "evidence": "In this study, we modified the PCAF inhibitor by chemical derivatization and selected compound C-30-27 as the most potent PCAF inhibitor. We demonstrated that C-30-27 selectively inhibited acetylation-dependent nuclear factor-κB (NF-κB) at Lys-122 and suppressed the NF-κB-mediated inflammatory response induced by lipopolysaccharide (LPS) or Aβ in both BV2 and Neuro-2A (N2A) cells. Finally, we demonstrated that C-30-27 improved cognitive deficits, as well as the capacity for locomotion and the damaged cholinergic system in the Aβ-treated rats.",
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       },
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     {
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       "citation": {
         "authors": [
-          "Berkovitch SS",
-          "Chattopadhyay S",
-          "Haggarty SJ",
-          "Huang JH",
-          "Iaconelli J",
-          "Karmacharya R",
-          "Mazitschek R",
-          "Schreiber SL"
+          "Campbell SN",
+          "Masliah E",
+          "Monte L",
+          "Rice KC",
+          "Rissman RA",
+          "Roe AD",
+          "Taché Y",
+          "Zhang C"
         ],
-        "date": "2015-03-20",
-        "first": "Iaconelli J",
-        "last": "Karmacharya R",
-        "name": "ACS chemical biology",
-        "pages": "883-90",
-        "reference": "25546293",
-        "title": "HDAC6 inhibitors modulate Lys49 acetylation and membrane localization of β-catenin in human iPSC-derived neuronal cells.",
+        "date": "2015-01-01",
+        "first": "Campbell SN",
+        "last": "Rissman RA",
+        "name": "Journal of Alzheimer's disease : JAD",
+        "pages": "967-76",
+        "reference": "25125464",
+        "title": "Increased tau phosphorylation and aggregation in the hippocampus of mice overexpressing corticotropin-releasing factor.",
         "type": "PubMed",
-        "volume": "10"
+        "volume": "43"
       },
-      "evidence": "The N-terminus of β-catenin has phosphorylation, ubiquitination, and acetylation sites that regulate its stability and signaling. In the absence of a Wnt signal, Ser33, Ser37, and Thr41 are constitutively phosphorylated by glycogen synthase kinase 3β (GSK3β). β-Catenin phosphorylated at these sites is recognized by β-transducin repeat-containing protein (βTrCP), which results in ubiquitination and degradation by the ubiquitin-proteasome pathway. The N-terminal regulatory domain of β-catenin also includes Ser45, a phosphorylation site for Casein Kinase 1α (CK1α) and Lys49, which is acetylated by the acetyltransferase p300/CBP-associated factor (PCAF). The relevance of Lys49 acetylation and Ser45 phosphorylation to the function of β-catenin is an active area of investigation. We find that HDAC6 inhibitors increase Lys49 acetylation and Ser45 phosphorylation but do not affect Ser33, Ser37, and Thr41 phosphorylation. Lys49 acetylation results in decreased ubiquitination of β-catenin in the presence of proteasome inhibition. While increased Lys49 acetylation does not affect total levels of β-catenin, it results in increased membrane localization of β-catenin.",
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     {
       "annotations": {
         "Anatomy": {
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       },
       "citation": {
         "authors": [
-          "Boutillier AL",
-          "Bradke F",
-          "Di Giovanni S",
-          "Gaub P",
-          "Hervera A",
-          "Joshi Y",
-          "Laskowski CJ",
-          "Lindner R",
-          "Nguyen T",
-          "Puttagunta R",
-          "Rathore KI",
-          "Schmandke A",
-          "Sória MG",
-          "Tedeschi A"
+          "Campbell SN",
+          "Masliah E",
+          "Monte L",
+          "Rice KC",
+          "Rissman RA",
+          "Roe AD",
+          "Taché Y",
+          "Zhang C"
         ],
-        "date": "2014-04-01",
-        "first": "Puttagunta R",
-        "last": "Di Giovanni S",
-        "name": "Nature communications",
-        "pages": "3527",
-        "reference": "24686445",
-        "title": "PCAF-dependent epigenetic changes promote axonal regeneration in the central nervous system.",
+        "date": "2015-01-01",
+        "first": "Campbell SN",
+        "last": "Rissman RA",
+        "name": "Journal of Alzheimer's disease : JAD",
+        "pages": "967-76",
+        "reference": "25125464",
+        "title": "Increased tau phosphorylation and aggregation in the hippocampus of mice overexpressing corticotropin-releasing factor.",
         "type": "PubMed",
-        "volume": "5"
-      },
-      "evidence": "Here we show through systematic epigenetic studies that the histone acetyltransferase p300/CBP-associated factor (PCAF) promotes acetylation of histone 3 Lys 9 at the promoters of established key regeneration-associated genes following a peripheral but not a central axonal injury. Furthermore, we find that extracellular signal-regulated kinase (ERK)-mediated retrograde signalling is required for PCAF-dependent regenerative gene reprogramming. Finally, PCAF is necessary for conditioning-dependent axonal regeneration and also singularly promotes regeneration after spinal cord injury. ",
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       },
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     {
       "annotations": {
         "Anatomy": {
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+        },
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         }
       },
       "citation": {
         "authors": [
-          "Boutillier AL",
-          "Bradke F",
-          "Di Giovanni S",
-          "Gaub P",
-          "Hervera A",
-          "Joshi Y",
-          "Laskowski CJ",
-          "Lindner R",
-          "Nguyen T",
-          "Puttagunta R",
-          "Rathore KI",
-          "Schmandke A",
-          "Sória MG",
-          "Tedeschi A"
+          "Campbell SN",
+          "Masliah E",
+          "Monte L",
+          "Rice KC",
+          "Rissman RA",
+          "Roe AD",
+          "Taché Y",
+          "Zhang C"
         ],
-        "date": "2014-04-01",
-        "first": "Puttagunta R",
-        "last": "Di Giovanni S",
-        "name": "Nature communications",
-        "pages": "3527",
-        "reference": "24686445",
-        "title": "PCAF-dependent epigenetic changes promote axonal regeneration in the central nervous system.",
+        "date": "2015-01-01",
+        "first": "Campbell SN",
+        "last": "Rissman RA",
+        "name": "Journal of Alzheimer's disease : JAD",
+        "pages": "967-76",
+        "reference": "25125464",
+        "title": "Increased tau phosphorylation and aggregation in the hippocampus of mice overexpressing corticotropin-releasing factor.",
         "type": "PubMed",
-        "volume": "5"
-      },
-      "evidence": "Here we show through systematic epigenetic studies that the histone acetyltransferase p300/CBP-associated factor (PCAF) promotes acetylation of histone 3 Lys 9 at the promoters of established key regeneration-associated genes following a peripheral but not a central axonal injury. Furthermore, we find that extracellular signal-regulated kinase (ERK)-mediated retrograde signalling is required for PCAF-dependent regenerative gene reprogramming. Finally, PCAF is necessary for conditioning-dependent axonal regeneration and also singularly promotes regeneration after spinal cord injury. ",
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       },
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     {
       "annotations": {
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       },
       "citation": {
         "authors": [
-          "Bae D",
-          "Kim MJ",
-          "Kim S",
-          "Kim YJ",
-          "Lee YH",
-          "Na Y",
-          "Park SY",
-          "Yoon HG"
+          "Campbell SN",
+          "Masliah E",
+          "Monte L",
+          "Rice KC",
+          "Rissman RA",
+          "Roe AD",
+          "Taché Y",
+          "Zhang C"
         ],
-        "date": "2015-04-01",
-        "first": "Park SY",
-        "last": "Yoon HG",
-        "name": "International journal of molecular medicine",
-        "pages": "1109-18",
-        "reference": "25672970",
-        "title": "Selective PCAF inhibitor ameliorates cognitive and behavioral deficits by suppressing NF-κB-mediated neuroinflammation induced by Aβ in a model of Alzheimer's disease.",
+        "date": "2015-01-01",
+        "first": "Campbell SN",
+        "last": "Rissman RA",
+        "name": "Journal of Alzheimer's disease : JAD",
+        "pages": "967-76",
+        "reference": "25125464",
+        "title": "Increased tau phosphorylation and aggregation in the hippocampus of mice overexpressing corticotropin-releasing factor.",
         "type": "PubMed",
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-      },
-      "evidence": "In this study, we modified the PCAF inhibitor by chemical derivatization and selected compound C-30-27 as the most potent PCAF inhibitor. We demonstrated that C-30-27 selectively inhibited acetylation-dependent nuclear factor-κB (NF-κB) at Lys-122 and suppressed the NF-κB-mediated inflammatory response induced by lipopolysaccharide (LPS) or Aβ in both BV2 and Neuro-2A (N2A) cells. Finally, we demonstrated that C-30-27 improved cognitive deficits, as well as the capacity for locomotion and the damaged cholinergic system in the Aβ-treated rats.",
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+      "evidence": "Analysis of synaptosomes revealed that FynCA accumulated at high levels in the spine, resulting in increased levels of the NMDA receptor subunit NR2b phosphorylated at residue Y1472. Tau was strongly phosphorylated at the AT8 epitope S202/T205 as shown by Western blot and immunohistochemistry indicating that an increased tyrosine kinase activity of Fyn has down-stream consequences for serine/threonine-directed phosphorylation.",
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       "citation": {
         "authors": [
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+          "name": "kin",
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+        },
         "modifier": "Activity"
       },
-      "relation": "negativeCorrelation",
-      "source": 421,
-      "target": 459
+      "target": 904
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "Research_Model": {
+          "LRRK2 transgenic mice": true
+        },
+        "Species": {
+          "10090": true
+        }
+      },
       "citation": {
         "authors": [
-          "Berkovitch SS",
-          "Chattopadhyay S",
-          "Haggarty SJ",
-          "Huang JH",
-          "Iaconelli J",
-          "Karmacharya R",
-          "Mazitschek R",
-          "Schreiber SL"
+          "Bailey RM",
+          "Covy JP",
+          "Dickson DW",
+          "Farrer MJ",
+          "Giasson BI",
+          "Knight J",
+          "Lewis J",
+          "Melrose HL",
+          "Miles S",
+          "Rousseau L",
+          "Watkinson R"
         ],
-        "date": "2015-03-20",
-        "first": "Iaconelli J",
-        "last": "Karmacharya R",
-        "name": "ACS chemical biology",
-        "pages": "883-90",
-        "reference": "25546293",
-        "title": "HDAC6 inhibitors modulate Lys49 acetylation and membrane localization of β-catenin in human iPSC-derived neuronal cells.",
+        "date": "2013-12-01",
+        "first": "Bailey RM",
+        "last": "Lewis J",
+        "name": "Acta neuropathologica",
+        "pages": "809-27",
+        "reference": "24113872",
+        "title": "LRRK2 phosphorylates novel tau epitopes and promotes tauopathy.",
         "type": "PubMed",
-        "volume": "10"
+        "volume": "126"
       },
-      "evidence": "The N-terminus of β-catenin has phosphorylation, ubiquitination, and acetylation sites that regulate its stability and signaling. In the absence of a Wnt signal, Ser33, Ser37, and Thr41 are constitutively phosphorylated by glycogen synthase kinase 3β (GSK3β). β-Catenin phosphorylated at these sites is recognized by β-transducin repeat-containing protein (βTrCP), which results in ubiquitination and degradation by the ubiquitin-proteasome pathway. The N-terminal regulatory domain of β-catenin also includes Ser45, a phosphorylation site for Casein Kinase 1α (CK1α) and Lys49, which is acetylated by the acetyltransferase p300/CBP-associated factor (PCAF). The relevance of Lys49 acetylation and Ser45 phosphorylation to the function of β-catenin is an active area of investigation. We find that HDAC6 inhibitors increase Lys49 acetylation and Ser45 phosphorylation but do not affect Ser33, Ser37, and Thr41 phosphorylation. Lys49 acetylation results in decreased ubiquitination of β-catenin in the presence of proteasome inhibition. While increased Lys49 acetylation does not affect total levels of β-catenin, it results in increased membrane localization of β-catenin.",
-      "key": "c94fc06403749b9304ff2a3c68c3a15fa803c14be598fbdc641a4295f4c2f55f0a29b9dc5af749cca37785cd81fdf53710d23a1f7170fe75cda3fd2274fe026a",
-      "line": 2999,
-      "object": {
+      "evidence": "Using mass spectrometry, we identified multiple sites on recombinant tau that are phosphorylated by LRRK2 in vitro, including pT149 and pT153, which are phospho-epitopes that to date have been largely unexplored. Importantly, we demonstrate that expression of transgenic LRRK2 in a mouse model of tauopathy increased the aggregation of insoluble tau and its phosphorylation at T149, T153, T205, and S199/S202/T205 epitopes.",
+      "key": "b2fc2ec89c67adb59dd289610baa51710c3014041f5e37656f8f2878fc625bd64f3c16cc2247cdc5f6be72cb16be8008c040940b2f86a023112793cdb2c0dd62",
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+      "relation": "directlyIncreases",
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+      "subject": {
+        "effect": {
+          "name": "kin",
+          "namespace": "bel"
+        },
         "modifier": "Activity"
       },
-      "relation": "directlyDecreases",
-      "source": 75,
-      "target": 459
+      "target": 905
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        },
+        "Disease_Progression": {
+          "Late Stage": true
+        },
+        "MeSHDisease": {
+          "Alzheimer Disease": true
+        }
+      },
       "citation": {
         "authors": [
-          "Berkovitch SS",
-          "Chattopadhyay S",
-          "Haggarty SJ",
-          "Huang JH",
-          "Iaconelli J",
-          "Karmacharya R",
-          "Mazitschek R",
-          "Schreiber SL"
+          "Castillo-Carranza DL",
+          "Jackson GR",
+          "Kayed R",
+          "Lasagna-Reeves CA",
+          "Sarmiento J",
+          "Sengupta U",
+          "Troncoso J"
         ],
-        "date": "2015-03-20",
-        "first": "Iaconelli J",
-        "last": "Karmacharya R",
-        "name": "ACS chemical biology",
-        "pages": "883-90",
-        "reference": "25546293",
-        "title": "HDAC6 inhibitors modulate Lys49 acetylation and membrane localization of β-catenin in human iPSC-derived neuronal cells.",
+        "date": "2012-05-01",
+        "first": "Lasagna-Reeves CA",
+        "last": "Kayed R",
+        "name": "FASEB journal : official publication of the Federation of American Societies for Experimental Biology",
+        "pages": "1946-59",
+        "reference": "22253473",
+        "title": "Identification of oligomers at early stages of tau aggregation in Alzheimer's disease.",
         "type": "PubMed",
-        "volume": "10"
+        "volume": "26"
       },
-      "evidence": "The N-terminus of β-catenin has phosphorylation, ubiquitination, and acetylation sites that regulate its stability and signaling. In the absence of a Wnt signal, Ser33, Ser37, and Thr41 are constitutively phosphorylated by glycogen synthase kinase 3β (GSK3β). β-Catenin phosphorylated at these sites is recognized by β-transducin repeat-containing protein (βTrCP), which results in ubiquitination and degradation by the ubiquitin-proteasome pathway. The N-terminal regulatory domain of β-catenin also includes Ser45, a phosphorylation site for Casein Kinase 1α (CK1α) and Lys49, which is acetylated by the acetyltransferase p300/CBP-associated factor (PCAF). The relevance of Lys49 acetylation and Ser45 phosphorylation to the function of β-catenin is an active area of investigation. We find that HDAC6 inhibitors increase Lys49 acetylation and Ser45 phosphorylation but do not affect Ser33, Ser37, and Thr41 phosphorylation. Lys49 acetylation results in decreased ubiquitination of β-catenin in the presence of proteasome inhibition. While increased Lys49 acetylation does not affect total levels of β-catenin, it results in increased membrane localization of β-catenin.",
-      "key": "19f3435478e7eff5a75800677011c1c188ec07d00f6d7db9c5cfffd6d4a97f691ed2488c5398c5aa5b6cd1e385ca339edb56edb482ca8ce48107a844e801b5ee",
-      "line": 3000,
-      "relation": "increases",
-      "source": 75,
-      "target": 421
+      "evidence": "Phosphorylation at the epitope Ser202/Thr205 is regarded as a good marker for late-stage NFTs (5, 72). Hyman and colleagues (5) demonstrated that AT8 immunoreactivity is present primarily in eNFTs and in certain cases in iNFTs. These investigators also found that AT8 revealed dense neuropil thread staining.",
+      "key": "8420f4659e5e62f6c98dd394657ad3e1c262a61ee6dd553491875f3f23bf858dcb99915567a4430dcf4d01595b8a616a6bc250c63c2125cb9e9f5297554d2d9f",
+      "line": 3233,
+      "relation": "positiveCorrelation",
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+      "target": 415
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
-          "Berkovitch SS",
-          "Chattopadhyay S",
-          "Haggarty SJ",
-          "Huang JH",
-          "Iaconelli J",
-          "Karmacharya R",
-          "Mazitschek R",
-          "Schreiber SL"
+          "Carlomagno Y",
+          "Castanedes-Casey M",
+          "Chung DC",
+          "Cook C",
+          "DeTure M",
+          "Dickson DW",
+          "Dunmore J",
+          "Madden BJ",
+          "Petrucelli L",
+          "Tong J",
+          "Yue M"
         ],
-        "date": "2015-03-20",
-        "first": "Iaconelli J",
-        "last": "Karmacharya R",
-        "name": "ACS chemical biology",
-        "pages": "883-90",
-        "reference": "25546293",
-        "title": "HDAC6 inhibitors modulate Lys49 acetylation and membrane localization of β-catenin in human iPSC-derived neuronal cells.",
+        "date": "2017-09-15",
+        "first": "Carlomagno Y",
+        "last": "Cook C",
+        "name": "The Journal of biological chemistry",
+        "pages": "15277-15286",
+        "reference": "28760828",
+        "title": "An acetylation-phosphorylation switch that regulates tau aggregation propensity and function.",
         "type": "PubMed",
-        "volume": "10"
-      },
-      "evidence": "The N-terminus of β-catenin has phosphorylation, ubiquitination, and acetylation sites that regulate its stability and signaling. In the absence of a Wnt signal, Ser33, Ser37, and Thr41 are constitutively phosphorylated by glycogen synthase kinase 3β (GSK3β). β-Catenin phosphorylated at these sites is recognized by β-transducin repeat-containing protein (βTrCP), which results in ubiquitination and degradation by the ubiquitin-proteasome pathway. The N-terminal regulatory domain of β-catenin also includes Ser45, a phosphorylation site for Casein Kinase 1α (CK1α) and Lys49, which is acetylated by the acetyltransferase p300/CBP-associated factor (PCAF). The relevance of Lys49 acetylation and Ser45 phosphorylation to the function of β-catenin is an active area of investigation. We find that HDAC6 inhibitors increase Lys49 acetylation and Ser45 phosphorylation but do not affect Ser33, Ser37, and Thr41 phosphorylation. Lys49 acetylation results in decreased ubiquitination of β-catenin in the presence of proteasome inhibition. While increased Lys49 acetylation does not affect total levels of β-catenin, it results in increased membrane localization of β-catenin.",
-      "key": "921c16ad8f88faed551202b7563fc2af35cc78f1175b1d73660d547a05a1a6577daf07b9b909fc461bf0d7f845ea8885ba01e78aa463f5cc04da33d54af43b90",
-      "line": 3001,
-      "object": {
-        "modifier": "Activity"
+        "volume": "292"
       },
-      "relation": "directlyDecreases",
-      "source": 147,
-      "target": 459
+      "evidence": "Our findings indicate that several acetylation sites in tau are responsive to HDAC6 and that acetylation on Lys-321 (within a KCGS motif) is both essential for acetylation-mediated inhibition of tau aggregation in vitro and a molecular tactic for preventing phosphorylation on the downstream Ser-324 residue. Tau phosphorylation of Ser-324 (pSer-324) has not previously been evaluated in the context of tauopathy, and here we observed increased deposition of pSer-324-positive tau both in mouse models of tauopathy and in patients with Alzheimer's disease. These findings uncover a novel acetylation-phosphorylation switch at Lys-321/Ser-324 that coordinately regulates tau polymerization and function.",
+      "key": "9b13786fb0f95e29472fe78b3fdb152663be80279e0e124ce9c6e04a9a8fc0a8fd1cc9a4c08443424d78f11d2f31fe8ee8062310a34104caebc197ad1597f0fb",
+      "line": 4159,
+      "relation": "positiveCorrelation",
+      "source": 646,
+      "target": 402
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
-          "Berkovitch SS",
-          "Chattopadhyay S",
-          "Haggarty SJ",
-          "Huang JH",
-          "Iaconelli J",
-          "Karmacharya R",
-          "Mazitschek R",
-          "Schreiber SL"
+          "Bibow S",
+          "Biernat J",
+          "Blackledge M",
+          "Jensen MR",
+          "Kadavath H",
+          "Mandelkow E",
+          "Ozenne V",
+          "Schwalbe M",
+          "Zweckstetter M"
         ],
-        "date": "2015-03-20",
-        "first": "Iaconelli J",
-        "last": "Karmacharya R",
-        "name": "ACS chemical biology",
-        "pages": "883-90",
-        "reference": "25546293",
-        "title": "HDAC6 inhibitors modulate Lys49 acetylation and membrane localization of β-catenin in human iPSC-derived neuronal cells.",
+        "date": "2013-12-17",
+        "first": "Schwalbe M",
+        "last": "Zweckstetter M",
+        "name": "Biochemistry",
+        "pages": "9068-79",
+        "reference": "24251416",
+        "title": "Phosphorylation of human Tau protein by microtubule affinity-regulating kinase 2.",
         "type": "PubMed",
-        "volume": "10"
+        "volume": "52"
       },
-      "evidence": "The N-terminus of β-catenin has phosphorylation, ubiquitination, and acetylation sites that regulate its stability and signaling. In the absence of a Wnt signal, Ser33, Ser37, and Thr41 are constitutively phosphorylated by glycogen synthase kinase 3β (GSK3β). β-Catenin phosphorylated at these sites is recognized by β-transducin repeat-containing protein (βTrCP), which results in ubiquitination and degradation by the ubiquitin-proteasome pathway. The N-terminal regulatory domain of β-catenin also includes Ser45, a phosphorylation site for Casein Kinase 1α (CK1α) and Lys49, which is acetylated by the acetyltransferase p300/CBP-associated factor (PCAF). The relevance of Lys49 acetylation and Ser45 phosphorylation to the function of β-catenin is an active area of investigation. We find that HDAC6 inhibitors increase Lys49 acetylation and Ser45 phosphorylation but do not affect Ser33, Ser37, and Thr41 phosphorylation. Lys49 acetylation results in decreased ubiquitination of β-catenin in the presence of proteasome inhibition. While increased Lys49 acetylation does not affect total levels of β-catenin, it results in increased membrane localization of β-catenin.",
-      "key": "0d4825f268bd1d25ee4ef8744c61adba6005279f4177949155b7766f224108f4c469e821c236f848f8f50ce5c7b03bef0cb7fb29db287f3cee9c2bbfe0c974e5",
-      "line": 3002,
-      "relation": "increases",
-      "source": 147,
-      "target": 421
+      "evidence": "While residues Ser-262, Ser-324, and Ser-356 were completely phosphorylated, Ser-293 in the second repeat was only 84% phosphorylated (Table 1). Furthermore, four non-KXGS phosphorylation sites were detected, two within the repeat domain (Ser-305 in R2 and Ser-352 in R4) and two more at the C-terminus (Ser-413 and Ser-416) (Figure 1B,C). Of these, Ser-305 was 66% phosphorylated and Ser-352, Ser-413, and Ser-416 were ∼45−58% phosphorylated (Table 1). Using wild-type MARK2cat at 25 °C and pH 6.8, the same phosphorylation sites were observed. The three primary sites, Ser-262, Ser-324, and Ser-356, were still completely phosphorylated.",
+      "key": "4c66fa5f88028e166d91fdfd92e15b37141153d1025b30903d40414f5610afd2502d98417b45bc59b41037b2302f1622683e9457e7578e7e28919c28a639744e",
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+      "source": 644,
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     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
-          "Battistuzzi G",
-          "Giannini G"
+          "Bibow S",
+          "Biernat J",
+          "Blackledge M",
+          "Jensen MR",
+          "Kadavath H",
+          "Mandelkow E",
+          "Ozenne V",
+          "Schwalbe M",
+          "Zweckstetter M"
         ],
-        "date": "2016-12-01",
-        "first": "Battistuzzi G",
-        "last": "Giannini G",
-        "name": "Current bioactive compounds",
-        "pages": "282-288",
-        "reference": "27917100",
-        "title": "Synthesis of ST7612AA1, a Novel Oral HDAC Inhibitor, via Radical 
Thioacetic Acid Addition.",
+        "date": "2013-12-17",
+        "first": "Schwalbe M",
+        "last": "Zweckstetter M",
+        "name": "Biochemistry",
+        "pages": "9068-79",
+        "reference": "24251416",
+        "title": "Phosphorylation of human Tau protein by microtubule affinity-regulating kinase 2.",
         "type": "PubMed",
-        "volume": "12"
-      },
-      "evidence": "In conclusion, ST7612AA1, prodrug of ST7464AA1, is the first of a new generation of HDAC inhibitors, very potent, orally administered, and well tolerated. It is a thiol derivative, pan-histone deacetylase inhibitor, active against a broad panel of cancer cell lines and in vivo tumor models.",
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-      "object": {
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+        "volume": "52"
       },
-      "relation": "directlyDecreases",
-      "source": 144,
-      "target": 290
+      "evidence": "While residues Ser-262, Ser-324, and Ser-356 were completely phosphorylated, Ser-293 in the second repeat was only 84% phosphorylated (Table 1). Furthermore, four non-KXGS phosphorylation sites were detected, two within the repeat domain (Ser-305 in R2 and Ser-352 in R4) and two more at the C-terminus (Ser-413 and Ser-416) (Figure 1B,C). Of these, Ser-305 was 66% phosphorylated and Ser-352, Ser-413, and Ser-416 were ∼45−58% phosphorylated (Table 1). Using wild-type MARK2cat at 25 °C and pH 6.8, the same phosphorylation sites were observed. The three primary sites, Ser-262, Ser-324, and Ser-356, were still completely phosphorylated.",
+      "key": "080988a692a49149f14e5ee55dfbeec948ee519b46215350ac14683bb8b810bc1d09a0a58388bac22398ac0418faec1219c93f43b68f57b0e67ef30763ed1422",
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     },
     {
       "annotations": {
-        "Cell_Line": {
-          "HEK293": true
+        "Confidence": {
+          "High": true
         }
       },
       "citation": {
         "authors": [
-          "Cohen TJ",
-          "Guo JL",
-          "Hurtado DE",
-          "Kwong LK",
-          "Lee VM",
-          "Mills IP",
-          "Trojanowski JQ"
+          "Bibow S",
+          "Biernat J",
+          "Blackledge M",
+          "Jensen MR",
+          "Kadavath H",
+          "Mandelkow E",
+          "Ozenne V",
+          "Schwalbe M",
+          "Zweckstetter M"
         ],
-        "date": "2011-01-01",
-        "first": "Cohen TJ",
-        "last": "Lee VM",
-        "name": "Nature communications",
-        "pages": "252",
-        "reference": "21427723",
-        "title": "The acetylation of tau inhibits its function and promotes pathological tau aggregation.",
+        "date": "2013-12-17",
+        "first": "Schwalbe M",
+        "last": "Zweckstetter M",
+        "name": "Biochemistry",
+        "pages": "9068-79",
+        "reference": "24251416",
+        "title": "Phosphorylation of human Tau protein by microtubule affinity-regulating kinase 2.",
         "type": "PubMed",
-        "volume": "2"
-      },
-      "evidence": "Although low-level tau acetylation was observed in untreated HEK-T40 cells, treatment with the pan histone deacetylase (HDAC) inhibitor trichostatin A (TSA), but not the Sir2 class inhibitor nicotinamide, resulted in a dramatic increase in acetylated tau levels.",
-      "key": "20d6b50679c62c007a2df5d9bbaa46c4e614371758f18784fdf4d1d1518a970877ca911b1d3acb6984e5827438fa0234c9775c6fd9265ee132450d84dfbedb07",
-      "line": 3265,
-      "relation": "decreases",
-      "source": 290,
-      "subject": {
-        "modifier": "Activity"
+        "volume": "52"
       },
-      "target": 490
+      "evidence": "While residues Ser-262, Ser-324, and Ser-356 were completely phosphorylated, Ser-293 in the second repeat was only 84% phosphorylated (Table 1). Furthermore, four non-KXGS phosphorylation sites were detected, two within the repeat domain (Ser-305 in R2 and Ser-352 in R4) and two more at the C-terminus (Ser-413 and Ser-416) (Figure 1B,C). Of these, Ser-305 was 66% phosphorylated and Ser-352, Ser-413, and Ser-416 were ∼45−58% phosphorylated (Table 1). Using wild-type MARK2cat at 25 °C and pH 6.8, the same phosphorylation sites were observed. The three primary sites, Ser-262, Ser-324, and Ser-356, were still completely phosphorylated.",
+      "key": "3fd4272075259da867ce23863c15b28f8f7b67334058ba026c73627e6ccdd5fe1b2cb71d1081594edacb205ed07096a7adfb93135fda2805d98da717aa0672ef",
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     },
     {
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+      "relation": "hasVariant",
+      "source": 395,
+      "target": 396
+    },
+    {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
-          "Cincinelli R",
-          "Cuendet M",
-          "Dallavalle S",
-          "De Cesare M",
-          "Giannini G",
-          "Musso L",
-          "Nurisso A",
-          "Simoes-Pires C",
-          "Zuco V",
-          "Zunino F",
-          "Zwick V"
+          "Carlomagno Y",
+          "Cook C",
+          "Petrucelli L",
+          "Stankowski JN",
+          "Stetler C"
         ],
-        "date": "2016-04-13",
-        "first": "Cincinelli R",
-        "last": "Dallavalle S",
-        "name": "European journal of medicinal chemistry",
-        "pages": "99-105",
-        "reference": "26890116",
-        "title": "Biphenyl-4-yl-acrylohydroxamic acids: Identification of a novel indolyl-substituted HDAC inhibitor with antitumor activity.",
+        "date": "2014-01-01",
+        "first": "Cook C",
+        "last": "Petrucelli L",
+        "name": "Alzheimer's research &amp; therapy",
+        "pages": "29",
+        "reference": "25031639",
+        "title": "Acetylation: a new key to unlock tau's role in neurodegeneration.",
         "type": "PubMed",
-        "volume": "112"
-      },
-      "evidence": "Modification of the cap group of biphenylacrylohydroxamic acid-based HDAC inhibitors led to the identification of a new derivative (3) characterized by an indolyl-substituted 4-phenylcinnamic skeleton.",
-      "key": "b0f39cc5f1708dc391c04837153527cc29879a0e04bea21a182ad85f3440c3bf211612aeeb0bd88d0d2dc31f5170f69b311064ffd5ad539903a1f6d30eff240b",
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+        "volume": "6"
       },
-      "relation": "directlyDecreases",
-      "source": 93,
-      "target": 290
+      "evidence": "We demonstrate that elevated HDAC6 activity increases phosphorylation of tau at the 12E8 epitope (pS262/356), a phospho-epitope present within the KXGS motifs of tau’s microtubule-binding domain. The phosphorylation of KXGS motifs within tau by the kinase Par-1/MARK2 is required for tau proteotoxicity in Drosophila [29], observed at very early stages of NFT formation in AD brain [30], and appears to prime tau for subsequent phosphorylation events",
+      "key": "01ff101f13bfaa8c3b409ddf0199524f02789f86b2c84fd988e3167d9b0457c724411ec0717e43a68e13a910bf7cc62901d34b90e9822a4243409117fc4d634a",
+      "line": 3281,
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+      "target": 94
+    },
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+      "target": 642
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+      "relation": "hasComponent",
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+      "target": 780
     },
     {
       "annotations": {
-        "IC50": {
-          "65 nM": true
-        },
-        "Ki": {
-          "110 nM": true
+        "Confidence": {
+          "High": true
         }
       },
       "citation": {
         "authors": [
-          "Beckers T",
-          "Burkhardt C",
-          "Ciossek T",
-          "Dehmel F",
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-        "title": "SIRT1 Deacetylates Tau and Reduces Pathogenic Tau Spread in a Mouse Model of Tauopathy.",
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+        "first": "Sahara N",
+        "last": "Lewis J",
+        "name": "Journal of Alzheimer's disease : JAD",
+        "pages": "249-63",
+        "reference": "22941973",
+        "title": "Characteristics of TBS-extractable hyperphosphorylated tau species: aggregation intermediates in rTg4510 mouse brain.",
         "type": "PubMed",
-        "volume": "38"
+        "volume": "33"
       },
-      "evidence": "After pretreating hTau neurons with oligo Aβ-42 (1000 ng/ml), Sirt3 levels were reduced (Fig. 6b and e). This reduction in Sirt3 was translated into an increase in total tau and Ac-tau.",
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+      "evidence": "When overexpressed in rat hippocampal primary neurons, 14-3-3z causes an increase in Ser(262) phosphorylation, a decrease in the amount of microtubule-bound tau, a reduction in the amount of polymerized microtubules, as well as microtubule instability. Downregulation of synaptophysin in 14-3-3z overexpressing neurons was mitigated by inhibiting the proteosome, indicating that 14-3-3z promotes proteosomal degradation of synaptophysin. When 14-3-3z overexpressing neurons were treated with the microtubule stabilizing drug taxol, tau Ser(262) phosphorylation decreased and synaptophysin level was restored.",
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     },
     {
       "annotations": {
         "Anatomy": {
-          "entorhinal cortex": true,
-          "middle temporal gyrus": true,
-          "superior frontal gyrus": true
+          "hippocampal formation": true
+        },
+        "Confidence": {
+          "Medium": true
+        },
+        "Species": {
+          "10116": true
         }
       },
       "citation": {
         "authors": [
-          "Devidze N",
-          "Gan L",
-          "Gestwicki JE",
-          "Johnson JR",
-          "Krogan NJ",
-          "Li Y",
-          "Masliah E",
-          "Min SW",
-          "Mok SA",
-          "Sohn PD"
+          "DeTure M",
+          "Dickson DW",
+          "Ebrahim AS",
+          "Kang D",
+          "Knight J",
+          "Lewis J",
+          "Pedersen JT",
+          "Ren Y",
+          "Sahara N",
+          "Volbracht C",
+          "Yen SH"
         ],
-        "date": "2018-04-11",
-        "first": "Min SW",
-        "last": "Gan L",
-        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
-        "pages": "3680-3688",
-        "reference": "29540553",
-        "title": "SIRT1 Deacetylates Tau and Reduces Pathogenic Tau Spread in a Mouse Model of Tauopathy.",
+        "date": "2013-01-01",
+        "first": "Sahara N",
+        "last": "Lewis J",
+        "name": "Journal of Alzheimer's disease : JAD",
+        "pages": "249-63",
+        "reference": "22941973",
+        "title": "Characteristics of TBS-extractable hyperphosphorylated tau species: aggregation intermediates in rTg4510 mouse brain.",
         "type": "PubMed",
-        "volume": "38"
+        "volume": "33"
       },
-      "evidence": "Sirt3 levels were reduced in the entorhinal cortex, the middle temporal gyrus, and the superior frontal gyrus of AD subjects compared to those of CN and was associated with poorer test scores of neuropsychological evaluation and the severity of tau pathology.",
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-      "relation": "negativeCorrelation",
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+      "evidence": "When overexpressed in rat hippocampal primary neurons, 14-3-3z causes an increase in Ser(262) phosphorylation, a decrease in the amount of microtubule-bound tau, a reduction in the amount of polymerized microtubules, as well as microtubule instability. Downregulation of synaptophysin in 14-3-3z overexpressing neurons was mitigated by inhibiting the proteosome, indicating that 14-3-3z promotes proteosomal degradation of synaptophysin. When 14-3-3z overexpressing neurons were treated with the microtubule stabilizing drug taxol, tau Ser(262) phosphorylation decreased and synaptophysin level was restored.",
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+      "subject": {
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+      },
+      "target": 998
     },
     {
       "annotations": {
+        "Anatomy": {
+          "hippocampal formation": true
+        },
+        "Confidence": {
+          "Medium": true
+        },
         "Species": {
-          "10090": true
+          "10116": true
         }
       },
       "citation": {
         "authors": [
-          "Devidze N",
-          "Gan L",
-          "Gestwicki JE",
-          "Johnson JR",
-          "Krogan NJ",
-          "Li Y",
-          "Masliah E",
-          "Min SW",
-          "Mok SA",
-          "Sohn PD"
+          "DeTure M",
+          "Dickson DW",
+          "Ebrahim AS",
+          "Kang D",
+          "Knight J",
+          "Lewis J",
+          "Pedersen JT",
+          "Ren Y",
+          "Sahara N",
+          "Volbracht C",
+          "Yen SH"
         ],
-        "date": "2018-04-11",
-        "first": "Min SW",
-        "last": "Gan L",
-        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
-        "pages": "3680-3688",
-        "reference": "29540553",
-        "title": "SIRT1 Deacetylates Tau and Reduces Pathogenic Tau Spread in a Mouse Model of Tauopathy.",
+        "date": "2013-01-01",
+        "first": "Sahara N",
+        "last": "Lewis J",
+        "name": "Journal of Alzheimer's disease : JAD",
+        "pages": "249-63",
+        "reference": "22941973",
+        "title": "Characteristics of TBS-extractable hyperphosphorylated tau species: aggregation intermediates in rTg4510 mouse brain.",
         "type": "PubMed",
-        "volume": "38"
+        "volume": "33"
       },
-      "evidence": "After pretreating hTau neurons with oligo Aβ-42 (1000 ng/ml), Sirt3 levels were reduced (Fig. 6b and e). This reduction in Sirt3 was translated into an increase in total tau and Ac-tau.",
-      "key": "8c15bf198407ba1ea2a05e55bb5a32610c9a163452572edbf6725ebc1308e3a8ae235f11fb0cddfe1e2d96655e0be12ed3de0b7749c8f328366e9db2d8aee265",
-      "line": 3047,
-      "relation": "negativeCorrelation",
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+      "evidence": "When overexpressed in rat hippocampal primary neurons, 14-3-3z causes an increase in Ser(262) phosphorylation, a decrease in the amount of microtubule-bound tau, a reduction in the amount of polymerized microtubules, as well as microtubule instability. Downregulation of synaptophysin in 14-3-3z overexpressing neurons was mitigated by inhibiting the proteosome, indicating that 14-3-3z promotes proteosomal degradation of synaptophysin. When 14-3-3z overexpressing neurons were treated with the microtubule stabilizing drug taxol, tau Ser(262) phosphorylation decreased and synaptophysin level was restored.",
+      "key": "e7d3e582b8de7cdedc1686fea31b878c631b60e8524d78dcc3a3ce8fddecc1a36df775bd02b340d0dac008c52123053929ab0bdc88bd40dcf88fa6392c18b889",
+      "line": 3342,
+      "object": {
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+      "relation": "increases",
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     },
     {
-      "citation": {
-        "authors": [
-          "Cong X",
-          "Ellerby LM",
-          "Gan L",
-          "Huganir RL",
-          "Le D",
-          "Li Y",
-          "Lo I",
-          "Min SW",
-          "Minami SS",
-          "Ponnusamy R",
-          "Schilling B",
-          "Sohn PD",
-          "Tracy TE",
-          "Wang C",
-          "Zhou Y"
-        ],
-        "date": "2016-04-20",
-        "first": "Tracy TE",
-        "last": "Gan L",
-        "name": "Neuron",
-        "pages": "245-60",
-        "reference": "27041503",
-        "title": "Acetylated Tau Obstructs KIBRA-Mediated Signaling in Synaptic Plasticity and Promotes Tauopathy-Related Memory Loss.",
-        "type": "PubMed",
-        "volume": "90"
-      },
-      "evidence": "Here we report abnormal acetylation of K274 and K281 on tau, identified in AD brains, promotes memory loss and disrupts synaptic plasticity by reducing postsynaptic KIdney/BRAin (KIBRA) protein, a memory-associated protein.Transgenic mice expressing human tau with lysine-to-glutamine mutations to mimic K274 and K281 acetylation (tauKQ) exhibit AD-related memory deficits and impaired hippocampal long-term potentiation (LTP). TauKQ reduces synaptic KIBRA levels and disrupts activity-induced postsynaptic actin remodeling and AMPA receptor insertion. The LTP deficit was rescued by promoting actin polymerization or by KIBRA expression. In AD patients with dementia, we found enhanced tau acetylation is linked to loss of KIBRA.",
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+      "relation": "hasComponent",
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+    {
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+      "relation": "hasComponent",
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     },
     {
+      "annotations": {
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+        },
+        "Confidence": {
+          "Medium": true
+        },
+        "Species": {
+          "10116": true
+        }
+      },
       "citation": {
         "authors": [
-          "Cho SH",
-          "Cole PA",
-          "Gan L",
-          "Haroutunian V",
-          "Huang EJ",
-          "Masliah E",
-          "Meyers D",
-          "Min SW",
-          "Mukherjee C",
-          "Ott M",
-          "Schroeder S",
-          "Seeley WW",
-          "Shen Y",
-          "Zhou Y"
+          "DeTure M",
+          "Dickson DW",
+          "Ebrahim AS",
+          "Kang D",
+          "Knight J",
+          "Lewis J",
+          "Pedersen JT",
+          "Ren Y",
+          "Sahara N",
+          "Volbracht C",
+          "Yen SH"
         ],
-        "date": "2010-09-23",
-        "first": "Min SW",
-        "last": "Gan L",
-        "name": "Neuron",
-        "pages": "953-66",
-        "reference": "20869593",
-        "title": "Acetylation of tau inhibits its degradation and contributes to tauopathy.",
+        "date": "2013-01-01",
+        "first": "Sahara N",
+        "last": "Lewis J",
+        "name": "Journal of Alzheimer's disease : JAD",
+        "pages": "249-63",
+        "reference": "22941973",
+        "title": "Characteristics of TBS-extractable hyperphosphorylated tau species: aggregation intermediates in rTg4510 mouse brain.",
         "type": "PubMed",
-        "volume": "67"
+        "volume": "33"
       },
-      "evidence": "Thus, the increase in ac-tau induced by SIRT1 deficiency is accompanied by accumulation of pathogenic p-tau in primary neurons. In mouse brains, deleting SIRT1, which elevated ac-tau, also increased AT8-positive p-tau.",
-      "key": "8a57ca510d6d965a54c74426e2496322c6028b9241b15359061bee2f6e0f0a25696d2f554a573207825543ebd0789be443f307631ff32aef18144174b987ce91",
-      "line": 3311,
+      "evidence": "When overexpressed in rat hippocampal primary neurons, 14-3-3z causes an increase in Ser(262) phosphorylation, a decrease in the amount of microtubule-bound tau, a reduction in the amount of polymerized microtubules, as well as microtubule instability. Downregulation of synaptophysin in 14-3-3z overexpressing neurons was mitigated by inhibiting the proteosome, indicating that 14-3-3z promotes proteosomal degradation of synaptophysin. When 14-3-3z overexpressing neurons were treated with the microtubule stabilizing drug taxol, tau Ser(262) phosphorylation decreased and synaptophysin level was restored.",
+      "key": "3efe9adfec3b5d950cc40550f526d425e1e85f5e4b29e48ce7334161ee1ad738f74f852285b030914c217153ea8e2197d6b9ce1df27d0ec98b469332c4975837",
+      "line": 3343,
       "object": {
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+      "relation": "increases",
+      "source": 378,
+      "subject": {
         "modifier": "Activity"
       },
-      "relation": "negativeCorrelation",
-      "source": 490,
-      "target": 677
+      "target": 998
     },
     {
       "annotations": {
-        "Species": {
-          "10090": true
+        "Confidence": {
+          "Medium": true
         }
       },
       "citation": {
         "authors": [
-          "Cho SH",
-          "Cole PA",
-          "Gan L",
-          "Haroutunian V",
-          "Huang EJ",
-          "Masliah E",
-          "Meyers D",
-          "Min SW",
-          "Mukherjee C",
-          "Ott M",
-          "Schroeder S",
-          "Seeley WW",
-          "Shen Y",
-          "Zhou Y"
+          "Berkovitch SS",
+          "Chattopadhyay S",
+          "Haggarty SJ",
+          "Huang JH",
+          "Iaconelli J",
+          "Karmacharya R",
+          "Mazitschek R",
+          "Schreiber SL"
         ],
-        "date": "2010-09-23",
-        "first": "Min SW",
-        "last": "Gan L",
-        "name": "Neuron",
-        "pages": "953-66",
-        "reference": "20869593",
-        "title": "Acetylation of tau inhibits its degradation and contributes to tauopathy.",
+        "date": "2015-03-20",
+        "first": "Iaconelli J",
+        "last": "Karmacharya R",
+        "name": "ACS chemical biology",
+        "pages": "883-90",
+        "reference": "25546293",
+        "title": "HDAC6 inhibitors modulate Lys49 acetylation and membrane localization of β-catenin in human iPSC-derived neuronal cells.",
         "type": "PubMed",
-        "volume": "67"
+        "volume": "10"
       },
-      "evidence": "Thus, the increase in ac-tau induced by SIRT1 deficiency is accompanied by accumulation of pathogenic p-tau in primary neurons. In mouse brains, deleting SIRT1, which elevated ac-tau, also increased AT8-positive p-tau.",
-      "key": "4fa19688170652ec68b9185b03e0aecc0dea2908a539904fd46f1b488e5c8ee9b6c722fe16347b4f3cd81291d44a109370551bd2394fea30a099c223412e7fbc",
-      "line": 3313,
-      "relation": "positiveCorrelation",
-      "source": 490,
-      "target": 336
+      "evidence": "The N-terminus of β-catenin has phosphorylation, ubiquitination, and acetylation sites that regulate its stability and signaling. In the absence of a Wnt signal, Ser33, Ser37, and Thr41 are constitutively phosphorylated by glycogen synthase kinase 3β (GSK3β). β-Catenin phosphorylated at these sites is recognized by β-transducin repeat-containing protein (βTrCP), which results in ubiquitination and degradation by the ubiquitin-proteasome pathway. The N-terminal regulatory domain of β-catenin also includes Ser45, a phosphorylation site for Casein Kinase 1α (CK1α) and Lys49, which is acetylated by the acetyltransferase p300/CBP-associated factor (PCAF). The relevance of Lys49 acetylation and Ser45 phosphorylation to the function of β-catenin is an active area of investigation. We find that HDAC6 inhibitors increase Lys49 acetylation and Ser45 phosphorylation but do not affect Ser33, Ser37, and Thr41 phosphorylation. Lys49 acetylation results in decreased ubiquitination of β-catenin in the presence of proteasome inhibition. While increased Lys49 acetylation does not affect total levels of β-catenin, it results in increased membrane localization of β-catenin.",
+      "key": "038a513ce3814b4ea8521622bd4a2b5ec016d63a8b4e784f7a8d323aeaa796587bdc9ccf578c31e71022094d294aeb88b8b74cff86d704757cbf2845044b47d9",
+      "line": 3688,
+      "object": {
+        "modifier": "Degradation"
+      },
+      "relation": "increases",
+      "source": 378,
+      "subject": {
+        "modifier": "Activity"
+      },
+      "target": 505
     },
     {
       "annotations": {
-        "Braak_Stage": {
-          "Stage I": true
+        "Confidence": {
+          "Medium": true
         },
         "MeSHDisease": {
           "Alzheimer Disease": true
@@ -64204,2979 +71820,3056 @@
       },
       "citation": {
         "authors": [
-          "Lucke-Wold B",
-          "Nolan R",
-          "Omalu B",
-          "Ornstein M",
-          "Rosen C",
-          "Ross J",
-          "Seidel K",
-          "Udo R"
+          "Arendt T",
+          "Brückner MK",
+          "Gruschka H",
+          "Hilbrich I",
+          "Holzer M",
+          "Rohn S",
+          "Ueberham E",
+          "Ueberham U",
+          "Wodischeck S"
         ],
-        "date": "2017-01-01",
-        "first": "Lucke-Wold B",
-        "last": "Ross J",
-        "name": "Journal of neurology and neurosurgery",
-        "reference": "29276758",
-        "title": "Role of Tau Acetylation in Alzheimer's Disease and Chronic Traumatic Encephalopathy: The Way Forward for Successful Treatment.",
+        "date": "2014-12-01",
+        "first": "Ueberham U",
+        "last": "Arendt T",
+        "name": "Neuropathology and applied neurobiology",
+        "pages": "815-32",
+        "reference": "24964035",
+        "title": "Pin1 promotes degradation of Smad proteins and their interaction with phosphorylated tau in Alzheimer's disease.",
         "type": "PubMed",
-        "volume": "4"
+        "volume": "40"
       },
-      "evidence": "We also tested for ac-tau 280 in early stage Alzheimer's disease (Braak stage 1). Histopathological examination using the ac tau 280 antibody was performed in three Alzheimer's cases and three CTE patients. Presence of ac-tau 280 was confirmed in all cases at early sites of disease manifestation. These findings suggest that tau acetylation may precede tau phosphorylation and could be the first ",
-      "key": "bc9de9728e03321d9ffa44a9200eaae02af383f5dfd678c7c7c8f6dcf812f0945485d81b0d1bfbdc451edb72c726e57d96fd5269f46992eec0f0ca90fc255ccd",
-      "line": 3064,
-      "relation": "positiveCorrelation",
-      "source": 498,
-      "target": 908
+      "evidence": "The high degree of colocalization between pSmad2/3 and ubiquitin (Figure 7) provides additional evidence for a forced degradation of Smad2 via the proteasome pathway in AD which is controlled through binding of Pin1",
+      "key": "0d71fe9459aed2deb13def442ff8b59ae29bab026243bb99561988529ffbf3b0797075c51980d04c921fb7d34135ac04593678fefb380bd45a219c5466fd1dff",
+      "line": 4901,
+      "object": {
+        "modifier": "Degradation"
+      },
+      "relation": "increases",
+      "source": 378,
+      "subject": {
+        "modifier": "Activity"
+      },
+      "target": 772
     },
     {
+      "annotations": {
+        "Anatomy": {
+          "hippocampal formation": true
+        },
+        "Confidence": {
+          "Medium": true
+        },
+        "Species": {
+          "10116": true
+        }
+      },
       "citation": {
         "authors": [
-          "Cohen TJ",
-          "Guo JL",
-          "Hurtado DE",
-          "Kwong LK",
-          "Lee VM",
-          "Mills IP",
-          "Trojanowski JQ"
+          "DeTure M",
+          "Dickson DW",
+          "Ebrahim AS",
+          "Kang D",
+          "Knight J",
+          "Lewis J",
+          "Pedersen JT",
+          "Ren Y",
+          "Sahara N",
+          "Volbracht C",
+          "Yen SH"
         ],
-        "date": "2011-01-01",
-        "first": "Cohen TJ",
-        "last": "Lee VM",
-        "name": "Nature communications",
-        "pages": "252",
-        "reference": "21427723",
-        "title": "The acetylation of tau inhibits its function and promotes pathological tau aggregation.",
+        "date": "2013-01-01",
+        "first": "Sahara N",
+        "last": "Lewis J",
+        "name": "Journal of Alzheimer's disease : JAD",
+        "pages": "249-63",
+        "reference": "22941973",
+        "title": "Characteristics of TBS-extractable hyperphosphorylated tau species: aggregation intermediates in rTg4510 mouse brain.",
         "type": "PubMed",
-        "volume": "2"
+        "volume": "33"
       },
-      "evidence": "Thus, K280 acetylation is a feature found in a variety of human 4R or 3R/4R tauopathies including AD, but not 3R-tauopathies such as PiD.",
-      "key": "3ff0fe4b54b45e77d32737d08b31c17bbcf78d7d59fb03c20d68d6764bca561be2a17bf82d1a8461fcaacc522fdcdd89e3dc68ab77f750e5169158e36d99d327",
-      "line": 3270,
-      "relation": "positiveCorrelation",
-      "source": 498,
-      "target": 908
+      "evidence": "When overexpressed in rat hippocampal primary neurons, 14-3-3z causes an increase in Ser(262) phosphorylation, a decrease in the amount of microtubule-bound tau, a reduction in the amount of polymerized microtubules, as well as microtubule instability. Downregulation of synaptophysin in 14-3-3z overexpressing neurons was mitigated by inhibiting the proteosome, indicating that 14-3-3z promotes proteosomal degradation of synaptophysin. When 14-3-3z overexpressing neurons were treated with the microtubule stabilizing drug taxol, tau Ser(262) phosphorylation decreased and synaptophysin level was restored.",
+      "key": "e820fc585f960392d4ad6d7016f2f97dabe16279e08b6a4459e2bd4fd614b106516aef24a53514023d00774687ef7a66f0665fa7f90f9e8ad87fb17c0135972e",
+      "line": 3344,
+      "relation": "decreases",
+      "source": 75,
+      "target": 974
     },
     {
       "annotations": {
-        "Braak_Stage": {
-          "Stage I": true
+        "Anatomy": {
+          "hippocampal formation": true
         },
-        "MeSHDisease": {
-          "Alzheimer Disease": true
+        "Confidence": {
+          "Medium": true
+        },
+        "Species": {
+          "10116": true
         }
       },
       "citation": {
         "authors": [
-          "Lucke-Wold B",
-          "Nolan R",
-          "Omalu B",
-          "Ornstein M",
-          "Rosen C",
-          "Ross J",
-          "Seidel K",
-          "Udo R"
+          "DeTure M",
+          "Dickson DW",
+          "Ebrahim AS",
+          "Kang D",
+          "Knight J",
+          "Lewis J",
+          "Pedersen JT",
+          "Ren Y",
+          "Sahara N",
+          "Volbracht C",
+          "Yen SH"
         ],
-        "date": "2017-01-01",
-        "first": "Lucke-Wold B",
-        "last": "Ross J",
-        "name": "Journal of neurology and neurosurgery",
-        "reference": "29276758",
-        "title": "Role of Tau Acetylation in Alzheimer's Disease and Chronic Traumatic Encephalopathy: The Way Forward for Successful Treatment.",
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+        "first": "Sahara N",
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         "type": "PubMed",
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       },
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-        "name": "Journal of neurology and neurosurgery",
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-        "title": "Role of Tau Acetylation in Alzheimer's Disease and Chronic Traumatic Encephalopathy: The Way Forward for Successful Treatment.",
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         "authors": [
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-          "Dols J",
-          "Gorsky MK",
-          "Grönke S",
-          "Partridge L",
-          "Sofola-Adesakin O",
-          "Weigelt CM"
+          "Marani L",
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-        "name": "Scientific reports",
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-        "title": "Pseudo-acetylation of multiple sites on human Tau proteins alters Tau phosphorylation and microtubule binding, and ameliorates amyloid beta toxicity.",
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-        "name": "Scientific reports",
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-        "reference": "26940749",
-        "title": "Acetylation mimic of lysine 280 exacerbates human Tau neurotoxicity in vivo.",
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-      "evidence": "hTau-K280Q mutants showed significantly increased phosphorylation on S262 as compared to both hTau-wt and hTau-K280R flies, when normalised to total hTau (K9JA) levels (**p < 0.01, one-way ANOVA, Fig. 4b,c). Mis-expression of pseudo-acetylated K280Q-hTau in the adult fly nervous system potently exacerbated fly locomotion defects and photoreceptor neurodegeneration.",
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       "citation": {
         "authors": [
-          "Burlingame AL",
-          "Ioanoviciu A",
-          "Knudsen GM",
-          "Maeda S",
-          "Morris M",
-          "Mucke L",
-          "Trinidad JC"
+          "Marani L",
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+          "Selvatici R",
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-        "date": "2015-08-01",
-        "first": "Morris M",
-        "last": "Mucke L",
-        "name": "Nature neuroscience",
-        "pages": "1183-9",
-        "reference": "26192747",
-        "title": "Tau post-translational modifications in wild-type and human amyloid precursor protein transgenic mice.",
+        "date": "2013-08-01",
+        "first": "Selvatici R",
+        "last": "Siniscalchi A",
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-          "Yoshikawa M",
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+          "Marani L",
+          "Marino S",
+          "Selvatici R",
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         "Species": {
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         }
       },
       "citation": {
         "authors": [
-          "Saha P",
-          "Sen N",
-          "Sen T"
+          "Iijima KM",
+          "Iijima-Ando K",
+          "Lu B",
+          "Maruko-Otake A",
+          "Ohtake Y",
+          "Sekiya M",
+          "Suzuki E"
         ],
-        "date": "2018-03-20",
-        "first": "Sen T",
-        "last": "Sen N",
-        "name": "Science signaling",
-        "reference": "29559585",
-        "title": "Nitrosylation of GAPDH augments pathological tau acetylation upon exposure to amyloid-β.",
+        "date": "2012-01-01",
+        "first": "Iijima-Ando K",
+        "last": "Iijima KM",
+        "name": "PLoS genetics",
+        "pages": "e1002918",
+        "reference": "22952452",
+        "title": "Loss of axonal mitochondria promotes tau-mediated neurodegeneration and Alzheimer's disease-related tau phosphorylation via PAR-1.",
         "type": "PubMed",
-        "volume": "11"
+        "volume": "8"
       },
-      "evidence": "We found that NO production and tau acetylation at Lys280 occurred in the brain tissue in mice and in cultured mouse cortical neurons in response to exposure to amyloid-β1-42 (Aβ1-42), a peptide that is also implicated in AD. An increased abundance of NO facilitated the S-nitrosylation (SNO) of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). S-nitrosylated GAPDH (GAPDH-SNO) promoted the acetylation and activation of the acetyltransferase p300 and facilitated the nitrosylation and inactivation of the deacetylase sirtuin 1 (SIRT1). The abundance of GAPDH-SNO was increased in postmortem brain samples from AD patients. Preventing the increase in GAPDH-SNO abundance in both cultured neurons and mice, either by overexpression of the nitrosylation mutant of GAPDH (GAPDH C150S) or by treatment with the GAPDH nitrosylation inhibitor CGP3466B (also known as omigapil), abrogated Aβ1-42-induced tau acetylation, memory impairment, and locomotor dysfunction in mice, suggesting that this drug might be repurposed to treat patients with AD.",
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+      "evidence": "Using transgenic Drosophila expressing human tau, we found that RNAi-mediated knockdown of milton or Miro, an adaptor protein essential for axonal transport of mitochondria, enhanced human tau-induced neurodegeneration. Tau phosphorylation at an AD-related site Ser262 increased with knockdown of milton or Miro; and partitioning defective-1 (PAR-1), the Drosophila homolog of mammalian microtubule affinity-regulating kinase, mediated this increase of tau phosphorylation. Tau phosphorylation at Ser262 has been reported to promote tau detachment from microtubules, and we found that the levels of microtubule-unbound free tau increased by milton knockdown. Blocking tau phosphorylation at Ser262 site by PAR-1 knockdown or by mutating the Ser262 site to unphosphorylatable alanine suppressed the enhancement of tau-induced neurodegeneration caused by milton knockdown. Furthermore, knockdown of milton or Miro increased the levels of active PAR-1.",
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     {
       "annotations": {
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       },
       "citation": {
         "authors": [
-          "Saha P",
-          "Sen N",
-          "Sen T"
+          "Agerman K",
+          "Eckersley S",
+          "Gu GJ",
+          "Kamali-Moghaddam M",
+          "Kvist AJ",
+          "Landegren U",
+          "Lund H",
+          "Milner R",
+          "Nilsson LN",
+          "Sunnemark D",
+          "Wu D"
         ],
-        "date": "2018-03-20",
-        "first": "Sen T",
-        "last": "Sen N",
-        "name": "Science signaling",
-        "reference": "29559585",
-        "title": "Nitrosylation of GAPDH augments pathological tau acetylation upon exposure to amyloid-β.",
+        "date": "2013-01-01",
+        "first": "Gu GJ",
+        "last": "Kamali-Moghaddam M",
+        "name": "Journal of Alzheimer's disease : JAD",
+        "pages": "699-713",
+        "reference": "23001711",
+        "title": "Elevated MARK2-dependent phosphorylation of Tau in Alzheimer's disease.",
         "type": "PubMed",
-        "volume": "11"
-      },
-      "evidence": "We found that NO production and tau acetylation at Lys280 occurred in the brain tissue in mice and in cultured mouse cortical neurons in response to exposure to amyloid-β1-42 (Aβ1-42), a peptide that is also implicated in AD. An increased abundance of NO facilitated the S-nitrosylation (SNO) of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). S-nitrosylated GAPDH (GAPDH-SNO) promoted the acetylation and activation of the acetyltransferase p300 and facilitated the nitrosylation and inactivation of the deacetylase sirtuin 1 (SIRT1). The abundance of GAPDH-SNO was increased in postmortem brain samples from AD patients. Preventing the increase in GAPDH-SNO abundance in both cultured neurons and mice, either by overexpression of the nitrosylation mutant of GAPDH (GAPDH C150S) or by treatment with the GAPDH nitrosylation inhibitor CGP3466B (also known as omigapil), abrogated Aβ1-42-induced tau acetylation, memory impairment, and locomotor dysfunction in mice, suggesting that this drug might be repurposed to treat patients with AD.",
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       "citation": {
         "authors": [
-          "Saha P",
-          "Sen N",
-          "Sen T"
+          "Agerman K",
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+          "Gu GJ",
+          "Kamali-Moghaddam M",
+          "Kvist AJ",
+          "Landegren U",
+          "Lund H",
+          "Milner R",
+          "Nilsson LN",
+          "Sunnemark D",
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-        "date": "2018-03-20",
-        "first": "Sen T",
-        "last": "Sen N",
-        "name": "Science signaling",
-        "reference": "29559585",
-        "title": "Nitrosylation of GAPDH augments pathological tau acetylation upon exposure to amyloid-β.",
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+        "first": "Gu GJ",
+        "last": "Kamali-Moghaddam M",
+        "name": "Journal of Alzheimer's disease : JAD",
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+        "reference": "23001711",
+        "title": "Elevated MARK2-dependent phosphorylation of Tau in Alzheimer's disease.",
         "type": "PubMed",
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       "citation": {
         "authors": [
-          "Saha P",
-          "Sen N",
-          "Sen T"
+          "Amniai L",
+          "Fauquant C",
+          "Huvent I",
+          "Landrieu I",
+          "Leroy A",
+          "Lippens G",
+          "Sibille N",
+          "Verdegem D",
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-        "date": "2018-03-20",
-        "first": "Sen T",
-        "last": "Sen N",
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-        "reference": "29559585",
-        "title": "Nitrosylation of GAPDH augments pathological tau acetylation upon exposure to amyloid-β.",
+        "date": "2012-02-01",
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+        "title": "Structural characterization by nuclear magnetic resonance of the impact of phosphorylation in the proline-rich region of the disordered Tau protein.",
         "type": "PubMed",
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       "citation": {
         "authors": [
-          "Augustin H",
-          "Burnouf S",
-          "Dols J",
-          "Gorsky MK",
-          "Grönke S",
-          "Partridge L",
-          "Sofola-Adesakin O",
-          "Weigelt CM"
+          "Amniai L",
+          "Fauquant C",
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+          "Lippens G",
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+          "Verdegem D",
+          "Wieruszeski JM"
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-        "last": "Partridge L",
-        "name": "Scientific reports",
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-        "reference": "28855586",
-        "title": "Pseudo-acetylation of multiple sites on human Tau proteins alters Tau phosphorylation and microtubule binding, and ameliorates amyloid beta toxicity.",
+        "date": "2012-02-01",
+        "first": "Sibille N",
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+        "title": "Structural characterization by nuclear magnetic resonance of the impact of phosphorylation in the proline-rich region of the disordered Tau protein.",
         "type": "PubMed",
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-      "evidence": "We have used a knock-out/knock-in strategy in Drosophila to generate a strain with hTau inserted into the endogenous fly tau locus and expressed under the control of the endogenous fly tau promoter, thus avoiding potential toxicity due to genetic over-expression. hTau knock-in (KI) proteins were expressed at normal, endogenous levels, bound to fly microtubules and were post-translationally modified, hence displaying physiological properties. We used this new model to investigate the effects of acetylation on hTau toxicity in vivo. The simultaneous pseudo-acetylation of hTau at lysines 163, 280, 281 and 369 drastically decreased hTau phosphorylation and significantly reduced its binding to microtubules in vivo. These molecular alterations were associated with ameliorated amyloid beta toxicity. Our results indicate acetylation of hTau on multiple sites regulates its biology and ameliorates amyloid beta toxicity in vivo.",
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       "citation": {
         "authors": [
-          "Burlingame AL",
-          "Ioanoviciu A",
-          "Knudsen GM",
-          "Maeda S",
-          "Morris M",
-          "Mucke L",
-          "Trinidad JC"
+          "Amniai L",
+          "Fauquant C",
+          "Huvent I",
+          "Landrieu I",
+          "Leroy A",
+          "Lippens G",
+          "Sibille N",
+          "Verdegem D",
+          "Wieruszeski JM"
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-        "first": "Morris M",
-        "last": "Mucke L",
-        "name": "Nature neuroscience",
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-        "reference": "26192747",
-        "title": "Tau post-translational modifications in wild-type and human amyloid precursor protein transgenic mice.",
+        "date": "2012-02-01",
+        "first": "Sibille N",
+        "last": "Landrieu I",
+        "name": "Proteins",
+        "pages": "454-62",
+        "reference": "22072628",
+        "title": "Structural characterization by nuclear magnetic resonance of the impact of phosphorylation in the proline-rich region of the disordered Tau protein.",
         "type": "PubMed",
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-          "Dols J",
-          "Gorsky MK",
-          "Grönke S",
-          "Partridge L",
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-        "title": "Pseudo-acetylation of multiple sites on human Tau proteins alters Tau phosphorylation and microtubule binding, and ameliorates amyloid beta toxicity.",
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         "type": "PubMed",
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-          "Madden V",
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-          "Trzeciakiewicz H",
-          "Tseng JH",
-          "Wander CM",
-          "Yuan CX"
+          "Alonso AC",
+          "Grundke-Iqbal I",
+          "Iqbal K",
+          "Köpke E",
+          "Shaikh S",
+          "Tung YC"
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-        "first": "Trzeciakiewicz H",
-        "last": "Cohen TJ",
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-        "title": "A Dual Pathogenic Mechanism Links Tau Acetylation to Sporadic Tauopathy.",
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-      "evidence": "Surprisingly, we show that tau acetylation alters phosphorylation at residues S202/T205 (comprising the AT8 epitope), indicating acetylation-dephosphorylation cross-talk. Using a series of biochemical approaches, we found that K280/K281 acetylation impaired tau-mediated MT assembly function and also significantly enhanced tau aggregation. We also demonstrate that methylene blue, a reported tau aggregation inhibitor, modulates tau acetylation, a novel mechanism of action for this class of compounds",
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-          "Wander CM",
-          "Yuan CX"
+          "Dehennaut V",
+          "Drougat L",
+          "Guinez C",
+          "Lefebvre T",
+          "Michalski JC",
+          "Mir AM",
+          "Mortuaire M",
+          "Olivier S",
+          "Vercoutter-Edouart AS"
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-        "first": "Trzeciakiewicz H",
-        "last": "Cohen TJ",
-        "name": "Scientific reports",
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-        "title": "A Dual Pathogenic Mechanism Links Tau Acetylation to Sporadic Tauopathy.",
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+        "last": "Michalski JC",
+        "name": "Biochimica et biophysica acta",
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+        "reference": "19732809",
+        "title": "Dysregulation of the nutrient/stress sensor O-GlcNAcylation is involved in the etiology of cardiovascular disorders, type-2 diabetes and Alzheimer's disease.",
         "type": "PubMed",
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+        "volume": "1800"
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-      "evidence": "Surprisingly, we show that tau acetylation alters phosphorylation at residues S202/T205 (comprising the AT8 epitope), indicating acetylation-dephosphorylation cross-talk. Using a series of biochemical approaches, we found that K280/K281 acetylation impaired tau-mediated MT assembly function and also significantly enhanced tau aggregation. We also demonstrate that methylene blue, a reported tau aggregation inhibitor, modulates tau acetylation, a novel mechanism of action for this class of compounds",
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-          "Cong X",
-          "Ellerby LM",
-          "Gan L",
-          "Huganir RL",
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-          "Li Y",
-          "Lo I",
-          "Min SW",
-          "Minami SS",
-          "Ponnusamy R",
-          "Schilling B",
-          "Sohn PD",
-          "Tracy TE",
-          "Wang C",
-          "Zhou Y"
+          "Alonso AC",
+          "Grundke-Iqbal I",
+          "Iqbal K",
+          "Köpke E",
+          "Shaikh S",
+          "Tung YC"
         ],
-        "date": "2016-04-20",
-        "first": "Tracy TE",
-        "last": "Gan L",
-        "name": "Neuron",
-        "pages": "245-60",
-        "reference": "27041503",
-        "title": "Acetylated Tau Obstructs KIBRA-Mediated Signaling in Synaptic Plasticity and Promotes Tauopathy-Related Memory Loss.",
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+        "first": "Köpke E",
+        "last": "Grundke-Iqbal I",
+        "name": "The Journal of biological chemistry",
+        "pages": "24374-84",
+        "reference": "8226987",
+        "title": "Microtubule-associated protein tau. Abnormal phosphorylation of a non-paired helical filament pool in Alzheimer disease.",
         "type": "PubMed",
-        "volume": "90"
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-      "evidence": "Here we report abnormal acetylation of K274 and K281 on tau, identified in AD brains, promotes memory loss and disrupts synaptic plasticity by reducing postsynaptic KIdney/BRAin (KIBRA) protein, a memory-associated protein.Transgenic mice expressing human tau with lysine-to-glutamine mutations to mimic K274 and K281 acetylation (tauKQ) exhibit AD-related memory deficits and impaired hippocampal long-term potentiation (LTP). TauKQ reduces synaptic KIBRA levels and disrupts activity-induced postsynaptic actin remodeling and AMPA receptor insertion. The LTP deficit was rescued by promoting actin polymerization or by KIBRA expression. In AD patients with dementia, we found enhanced tau acetylation is linked to loss of KIBRA.",
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-          "Ellerby LM",
-          "Gan L",
-          "Huganir RL",
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-          "Lo I",
-          "Min SW",
-          "Minami SS",
-          "Ponnusamy R",
-          "Schilling B",
-          "Sohn PD",
-          "Tracy TE",
-          "Wang C",
-          "Zhou Y"
+          "Ando K",
+          "Brion JP",
+          "D'Amico E",
+          "Duyckaerts C",
+          "Erneux C",
+          "Jia Y",
+          "Leroy K",
+          "Luo HR",
+          "Pouillon V",
+          "Schurmans S",
+          "Stygelbout V"
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-        "first": "Tracy TE",
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-        "title": "Acetylated Tau Obstructs KIBRA-Mediated Signaling in Synaptic Plasticity and Promotes Tauopathy-Related Memory Loss.",
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+        "first": "Stygelbout V",
+        "last": "Brion JP",
+        "name": "Brain : a journal of neurology",
+        "pages": "537-52",
+        "reference": "24401760",
+        "title": "Inositol trisphosphate 3-kinase B is increased in human Alzheimer brain and exacerbates mouse Alzheimer pathology.",
         "type": "PubMed",
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       },
-      "evidence": "Here we report abnormal acetylation of K274 and K281 on tau, identified in AD brains, promotes memory loss and disrupts synaptic plasticity by reducing postsynaptic KIdney/BRAin (KIBRA) protein, a memory-associated protein.Transgenic mice expressing human tau with lysine-to-glutamine mutations to mimic K274 and K281 acetylation (tauKQ) exhibit AD-related memory deficits and impaired hippocampal long-term potentiation (LTP). TauKQ reduces synaptic KIBRA levels and disrupts activity-induced postsynaptic actin remodeling and AMPA receptor insertion. The LTP deficit was rescued by promoting actin polymerization or by KIBRA expression. In AD patients with dementia, we found enhanced tau acetylation is linked to loss of KIBRA.",
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-          "Burnouf S",
-          "Dols J",
-          "Gorsky MK",
-          "Grönke S",
-          "Partridge L",
-          "Sofola-Adesakin O",
-          "Weigelt CM"
+          "Ando K",
+          "Brion JP",
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+          "Jia Y",
+          "Leroy K",
+          "Luo HR",
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-        "reference": "28855586",
-        "title": "Pseudo-acetylation of multiple sites on human Tau proteins alters Tau phosphorylation and microtubule binding, and ameliorates amyloid beta toxicity.",
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+          "Biernat J",
+          "Mandelkow E",
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         "type": "PubMed",
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-        "date": "2015-08-01",
-        "first": "Morris M",
-        "last": "Mucke L",
-        "name": "Nature neuroscience",
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         "type": "PubMed",
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       "citation": {
         "authors": [
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-          "Castanedes-Casey M",
-          "Chung DC",
-          "Cook C",
-          "DeTure M",
-          "Dickson DW",
-          "Dunmore J",
-          "Madden BJ",
-          "Petrucelli L",
-          "Tong J",
-          "Yue M"
+          "Bae D",
+          "Kim MJ",
+          "Kim S",
+          "Kim YJ",
+          "Lee YH",
+          "Na Y",
+          "Park SY",
+          "Yoon HG"
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-        "date": "2017-09-15",
-        "first": "Carlomagno Y",
-        "last": "Cook C",
-        "name": "The Journal of biological chemistry",
-        "pages": "15277-15286",
-        "reference": "28760828",
-        "title": "An acetylation-phosphorylation switch that regulates tau aggregation propensity and function.",
+        "date": "2015-04-01",
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+        "name": "International journal of molecular medicine",
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-        "first": "Carlomagno Y",
-        "last": "Cook C",
-        "name": "The Journal of biological chemistry",
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-        "reference": "28760828",
-        "title": "An acetylation-phosphorylation switch that regulates tau aggregation propensity and function.",
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+        "first": "Park SY",
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         "type": "PubMed",
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-      "evidence": "Our findings indicate that several acetylation sites in tau are responsive to HDAC6 and that acetylation on Lys-321 (within a KCGS motif) is both essential for acetylation-mediated inhibition of tau aggregation in vitro and a molecular tactic for preventing phosphorylation on the downstream Ser-324 residue. Tau phosphorylation of Ser-324 (pSer-324) has not previously been evaluated in the context of tauopathy, and here we observed increased deposition of pSer-324-positive tau both in mouse models of tauopathy and in patients with Alzheimer's disease. These findings uncover a novel acetylation-phosphorylation switch at Lys-321/Ser-324 that coordinately regulates tau polymerization and function.",
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-      "evidence": "Clear evidence for acetylation and ubiquitination of the same lysine residues; some sites were also targeted by lysine methylation. Our findings refute the hypothesis of extensive O-linked N-acetylglucosamine (O-GlcNAc) modification of endogenous tau.",
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-        "date": "2015-08-01",
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         "type": "PubMed",
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-      "evidence": "Clear evidence for acetylation and ubiquitination of the same lysine residues; some sites were also targeted by lysine methylation. Our findings refute the hypothesis of extensive O-linked N-acetylglucosamine (O-GlcNAc) modification of endogenous tau.",
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+          "Bae D",
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-        "date": "2015-08-01",
-        "first": "Morris M",
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-        "name": "Nature neuroscience",
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         "type": "PubMed",
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-      "evidence": "Clear evidence for acetylation and ubiquitination of the same lysine residues; some sites were also targeted by lysine methylation. Our findings refute the hypothesis of extensive O-linked N-acetylglucosamine (O-GlcNAc) modification of endogenous tau.",
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-        "date": "2015-08-01",
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+      "evidence": "In this study, we modified the PCAF inhibitor by chemical derivatization and selected compound C-30-27 as the most potent PCAF inhibitor. We demonstrated that C-30-27 selectively inhibited acetylation-dependent nuclear factor-κB (NF-κB) at Lys-122 and suppressed the NF-κB-mediated inflammatory response induced by lipopolysaccharide (LPS) or Aβ in both BV2 and Neuro-2A (N2A) cells. Finally, we demonstrated that C-30-27 improved cognitive deficits, as well as the capacity for locomotion and the damaged cholinergic system in the Aβ-treated rats.",
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     {
       "annotations": {
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       "citation": {
         "authors": [
-          "Boutillier AL",
-          "Bradke F",
-          "Di Giovanni S",
-          "Gaub P",
-          "Hervera A",
-          "Joshi Y",
-          "Laskowski CJ",
-          "Lindner R",
-          "Nguyen T",
-          "Puttagunta R",
-          "Rathore KI",
-          "Schmandke A",
-          "Sória MG",
-          "Tedeschi A"
+          "Berkovitch SS",
+          "Chattopadhyay S",
+          "Haggarty SJ",
+          "Huang JH",
+          "Iaconelli J",
+          "Karmacharya R",
+          "Mazitschek R",
+          "Schreiber SL"
         ],
-        "date": "2014-04-01",
-        "first": "Puttagunta R",
-        "last": "Di Giovanni S",
-        "name": "Nature communications",
-        "pages": "3527",
-        "reference": "24686445",
-        "title": "PCAF-dependent epigenetic changes promote axonal regeneration in the central nervous system.",
+        "date": "2015-03-20",
+        "first": "Iaconelli J",
+        "last": "Karmacharya R",
+        "name": "ACS chemical biology",
+        "pages": "883-90",
+        "reference": "25546293",
+        "title": "HDAC6 inhibitors modulate Lys49 acetylation and membrane localization of β-catenin in human iPSC-derived neuronal cells.",
         "type": "PubMed",
-        "volume": "5"
+        "volume": "10"
       },
-      "evidence": "Here we show through systematic epigenetic studies that the histone acetyltransferase p300/CBP-associated factor (PCAF) promotes acetylation of histone 3 Lys 9 at the promoters of established key regeneration-associated genes following a peripheral but not a central axonal injury. Furthermore, we find that extracellular signal-regulated kinase (ERK)-mediated retrograde signalling is required for PCAF-dependent regenerative gene reprogramming. Finally, PCAF is necessary for conditioning-dependent axonal regeneration and also singularly promotes regeneration after spinal cord injury. ",
-      "key": "8f2a778c7d3e7dec9ad8686d0d18270e608a9f68e40b2e8a1be75af5ffa31800b17fc84a7d6c5f5ca4b2e09b4ac75a0d2f61f11d2a7c029b59f272349d779252",
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+      "evidence": "The N-terminus of β-catenin has phosphorylation, ubiquitination, and acetylation sites that regulate its stability and signaling. In the absence of a Wnt signal, Ser33, Ser37, and Thr41 are constitutively phosphorylated by glycogen synthase kinase 3β (GSK3β). β-Catenin phosphorylated at these sites is recognized by β-transducin repeat-containing protein (βTrCP), which results in ubiquitination and degradation by the ubiquitin-proteasome pathway. The N-terminal regulatory domain of β-catenin also includes Ser45, a phosphorylation site for Casein Kinase 1α (CK1α) and Lys49, which is acetylated by the acetyltransferase p300/CBP-associated factor (PCAF). The relevance of Lys49 acetylation and Ser45 phosphorylation to the function of β-catenin is an active area of investigation. We find that HDAC6 inhibitors increase Lys49 acetylation and Ser45 phosphorylation but do not affect Ser33, Ser37, and Thr41 phosphorylation. Lys49 acetylation results in decreased ubiquitination of β-catenin in the presence of proteasome inhibition. While increased Lys49 acetylation does not affect total levels of β-catenin, it results in increased membrane localization of β-catenin.",
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       "citation": {
@@ -67207,370 +74900,416 @@
         "volume": "5"
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       "evidence": "Here we show through systematic epigenetic studies that the histone acetyltransferase p300/CBP-associated factor (PCAF) promotes acetylation of histone 3 Lys 9 at the promoters of established key regeneration-associated genes following a peripheral but not a central axonal injury. Furthermore, we find that extracellular signal-regulated kinase (ERK)-mediated retrograde signalling is required for PCAF-dependent regenerative gene reprogramming. Finally, PCAF is necessary for conditioning-dependent axonal regeneration and also singularly promotes regeneration after spinal cord injury. ",
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     {
       "annotations": {
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       "citation": {
         "authors": [
-          "Boutillier AL",
-          "Bradke F",
-          "Di Giovanni S",
-          "Gaub P",
-          "Hervera A",
-          "Joshi Y",
-          "Laskowski CJ",
-          "Lindner R",
-          "Nguyen T",
-          "Puttagunta R",
-          "Rathore KI",
-          "Schmandke A",
-          "Sória MG",
-          "Tedeschi A"
+          "Bae D",
+          "Kim MJ",
+          "Kim S",
+          "Kim YJ",
+          "Lee YH",
+          "Na Y",
+          "Park SY",
+          "Yoon HG"
         ],
-        "date": "2014-04-01",
-        "first": "Puttagunta R",
-        "last": "Di Giovanni S",
-        "name": "Nature communications",
-        "pages": "3527",
-        "reference": "24686445",
-        "title": "PCAF-dependent epigenetic changes promote axonal regeneration in the central nervous system.",
+        "date": "2015-04-01",
+        "first": "Park SY",
+        "last": "Yoon HG",
+        "name": "International journal of molecular medicine",
+        "pages": "1109-18",
+        "reference": "25672970",
+        "title": "Selective PCAF inhibitor ameliorates cognitive and behavioral deficits by suppressing NF-κB-mediated neuroinflammation induced by Aβ in a model of Alzheimer's disease.",
         "type": "PubMed",
-        "volume": "5"
-      },
-      "evidence": "Here we show through systematic epigenetic studies that the histone acetyltransferase p300/CBP-associated factor (PCAF) promotes acetylation of histone 3 Lys 9 at the promoters of established key regeneration-associated genes following a peripheral but not a central axonal injury. Furthermore, we find that extracellular signal-regulated kinase (ERK)-mediated retrograde signalling is required for PCAF-dependent regenerative gene reprogramming. Finally, PCAF is necessary for conditioning-dependent axonal regeneration and also singularly promotes regeneration after spinal cord injury. ",
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+          "Fluorescence Resonance Energy Transfer": true
         }
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       "citation": {
         "authors": [
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-          "Bradke F",
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+          "Chen X",
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+          "Johnson J",
+          "Krogan N",
+          "Li Y",
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+          "Mok SA",
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+          "Shamloo M",
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@@ -67598,17 +75337,25 @@
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@@ -67636,14 +75383,25 @@
         "type": "PubMed",
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       "citation": {
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@@ -67671,20 +75429,23 @@
         "type": "PubMed",
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@@ -67714,422 +75475,483 @@
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-          "Gestwicki JE",
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         "first": "Min SW",
         "last": "Gan L",
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         "first": "Min SW",
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-        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
-        "pages": "3680-3688",
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-        "title": "SIRT1 Deacetylates SC35 and Suppresses Its Function in Tau Exon 10 Inclusion.",
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-      "evidence": "We found that SIRT1 interacts with and deacetylates SC35, and inhibits SC35-promoted tau exon 10 inclusion. Substituting K52 residue of SC35 by arginine impairs the role of SC35 in tau exon 10 inclusion. These results suggest that SIRT1 may serve as a therapeutic target for tauopathy by regulating SC35-mediated tau exon 10 splicing.",
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       "citation": {
         "authors": [
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-          "Drougat L",
-          "Guinez C",
-          "Lefebvre T",
-          "Michalski JC",
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-          "Michalski JC",
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-          "Mortuaire M",
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+          "Huang JH",
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-        "title": "Dysregulation of the nutrient/stress sensor O-GlcNAcylation is involved in the etiology of cardiovascular disorders, type-2 diabetes and Alzheimer's disease.",
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+        "first": "Iaconelli J",
+        "last": "Karmacharya R",
+        "name": "ACS chemical biology",
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+        "reference": "25546293",
+        "title": "HDAC6 inhibitors modulate Lys49 acetylation and membrane localization of β-catenin in human iPSC-derived neuronal cells.",
         "type": "PubMed",
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       },
-      "evidence": " This post-translational modification is likely an indicator of good health since its intracellular level correlates with the availability of extracellular glucose. From a more practical point of view, it has been shown that O-GlcNAcylation impairments contribute to the etiology of cardiovascular diseases, type-2 diabetes and Alzheimer's disease (AD), three illnesses common in occidental societies.",
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       "citation": {
         "authors": [
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-          "Drougat L",
-          "Guinez C",
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-          "Michalski JC",
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-          "Mortuaire M",
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+          "Haggarty SJ",
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+          "Mazitschek R",
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-        "title": "Dysregulation of the nutrient/stress sensor O-GlcNAcylation is involved in the etiology of cardiovascular disorders, type-2 diabetes and Alzheimer's disease.",
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         "type": "PubMed",
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-      "evidence": " This post-translational modification is likely an indicator of good health since its intracellular level correlates with the availability of extracellular glucose. From a more practical point of view, it has been shown that O-GlcNAcylation impairments contribute to the etiology of cardiovascular diseases, type-2 diabetes and Alzheimer's disease (AD), three illnesses common in occidental societies.",
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       "citation": {
         "authors": [
-          "Dehennaut V",
-          "Drougat L",
-          "Guinez C",
-          "Lefebvre T",
-          "Michalski JC",
-          "Mir AM",
-          "Mortuaire M",
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-          "Vercoutter-Edouart AS"
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+          "Haggarty SJ",
+          "Huang JH",
+          "Iaconelli J",
+          "Karmacharya R",
+          "Mazitschek R",
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-        "first": "Lefebvre T",
-        "last": "Michalski JC",
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-        "reference": "19732809",
-        "title": "Dysregulation of the nutrient/stress sensor O-GlcNAcylation is involved in the etiology of cardiovascular disorders, type-2 diabetes and Alzheimer's disease.",
+        "date": "2015-03-20",
+        "first": "Iaconelli J",
+        "last": "Karmacharya R",
+        "name": "ACS chemical biology",
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+        "reference": "25546293",
+        "title": "HDAC6 inhibitors modulate Lys49 acetylation and membrane localization of β-catenin in human iPSC-derived neuronal cells.",
         "type": "PubMed",
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-      "evidence": "It has been reported that the proteasomal machinery is modified by O-GlcNAcylation [53,126] and that after modification by OGT, the proteasome is inhibited [53]. Intriguingly, it has been proposed that a genetic impairment in the OGA gene results in proteasomal dysfunction through a lack of hydrolysis of the inhibitory O-GlcNAc residues of the 19S regulatory cap. Indeed, the OGA gene is located in the 10q locus [127,128], a chromosomal region frequently mutated in AD. The impairment of OGA in AD and the subsequent static OGlcNAcylation of the proteasome may explain why the latter fails to degrade neuronal aggregates. In addition, it has been reported that OGlcNAcylation reduces the sensitivity of intracellular proteins to proteasomal degradation by directly modifying them [43,129,130]. The two phenomena could thus act synergistically: a protein could escape degradation by means of its own O-GlcNAcylation and by the inhibitory effect of glycosylation on the proteasome, leading to a considerable decrease in the turnover of proteins that in turn may aggregate and cause neuronal death.",
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         "authors": [
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-          "Drougat L",
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-          "Michalski JC",
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-          "Mortuaire M",
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+          "Haggarty SJ",
+          "Huang JH",
+          "Iaconelli J",
+          "Karmacharya R",
+          "Mazitschek R",
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-        "first": "Lefebvre T",
-        "last": "Michalski JC",
-        "name": "Biochimica et biophysica acta",
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-        "reference": "19732809",
-        "title": "Dysregulation of the nutrient/stress sensor O-GlcNAcylation is involved in the etiology of cardiovascular disorders, type-2 diabetes and Alzheimer's disease.",
+        "date": "2015-03-20",
+        "first": "Iaconelli J",
+        "last": "Karmacharya R",
+        "name": "ACS chemical biology",
+        "pages": "883-90",
+        "reference": "25546293",
+        "title": "HDAC6 inhibitors modulate Lys49 acetylation and membrane localization of β-catenin in human iPSC-derived neuronal cells.",
         "type": "PubMed",
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+        "volume": "10"
       },
-      "evidence": " This post-translational modification is likely an indicator of good health since its intracellular level correlates with the availability of extracellular glucose. From a more practical point of view, it has been shown that O-GlcNAcylation impairments contribute to the etiology of cardiovascular diseases, type-2 diabetes and Alzheimer's disease (AD), three illnesses common in occidental societies.",
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       "citation": {
         "authors": [
-          "Dehennaut V",
-          "Drougat L",
-          "Guinez C",
-          "Lefebvre T",
-          "Michalski JC",
-          "Mir AM",
-          "Mortuaire M",
-          "Olivier S",
-          "Vercoutter-Edouart AS"
+          "Berkovitch SS",
+          "Chattopadhyay S",
+          "Haggarty SJ",
+          "Huang JH",
+          "Iaconelli J",
+          "Karmacharya R",
+          "Mazitschek R",
+          "Schreiber SL"
         ],
-        "date": "2010-02-01",
-        "first": "Lefebvre T",
-        "last": "Michalski JC",
-        "name": "Biochimica et biophysica acta",
-        "pages": "67-79",
-        "reference": "19732809",
-        "title": "Dysregulation of the nutrient/stress sensor O-GlcNAcylation is involved in the etiology of cardiovascular disorders, type-2 diabetes and Alzheimer's disease.",
+        "date": "2015-03-20",
+        "first": "Iaconelli J",
+        "last": "Karmacharya R",
+        "name": "ACS chemical biology",
+        "pages": "883-90",
+        "reference": "25546293",
+        "title": "HDAC6 inhibitors modulate Lys49 acetylation and membrane localization of β-catenin in human iPSC-derived neuronal cells.",
         "type": "PubMed",
-        "volume": "1800"
+        "volume": "10"
       },
-      "evidence": "It has been reported that the proteasomal machinery is modified by O-GlcNAcylation [53,126] and that after modification by OGT, the proteasome is inhibited [53]. Intriguingly, it has been proposed that a genetic impairment in the OGA gene results in proteasomal dysfunction through a lack of hydrolysis of the inhibitory O-GlcNAc residues of the 19S regulatory cap. Indeed, the OGA gene is located in the 10q locus [127,128], a chromosomal region frequently mutated in AD. The impairment of OGA in AD and the subsequent static OGlcNAcylation of the proteasome may explain why the latter fails to degrade neuronal aggregates. In addition, it has been reported that OGlcNAcylation reduces the sensitivity of intracellular proteins to proteasomal degradation by directly modifying them [43,129,130]. The two phenomena could thus act synergistically: a protein could escape degradation by means of its own O-GlcNAcylation and by the inhibitory effect of glycosylation on the proteasome, leading to a considerable decrease in the turnover of proteins that in turn may aggregate and cause neuronal death.",
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     {
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       "citation": {
         "authors": [
-          "Choi WH",
-          "Hong C",
-          "Jiang Y",
-          "Kim DE",
-          "Lee JH",
-          "Lee MJ",
-          "Shin SK"
+          "Berkovitch SS",
+          "Chattopadhyay S",
+          "Haggarty SJ",
+          "Huang JH",
+          "Iaconelli J",
+          "Karmacharya R",
+          "Mazitschek R",
+          "Schreiber SL"
         ],
-        "date": "2015-06-04",
-        "first": "Lee JH",
-        "last": "Lee MJ",
-        "name": "Scientific reports",
-        "pages": "10757",
-        "reference": "26041011",
-        "title": "Facilitated Tau Degradation by USP14 Aptamers via Enhanced Proteasome Activity.",
+        "date": "2015-03-20",
+        "first": "Iaconelli J",
+        "last": "Karmacharya R",
+        "name": "ACS chemical biology",
+        "pages": "883-90",
+        "reference": "25546293",
+        "title": "HDAC6 inhibitors modulate Lys49 acetylation and membrane localization of β-catenin in human iPSC-derived neuronal cells.",
         "type": "PubMed",
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+        "volume": "10"
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-      "evidence": "We identified three specific RNA aptamers of USP14 (USP14-1, USP14-2, and USP14-3) that inhibited its deubiquitinating activity. The nucleotide sequences of these non-cytotoxic USP14 aptamers contained conserved GGAGG motifs, with G-rich regions upstream, and similar secondary structures. They efficiently elevated proteasomal activity, as determined by the increased degradation of small fluorogenic peptide substrates and physiological polyubiquitinated Sic1 proteins. Additionally, proteasomal degradation of tau proteins was facilitated in the presence of the UPS14 aptamers in vitro.",
-      "key": "d0a336e1e6e87067f0ee6fca1fd775dd76a771572c0566e6f55d243fca33c60789b1fbf7c851ace1fa6854d827171c1edc29b486f605f18ac725e09eef3cbbbd",
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+      "evidence": "The N-terminus of β-catenin has phosphorylation, ubiquitination, and acetylation sites that regulate its stability and signaling. In the absence of a Wnt signal, Ser33, Ser37, and Thr41 are constitutively phosphorylated by glycogen synthase kinase 3β (GSK3β). β-Catenin phosphorylated at these sites is recognized by β-transducin repeat-containing protein (βTrCP), which results in ubiquitination and degradation by the ubiquitin-proteasome pathway. The N-terminal regulatory domain of β-catenin also includes Ser45, a phosphorylation site for Casein Kinase 1α (CK1α) and Lys49, which is acetylated by the acetyltransferase p300/CBP-associated factor (PCAF). The relevance of Lys49 acetylation and Ser45 phosphorylation to the function of β-catenin is an active area of investigation. We find that HDAC6 inhibitors increase Lys49 acetylation and Ser45 phosphorylation but do not affect Ser33, Ser37, and Thr41 phosphorylation. Lys49 acetylation results in decreased ubiquitination of β-catenin in the presence of proteasome inhibition. While increased Lys49 acetylation does not affect total levels of β-catenin, it results in increased membrane localization of β-catenin.",
+      "key": "a0b2f751f5d9b0fc36c1cf81d92446728350d9092dbcad46fe790408503077a88293d82845bd68906e6af468e74a4de9cd0a5411f45a8fae092be614f866b251",
+      "line": 3687,
       "object": {
         "modifier": "Activity"
       },
-      "relation": "decreases",
-      "source": 743,
-      "subject": {
-        "modifier": "Activity"
-      },
-      "target": 213
+      "relation": "increases",
+      "source": 505,
+      "target": 378
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
-          "Choi WH",
-          "Hong C",
-          "Jiang Y",
-          "Kim DE",
-          "Lee JH",
-          "Lee MJ",
-          "Shin SK"
+          "Berkovitch SS",
+          "Chattopadhyay S",
+          "Haggarty SJ",
+          "Huang JH",
+          "Iaconelli J",
+          "Karmacharya R",
+          "Mazitschek R",
+          "Schreiber SL"
         ],
-        "date": "2015-06-04",
-        "first": "Lee JH",
-        "last": "Lee MJ",
-        "name": "Scientific reports",
-        "pages": "10757",
-        "reference": "26041011",
-        "title": "Facilitated Tau Degradation by USP14 Aptamers via Enhanced Proteasome Activity.",
+        "date": "2015-03-20",
+        "first": "Iaconelli J",
+        "last": "Karmacharya R",
+        "name": "ACS chemical biology",
+        "pages": "883-90",
+        "reference": "25546293",
+        "title": "HDAC6 inhibitors modulate Lys49 acetylation and membrane localization of β-catenin in human iPSC-derived neuronal cells.",
         "type": "PubMed",
-        "volume": "5"
-      },
-      "evidence": "We identified three specific RNA aptamers of USP14 (USP14-1, USP14-2, and USP14-3) that inhibited its deubiquitinating activity. The nucleotide sequences of these non-cytotoxic USP14 aptamers contained conserved GGAGG motifs, with G-rich regions upstream, and similar secondary structures. They efficiently elevated proteasomal activity, as determined by the increased degradation of small fluorogenic peptide substrates and physiological polyubiquitinated Sic1 proteins. Additionally, proteasomal degradation of tau proteins was facilitated in the presence of the UPS14 aptamers in vitro.",
-      "key": "a36aac5ee3accc9d4c6124af54c5f12baaa28714273e543aa951323339bcea7c363843f424346e743ad3c691665e09bbfa4ff3a414d0a3a20b1f34804bd87ebd",
-      "line": 3441,
-      "object": {
-        "modifier": "Activity"
+        "volume": "10"
       },
+      "evidence": "The N-terminus of β-catenin has phosphorylation, ubiquitination, and acetylation sites that regulate its stability and signaling. In the absence of a Wnt signal, Ser33, Ser37, and Thr41 are constitutively phosphorylated by glycogen synthase kinase 3β (GSK3β). β-Catenin phosphorylated at these sites is recognized by β-transducin repeat-containing protein (βTrCP), which results in ubiquitination and degradation by the ubiquitin-proteasome pathway. The N-terminal regulatory domain of β-catenin also includes Ser45, a phosphorylation site for Casein Kinase 1α (CK1α) and Lys49, which is acetylated by the acetyltransferase p300/CBP-associated factor (PCAF). The relevance of Lys49 acetylation and Ser45 phosphorylation to the function of β-catenin is an active area of investigation. We find that HDAC6 inhibitors increase Lys49 acetylation and Ser45 phosphorylation but do not affect Ser33, Ser37, and Thr41 phosphorylation. Lys49 acetylation results in decreased ubiquitination of β-catenin in the presence of proteasome inhibition. While increased Lys49 acetylation does not affect total levels of β-catenin, it results in increased membrane localization of β-catenin.",
+      "key": "739a0309876d5a779b1c71612b1068604feb62e7be4c58fa8b82b272a55f84be8be7824b9bebe7a75a01a13875280cbb70b1eb95391601174f9bda98f786e58f",
+      "line": 3696,
       "relation": "decreases",
-      "source": 121,
-      "target": 743
+      "source": 500,
+      "target": 505
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
       "citation": {
         "authors": [
-          "D'Adamio L",
-          "Del Prete D",
-          "Rajadhyaksha AM",
-          "Rice RC"
+          "Berkovitch SS",
+          "Chattopadhyay S",
+          "Haggarty SJ",
+          "Huang JH",
+          "Iaconelli J",
+          "Karmacharya R",
+          "Mazitschek R",
+          "Schreiber SL"
         ],
-        "date": "2016-08-12",
-        "first": "Del Prete D",
-        "last": "D'Adamio L",
-        "name": "The Journal of biological chemistry",
-        "pages": "17209-27",
-        "reference": "27325702",
-        "title": "Amyloid Precursor Protein (APP) May Act as a Substrate and a Recognition Unit for CRL4CRBN and Stub1 E3 Ligases Facilitating Ubiquitination of Proteins Involved in Presynaptic Functions and Neurodegeneration.",
+        "date": "2015-03-20",
+        "first": "Iaconelli J",
+        "last": "Karmacharya R",
+        "name": "ACS chemical biology",
+        "pages": "883-90",
+        "reference": "25546293",
+        "title": "HDAC6 inhibitors modulate Lys49 acetylation and membrane localization of β-catenin in human iPSC-derived neuronal cells.",
         "type": "PubMed",
-        "volume": "291"
+        "volume": "10"
       },
-      "evidence": "the ACR (APP cytosolic region) interacts with the E3 ubiquitin-protein ligases Stub1, which binds the NH2 terminus of the ACR, and CRL4(CRBN), which is formed by Cul4a/b, Ddb1, and Crbn, and interacts with the COOH terminus of the ACR via Crbn.",
-      "key": "3e13a91fc0d63bb3cc3e42ceca66848f108b586b2aac2218fe90e40a8951f4de11189e709d8f05bf622df676f296c9fb1cfedf1b504d6b5a93e775f6dfcf1696",
-      "line": 3446,
-      "relation": "association",
-      "source": 310,
-      "target": 691
+      "evidence": "The N-terminus of β-catenin has phosphorylation, ubiquitination, and acetylation sites that regulate its stability and signaling. In the absence of a Wnt signal, Ser33, Ser37, and Thr41 are constitutively phosphorylated by glycogen synthase kinase 3β (GSK3β). β-Catenin phosphorylated at these sites is recognized by β-transducin repeat-containing protein (βTrCP), which results in ubiquitination and degradation by the ubiquitin-proteasome pathway. The N-terminal regulatory domain of β-catenin also includes Ser45, a phosphorylation site for Casein Kinase 1α (CK1α) and Lys49, which is acetylated by the acetyltransferase p300/CBP-associated factor (PCAF). The relevance of Lys49 acetylation and Ser45 phosphorylation to the function of β-catenin is an active area of investigation. We find that HDAC6 inhibitors increase Lys49 acetylation and Ser45 phosphorylation but do not affect Ser33, Ser37, and Thr41 phosphorylation. Lys49 acetylation results in decreased ubiquitination of β-catenin in the presence of proteasome inhibition. While increased Lys49 acetylation does not affect total levels of β-catenin, it results in increased membrane localization of β-catenin.",
+      "key": "012eeeca201b8743494005f8e679260cef7a541d8fa5a9068be57e44c1696a4e6faff03b506bd10c02132e56f9ae8d42a67702483f8fb36e34e1186c2f1b4a51",
+      "line": 3697,
+      "object": {
+        "location": {
+          "name": "membrane",
+          "namespace": "GO"
+        }
+      },
+      "relation": "increases",
+      "source": 500,
+      "target": 499
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
-          "D'Adamio L",
-          "Del Prete D",
-          "Rajadhyaksha AM",
-          "Rice RC"
+          "Battistuzzi G",
+          "Giannini G"
         ],
-        "date": "2016-08-12",
-        "first": "Del Prete D",
-        "last": "D'Adamio L",
-        "name": "The Journal of biological chemistry",
-        "pages": "17209-27",
-        "reference": "27325702",
-        "title": "Amyloid Precursor Protein (APP) May Act as a Substrate and a Recognition Unit for CRL4CRBN and Stub1 E3 Ligases Facilitating Ubiquitination of Proteins Involved in Presynaptic Functions and Neurodegeneration.",
+        "date": "2016-12-01",
+        "first": "Battistuzzi G",
+        "last": "Giannini G",
+        "name": "Current bioactive compounds",
+        "pages": "282-288",
+        "reference": "27917100",
+        "title": "Synthesis of ST7612AA1, a Novel Oral HDAC Inhibitor, via Radical 
Thioacetic Acid Addition.",
         "type": "PubMed",
-        "volume": "291"
+        "volume": "12"
       },
-      "evidence": "the ACR (APP cytosolic region) interacts with the E3 ubiquitin-protein ligases Stub1, which binds the NH2 terminus of the ACR, and CRL4(CRBN), which is formed by Cul4a/b, Ddb1, and Crbn, and interacts with the COOH terminus of the ACR via Crbn.",
-      "key": "98cc745a7c0cca8ff043b0abc3316cc78d0baf7e5a0de8417231bd342968c8f1d00020ec25e4225ab404a2a71c1118c5706b36d2809e1588b64cc18fe85cf101",
-      "line": 3448,
-      "relation": "association",
-      "source": 310,
-      "target": 313
+      "evidence": "In conclusion, ST7612AA1, prodrug of ST7464AA1, is the first of a new generation of HDAC inhibitors, very potent, orally administered, and well tolerated. It is a thiol derivative, pan-histone deacetylase inhibitor, active against a broad panel of cancer cell lines and in vivo tumor models.",
+      "key": "dbebd975e23a5a93eba7d95798cf1477a2ba4c6fd73dfe644fc8812140615c8bfa6d57b30bf8b7f3ef90c5ec3224317c0fc6a6090592739b81b1c312ab7a6f2a",
+      "line": 3706,
+      "object": {
+        "modifier": "Activity"
+      },
+      "relation": "directlyDecreases",
+      "source": 130,
+      "target": 360
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "Species": {
+          "10090": true
+        }
+      },
       "citation": {
         "authors": [
-          "D'Adamio L",
-          "Del Prete D",
-          "Rajadhyaksha AM",
-          "Rice RC"
+          "Cuadrado-Tejedor M",
+          "Franco R",
+          "Garcia-Barroso C",
+          "Garcia-Osta A",
+          "Mederos S",
+          "Oyarzabal J",
+          "Perea G",
+          "Pérez-González M",
+          "Rabal O",
+          "Segura V",
+          "Sánchez-Arias JA",
+          "Ugarte A"
         ],
-        "date": "2016-08-12",
-        "first": "Del Prete D",
-        "last": "D'Adamio L",
-        "name": "The Journal of biological chemistry",
-        "pages": "17209-27",
-        "reference": "27325702",
-        "title": "Amyloid Precursor Protein (APP) May Act as a Substrate and a Recognition Unit for CRL4CRBN and Stub1 E3 Ligases Facilitating Ubiquitination of Proteins Involved in Presynaptic Functions and Neurodegeneration.",
+        "date": "2017-01-01",
+        "first": "Cuadrado-Tejedor M",
+        "last": "Garcia-Osta A",
+        "name": "Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology",
+        "pages": "524-539",
+        "reference": "27550730",
+        "title": "A First-in-Class Small-Molecule that Acts as a Dual Inhibitor of HDAC and PDE5 and that Rescues Hippocampal Synaptic Impairment in Alzheimer's Disease Mice.",
         "type": "PubMed",
-        "volume": "291"
+        "volume": "42"
       },
-      "evidence": "As reported in Table 6, several brain-derived proteins associated with the ACR bait were ubiquitinated. These proteins can be separated into four groups as follows: (a) group 1, proteins of the ubiquitin-conjugating system; (b) group 2, presynaptic proteins; (c) group 3, other proteins implicated in AD; and (d) group 4, phosphorylation-dependent ACR interactors.",
-      "key": "af26fbcba6e062ecd8fe6ecb066cb41189d3c43a6931358e6cd6397c9843f20ac105b047e6d115a5a94ac8f0c0d6260770e0936d5ac3a800bcc21fcf192d4b33",
-      "line": 3454,
-      "relation": "increases",
-      "source": 310,
-      "target": 675
+      "evidence": "Here we report the discovery of a new first-in-class small-molecule (CM-414) that acts as a dual inhibitor of PDE5 and HDACs. We have used this compound as a chemical probe to validate this systems therapeutics strategy, where an increase in the activation of cAMP/cGMP-responsive element-binding protein (CREB) induced by PDE5 inhibition, combined with moderate HDAC class I inhibition, leads to efficient histone acetylation. This molecule rescued the impaired long-term potentiation evident in hippocampal slices from APP/PS1 mice. Chronic treatment of Tg2576 mice with CM-414 diminished brain Aβ and tau phosphorylation (pTau) levels, increased the inactive form of GSK3β, reverted the decrease in dendritic spine density on hippocampal neurons, and reversed their cognitive deficits, at least in part by inducing the expression of genes related to synaptic transmission.",
+      "key": "76854f3894cf8158ba456ae0ec67958fe9737f31fe135ac19f5573330e3854dedf9465e6be3981b3056aa70aec770518e37cafb06531f77b94536796e45650f1",
+      "line": 3802,
+      "object": {
+        "modifier": "Activity"
+      },
+      "relation": "negativeCorrelation",
+      "source": 360,
+      "subject": {
+        "modifier": "Activity"
+      },
+      "target": 354
     },
     {
+      "annotations": {
+        "Cell_Line": {
+          "HEK293": true
+        },
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
-          "D'Adamio L",
-          "Del Prete D",
-          "Rajadhyaksha AM",
-          "Rice RC"
+          "Cohen TJ",
+          "Guo JL",
+          "Hurtado DE",
+          "Kwong LK",
+          "Lee VM",
+          "Mills IP",
+          "Trojanowski JQ"
         ],
-        "date": "2016-08-12",
-        "first": "Del Prete D",
-        "last": "D'Adamio L",
-        "name": "The Journal of biological chemistry",
-        "pages": "17209-27",
-        "reference": "27325702",
-        "title": "Amyloid Precursor Protein (APP) May Act as a Substrate and a Recognition Unit for CRL4CRBN and Stub1 E3 Ligases Facilitating Ubiquitination of Proteins Involved in Presynaptic Functions and Neurodegeneration.",
+        "date": "2011-01-01",
+        "first": "Cohen TJ",
+        "last": "Lee VM",
+        "name": "Nature communications",
+        "pages": "252",
+        "reference": "21427723",
+        "title": "The acetylation of tau inhibits its function and promotes pathological tau aggregation.",
         "type": "PubMed",
-        "volume": "291"
+        "volume": "2"
       },
-      "evidence": "As reported in Table 6, several brain-derived proteins associated with the ACR bait were ubiquitinated. These proteins can be separated into four groups as follows: (a) group 1, proteins of the ubiquitin-conjugating system; (b) group 2, presynaptic proteins; (c) group 3, other proteins implicated in AD; and (d) group 4, phosphorylation-dependent ACR interactors.",
-      "key": "d43078a39756a201560dbb0c10c3f18b5326c6d1e1b7e4555d66871b7d85be7e6fca90319121741a2fb25c24faf19883168b7e5e1ad37f4871cb1967588085e4",
-      "line": 3455,
-      "relation": "increases",
-      "source": 310,
-      "target": 702
+      "evidence": "Although low-level tau acetylation was observed in untreated HEK-T40 cells, treatment with the pan histone deacetylase (HDAC) inhibitor trichostatin A (TSA), but not the Sir2 class inhibitor nicotinamide, resulted in a dramatic increase in acetylated tau levels.",
+      "key": "20d6b50679c62c007a2df5d9bbaa46c4e614371758f18784fdf4d1d1518a970877ca911b1d3acb6984e5827438fa0234c9775c6fd9265ee132450d84dfbedb07",
+      "line": 4049,
+      "relation": "decreases",
+      "source": 360,
+      "subject": {
+        "modifier": "Activity"
+      },
+      "target": 571
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
-          "D'Adamio L",
-          "Del Prete D",
-          "Rajadhyaksha AM",
-          "Rice RC"
+          "Cincinelli R",
+          "Cuendet M",
+          "Dallavalle S",
+          "De Cesare M",
+          "Giannini G",
+          "Musso L",
+          "Nurisso A",
+          "Simoes-Pires C",
+          "Zuco V",
+          "Zunino F",
+          "Zwick V"
         ],
-        "date": "2016-08-12",
-        "first": "Del Prete D",
-        "last": "D'Adamio L",
-        "name": "The Journal of biological chemistry",
-        "pages": "17209-27",
-        "reference": "27325702",
-        "title": "Amyloid Precursor Protein (APP) May Act as a Substrate and a Recognition Unit for CRL4CRBN and Stub1 E3 Ligases Facilitating Ubiquitination of Proteins Involved in Presynaptic Functions and Neurodegeneration.",
+        "date": "2016-04-13",
+        "first": "Cincinelli R",
+        "last": "Dallavalle S",
+        "name": "European journal of medicinal chemistry",
+        "pages": "99-105",
+        "reference": "26890116",
+        "title": "Biphenyl-4-yl-acrylohydroxamic acids: Identification of a novel indolyl-substituted HDAC inhibitor with antitumor activity.",
         "type": "PubMed",
-        "volume": "291"
+        "volume": "112"
       },
-      "evidence": "As reported in Table 6, several brain-derived proteins associated with the ACR bait were ubiquitinated. These proteins can be separated into four groups as follows: (a) group 1, proteins of the ubiquitin-conjugating system; (b) group 2, presynaptic proteins; (c) group 3, other proteins implicated in AD; and (d) group 4, phosphorylation-dependent ACR interactors.",
-      "key": "e34f3e4f04a1c346d5f049b2798fb0ee785f4e584c2800dfb570f2f23656c39771c8d8b5cce653bd3a328717a86d78d241aea2dd16876de64961e351ddf870e6",
-      "line": 3456,
-      "relation": "increases",
-      "source": 310,
-      "target": 704
+      "evidence": "Modification of the cap group of biphenylacrylohydroxamic acid-based HDAC inhibitors led to the identification of a new derivative (3) characterized by an indolyl-substituted 4-phenylcinnamic skeleton.",
+      "key": "b0f39cc5f1708dc391c04837153527cc29879a0e04bea21a182ad85f3440c3bf211612aeeb0bd88d0d2dc31f5170f69b311064ffd5ad539903a1f6d30eff240b",
+      "line": 3714,
+      "object": {
+        "modifier": "Activity"
+      },
+      "relation": "directlyDecreases",
+      "source": 104,
+      "target": 360
     },
     {
+      "annotations": {
+        "Confidence": {
+          "High": true
+        },
+        "IC50": {
+          "65 nM": true
+        },
+        "Ki": {
+          "110 nM": true
+        }
+      },
       "citation": {
         "authors": [
-          "D'Adamio L",
-          "Del Prete D",
-          "Rajadhyaksha AM",
-          "Rice RC"
+          "Beckers T",
+          "Burkhardt C",
+          "Ciossek T",
+          "Dehmel F",
+          "Fettis K",
+          "Julius H",
+          "Maier T",
+          "Stengel T",
+          "Weinbrenner S",
+          "Wieland H"
         ],
-        "date": "2016-08-12",
-        "first": "Del Prete D",
-        "last": "D'Adamio L",
-        "name": "The Journal of biological chemistry",
-        "pages": "17209-27",
-        "reference": "27325702",
-        "title": "Amyloid Precursor Protein (APP) May Act as a Substrate and a Recognition Unit for CRL4CRBN and Stub1 E3 Ligases Facilitating Ubiquitination of Proteins Involved in Presynaptic Functions and Neurodegeneration.",
+        "date": "2008-07-10",
+        "first": "Dehmel F",
+        "last": "Beckers T",
+        "name": "Journal of medicinal chemistry",
+        "pages": "3985-4001",
+        "reference": "18558669",
+        "title": "Trithiocarbonates as a novel class of HDAC inhibitors: SAR studies, isoenzyme selectivity, and pharmacological profiles.",
         "type": "PubMed",
-        "volume": "291"
+        "volume": "51"
       },
-      "evidence": "As reported in Table 6, several brain-derived proteins associated with the ACR bait were ubiquitinated. These proteins can be separated into four groups as follows: (a) group 1, proteins of the ubiquitin-conjugating system; (b) group 2, presynaptic proteins; (c) group 3, other proteins implicated in AD; and (d) group 4, phosphorylation-dependent ACR interactors.",
-      "key": "89f2a2fd9a7242aebeed93b355371f7bc51e25ad5f259858e45c82b32c5d4b1a83c57aec9a6e44658abfb22c6a26e64b497d048682b6376e5cf8a23a866859cb",
-      "line": 3457,
-      "relation": "increases",
-      "source": 310,
-      "target": 745
+      "evidence": "Highly potent, substrate competitive HDAC6 selective inhibitors were identified (12ac:IC 50 = 65 nM and K i = 110 nM). Trithiocarbonate analogues with an aminoquinoline-substituted pyridinyl-thienoacetyl cap demonstrate a cytotoxicity profile and potency comparable to that of suberoylanilide hydroxamic acid (SAHA) as an approved cancer drug.",
+      "key": "382c980f11cd72afbfa20087b26b8b0238fa8eb4c6797925b162e8e1a5be04b1e1cc4c4121b063e3e74920fc1f13726c8ec15e84ad13ec3599f521473dfc46e9",
+      "line": 3725,
+      "object": {
+        "modifier": "Activity"
+      },
+      "relation": "directlyDecreases",
+      "source": 131,
+      "target": 540
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "Research_Model": {
+          "P301S mice": true
+        },
+        "Species": {
+          "10090": true
+        }
+      },
       "citation": {
         "authors": [
-          "D'Adamio L",
-          "Del Prete D",
-          "Rajadhyaksha AM",
-          "Rice RC"
+          "Devidze N",
+          "Gan L",
+          "Gestwicki JE",
+          "Johnson JR",
+          "Krogan NJ",
+          "Li Y",
+          "Masliah E",
+          "Min SW",
+          "Mok SA",
+          "Sohn PD"
         ],
-        "date": "2016-08-12",
-        "first": "Del Prete D",
-        "last": "D'Adamio L",
-        "name": "The Journal of biological chemistry",
-        "pages": "17209-27",
-        "reference": "27325702",
-        "title": "Amyloid Precursor Protein (APP) May Act as a Substrate and a Recognition Unit for CRL4CRBN and Stub1 E3 Ligases Facilitating Ubiquitination of Proteins Involved in Presynaptic Functions and Neurodegeneration.",
+        "date": "2018-04-11",
+        "first": "Min SW",
+        "last": "Gan L",
+        "name": "The Journal of neuroscience : the official journal of the Society for Neuroscience",
+        "pages": "3680-3688",
+        "reference": "29540553",
+        "title": "SIRT1 Deacetylates Tau and Reduces Pathogenic Tau Spread in a Mouse Model of Tauopathy.",
         "type": "PubMed",
-        "volume": "291"
+        "volume": "38"
       },
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-        "name": "The Journal of biological chemistry",
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-        "title": "Amyloid Precursor Protein (APP) May Act as a Substrate and a Recognition Unit for CRL4CRBN and Stub1 E3 Ligases Facilitating Ubiquitination of Proteins Involved in Presynaptic Functions and Neurodegeneration.",
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       "citation": {
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-        "name": "The Journal of biological chemistry",
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       "citation": {
         "authors": [
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-        "first": "Del Prete D",
-        "last": "D'Adamio L",
-        "name": "The Journal of biological chemistry",
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-        "title": "Amyloid Precursor Protein (APP) May Act as a Substrate and a Recognition Unit for CRL4CRBN and Stub1 E3 Ligases Facilitating Ubiquitination of Proteins Involved in Presynaptic Functions and Neurodegeneration.",
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-        "last": "D'Adamio L",
-        "name": "The Journal of biological chemistry",
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-        "title": "Amyloid Precursor Protein (APP) May Act as a Substrate and a Recognition Unit for CRL4CRBN and Stub1 E3 Ligases Facilitating Ubiquitination of Proteins Involved in Presynaptic Functions and Neurodegeneration.",
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-        "last": "D'Adamio L",
-        "name": "The Journal of biological chemistry",
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-        "title": "Amyloid Precursor Protein (APP) May Act as a Substrate and a Recognition Unit for CRL4CRBN and Stub1 E3 Ligases Facilitating Ubiquitination of Proteins Involved in Presynaptic Functions and Neurodegeneration.",
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-        "name": "The Journal of biological chemistry",
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-        "title": "Amyloid Precursor Protein (APP) May Act as a Substrate and a Recognition Unit for CRL4CRBN and Stub1 E3 Ligases Facilitating Ubiquitination of Proteins Involved in Presynaptic Functions and Neurodegeneration.",
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-        "first": "Del Prete D",
-        "last": "D'Adamio L",
-        "name": "The Journal of biological chemistry",
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-        "reference": "27325702",
-        "title": "Amyloid Precursor Protein (APP) May Act as a Substrate and a Recognition Unit for CRL4CRBN and Stub1 E3 Ligases Facilitating Ubiquitination of Proteins Involved in Presynaptic Functions and Neurodegeneration.",
+        "date": "2018-04-11",
+        "first": "Min SW",
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         "type": "PubMed",
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       "citation": {
         "authors": [
-          "D'Adamio L",
-          "Del Prete D",
-          "Rajadhyaksha AM",
-          "Rice RC"
+          "Cong X",
+          "Ellerby LM",
+          "Gan L",
+          "Huganir RL",
+          "Le D",
+          "Li Y",
+          "Lo I",
+          "Min SW",
+          "Minami SS",
+          "Ponnusamy R",
+          "Schilling B",
+          "Sohn PD",
+          "Tracy TE",
+          "Wang C",
+          "Zhou Y"
         ],
-        "date": "2016-08-12",
-        "first": "Del Prete D",
-        "last": "D'Adamio L",
-        "name": "The Journal of biological chemistry",
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-        "reference": "27325702",
-        "title": "Amyloid Precursor Protein (APP) May Act as a Substrate and a Recognition Unit for CRL4CRBN and Stub1 E3 Ligases Facilitating Ubiquitination of Proteins Involved in Presynaptic Functions and Neurodegeneration.",
+        "date": "2016-04-20",
+        "first": "Tracy TE",
+        "last": "Gan L",
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+        "title": "Acetylated Tau Obstructs KIBRA-Mediated Signaling in Synaptic Plasticity and Promotes Tauopathy-Related Memory Loss.",
         "type": "PubMed",
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-      "evidence": "As reported in Table 6, several brain-derived proteins associated with the ACR bait were ubiquitinated. These proteins can be separated into four groups as follows: (a) group 1, proteins of the ubiquitin-conjugating system; (b) group 2, presynaptic proteins; (c) group 3, other proteins implicated in AD; and (d) group 4, phosphorylation-dependent ACR interactors.",
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+      "evidence": "Here we report abnormal acetylation of K274 and K281 on tau, identified in AD brains, promotes memory loss and disrupts synaptic plasticity by reducing postsynaptic KIdney/BRAin (KIBRA) protein, a memory-associated protein.Transgenic mice expressing human tau with lysine-to-glutamine mutations to mimic K274 and K281 acetylation (tauKQ) exhibit AD-related memory deficits and impaired hippocampal long-term potentiation (LTP). TauKQ reduces synaptic KIBRA levels and disrupts activity-induced postsynaptic actin remodeling and AMPA receptor insertion. The LTP deficit was rescued by promoting actin polymerization or by KIBRA expression. In AD patients with dementia, we found enhanced tau acetylation is linked to loss of KIBRA.",
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       "citation": {
         "authors": [
-          "D'Adamio L",
-          "Del Prete D",
-          "Rajadhyaksha AM",
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+          "Schroeder S",
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+          "Zhou Y"
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-        "first": "Del Prete D",
-        "last": "D'Adamio L",
-        "name": "The Journal of biological chemistry",
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-        "title": "Amyloid Precursor Protein (APP) May Act as a Substrate and a Recognition Unit for CRL4CRBN and Stub1 E3 Ligases Facilitating Ubiquitination of Proteins Involved in Presynaptic Functions and Neurodegeneration.",
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+        "first": "Min SW",
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         "type": "PubMed",
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         "authors": [
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-          "Del Prete D",
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-        "last": "D'Adamio L",
-        "name": "The Journal of biological chemistry",
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-        "title": "Amyloid Precursor Protein (APP) May Act as a Substrate and a Recognition Unit for CRL4CRBN and Stub1 E3 Ligases Facilitating Ubiquitination of Proteins Involved in Presynaptic Functions and Neurodegeneration.",
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-          "Rice RC"
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-        "last": "D'Adamio L",
-        "name": "The Journal of biological chemistry",
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-        "title": "Amyloid Precursor Protein (APP) May Act as a Substrate and a Recognition Unit for CRL4CRBN and Stub1 E3 Ligases Facilitating Ubiquitination of Proteins Involved in Presynaptic Functions and Neurodegeneration.",
+        "date": "2017-01-01",
+        "first": "Lucke-Wold B",
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         "type": "PubMed",
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         "authors": [
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-          "Del Prete D",
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+          "Cohen TJ",
+          "Guo JL",
+          "Hurtado DE",
+          "Kwong LK",
+          "Lee VM",
+          "Mills IP",
+          "Trojanowski JQ"
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-        "date": "2016-08-12",
-        "first": "Del Prete D",
-        "last": "D'Adamio L",
-        "name": "The Journal of biological chemistry",
-        "pages": "17209-27",
-        "reference": "27325702",
-        "title": "Amyloid Precursor Protein (APP) May Act as a Substrate and a Recognition Unit for CRL4CRBN and Stub1 E3 Ligases Facilitating Ubiquitination of Proteins Involved in Presynaptic Functions and Neurodegeneration.",
+        "date": "2011-01-01",
+        "first": "Cohen TJ",
+        "last": "Lee VM",
+        "name": "Nature communications",
+        "pages": "252",
+        "reference": "21427723",
+        "title": "The acetylation of tau inhibits its function and promotes pathological tau aggregation.",
         "type": "PubMed",
-        "volume": "291"
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-        "last": "D'Adamio L",
-        "name": "The Journal of biological chemistry",
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-        "title": "Amyloid Precursor Protein (APP) May Act as a Substrate and a Recognition Unit for CRL4CRBN and Stub1 E3 Ligases Facilitating Ubiquitination of Proteins Involved in Presynaptic Functions and Neurodegeneration.",
+        "date": "2017-01-01",
+        "first": "Lucke-Wold B",
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         "type": "PubMed",
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-        "first": "Del Prete D",
-        "last": "D'Adamio L",
-        "name": "The Journal of biological chemistry",
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-        "title": "Amyloid Precursor Protein (APP) May Act as a Substrate and a Recognition Unit for CRL4CRBN and Stub1 E3 Ligases Facilitating Ubiquitination of Proteins Involved in Presynaptic Functions and Neurodegeneration.",
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+      "evidence": "Thus, K280 acetylation is a feature found in a variety of human 4R or 3R/4R tauopathies including AD, but not 3R-tauopathies such as PiD.",
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     },
     {
+      "annotations": {
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+        "Species": {
+          "10090": true
+        }
+      },
       "citation": {
         "authors": [
-          "Feng Y",
-          "Jiang J",
-          "Liu XH",
-          "Liu ZC",
-          "Luo HB",
-          "Shu XJ",
-          "Wang JZ",
-          "Wang XC",
-          "Xia YY",
-          "Xiong YS",
-          "Ye K",
-          "Yin G",
-          "Yu G",
-          "Zeng K"
+          "Cuadrado-Tejedor M",
+          "Franco R",
+          "Garcia-Barroso C",
+          "Garcia-Osta A",
+          "Mederos S",
+          "Oyarzabal J",
+          "Perea G",
+          "Pérez-González M",
+          "Rabal O",
+          "Segura V",
+          "Sánchez-Arias JA",
+          "Ugarte A"
         ],
-        "date": "2014-11-18",
-        "first": "Luo HB",
-        "last": "Wang JZ",
-        "name": "Proceedings of the National Academy of Sciences of the United States of America",
-        "pages": "16586-91",
-        "reference": "25378699",
-        "title": "SUMOylation at K340 inhibits tau degradation through deregulating its phosphorylation and ubiquitination.",
+        "date": "2017-01-01",
+        "first": "Cuadrado-Tejedor M",
+        "last": "Garcia-Osta A",
+        "name": "Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology",
+        "pages": "524-539",
+        "reference": "27550730",
+        "title": "A First-in-Class Small-Molecule that Acts as a Dual Inhibitor of HDAC and PDE5 and that Rescues Hippocampal Synaptic Impairment in Alzheimer's Disease Mice.",
         "type": "PubMed",
-        "volume": "111"
+        "volume": "42"
       },
-      "evidence": "Furthermore, the enhanced SUMO-immunoreactivity, costained with the hyperphosphorylated tau, is detected in cerebral cortex of the AD brains, and β-amyloid exposure of rat primary hippocampal neurons induces a dose-dependent SUMOylation of the hyperphosphorylated tau. Our findings suggest that tau SUMOylation reciprocally stimulates its phosphorylation and inhibits the ubiquitination-mediated tau degradation, which provides a new insight into the AD-like tau accumulation.",
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+      "evidence": "Here we report the discovery of a new first-in-class small-molecule (CM-414) that acts as a dual inhibitor of PDE5 and HDACs. We have used this compound as a chemical probe to validate this systems therapeutics strategy, where an increase in the activation of cAMP/cGMP-responsive element-binding protein (CREB) induced by PDE5 inhibition, combined with moderate HDAC class I inhibition, leads to efficient histone acetylation. This molecule rescued the impaired long-term potentiation evident in hippocampal slices from APP/PS1 mice. Chronic treatment of Tg2576 mice with CM-414 diminished brain Aβ and tau phosphorylation (pTau) levels, increased the inactive form of GSK3β, reverted the decrease in dendritic spine density on hippocampal neurons, and reversed their cognitive deficits, at least in part by inducing the expression of genes related to synaptic transmission.",
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       "object": {
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+        "modifier": "Activity"
       },
-      "relation": "positiveCorrelation",
-      "source": 594,
-      "target": 486
+      "relation": "directlyDecreases",
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     },
     {
+      "annotations": {
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       "citation": {
         "authors": [
-          "Albrecht F",
-          "Arendt T",
-          "Arsalan-Werner A",
-          "Flach K",
-          "Goedert M",
-          "Herrmann L",
-          "Hilbrich I",
-          "Holzer M",
-          "Ramminger E"
+          "Cuadrado-Tejedor M",
+          "Franco R",
+          "Garcia-Barroso C",
+          "Garcia-Osta A",
+          "Mederos S",
+          "Oyarzabal J",
+          "Perea G",
+          "Pérez-González M",
+          "Rabal O",
+          "Segura V",
+          "Sánchez-Arias JA",
+          "Ugarte A"
         ],
-        "date": "2014-09-01",
-        "first": "Flach K",
-        "last": "Holzer M",
-        "name": "Biochimica et biophysica acta",
-        "pages": "1527-38",
-        "reference": "24905733",
-        "title": "Axotrophin/MARCH7 acts as an E3 ubiquitin ligase and ubiquitinates tau protein in vitro impairing microtubule binding.",
+        "date": "2017-01-01",
+        "first": "Cuadrado-Tejedor M",
+        "last": "Garcia-Osta A",
+        "name": "Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology",
+        "pages": "524-539",
+        "reference": "27550730",
+        "title": "A First-in-Class Small-Molecule that Acts as a Dual Inhibitor of HDAC and PDE5 and that Rescues Hippocampal Synaptic Impairment in Alzheimer's Disease Mice.",
         "type": "PubMed",
-        "volume": "1842"
+        "volume": "42"
       },
-      "evidence": "We show that axotrophin/MARCH7, a RING-variant domain containing protein with similarity to E3 ubiquitin ligases interacts with tau. We find here that tau becomes mono-ubiquitinated by recombinant tau-interacting RING-variant domain, which diminishes its microtubule-binding. Tau becomes mono-ubiquitinated by recombinant tau-interacting RING-variant domain reducing microtubule-binding.",
-      "key": "e856eff13673c13b561a538ba6599f372fc27b64faac2957fd2e55761679d129a87502b4099bc308ee5f269a33d9a80984624881d2a08a480bc4d1c848d39fa9",
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+      "evidence": "Here we report the discovery of a new first-in-class small-molecule (CM-414) that acts as a dual inhibitor of PDE5 and HDACs. We have used this compound as a chemical probe to validate this systems therapeutics strategy, where an increase in the activation of cAMP/cGMP-responsive element-binding protein (CREB) induced by PDE5 inhibition, combined with moderate HDAC class I inhibition, leads to efficient histone acetylation. This molecule rescued the impaired long-term potentiation evident in hippocampal slices from APP/PS1 mice. Chronic treatment of Tg2576 mice with CM-414 diminished brain Aβ and tau phosphorylation (pTau) levels, increased the inactive form of GSK3β, reverted the decrease in dendritic spine density on hippocampal neurons, and reversed their cognitive deficits, at least in part by inducing the expression of genes related to synaptic transmission.",
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       "object": {
         "modifier": "Activity"
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     },
     {
+      "annotations": {
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+        },
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       "citation": {
         "authors": [
-          "Feng Y",
-          "Jiang J",
-          "Liu XH",
-          "Liu ZC",
-          "Luo HB",
-          "Shu XJ",
-          "Wang JZ",
-          "Wang XC",
-          "Xia YY",
-          "Xiong YS",
-          "Ye K",
-          "Yin G",
-          "Yu G",
-          "Zeng K"
+          "Cuadrado-Tejedor M",
+          "Franco R",
+          "Garcia-Barroso C",
+          "Garcia-Osta A",
+          "Mederos S",
+          "Oyarzabal J",
+          "Perea G",
+          "Pérez-González M",
+          "Rabal O",
+          "Segura V",
+          "Sánchez-Arias JA",
+          "Ugarte A"
         ],
-        "date": "2014-11-18",
-        "first": "Luo HB",
-        "last": "Wang JZ",
-        "name": "Proceedings of the National Academy of Sciences of the United States of America",
-        "pages": "16586-91",
-        "reference": "25378699",
-        "title": "SUMOylation at K340 inhibits tau degradation through deregulating its phosphorylation and ubiquitination.",
+        "date": "2017-01-01",
+        "first": "Cuadrado-Tejedor M",
+        "last": "Garcia-Osta A",
+        "name": "Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology",
+        "pages": "524-539",
+        "reference": "27550730",
+        "title": "A First-in-Class Small-Molecule that Acts as a Dual Inhibitor of HDAC and PDE5 and that Rescues Hippocampal Synaptic Impairment in Alzheimer's Disease Mice.",
         "type": "PubMed",
-        "volume": "111"
+        "volume": "42"
       },
-      "evidence": "Furthermore, the enhanced SUMO-immunoreactivity, costained with the hyperphosphorylated tau, is detected in cerebral cortex of the AD brains, and β-amyloid exposure of rat primary hippocampal neurons induces a dose-dependent SUMOylation of the hyperphosphorylated tau. Our findings suggest that tau SUMOylation reciprocally stimulates its phosphorylation and inhibits the ubiquitination-mediated tau degradation, which provides a new insight into the AD-like tau accumulation.",
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+      "evidence": "Here we report the discovery of a new first-in-class small-molecule (CM-414) that acts as a dual inhibitor of PDE5 and HDACs. We have used this compound as a chemical probe to validate this systems therapeutics strategy, where an increase in the activation of cAMP/cGMP-responsive element-binding protein (CREB) induced by PDE5 inhibition, combined with moderate HDAC class I inhibition, leads to efficient histone acetylation. This molecule rescued the impaired long-term potentiation evident in hippocampal slices from APP/PS1 mice. Chronic treatment of Tg2576 mice with CM-414 diminished brain Aβ and tau phosphorylation (pTau) levels, increased the inactive form of GSK3β, reverted the decrease in dendritic spine density on hippocampal neurons, and reversed their cognitive deficits, at least in part by inducing the expression of genes related to synaptic transmission.",
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     },
     {
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       "citation": {
         "authors": [
-          "Feng Y",
-          "Jiang J",
-          "Liu XH",
-          "Liu ZC",
-          "Luo HB",
-          "Shu XJ",
-          "Wang JZ",
-          "Wang XC",
-          "Xia YY",
-          "Xiong YS",
-          "Ye K",
-          "Yin G",
-          "Yu G",
-          "Zeng K"
+          "Cuadrado-Tejedor M",
+          "Franco R",
+          "Garcia-Barroso C",
+          "Garcia-Osta A",
+          "Mederos S",
+          "Oyarzabal J",
+          "Perea G",
+          "Pérez-González M",
+          "Rabal O",
+          "Segura V",
+          "Sánchez-Arias JA",
+          "Ugarte A"
         ],
-        "date": "2014-11-18",
-        "first": "Luo HB",
-        "last": "Wang JZ",
-        "name": "Proceedings of the National Academy of Sciences of the United States of America",
-        "pages": "16586-91",
-        "reference": "25378699",
-        "title": "SUMOylation at K340 inhibits tau degradation through deregulating its phosphorylation and ubiquitination.",
+        "date": "2017-01-01",
+        "first": "Cuadrado-Tejedor M",
+        "last": "Garcia-Osta A",
+        "name": "Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology",
+        "pages": "524-539",
+        "reference": "27550730",
+        "title": "A First-in-Class Small-Molecule that Acts as a Dual Inhibitor of HDAC and PDE5 and that Rescues Hippocampal Synaptic Impairment in Alzheimer's Disease Mice.",
         "type": "PubMed",
-        "volume": "111"
+        "volume": "42"
       },
-      "evidence": "Furthermore, the enhanced SUMO-immunoreactivity, costained with the hyperphosphorylated tau, is detected in cerebral cortex of the AD brains, and β-amyloid exposure of rat primary hippocampal neurons induces a dose-dependent SUMOylation of the hyperphosphorylated tau. Our findings suggest that tau SUMOylation reciprocally stimulates its phosphorylation and inhibits the ubiquitination-mediated tau degradation, which provides a new insight into the AD-like tau accumulation.",
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+      "evidence": "Here we report the discovery of a new first-in-class small-molecule (CM-414) that acts as a dual inhibitor of PDE5 and HDACs. We have used this compound as a chemical probe to validate this systems therapeutics strategy, where an increase in the activation of cAMP/cGMP-responsive element-binding protein (CREB) induced by PDE5 inhibition, combined with moderate HDAC class I inhibition, leads to efficient histone acetylation. This molecule rescued the impaired long-term potentiation evident in hippocampal slices from APP/PS1 mice. Chronic treatment of Tg2576 mice with CM-414 diminished brain Aβ and tau phosphorylation (pTau) levels, increased the inactive form of GSK3β, reverted the decrease in dendritic spine density on hippocampal neurons, and reversed their cognitive deficits, at least in part by inducing the expression of genes related to synaptic transmission.",
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       "relation": "decreases",
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     },
     {
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+        },
+        "Species": {
+          "10090": true
+        }
+      },
       "citation": {
         "authors": [
-          "Dorval V",
-          "Fraser PE"
+          "Cuadrado-Tejedor M",
+          "Franco R",
+          "Garcia-Barroso C",
+          "Garcia-Osta A",
+          "Mederos S",
+          "Oyarzabal J",
+          "Perea G",
+          "Pérez-González M",
+          "Rabal O",
+          "Segura V",
+          "Sánchez-Arias JA",
+          "Ugarte A"
         ],
-        "date": "2006-04-14",
-        "first": "Dorval V",
-        "last": "Fraser PE",
-        "name": "The Journal of biological chemistry",
-        "pages": "9919-24",
-        "reference": "16464864",
-        "title": "Small ubiquitin-like modifier (SUMO) modification of natively unfolded proteins tau and alpha-synuclein.",
+        "date": "2017-01-01",
+        "first": "Cuadrado-Tejedor M",
+        "last": "Garcia-Osta A",
+        "name": "Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology",
+        "pages": "524-539",
+        "reference": "27550730",
+        "title": "A First-in-Class Small-Molecule that Acts as a Dual Inhibitor of HDAC and PDE5 and that Rescues Hippocampal Synaptic Impairment in Alzheimer's Disease Mice.",
         "type": "PubMed",
-        "volume": "281"
+        "volume": "42"
       },
-      "evidence": "Both brain proteins were preferentially modified by SUMO1, as compared with SUMO2 or SUMO3. Tau contains two SUMO consensus sequences with Lys(340) as the major sumoylation site. Although both tau and alpha-synuclein are targets for proteasomal degradation, only tau sumoylation was affected by inhibitors of the proteasome pathway. Treatment with the phosphatase inhibitor, okadaic acid, or the microtubule depolymerizing drug, colchicine, up-regulated tau sumoylation.",
-      "key": "4d352ba5efc18c1eb450a2b6ef80da33dd5705ef9f3ab56c7186cfa4f81fab3c0b14d64c24609d6b4127156a4f7a7d051e8c98c43b107364f4ab2f433f23ead8",
-      "line": 3710,
-      "relation": "positiveCorrelation",
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-      "target": 544
+      "evidence": "Here we report the discovery of a new first-in-class small-molecule (CM-414) that acts as a dual inhibitor of PDE5 and HDACs. We have used this compound as a chemical probe to validate this systems therapeutics strategy, where an increase in the activation of cAMP/cGMP-responsive element-binding protein (CREB) induced by PDE5 inhibition, combined with moderate HDAC class I inhibition, leads to efficient histone acetylation. This molecule rescued the impaired long-term potentiation evident in hippocampal slices from APP/PS1 mice. Chronic treatment of Tg2576 mice with CM-414 diminished brain Aβ and tau phosphorylation (pTau) levels, increased the inactive form of GSK3β, reverted the decrease in dendritic spine density on hippocampal neurons, and reversed their cognitive deficits, at least in part by inducing the expression of genes related to synaptic transmission.",
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+      "line": 3806,
+      "relation": "decreases",
+      "source": 158,
+      "target": 900
     },
     {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        },
+        "Species": {
+          "10090": true
+        }
+      },
       "citation": {
         "authors": [
-          "Clelland CL",
-          "Duff KE",
-          "Emrani S",
-          "Goldberg AL",
-          "Kukushkin NV",
-          "Myeku N",
-          "Yu WH"
+          "Cuadrado-Tejedor M",
+          "Franco R",
+          "Garcia-Barroso C",
+          "Garcia-Osta A",
+          "Mederos S",
+          "Oyarzabal J",
+          "Perea G",
+          "Pérez-González M",
+          "Rabal O",
+          "Segura V",
+          "Sánchez-Arias JA",
+          "Ugarte A"
         ],
-        "date": "2016-01-01",
-        "first": "Myeku N",
-        "last": "Duff KE",
-        "name": "Nature medicine",
-        "pages": "46-53",
-        "reference": "26692334",
-        "title": "Tau-driven 26S proteasome impairment and cognitive dysfunction can be prevented early in disease by activating cAMP-PKA signaling.",
+        "date": "2017-01-01",
+        "first": "Cuadrado-Tejedor M",
+        "last": "Garcia-Osta A",
+        "name": "Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology",
+        "pages": "524-539",
+        "reference": "27550730",
+        "title": "A First-in-Class Small-Molecule that Acts as a Dual Inhibitor of HDAC and PDE5 and that Rescues Hippocampal Synaptic Impairment in Alzheimer's Disease Mice.",
         "type": "PubMed",
-        "volume": "22"
+        "volume": "42"
       },
-      "evidence": "Rolipram is a specific phosphodiesterase type 4 (PDE4) inhibitor that increases cAMP levels in multiple tissues in vivo. The chymotrypsin-like activity of the 26S proteasomes in crude extracts was elevated after administration of db-cAMP or rolipram but was blocked by epoxomicin",
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+      "evidence": "Here we report the discovery of a new first-in-class small-molecule (CM-414) that acts as a dual inhibitor of PDE5 and HDACs. We have used this compound as a chemical probe to validate this systems therapeutics strategy, where an increase in the activation of cAMP/cGMP-responsive element-binding protein (CREB) induced by PDE5 inhibition, combined with moderate HDAC class I inhibition, leads to efficient histone acetylation. This molecule rescued the impaired long-term potentiation evident in hippocampal slices from APP/PS1 mice. Chronic treatment of Tg2576 mice with CM-414 diminished brain Aβ and tau phosphorylation (pTau) levels, increased the inactive form of GSK3β, reverted the decrease in dendritic spine density on hippocampal neurons, and reversed their cognitive deficits, at least in part by inducing the expression of genes related to synaptic transmission.",
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         "modifier": "Activity"
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+      "relation": "decreases",
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     },
     {
+      "annotations": {
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+        },
+        "Species": {
+          "10090": true
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       "citation": {
         "authors": [
-          "Clelland CL",
-          "Duff KE",
-          "Emrani S",
-          "Goldberg AL",
-          "Kukushkin NV",
-          "Myeku N",
-          "Yu WH"
+          "Cuadrado-Tejedor M",
+          "Franco R",
+          "Garcia-Barroso C",
+          "Garcia-Osta A",
+          "Mederos S",
+          "Oyarzabal J",
+          "Perea G",
+          "Pérez-González M",
+          "Rabal O",
+          "Segura V",
+          "Sánchez-Arias JA",
+          "Ugarte A"
         ],
-        "date": "2016-01-01",
-        "first": "Myeku N",
-        "last": "Duff KE",
-        "name": "Nature medicine",
-        "pages": "46-53",
-        "reference": "26692334",
-        "title": "Tau-driven 26S proteasome impairment and cognitive dysfunction can be prevented early in disease by activating cAMP-PKA signaling.",
+        "date": "2017-01-01",
+        "first": "Cuadrado-Tejedor M",
+        "last": "Garcia-Osta A",
+        "name": "Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology",
+        "pages": "524-539",
+        "reference": "27550730",
+        "title": "A First-in-Class Small-Molecule that Acts as a Dual Inhibitor of HDAC and PDE5 and that Rescues Hippocampal Synaptic Impairment in Alzheimer's Disease Mice.",
         "type": "PubMed",
-        "volume": "22"
+        "volume": "42"
       },
-      "evidence": "Rolipram is a specific phosphodiesterase type 4 (PDE4) inhibitor that increases cAMP levels in multiple tissues in vivo. The chymotrypsin-like activity of the 26S proteasomes in crude extracts was elevated after administration of db-cAMP or rolipram but was blocked by epoxomicin",
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+      "evidence": "Here we report the discovery of a new first-in-class small-molecule (CM-414) that acts as a dual inhibitor of PDE5 and HDACs. We have used this compound as a chemical probe to validate this systems therapeutics strategy, where an increase in the activation of cAMP/cGMP-responsive element-binding protein (CREB) induced by PDE5 inhibition, combined with moderate HDAC class I inhibition, leads to efficient histone acetylation. This molecule rescued the impaired long-term potentiation evident in hippocampal slices from APP/PS1 mice. Chronic treatment of Tg2576 mice with CM-414 diminished brain Aβ and tau phosphorylation (pTau) levels, increased the inactive form of GSK3β, reverted the decrease in dendritic spine density on hippocampal neurons, and reversed their cognitive deficits, at least in part by inducing the expression of genes related to synaptic transmission.",
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     {
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+        "MeSHAnatomy": {
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+        "Species": {
+          "10090": true
+        }
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       "citation": {
         "authors": [
-          "Clelland CL",
-          "Duff KE",
-          "Emrani S",
-          "Goldberg AL",
-          "Kukushkin NV",
-          "Myeku N",
-          "Yu WH"
+          "Saha P",
+          "Sen N",
+          "Sen T"
         ],
-        "date": "2016-01-01",
-        "first": "Myeku N",
-        "last": "Duff KE",
-        "name": "Nature medicine",
-        "pages": "46-53",
-        "reference": "26692334",
-        "title": "Tau-driven 26S proteasome impairment and cognitive dysfunction can be prevented early in disease by activating cAMP-PKA signaling.",
+        "date": "2018-03-20",
+        "first": "Sen T",
+        "last": "Sen N",
+        "name": "Science signaling",
+        "reference": "29559585",
+        "title": "Nitrosylation of GAPDH augments pathological tau acetylation upon exposure to amyloid-β.",
         "type": "PubMed",
-        "volume": "22"
-      },
-      "evidence": "Rolipram is a specific phosphodiesterase type 4 (PDE4) inhibitor that increases cAMP levels in multiple tissues in vivo. The chymotrypsin-like activity of the 26S proteasomes in crude extracts was elevated after administration of db-cAMP or rolipram but was blocked by epoxomicin",
-      "key": "0bbed4c6b46aee6bdd2be1653d48eebaabecc7f8536f12ff8543ae46ead3a13f9775d193f5c7b1e8d2c15edccb8de299615b270058fa2e4dcbe0e4e466ee0aef",
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-      "object": {
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       },
+      "evidence": "We found that NO production and tau acetylation at Lys280 occurred in the brain tissue in mice and in cultured mouse cortical neurons in response to exposure to amyloid-β1-42 (Aβ1-42), a peptide that is also implicated in AD. An increased abundance of NO facilitated the S-nitrosylation (SNO) of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). S-nitrosylated GAPDH (GAPDH-SNO) promoted the acetylation and activation of the acetyltransferase p300 and facilitated the nitrosylation and inactivation of the deacetylase sirtuin 1 (SIRT1). The abundance of GAPDH-SNO was increased in postmortem brain samples from AD patients. Preventing the increase in GAPDH-SNO abundance in both cultured neurons and mice, either by overexpression of the nitrosylation mutant of GAPDH (GAPDH C150S) or by treatment with the GAPDH nitrosylation inhibitor CGP3466B (also known as omigapil), abrogated Aβ1-42-induced tau acetylation, memory impairment, and locomotor dysfunction in mice, suggesting that this drug might be repurposed to treat patients with AD.",
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       "relation": "increases",
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     },
     {
+      "annotations": {
+        "Cell_Line": {
+          "HEK293T": true,
+          "N2a": true
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+        "Confidence": {
+          "High": true
+        }
+      },
       "citation": {
         "authors": [
-          "Clelland CL",
-          "Duff KE",
-          "Emrani S",
-          "Goldberg AL",
-          "Kukushkin NV",
-          "Myeku N",
-          "Yu WH"
+          "Akaike T",
+          "Ida T",
+          "Matsushita K",
+          "Soeda Y",
+          "Sumioka A",
+          "Takashima A",
+          "Yoshikawa M",
+          "Yoshitake J"
         ],
-        "date": "2016-01-01",
-        "first": "Myeku N",
-        "last": "Duff KE",
-        "name": "Nature medicine",
-        "pages": "46-53",
-        "reference": "26692334",
-        "title": "Tau-driven 26S proteasome impairment and cognitive dysfunction can be prevented early in disease by activating cAMP-PKA signaling.",
+        "date": "2016-10-21",
+        "first": "Yoshitake J",
+        "last": "Takashima A",
+        "name": "The Journal of biological chemistry",
+        "pages": "22714-22720",
+        "reference": "27601475",
+        "title": "Modification of Tau by 8-Nitroguanosine 3',5'-Cyclic Monophosphate (8-Nitro-cGMP): EFFECTS OF NITRIC OXIDE-LINKED CHEMICAL MODIFICATION ON TAU AGGREGATION.",
         "type": "PubMed",
-        "volume": "22"
+        "volume": "291"
       },
-      "evidence": "Rolipram is a specific phosphodiesterase type 4 (PDE4) inhibitor that increases cAMP levels in multiple tissues in vivo. The chymotrypsin-like activity of the 26S proteasomes in crude extracts was elevated after administration of db-cAMP or rolipram but was blocked by epoxomicin",
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-      "line": 3494,
-      "relation": "decreases",
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+      "evidence": "Tau contains cysteine residues in the microtubule binding region following alternative splicing of exon 10, and formation of intermolecular cysteine disulfide bonds accelerates tau aggregation. 8-Nitro-cGMP (novel second messenger of NO) exposure induced S-guanylation of tau both in vitro and in tau-overexpressed HEK293T cells. S-guanylated tau inhibited heparin-induced tau aggregation (thioflavin T). S-guanylated tau could not form tau granules and fibrils (AFM) inhibited at the step of tau oligomer formation. In P301L tau-expressing Neuro2A cells, 8-nitro-cGMP reduced the amount of sarcosyl-insoluble tau. NO-linked chemical modification on cysteine residues of tau could block tau aggregation",
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     },
     {
+      "annotations": {
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+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
+        "Species": {
+          "10090": true
+        }
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       "citation": {
         "authors": [
-          "Albrecht F",
-          "Arendt T",
-          "Arsalan-Werner A",
-          "Flach K",
-          "Goedert M",
-          "Herrmann L",
-          "Hilbrich I",
-          "Holzer M",
-          "Ramminger E"
+          "Saha P",
+          "Sen N",
+          "Sen T"
         ],
-        "date": "2014-09-01",
-        "first": "Flach K",
-        "last": "Holzer M",
-        "name": "Biochimica et biophysica acta",
-        "pages": "1527-38",
-        "reference": "24905733",
-        "title": "Axotrophin/MARCH7 acts as an E3 ubiquitin ligase and ubiquitinates tau protein in vitro impairing microtubule binding.",
+        "date": "2018-03-20",
+        "first": "Sen T",
+        "last": "Sen N",
+        "name": "Science signaling",
+        "reference": "29559585",
+        "title": "Nitrosylation of GAPDH augments pathological tau acetylation upon exposure to amyloid-β.",
         "type": "PubMed",
-        "volume": "1842"
+        "volume": "11"
       },
-      "evidence": "We show that axotrophin/MARCH7, a RING-variant domain containing protein with similarity to E3 ubiquitin ligases interacts with tau. We find here that tau becomes mono-ubiquitinated by recombinant tau-interacting RING-variant domain, which diminishes its microtubule-binding. Tau becomes mono-ubiquitinated by recombinant tau-interacting RING-variant domain reducing microtubule-binding.",
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     },
     {
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+        "MeSHAnatomy": {
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+        "Species": {
+          "10090": true
+        }
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       "citation": {
         "authors": [
-          "Hasegawa M",
-          "Ihara Y",
-          "Morishima-Kawashima M",
-          "Suzuki M",
-          "Takio K",
-          "Titani K"
+          "Saha P",
+          "Sen N",
+          "Sen T"
         ],
-        "date": "1993-06-01",
-        "first": "Morishima-Kawashima M",
-        "last": "Ihara Y",
-        "name": "Neuron",
-        "pages": "1151-60",
-        "reference": "8391280",
-        "title": "Ubiquitin is conjugated with amino-terminally processed tau in paired helical filaments.",
+        "date": "2018-03-20",
+        "first": "Sen T",
+        "last": "Sen N",
+        "name": "Science signaling",
+        "reference": "29559585",
+        "title": "Nitrosylation of GAPDH augments pathological tau acetylation upon exposure to amyloid-β.",
         "type": "PubMed",
-        "volume": "10"
+        "volume": "11"
       },
-      "evidence": "Ubiquitination occurs at lysines (K254, K257 K311) in repeat domain; participates in triage process",
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-      "relation": "positiveCorrelation",
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     {
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+          "10090": true
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+      },
       "citation": {
         "authors": [
-          "Hasegawa M",
-          "Ihara Y",
-          "Morishima-Kawashima M",
-          "Suzuki M",
-          "Takio K",
-          "Titani K"
+          "Saha P",
+          "Sen N",
+          "Sen T"
         ],
-        "date": "1993-06-01",
-        "first": "Morishima-Kawashima M",
-        "last": "Ihara Y",
-        "name": "Neuron",
-        "pages": "1151-60",
-        "reference": "8391280",
-        "title": "Ubiquitin is conjugated with amino-terminally processed tau in paired helical filaments.",
+        "date": "2018-03-20",
+        "first": "Sen T",
+        "last": "Sen N",
+        "name": "Science signaling",
+        "reference": "29559585",
+        "title": "Nitrosylation of GAPDH augments pathological tau acetylation upon exposure to amyloid-β.",
         "type": "PubMed",
-        "volume": "10"
+        "volume": "11"
       },
-      "evidence": "Ubiquitination occurs at lysines (K254, K257 K311) in repeat domain; participates in triage process",
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-      "line": 3512,
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+      "evidence": "We found that NO production and tau acetylation at Lys280 occurred in the brain tissue in mice and in cultured mouse cortical neurons in response to exposure to amyloid-β1-42 (Aβ1-42), a peptide that is also implicated in AD. An increased abundance of NO facilitated the S-nitrosylation (SNO) of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). S-nitrosylated GAPDH (GAPDH-SNO) promoted the acetylation and activation of the acetyltransferase p300 and facilitated the nitrosylation and inactivation of the deacetylase sirtuin 1 (SIRT1). The abundance of GAPDH-SNO was increased in postmortem brain samples from AD patients. Preventing the increase in GAPDH-SNO abundance in both cultured neurons and mice, either by overexpression of the nitrosylation mutant of GAPDH (GAPDH C150S) or by treatment with the GAPDH nitrosylation inhibitor CGP3466B (also known as omigapil), abrogated Aβ1-42-induced tau acetylation, memory impairment, and locomotor dysfunction in mice, suggesting that this drug might be repurposed to treat patients with AD.",
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     {
       "annotations": {
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-          "Stage I": true,
-          "Stage II": true
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+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
+        },
+        "Species": {
+          "10090": true
         }
       },
       "citation": {
         "authors": [
-          "Combs B",
-          "Hamel C",
-          "Kanaan NM"
+          "Saha P",
+          "Sen N",
+          "Sen T"
         ],
-        "date": "2016-10-01",
-        "first": "Combs B",
-        "last": "Kanaan NM",
-        "name": "Neurobiology of disease",
-        "pages": "18-31",
-        "reference": "27260838",
-        "title": "Pathological conformations involving the amino terminus of tau occur early in Alzheimer's disease and are differentially detected by monoclonal antibodies.",
+        "date": "2018-03-20",
+        "first": "Sen T",
+        "last": "Sen N",
+        "name": "Science signaling",
+        "reference": "29559585",
+        "title": "Nitrosylation of GAPDH augments pathological tau acetylation upon exposure to amyloid-β.",
         "type": "PubMed",
-        "volume": "94"
+        "volume": "11"
       },
-      "evidence": "Previously, we have shown that TNT1 is a marker of PAD exposure and that this event occurs early in the progression of Alzheimer’s disease. Establishing whether this was true for all N-terminal antibodies was important for understanding more about PAD exposure in Alzheimer’s disease. We significantly extend these findings with TNT1 and show that TNT2 behaves similarly as a marker of PAD exposure. In contrast, other N-terminal antibodies, with slightly different epitopes, do not function as pathological, PAD exposure-specific markers and recognize all forms of tau similarly. Here, we found that TNT1 and TNT2 appear in Braak I–II stages and do not colocalize with ThR in the diffuse, granular pre-tangle pathology conclusively demonstrating that PAD exposure is an early event.",
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     {
       "annotations": {
-        "Braak_Stage": {
-          "Stage I": true,
-          "Stage II": true
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
         }
       },
       "citation": {
         "authors": [
-          "Combs B",
-          "Hamel C",
-          "Kanaan NM"
+          "Saha P",
+          "Sen N",
+          "Sen T"
         ],
-        "date": "2016-10-01",
-        "first": "Combs B",
-        "last": "Kanaan NM",
-        "name": "Neurobiology of disease",
-        "pages": "18-31",
-        "reference": "27260838",
-        "title": "Pathological conformations involving the amino terminus of tau occur early in Alzheimer's disease and are differentially detected by monoclonal antibodies.",
+        "date": "2018-03-20",
+        "first": "Sen T",
+        "last": "Sen N",
+        "name": "Science signaling",
+        "reference": "29559585",
+        "title": "Nitrosylation of GAPDH augments pathological tau acetylation upon exposure to amyloid-β.",
         "type": "PubMed",
-        "volume": "94"
+        "volume": "11"
       },
-      "evidence": "Previously, we have shown that TNT1 is a marker of PAD exposure and that this event occurs early in the progression of Alzheimer’s disease. Establishing whether this was true for all N-terminal antibodies was important for understanding more about PAD exposure in Alzheimer’s disease. We significantly extend these findings with TNT1 and show that TNT2 behaves similarly as a marker of PAD exposure. In contrast, other N-terminal antibodies, with slightly different epitopes, do not function as pathological, PAD exposure-specific markers and recognize all forms of tau similarly. Here, we found that TNT1 and TNT2 appear in Braak I–II stages and do not colocalize with ThR in the diffuse, granular pre-tangle pathology conclusively demonstrating that PAD exposure is an early event.",
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     {
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+        "MeSHAnatomy": {
+          "Brain": true
+        }
+      },
       "citation": {
         "authors": [
-          "Combs B",
-          "Hamel C",
-          "Kanaan NM"
+          "Saha P",
+          "Sen N",
+          "Sen T"
         ],
-        "date": "2016-10-01",
-        "first": "Combs B",
-        "last": "Kanaan NM",
-        "name": "Neurobiology of disease",
-        "pages": "18-31",
-        "reference": "27260838",
-        "title": "Pathological conformations involving the amino terminus of tau occur early in Alzheimer's disease and are differentially detected by monoclonal antibodies.",
+        "date": "2018-03-20",
+        "first": "Sen T",
+        "last": "Sen N",
+        "name": "Science signaling",
+        "reference": "29559585",
+        "title": "Nitrosylation of GAPDH augments pathological tau acetylation upon exposure to amyloid-β.",
         "type": "PubMed",
-        "volume": "94"
+        "volume": "11"
       },
-      "evidence": "Apparent ThR-positive ghost tangles (i.e., without nuclei (Braak et al., 1994)) are no longer labeled by TNT1 or TNT2, which confirms that PAD exposure is lost in the latest stages of NFT evolution.",
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+      "evidence": "We found that NO production and tau acetylation at Lys280 occurred in the brain tissue in mice and in cultured mouse cortical neurons in response to exposure to amyloid-β1-42 (Aβ1-42), a peptide that is also implicated in AD. An increased abundance of NO facilitated the S-nitrosylation (SNO) of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). S-nitrosylated GAPDH (GAPDH-SNO) promoted the acetylation and activation of the acetyltransferase p300 and facilitated the nitrosylation and inactivation of the deacetylase sirtuin 1 (SIRT1). The abundance of GAPDH-SNO was increased in postmortem brain samples from AD patients. Preventing the increase in GAPDH-SNO abundance in both cultured neurons and mice, either by overexpression of the nitrosylation mutant of GAPDH (GAPDH C150S) or by treatment with the GAPDH nitrosylation inhibitor CGP3466B (also known as omigapil), abrogated Aβ1-42-induced tau acetylation, memory impairment, and locomotor dysfunction in mice, suggesting that this drug might be repurposed to treat patients with AD.",
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     {
       "annotations": {
-        "Cell_Line": {
-          "HEK293T": true,
-          "N2a": true
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+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
         }
       },
       "citation": {
         "authors": [
-          "Akaike T",
-          "Ida T",
-          "Matsushita K",
-          "Soeda Y",
-          "Sumioka A",
-          "Takashima A",
-          "Yoshikawa M",
-          "Yoshitake J"
+          "Saha P",
+          "Sen N",
+          "Sen T"
         ],
-        "date": "2016-10-21",
-        "first": "Yoshitake J",
-        "last": "Takashima A",
-        "name": "The Journal of biological chemistry",
-        "pages": "22714-22720",
-        "reference": "27601475",
-        "title": "Modification of Tau by 8-Nitroguanosine 3',5'-Cyclic Monophosphate (8-Nitro-cGMP): EFFECTS OF NITRIC OXIDE-LINKED CHEMICAL MODIFICATION ON TAU AGGREGATION.",
+        "date": "2018-03-20",
+        "first": "Sen T",
+        "last": "Sen N",
+        "name": "Science signaling",
+        "reference": "29559585",
+        "title": "Nitrosylation of GAPDH augments pathological tau acetylation upon exposure to amyloid-β.",
         "type": "PubMed",
-        "volume": "291"
+        "volume": "11"
       },
-      "evidence": "Tau contains cysteine residues in the microtubule binding region following alternative splicing of exon 10, and formation of intermolecular cysteine disulfide bonds accelerates tau aggregation. 8-Nitro-cGMP (novel second messenger of NO) exposure induced S-guanylation of tau both in vitro and in tau-overexpressed HEK293T cells. S-guanylated tau inhibited heparin-induced tau aggregation (thioflavin T). S-guanylated tau could not form tau granules and fibrils (AFM) inhibited at the step of tau oligomer formation. In P301L tau-expressing Neuro2A cells, 8-nitro-cGMP reduced the amount of sarcosyl-insoluble tau. NO-linked chemical modification on cysteine residues of tau could block tau aggregation",
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       "relation": "decreases",
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     },
     {
       "annotations": {
-        "Cell_Line": {
-          "HEK293T": true,
-          "N2a": true
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Brain": true
         }
       },
       "citation": {
         "authors": [
-          "Akaike T",
-          "Ida T",
-          "Matsushita K",
-          "Soeda Y",
-          "Sumioka A",
-          "Takashima A",
-          "Yoshikawa M",
-          "Yoshitake J"
+          "Saha P",
+          "Sen N",
+          "Sen T"
         ],
-        "date": "2016-10-21",
-        "first": "Yoshitake J",
-        "last": "Takashima A",
-        "name": "The Journal of biological chemistry",
-        "pages": "22714-22720",
-        "reference": "27601475",
-        "title": "Modification of Tau by 8-Nitroguanosine 3',5'-Cyclic Monophosphate (8-Nitro-cGMP): EFFECTS OF NITRIC OXIDE-LINKED CHEMICAL MODIFICATION ON TAU AGGREGATION.",
+        "date": "2018-03-20",
+        "first": "Sen T",
+        "last": "Sen N",
+        "name": "Science signaling",
+        "reference": "29559585",
+        "title": "Nitrosylation of GAPDH augments pathological tau acetylation upon exposure to amyloid-β.",
         "type": "PubMed",
-        "volume": "291"
+        "volume": "11"
       },
-      "evidence": "Tau contains cysteine residues in the microtubule binding region following alternative splicing of exon 10, and formation of intermolecular cysteine disulfide bonds accelerates tau aggregation. 8-Nitro-cGMP (novel second messenger of NO) exposure induced S-guanylation of tau both in vitro and in tau-overexpressed HEK293T cells. S-guanylated tau inhibited heparin-induced tau aggregation (thioflavin T). S-guanylated tau could not form tau granules and fibrils (AFM) inhibited at the step of tau oligomer formation. In P301L tau-expressing Neuro2A cells, 8-nitro-cGMP reduced the amount of sarcosyl-insoluble tau. NO-linked chemical modification on cysteine residues of tau could block tau aggregation",
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+      "evidence": "We found that NO production and tau acetylation at Lys280 occurred in the brain tissue in mice and in cultured mouse cortical neurons in response to exposure to amyloid-β1-42 (Aβ1-42), a peptide that is also implicated in AD. An increased abundance of NO facilitated the S-nitrosylation (SNO) of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). S-nitrosylated GAPDH (GAPDH-SNO) promoted the acetylation and activation of the acetyltransferase p300 and facilitated the nitrosylation and inactivation of the deacetylase sirtuin 1 (SIRT1). The abundance of GAPDH-SNO was increased in postmortem brain samples from AD patients. Preventing the increase in GAPDH-SNO abundance in both cultured neurons and mice, either by overexpression of the nitrosylation mutant of GAPDH (GAPDH C150S) or by treatment with the GAPDH nitrosylation inhibitor CGP3466B (also known as omigapil), abrogated Aβ1-42-induced tau acetylation, memory impairment, and locomotor dysfunction in mice, suggesting that this drug might be repurposed to treat patients with AD.",
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     },
     {
       "annotations": {
-        "Cell_Line": {
-          "HEK293T": true,
-          "N2a": true
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+        },
+        "MeSHAnatomy": {
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       },
       "citation": {
         "authors": [
-          "Akaike T",
-          "Ida T",
-          "Matsushita K",
-          "Soeda Y",
-          "Sumioka A",
-          "Takashima A",
-          "Yoshikawa M",
-          "Yoshitake J"
+          "Saha P",
+          "Sen N",
+          "Sen T"
         ],
-        "date": "2016-10-21",
-        "first": "Yoshitake J",
-        "last": "Takashima A",
-        "name": "The Journal of biological chemistry",
-        "pages": "22714-22720",
-        "reference": "27601475",
-        "title": "Modification of Tau by 8-Nitroguanosine 3',5'-Cyclic Monophosphate (8-Nitro-cGMP): EFFECTS OF NITRIC OXIDE-LINKED CHEMICAL MODIFICATION ON TAU AGGREGATION.",
+        "date": "2018-03-20",
+        "first": "Sen T",
+        "last": "Sen N",
+        "name": "Science signaling",
+        "reference": "29559585",
+        "title": "Nitrosylation of GAPDH augments pathological tau acetylation upon exposure to amyloid-β.",
         "type": "PubMed",
-        "volume": "291"
-      },
-      "evidence": "Tau contains cysteine residues in the microtubule binding region following alternative splicing of exon 10, and formation of intermolecular cysteine disulfide bonds accelerates tau aggregation. 8-Nitro-cGMP (novel second messenger of NO) exposure induced S-guanylation of tau both in vitro and in tau-overexpressed HEK293T cells. S-guanylated tau inhibited heparin-induced tau aggregation (thioflavin T). S-guanylated tau could not form tau granules and fibrils (AFM) inhibited at the step of tau oligomer formation. In P301L tau-expressing Neuro2A cells, 8-nitro-cGMP reduced the amount of sarcosyl-insoluble tau. NO-linked chemical modification on cysteine residues of tau could block tau aggregation",
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-      "line": 3550,
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-      "subject": {
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+      "evidence": "We found that NO production and tau acetylation at Lys280 occurred in the brain tissue in mice and in cultured mouse cortical neurons in response to exposure to amyloid-β1-42 (Aβ1-42), a peptide that is also implicated in AD. An increased abundance of NO facilitated the S-nitrosylation (SNO) of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). S-nitrosylated GAPDH (GAPDH-SNO) promoted the acetylation and activation of the acetyltransferase p300 and facilitated the nitrosylation and inactivation of the deacetylase sirtuin 1 (SIRT1). The abundance of GAPDH-SNO was increased in postmortem brain samples from AD patients. Preventing the increase in GAPDH-SNO abundance in both cultured neurons and mice, either by overexpression of the nitrosylation mutant of GAPDH (GAPDH C150S) or by treatment with the GAPDH nitrosylation inhibitor CGP3466B (also known as omigapil), abrogated Aβ1-42-induced tau acetylation, memory impairment, and locomotor dysfunction in mice, suggesting that this drug might be repurposed to treat patients with AD.",
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     {
+      "annotations": {
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+          "Medium": true
+        },
+        "Species": {
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       "citation": {
         "authors": [
-          "Brady ST",
-          "Combs B",
-          "Counts SE",
-          "Cox K",
-          "Kanaan NM",
-          "Morfini G",
-          "Tiernan CT"
+          "Augustin H",
+          "Burnouf S",
+          "Dols J",
+          "Gorsky MK",
+          "Grönke S",
+          "Partridge L",
+          "Sofola-Adesakin O",
+          "Weigelt CM"
         ],
-        "date": "2016-09-01",
-        "first": "Tiernan CT",
-        "last": "Kanaan NM",
-        "name": "Experimental neurology",
-        "pages": "318-29",
-        "reference": "27373205",
-        "title": "Pseudophosphorylation of tau at S422 enhances SDS-stable dimer formation and impairs both anterograde and retrograde fast axonal transport.",
+        "date": "2017-08-30",
+        "first": "Gorsky MK",
+        "last": "Partridge L",
+        "name": "Scientific reports",
+        "pages": "9984",
+        "reference": "28855586",
+        "title": "Pseudo-acetylation of multiple sites on human Tau proteins alters Tau phosphorylation and microtubule binding, and ameliorates amyloid beta toxicity.",
         "type": "PubMed",
-        "volume": "283"
+        "volume": "7"
       },
-      "evidence": "Highlighting the relevance of these findings to human disease, pS422 tau was found to colocalize with tau oligomers and with a fraction of tau showing increased PAD exposure in the human AD brain. This study identifies novel effects of pS422 on tau biochemical properties, including prolonged nucleation and enhanced dimer formation, which correlate with a distinct inhibitory effect on FAT.",
-      "key": "6eea12dea54e5271d8900b88e645db9aa4afde646001c69aac9a46138abb4ffa5efc78a6b604ae3edb81e357b808de5c39910a62cfa12150cf542346751250d8",
-      "line": 3560,
-      "relation": "positiveCorrelation",
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+      "evidence": "We have used a knock-out/knock-in strategy in Drosophila to generate a strain with hTau inserted into the endogenous fly tau locus and expressed under the control of the endogenous fly tau promoter, thus avoiding potential toxicity due to genetic over-expression. hTau knock-in (KI) proteins were expressed at normal, endogenous levels, bound to fly microtubules and were post-translationally modified, hence displaying physiological properties. We used this new model to investigate the effects of acetylation on hTau toxicity in vivo. The simultaneous pseudo-acetylation of hTau at lysines 163, 280, 281 and 369 drastically decreased hTau phosphorylation and significantly reduced its binding to microtubules in vivo. These molecular alterations were associated with ameliorated amyloid beta toxicity. Our results indicate acetylation of hTau on multiple sites regulates its biology and ameliorates amyloid beta toxicity in vivo.",
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     {
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+        },
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       "citation": {
         "authors": [
-          "Barghorn S",
-          "Biernat J",
-          "Li L",
-          "Mandelkow E",
-          "Mandelkow EM",
-          "Marx A",
-          "von Bergen M"
+          "Augustin H",
+          "Burnouf S",
+          "Dols J",
+          "Gorsky MK",
+          "Grönke S",
+          "Partridge L",
+          "Sofola-Adesakin O",
+          "Weigelt CM"
         ],
-        "date": "2001-12-21",
-        "first": "von Bergen M",
-        "last": "Mandelkow E",
-        "name": "The Journal of biological chemistry",
-        "pages": "48165-74",
-        "reference": "11606569",
-        "title": "Mutations of tau protein in frontotemporal dementia promote aggregation of paired helical filaments by enhancing local beta-structure.",
+        "date": "2017-08-30",
+        "first": "Gorsky MK",
+        "last": "Partridge L",
+        "name": "Scientific reports",
+        "pages": "9984",
+        "reference": "28855586",
+        "title": "Pseudo-acetylation of multiple sites on human Tau proteins alters Tau phosphorylation and microtubule binding, and ameliorates amyloid beta toxicity.",
         "type": "PubMed",
-        "volume": "276"
+        "volume": "7"
       },
-      "evidence": "We also show that two of the tau mutations found in hereditary frontotemporal dementias, DeltaK280 and P301L, have a much stronger tendency for PHF aggregation which correlates with their high propensity for beta-structure around the hexapeptide motifs.",
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+      "evidence": "We have used a knock-out/knock-in strategy in Drosophila to generate a strain with hTau inserted into the endogenous fly tau locus and expressed under the control of the endogenous fly tau promoter, thus avoiding potential toxicity due to genetic over-expression. hTau knock-in (KI) proteins were expressed at normal, endogenous levels, bound to fly microtubules and were post-translationally modified, hence displaying physiological properties. We used this new model to investigate the effects of acetylation on hTau toxicity in vivo. The simultaneous pseudo-acetylation of hTau at lysines 163, 280, 281 and 369 drastically decreased hTau phosphorylation and significantly reduced its binding to microtubules in vivo. These molecular alterations were associated with ameliorated amyloid beta toxicity. Our results indicate acetylation of hTau on multiple sites regulates its biology and ameliorates amyloid beta toxicity in vivo.",
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     {
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       "citation": {
         "authors": [
-          "Barghorn S",
-          "Biernat J",
-          "Li L",
-          "Mandelkow E",
-          "Mandelkow EM",
-          "Marx A",
-          "von Bergen M"
+          "Augustin H",
+          "Burnouf S",
+          "Dols J",
+          "Gorsky MK",
+          "Grönke S",
+          "Partridge L",
+          "Sofola-Adesakin O",
+          "Weigelt CM"
         ],
-        "date": "2001-12-21",
-        "first": "von Bergen M",
-        "last": "Mandelkow E",
-        "name": "The Journal of biological chemistry",
-        "pages": "48165-74",
-        "reference": "11606569",
-        "title": "Mutations of tau protein in frontotemporal dementia promote aggregation of paired helical filaments by enhancing local beta-structure.",
+        "date": "2017-08-30",
+        "first": "Gorsky MK",
+        "last": "Partridge L",
+        "name": "Scientific reports",
+        "pages": "9984",
+        "reference": "28855586",
+        "title": "Pseudo-acetylation of multiple sites on human Tau proteins alters Tau phosphorylation and microtubule binding, and ameliorates amyloid beta toxicity.",
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-          "Li L",
-          "Mandelkow E",
-          "Mandelkow EM",
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+          "Ishiguro K",
+          "Kimura T",
+          "Oikawa T",
+          "Saito T",
+          "Uchida C",
+          "Uchida T",
+          "Yotsumoto K"
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         "name": "The Journal of biological chemistry",
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-        "title": "Mutations of tau protein in frontotemporal dementia promote aggregation of paired helical filaments by enhancing local beta-structure.",
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+        "title": "Effect of Pin1 or microtubule binding on dephosphorylation of FTDP-17 mutant Tau.",
         "type": "PubMed",
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-          "Biernat J",
-          "Li L",
-          "Mandelkow E",
-          "Mandelkow EM",
-          "Marx A",
-          "von Bergen M"
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-        "name": "The Journal of biological chemistry",
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+        "title": "A Dual Pathogenic Mechanism Links Tau Acetylation to Sporadic Tauopathy.",
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-          "Richter-Landsberg C",
-          "Wong MB"
+          "Cohen TJ",
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-        "title": "SUMO-1 is associated with a subset of lysosomes in glial protein aggregate diseases.",
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+          "Giustiniani J",
+          "Guillemeau K",
+          "Huvent I",
+          "Jacquot Y",
+          "Kamah A",
+          "Landrieu I",
+          "Lippens G",
+          "Smet C"
         ],
-        "date": "2011-09-20",
-        "first": "McMillan LE",
-        "last": "Cimarosti H",
-        "name": "Neuroscience letters",
-        "pages": "201-8",
-        "reference": "21843595",
-        "title": "Profiles of SUMO and ubiquitin conjugation in an Alzheimer's disease model.",
+        "date": "2016-03-27",
+        "first": "Kamah A",
+        "last": "Lippens G",
+        "name": "Journal of molecular biology",
+        "pages": "1080-1090",
+        "reference": "26903089",
+        "title": "Isomerization and Oligomerization of Truncated and Mutated Tau Forms by FKBP52 are Independent Processes.",
         "type": "PubMed",
-        "volume": "502"
+        "volume": "428"
       },
-      "evidence": "In 25-month-old mice, the number of errors and the latency in the learning phase negatively correlated with the Sumo3 level in the dorsal hippocampus.",
-      "key": "9a7ed6909d12911f8b47785bd649f6f9985ef8ac45e19f26ff10cc73c26e93f5a277f5d73695850b2c71a33e6caccdab3d022c4490eb9a5323672ddb60935142",
-      "line": 3642,
-      "relation": "negativeCorrelation",
-      "source": 850,
-      "target": 200
+      "evidence": "We identified a novel molecular interaction implying the PHF6 peptide of Tau and the FK1/FK2 domains of FKBP52 independent of FK506 binding; suggesting a non-catalytic molecular interaction that might govern the effect of FKBP52 on Tau.",
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     },
     {
       "annotations": {
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-        "Species": {
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+          "Medium": true
         }
       },
       "citation": {
         "authors": [
-          "Joe EH",
-          "Jou I",
-          "Kim OS",
-          "Lee CS",
-          "Lee JH",
-          "Park SJ",
-          "Park SM",
-          "Woo JH"
+          "Cohen TJ",
+          "Friedmann D",
+          "Hwang AW",
+          "Lee VM",
+          "Marmorstein R",
+          "Trzeciakiewicz H",
+          "Yuan CX"
         ],
-        "date": "2009-09-24",
-        "first": "Lee JH",
-        "last": "Jou I",
-        "name": "Molecular cell",
-        "pages": "806-17",
-        "reference": "19782030",
-        "title": "Differential SUMOylation of LXRalpha and LXRbeta mediates transrepression of STAT1 inflammatory signaling in IFN-gamma-stimulated brain astrocytes.",
+        "date": "2016-01-01",
+        "first": "Hwang AW",
+        "last": "Cohen TJ",
+        "name": "PloS one",
+        "pages": "e0168913",
+        "reference": "28002468",
+        "title": "Conserved Lysine Acetylation within the Microtubule-Binding Domain Regulates MAP2/Tau Family Members.",
         "type": "PubMed",
-        "volume": "35"
+        "volume": "11"
       },
-      "evidence": "LXR ligands inhibit neither STAT1 phosphorylation nor STAT1 translocation to the nucleus but, rather, inhibit STAT1 binding to promoters and the expression of IRF1, TNFalpha, and IL-6, downstream effectors of STAT1 action. LXRbeta forms a trimer with PIAS1-pSTAT1, whereas LXRalpha formed a trimer with HDAC4-pSTAT1, mediated by direct ligand binding to the LXR proteins. Both PIAS1 and HDAC4 belong to the SUMO E3 ligase family and LXRbeta and LXRalpha were SUMO-conjugated by PIAS1 or HDAC4, respectively, and SUMOylation was blocked by transient transfection of appropriate individual siRNAs, reversing LXR-induced suppression of IRF1 and TNFalpha expression.",
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+      "evidence": "Similar to tau, MAP2 acetylation can occur in a cysteine-dependent auto-regulatory manner in the presence of acetyl-CoA. Tubulin reduced MAP2 acetylation, suggesting tubulin binding dictates MAP acetylation status.",
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     {
       "annotations": {
-        "Cell": {
-          "astrocyte": true
+        "Confidence": {
+          "Medium": true
         },
-        "Species": {
-          "10116": true
+        "MeSHDisease": {
+          "Alzheimer Disease": true
         }
       },
       "citation": {
         "authors": [
-          "Joe EH",
-          "Jou I",
-          "Kim OS",
-          "Lee CS",
-          "Lee JH",
-          "Park SJ",
-          "Park SM",
-          "Woo JH"
+          "Cong X",
+          "Ellerby LM",
+          "Gan L",
+          "Huganir RL",
+          "Le D",
+          "Li Y",
+          "Lo I",
+          "Min SW",
+          "Minami SS",
+          "Ponnusamy R",
+          "Schilling B",
+          "Sohn PD",
+          "Tracy TE",
+          "Wang C",
+          "Zhou Y"
         ],
-        "date": "2009-09-24",
-        "first": "Lee JH",
-        "last": "Jou I",
-        "name": "Molecular cell",
-        "pages": "806-17",
-        "reference": "19782030",
-        "title": "Differential SUMOylation of LXRalpha and LXRbeta mediates transrepression of STAT1 inflammatory signaling in IFN-gamma-stimulated brain astrocytes.",
+        "date": "2016-04-20",
+        "first": "Tracy TE",
+        "last": "Gan L",
+        "name": "Neuron",
+        "pages": "245-60",
+        "reference": "27041503",
+        "title": "Acetylated Tau Obstructs KIBRA-Mediated Signaling in Synaptic Plasticity and Promotes Tauopathy-Related Memory Loss.",
         "type": "PubMed",
-        "volume": "35"
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-      "evidence": "LXR ligands inhibit neither STAT1 phosphorylation nor STAT1 translocation to the nucleus but, rather, inhibit STAT1 binding to promoters and the expression of IRF1, TNFalpha, and IL-6, downstream effectors of STAT1 action. LXRbeta forms a trimer with PIAS1-pSTAT1, whereas LXRalpha formed a trimer with HDAC4-pSTAT1, mediated by direct ligand binding to the LXR proteins. Both PIAS1 and HDAC4 belong to the SUMO E3 ligase family and LXRbeta and LXRalpha were SUMO-conjugated by PIAS1 or HDAC4, respectively, and SUMOylation was blocked by transient transfection of appropriate individual siRNAs, reversing LXR-induced suppression of IRF1 and TNFalpha expression.",
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-      "source": 900,
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     {
       "annotations": {
-        "Cell": {
-          "astrocyte": true
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+          "Medium": true
         },
-        "Species": {
-          "10116": true
+        "MeSHDisease": {
+          "Alzheimer Disease": true
         }
       },
       "citation": {
         "authors": [
-          "Joe EH",
-          "Jou I",
-          "Kim OS",
-          "Lee CS",
-          "Lee JH",
-          "Park SJ",
-          "Park SM",
-          "Woo JH"
+          "Cong X",
+          "Ellerby LM",
+          "Gan L",
+          "Huganir RL",
+          "Le D",
+          "Li Y",
+          "Lo I",
+          "Min SW",
+          "Minami SS",
+          "Ponnusamy R",
+          "Schilling B",
+          "Sohn PD",
+          "Tracy TE",
+          "Wang C",
+          "Zhou Y"
         ],
-        "date": "2009-09-24",
-        "first": "Lee JH",
-        "last": "Jou I",
-        "name": "Molecular cell",
-        "pages": "806-17",
-        "reference": "19782030",
-        "title": "Differential SUMOylation of LXRalpha and LXRbeta mediates transrepression of STAT1 inflammatory signaling in IFN-gamma-stimulated brain astrocytes.",
+        "date": "2016-04-20",
+        "first": "Tracy TE",
+        "last": "Gan L",
+        "name": "Neuron",
+        "pages": "245-60",
+        "reference": "27041503",
+        "title": "Acetylated Tau Obstructs KIBRA-Mediated Signaling in Synaptic Plasticity and Promotes Tauopathy-Related Memory Loss.",
         "type": "PubMed",
-        "volume": "35"
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-      "evidence": "LXR ligands inhibit neither STAT1 phosphorylation nor STAT1 translocation to the nucleus but, rather, inhibit STAT1 binding to promoters and the expression of IRF1, TNFalpha, and IL-6, downstream effectors of STAT1 action. LXRbeta forms a trimer with PIAS1-pSTAT1, whereas LXRalpha formed a trimer with HDAC4-pSTAT1, mediated by direct ligand binding to the LXR proteins. Both PIAS1 and HDAC4 belong to the SUMO E3 ligase family and LXRbeta and LXRalpha were SUMO-conjugated by PIAS1 or HDAC4, respectively, and SUMOylation was blocked by transient transfection of appropriate individual siRNAs, reversing LXR-induced suppression of IRF1 and TNFalpha expression.",
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     {
       "annotations": {
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-          "astrocyte": true
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+          "Medium": true
         },
-        "Species": {
-          "10116": true
+        "MeSHDisease": {
+          "Alzheimer Disease": true
         }
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       "citation": {
         "authors": [
-          "Joe EH",
-          "Jou I",
-          "Kim OS",
-          "Lee CS",
-          "Lee JH",
-          "Park SJ",
-          "Park SM",
-          "Woo JH"
+          "Cong X",
+          "Ellerby LM",
+          "Gan L",
+          "Huganir RL",
+          "Le D",
+          "Li Y",
+          "Lo I",
+          "Min SW",
+          "Minami SS",
+          "Ponnusamy R",
+          "Schilling B",
+          "Sohn PD",
+          "Tracy TE",
+          "Wang C",
+          "Zhou Y"
         ],
-        "date": "2009-09-24",
-        "first": "Lee JH",
-        "last": "Jou I",
-        "name": "Molecular cell",
-        "pages": "806-17",
-        "reference": "19782030",
-        "title": "Differential SUMOylation of LXRalpha and LXRbeta mediates transrepression of STAT1 inflammatory signaling in IFN-gamma-stimulated brain astrocytes.",
+        "date": "2016-04-20",
+        "first": "Tracy TE",
+        "last": "Gan L",
+        "name": "Neuron",
+        "pages": "245-60",
+        "reference": "27041503",
+        "title": "Acetylated Tau Obstructs KIBRA-Mediated Signaling in Synaptic Plasticity and Promotes Tauopathy-Related Memory Loss.",
         "type": "PubMed",
-        "volume": "35"
+        "volume": "90"
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-      "evidence": "LXR ligands inhibit neither STAT1 phosphorylation nor STAT1 translocation to the nucleus but, rather, inhibit STAT1 binding to promoters and the expression of IRF1, TNFalpha, and IL-6, downstream effectors of STAT1 action. LXRbeta forms a trimer with PIAS1-pSTAT1, whereas LXRalpha formed a trimer with HDAC4-pSTAT1, mediated by direct ligand binding to the LXR proteins. Both PIAS1 and HDAC4 belong to the SUMO E3 ligase family and LXRbeta and LXRalpha were SUMO-conjugated by PIAS1 or HDAC4, respectively, and SUMOylation was blocked by transient transfection of appropriate individual siRNAs, reversing LXR-induced suppression of IRF1 and TNFalpha expression.",
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       "citation": {
         "authors": [
-          "Joe EH",
-          "Jou I",
-          "Kim OS",
-          "Lee CS",
-          "Lee JH",
-          "Park SJ",
-          "Park SM",
-          "Woo JH"
+          "Cong X",
+          "Ellerby LM",
+          "Gan L",
+          "Huganir RL",
+          "Le D",
+          "Li Y",
+          "Lo I",
+          "Min SW",
+          "Minami SS",
+          "Ponnusamy R",
+          "Schilling B",
+          "Sohn PD",
+          "Tracy TE",
+          "Wang C",
+          "Zhou Y"
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-        "date": "2009-09-24",
-        "first": "Lee JH",
-        "last": "Jou I",
-        "name": "Molecular cell",
-        "pages": "806-17",
-        "reference": "19782030",
-        "title": "Differential SUMOylation of LXRalpha and LXRbeta mediates transrepression of STAT1 inflammatory signaling in IFN-gamma-stimulated brain astrocytes.",
+        "date": "2016-04-20",
+        "first": "Tracy TE",
+        "last": "Gan L",
+        "name": "Neuron",
+        "pages": "245-60",
+        "reference": "27041503",
+        "title": "Acetylated Tau Obstructs KIBRA-Mediated Signaling in Synaptic Plasticity and Promotes Tauopathy-Related Memory Loss.",
         "type": "PubMed",
-        "volume": "35"
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-      "evidence": "LXR ligands inhibit neither STAT1 phosphorylation nor STAT1 translocation to the nucleus but, rather, inhibit STAT1 binding to promoters and the expression of IRF1, TNFalpha, and IL-6, downstream effectors of STAT1 action. LXRbeta forms a trimer with PIAS1-pSTAT1, whereas LXRalpha formed a trimer with HDAC4-pSTAT1, mediated by direct ligand binding to the LXR proteins. Both PIAS1 and HDAC4 belong to the SUMO E3 ligase family and LXRbeta and LXRalpha were SUMO-conjugated by PIAS1 or HDAC4, respectively, and SUMOylation was blocked by transient transfection of appropriate individual siRNAs, reversing LXR-induced suppression of IRF1 and TNFalpha expression.",
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         },
-        "Species": {
-          "10116": true
+        "MeSHDisease": {
+          "Alzheimer Disease": true,
+          "Dementia": true
         }
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       "citation": {
         "authors": [
-          "Joe EH",
-          "Jou I",
-          "Kim OS",
-          "Lee CS",
-          "Lee JH",
-          "Park SJ",
-          "Park SM",
-          "Woo JH"
+          "Cong X",
+          "Ellerby LM",
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+          "Huganir RL",
+          "Le D",
+          "Li Y",
+          "Lo I",
+          "Min SW",
+          "Minami SS",
+          "Ponnusamy R",
+          "Schilling B",
+          "Sohn PD",
+          "Tracy TE",
+          "Wang C",
+          "Zhou Y"
         ],
-        "date": "2009-09-24",
-        "first": "Lee JH",
-        "last": "Jou I",
-        "name": "Molecular cell",
-        "pages": "806-17",
-        "reference": "19782030",
-        "title": "Differential SUMOylation of LXRalpha and LXRbeta mediates transrepression of STAT1 inflammatory signaling in IFN-gamma-stimulated brain astrocytes.",
+        "date": "2016-04-20",
+        "first": "Tracy TE",
+        "last": "Gan L",
+        "name": "Neuron",
+        "pages": "245-60",
+        "reference": "27041503",
+        "title": "Acetylated Tau Obstructs KIBRA-Mediated Signaling in Synaptic Plasticity and Promotes Tauopathy-Related Memory Loss.",
         "type": "PubMed",
-        "volume": "35"
+        "volume": "90"
       },
-      "evidence": "LXR ligands inhibit neither STAT1 phosphorylation nor STAT1 translocation to the nucleus but, rather, inhibit STAT1 binding to promoters and the expression of IRF1, TNFalpha, and IL-6, downstream effectors of STAT1 action. LXRbeta forms a trimer with PIAS1-pSTAT1, whereas LXRalpha formed a trimer with HDAC4-pSTAT1, mediated by direct ligand binding to the LXR proteins. Both PIAS1 and HDAC4 belong to the SUMO E3 ligase family and LXRbeta and LXRalpha were SUMO-conjugated by PIAS1 or HDAC4, respectively, and SUMOylation was blocked by transient transfection of appropriate individual siRNAs, reversing LXR-induced suppression of IRF1 and TNFalpha expression.",
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     },
     {
       "annotations": {
-        "Cell": {
-          "astrocyte": true
+        "Confidence": {
+          "Medium": true
+        },
+        "MeSHAnatomy": {
+          "Hippocampus": true
         },
         "Species": {
-          "10116": true
+          "10090": true
         }
       },
       "citation": {
         "authors": [
-          "Joe EH",
-          "Jou I",
-          "Kim OS",
-          "Lee CS",
-          "Lee JH",
-          "Park SJ",
-          "Park SM",
-          "Woo JH"
+          "Cong X",
+          "Ellerby LM",
+          "Gan L",
+          "Huganir RL",
+          "Le D",
+          "Li Y",
+          "Lo I",
+          "Min SW",
+          "Minami SS",
+          "Ponnusamy R",
+          "Schilling B",
+          "Sohn PD",
+          "Tracy TE",
+          "Wang C",
+          "Zhou Y"
         ],
-        "date": "2009-09-24",
-        "first": "Lee JH",
-        "last": "Jou I",
-        "name": "Molecular cell",
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       },
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         "authors": [
-          "Akar CA",
-          "Feinstein DL"
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       "citation": {
         "authors": [
-          "Sarge KD",
-          "Zhang YQ"
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-        "title": "Sumoylation of amyloid precursor protein negatively regulates Abeta aggregate levels.",
+        "date": "2016-04-20",
+        "first": "Tracy TE",
+        "last": "Gan L",
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         "type": "PubMed",
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-          "Zhang YQ"
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       "citation": {
         "authors": [
-          "Sarge KD",
-          "Zhang YQ"
+          "Chen X",
+          "Cong X",
+          "Defensor E",
+          "Ellerby L",
+          "Gan L",
+          "Gestwicki J",
+          "Gibson BW",
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+          "Krogan N",
+          "Li Y",
+          "Masliah E",
+          "Min SW",
+          "Minami SS",
+          "Mok SA",
+          "Schilling B",
+          "Shamloo M",
+          "Shirakawa K",
+          "Sohn PD",
+          "Tracy TE",
+          "Verdin E",
+          "Wang C",
+          "Zhou Y"
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-        "first": "Zhang YQ",
-        "last": "Sarge KD",
-        "name": "Biochemical and biophysical research communications",
-        "pages": "673-8",
-        "reference": "18675254",
-        "title": "Sumoylation of amyloid precursor protein negatively regulates Abeta aggregate levels.",
+        "date": "2015-10-01",
+        "first": "Min SW",
+        "last": "Gan L",
+        "name": "Nature medicine",
+        "pages": "1154-62",
+        "reference": "26390242",
+        "title": "Critical role of acetylation in tau-mediated neurodegeneration and cognitive deficits.",
         "type": "PubMed",
-        "volume": "374"
+        "volume": "21"
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       "citation": {
         "authors": [
-          "Sarge KD",
-          "Zhang YQ"
+          "Chen X",
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+          "Gestwicki J",
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+          "Shamloo M",
+          "Shirakawa K",
+          "Sohn PD",
+          "Tracy TE",
+          "Verdin E",
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-        "first": "Zhang YQ",
-        "last": "Sarge KD",
-        "name": "Biochemical and biophysical research communications",
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-        "title": "Sumoylation of amyloid precursor protein negatively regulates Abeta aggregate levels.",
+        "date": "2015-10-01",
+        "first": "Min SW",
+        "last": "Gan L",
+        "name": "Nature medicine",
+        "pages": "1154-62",
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+        "title": "Critical role of acetylation in tau-mediated neurodegeneration and cognitive deficits.",
         "type": "PubMed",
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       "citation": {
         "authors": [
-          "Sarge KD",
-          "Zhang YQ"
+          "Chen X",
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+          "Shirakawa K",
+          "Sohn PD",
+          "Tracy TE",
+          "Verdin E",
+          "Wang C",
+          "Zhou Y"
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-        "first": "Zhang YQ",
-        "last": "Sarge KD",
-        "name": "Biochemical and biophysical research communications",
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-        "reference": "18675254",
-        "title": "Sumoylation of amyloid precursor protein negatively regulates Abeta aggregate levels.",
+        "date": "2015-10-01",
+        "first": "Min SW",
+        "last": "Gan L",
+        "name": "Nature medicine",
+        "pages": "1154-62",
+        "reference": "26390242",
+        "title": "Critical role of acetylation in tau-mediated neurodegeneration and cognitive deficits.",
         "type": "PubMed",
-        "volume": "374"
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       },
-      "evidence": "Lysines 587 and 595 of APP, immediately adjacent to the site of beta-secretase cleavage, are covalently modified by SUMO proteins in vivo. Sumoylation of these lysine residues is associated with decreased levels of Abeta aggregates. The results demonstrate that the SUMO E2 enzyme (ubc9) is present within the endoplasmic reticulum, indicating how APP, and perhaps other proteins that enter this compartment, can be sumoylated.",
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       "citation": {
         "authors": [
-          "Dorval V",
-          "Fraser PE",
-          "Hay RT",
-          "Mathews PM",
-          "Mazzella MJ"
+          "Chen X",
+          "Cong X",
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+          "Ellerby L",
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+          "Gibson BW",
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+          "Krogan N",
+          "Li Y",
+          "Masliah E",
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+          "Schilling B",
+          "Shamloo M",
+          "Shirakawa K",
+          "Sohn PD",
+          "Tracy TE",
+          "Verdin E",
+          "Wang C",
+          "Zhou Y"
         ],
-        "date": "2007-06-01",
-        "first": "Dorval V",
-        "last": "Fraser PE",
-        "name": "The Biochemical journal",
-        "pages": "309-16",
-        "reference": "17346237",
-        "title": "Modulation of Abeta generation by small ubiquitin-like modifiers does not require conjugation to target proteins.",
+        "date": "2015-10-01",
+        "first": "Min SW",
+        "last": "Gan L",
+        "name": "Nature medicine",
+        "pages": "1154-62",
+        "reference": "26390242",
+        "title": "Critical role of acetylation in tau-mediated neurodegeneration and cognitive deficits.",
         "type": "PubMed",
-        "volume": "404"
+        "volume": "21"
       },
-      "evidence": "SUMO3 overexpression significantly increased Abeta40 and Abeta42 secretion, which was accompanied by an increase in full-length APP and its C-terminal fragments. These effects of SUMO3 were independent of its covalent attachment or chain formation, as mutants lacking the motifs responsible for SUMO chain formation or SUMO conjugation led to similar changes in Abeta. SUMO3 overexpression also up-regulated the expression of the transmembrane protease BACE (beta-amyloid-cleaving enzyme), but failed to affect levels of several other unrelated proteins.",
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       "citation": {
         "authors": [
-          "Dorval V",
-          "Fraser PE",
-          "Hay RT",
-          "Mathews PM",
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+          "Chen X",
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+          "Gestwicki J",
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+          "Li Y",
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+          "Shamloo M",
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+          "Tracy TE",
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-        "date": "2007-06-01",
-        "first": "Dorval V",
-        "last": "Fraser PE",
-        "name": "The Biochemical journal",
-        "pages": "309-16",
-        "reference": "17346237",
-        "title": "Modulation of Abeta generation by small ubiquitin-like modifiers does not require conjugation to target proteins.",
+        "date": "2015-10-01",
+        "first": "Min SW",
+        "last": "Gan L",
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+        "pages": "1154-62",
+        "reference": "26390242",
+        "title": "Critical role of acetylation in tau-mediated neurodegeneration and cognitive deficits.",
         "type": "PubMed",
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-      "evidence": "SUMO3 overexpression significantly increased Abeta40 and Abeta42 secretion, which was accompanied by an increase in full-length APP and its C-terminal fragments. These effects of SUMO3 were independent of its covalent attachment or chain formation, as mutants lacking the motifs responsible for SUMO chain formation or SUMO conjugation led to similar changes in Abeta. SUMO3 overexpression also up-regulated the expression of the transmembrane protease BACE (beta-amyloid-cleaving enzyme), but failed to affect levels of several other unrelated proteins.",
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         "authors": [
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-          "Fraser PE",
-          "Hay RT",
-          "Mathews PM",
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+          "Chen X",
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+          "Tracy TE",
+          "Verdin E",
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-        "first": "Dorval V",
-        "last": "Fraser PE",
-        "name": "The Biochemical journal",
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-        "reference": "17346237",
-        "title": "Modulation of Abeta generation by small ubiquitin-like modifiers does not require conjugation to target proteins.",
+        "date": "2015-10-01",
+        "first": "Min SW",
+        "last": "Gan L",
+        "name": "Nature medicine",
+        "pages": "1154-62",
+        "reference": "26390242",
+        "title": "Critical role of acetylation in tau-mediated neurodegeneration and cognitive deficits.",
         "type": "PubMed",
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       "citation": {
         "authors": [
-          "Dorval V",
-          "Fraser PE"
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+          "Ellerby L",
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+          "Shamloo M",
+          "Shirakawa K",
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+          "Tracy TE",
+          "Verdin E",
+          "Wang C",
+          "Zhou Y"
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-        "first": "Dorval V",
-        "last": "Fraser PE",
-        "name": "The Journal of biological chemistry",
-        "pages": "9919-24",
-        "reference": "16464864",
-        "title": "Small ubiquitin-like modifier (SUMO) modification of natively unfolded proteins tau and alpha-synuclein.",
+        "date": "2015-10-01",
+        "first": "Min SW",
+        "last": "Gan L",
+        "name": "Nature medicine",
+        "pages": "1154-62",
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+        "title": "Critical role of acetylation in tau-mediated neurodegeneration and cognitive deficits.",
         "type": "PubMed",
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       "citation": {
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-          "Fraser PE"
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+          "Krogan N",
+          "Li Y",
+          "Masliah E",
+          "Min SW",
+          "Minami SS",
+          "Mok SA",
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+          "Gaub P",
+          "Hervera A",
+          "Joshi Y",
+          "Laskowski CJ",
+          "Lindner R",
+          "Nguyen T",
+          "Puttagunta R",
+          "Rathore KI",
+          "Schmandke A",
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-        "title": "Downregulation of protein phosphatase 2A by apolipoprotein E: Implications for Alzheimer's disease.",
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@@ -72462,33 +81445,51 @@
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-          "Huang G",
-          "Li M",
-          "Liu H",
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-        "first": "Zheng M",
-        "last": "Liu H",
-        "name": "International journal of molecular sciences",
-        "reference": "28422052",
-        "title": "Folic Acid Reduces Tau Phosphorylation by Regulating PP2A Methylation in Streptozotocin-Induced Diabetic Mice.",
+        "date": "2010-09-23",
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@@ -72496,33 +81497,44 @@
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@@ -72530,1494 +81542,8133 @@
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-          "Huvent I",
-          "Jacquot Y",
-          "Kamah A",
-          "Landrieu I",
-          "Lippens G",
-          "Smet C"
+          "D'Adamio L",
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+          "Rajadhyaksha AM",
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-        "title": "Isomerization and Oligomerization of Truncated and Mutated Tau Forms by FKBP52 are Independent Processes.",
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+        "title": "Amyloid Precursor Protein (APP) May Act as a Substrate and a Recognition Unit for CRL4CRBN and Stub1 E3 Ligases Facilitating Ubiquitination of Proteins Involved in Presynaptic Functions and Neurodegeneration.",
         "type": "PubMed",
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       "citation": {
         "authors": [
-          "Ikura T",
-          "Ito N"
+          "D'Adamio L",
+          "Del Prete D",
+          "Rajadhyaksha AM",
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-        "date": "2013-09-01",
-        "first": "Ikura T",
-        "last": "Ito N",
-        "name": "Protein engineering, design &amp; selection : PEDS",
-        "pages": "539-46",
-        "reference": "23832849",
-        "title": "Peptidyl-prolyl isomerase activity of FK506 binding protein 12 prevents tau peptide from aggregating.",
+        "date": "2016-08-12",
+        "first": "Del Prete D",
+        "last": "D'Adamio L",
+        "name": "The Journal of biological chemistry",
+        "pages": "17209-27",
+        "reference": "27325702",
+        "title": "Amyloid Precursor Protein (APP) May Act as a Substrate and a Recognition Unit for CRL4CRBN and Stub1 E3 Ligases Facilitating Ubiquitination of Proteins Involved in Presynaptic Functions and Neurodegeneration.",
         "type": "PubMed",
-        "volume": "26"
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-      "evidence": "We then investigated the function of FK506-binding protein (FKBP) 12, which is known to accumulate in neurofibrillary tangles in vivo, on aggregation of the R3 peptide and found that FKBP12 completely prevented the peptide from aggregating at a concentration ratio of 1 : 4 (peptide:FKBP12). FKBP12 also restored the oligomer of the peptide to its monomeric status. Mutational studies on the catalytic center of FKBP12 indicated that peptidyl-prolyl isomerase activity of FKBP12 was essential for prevention of aggregation. Assuming that the propensity of aggregation of the peptide is different in each cis-/trans-isomer, we propose that the aggregation behavior of the R3 peptide can be theoretically described with a simple kinetic scheme, in which only the cis-isomer can aggregate and FKBP12 catalyzes isomerization of the peptide in both the monomeric and aggregative states.",
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     {
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+          "High": true
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       "citation": {
         "authors": [
-          "Ando K",
-          "Blum D",
-          "Bretteville A",
-          "Buée L",
-          "Bégard S",
-          "Bélarbi K",
-          "Caillet-Boudin ML",
-          "Demey-Thomas E",
-          "Dourlen P",
-          "Drobecq H",
-          "Eddarkaoui S",
-          "Galas MC",
-          "Ghestem A",
-          "Hamdane M",
-          "Landrieu I",
-          "Lippens G",
-          "Maurage CA",
-          "Melnyk P",
-          "Sambo AV",
-          "Sergeant N",
-          "Smet C",
-          "Verdier Y",
-          "Vingtdeux V",
-          "Vinh J"
+          "D'Adamio L",
+          "Del Prete D",
+          "Rajadhyaksha AM",
+          "Rice RC"
         ],
-        "date": "2013-03-01",
-        "first": "Ando K",
-        "last": "Buée L",
-        "name": "Neurobiology of aging",
-        "pages": "757-69",
-        "reference": "22926167",
-        "title": "Tau pathology modulates Pin1 post-translational modifications and may be relevant as biomarker.",
+        "date": "2016-08-12",
+        "first": "Del Prete D",
+        "last": "D'Adamio L",
+        "name": "The Journal of biological chemistry",
+        "pages": "17209-27",
+        "reference": "27325702",
+        "title": "Amyloid Precursor Protein (APP) May Act as a Substrate and a Recognition Unit for CRL4CRBN and Stub1 E3 Ligases Facilitating Ubiquitination of Proteins Involved in Presynaptic Functions and Neurodegeneration.",
         "type": "PubMed",
-        "volume": "34"
+        "volume": "291"
       },
-      "evidence": "Because Pin1 has at least 4 major isovariants in addition to the native polypeptide, this means that Pin1 has 4 (possibly more) posttranslational modifications including phosphorylation at 3 sites (Ser16 and Ser65/Ser71), N-acetylation (amino-terminus and Lys46) and oxidation (Met130 and 146). In all experimental conditions, including tau-overexpressing cells, tau transgenic mice and AD brains, global levels of Pin1 posttranslational modifications were decreased compared with control conditions.",
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     {
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       "citation": {
         "authors": [
-          "Ando K",
-          "Blum D",
-          "Bretteville A",
-          "Buée L",
-          "Bégard S",
-          "Bélarbi K",
-          "Caillet-Boudin ML",
-          "Demey-Thomas E",
-          "Dourlen P",
-          "Drobecq H",
-          "Eddarkaoui S",
-          "Galas MC",
-          "Ghestem A",
-          "Hamdane M",
-          "Landrieu I",
-          "Lippens G",
-          "Maurage CA",
-          "Melnyk P",
-          "Sambo AV",
-          "Sergeant N",
-          "Smet C",
-          "Verdier Y",
-          "Vingtdeux V",
-          "Vinh J"
+          "D'Adamio L",
+          "Del Prete D",
+          "Rajadhyaksha AM",
+          "Rice RC"
         ],
-        "date": "2013-03-01",
-        "first": "Ando K",
-        "last": "Buée L",
-        "name": "Neurobiology of aging",
-        "pages": "757-69",
-        "reference": "22926167",
-        "title": "Tau pathology modulates Pin1 post-translational modifications and may be relevant as biomarker.",
+        "date": "2016-08-12",
+        "first": "Del Prete D",
+        "last": "D'Adamio L",
+        "name": "The Journal of biological chemistry",
+        "pages": "17209-27",
+        "reference": "27325702",
+        "title": "Amyloid Precursor Protein (APP) May Act as a Substrate and a Recognition Unit for CRL4CRBN and Stub1 E3 Ligases Facilitating Ubiquitination of Proteins Involved in Presynaptic Functions and Neurodegeneration.",
         "type": "PubMed",
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-      "evidence": "In fact, phosphorylation of Pin1 at Ser16 inhibits its nuclear localization possibly through inhibition of Pin1 substrate-binding property (Lu et al., 2002) while phosphorylation at Ser65 does not change activity of localization but stabilizes Pin1 by preventing its ubiquitination",
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+      "evidence": "As reported in Table 6, several brain-derived proteins associated with the ACR bait were ubiquitinated. These proteins can be separated into four groups as follows: (a) group 1, proteins of the ubiquitin-conjugating system; (b) group 2, presynaptic proteins; (c) group 3, other proteins implicated in AD; and (d) group 4, phosphorylation-dependent ACR interactors.",
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     {
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       "citation": {
         "authors": [
-          "Ando K",
-          "Blum D",
-          "Bretteville A",
-          "Buée L",
-          "Bégard S",
-          "Bélarbi K",
-          "Caillet-Boudin ML",
-          "Demey-Thomas E",
-          "Dourlen P",
-          "Drobecq H",
-          "Eddarkaoui S",
-          "Galas MC",
-          "Ghestem A",
-          "Hamdane M",
-          "Landrieu I",
-          "Lippens G",
-          "Maurage CA",
-          "Melnyk P",
-          "Sambo AV",
-          "Sergeant N",
-          "Smet C",
-          "Verdier Y",
-          "Vingtdeux V",
-          "Vinh J"
+          "D'Adamio L",
+          "Del Prete D",
+          "Rajadhyaksha AM",
+          "Rice RC"
         ],
-        "date": "2013-03-01",
-        "first": "Ando K",
-        "last": "Buée L",
-        "name": "Neurobiology of aging",
-        "pages": "757-69",
-        "reference": "22926167",
-        "title": "Tau pathology modulates Pin1 post-translational modifications and may be relevant as biomarker.",
+        "date": "2016-08-12",
+        "first": "Del Prete D",
+        "last": "D'Adamio L",
+        "name": "The Journal of biological chemistry",
+        "pages": "17209-27",
+        "reference": "27325702",
+        "title": "Amyloid Precursor Protein (APP) May Act as a Substrate and a Recognition Unit for CRL4CRBN and Stub1 E3 Ligases Facilitating Ubiquitination of Proteins Involved in Presynaptic Functions and Neurodegeneration.",
         "type": "PubMed",
-        "volume": "34"
+        "volume": "291"
       },
-      "evidence": "Because Pin1 has at least 4 major isovariants in addition to the native polypeptide, this means that Pin1 has 4 (possibly more) posttranslational modifications including phosphorylation at 3 sites (Ser16 and Ser65/Ser71), N-acetylation (amino-terminus and Lys46) and oxidation (Met130 and 146). In all experimental conditions, including tau-overexpressing cells, tau transgenic mice and AD brains, global levels of Pin1 posttranslational modifications were decreased compared with control conditions.",
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     {
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       "citation": {
         "authors": [
-          "Ando K",
-          "Blum D",
-          "Bretteville A",
-          "Buée L",
-          "Bégard S",
-          "Bélarbi K",
-          "Caillet-Boudin ML",
-          "Demey-Thomas E",
-          "Dourlen P",
-          "Drobecq H",
-          "Eddarkaoui S",
-          "Galas MC",
-          "Ghestem A",
-          "Hamdane M",
-          "Landrieu I",
-          "Lippens G",
-          "Maurage CA",
-          "Melnyk P",
-          "Sambo AV",
-          "Sergeant N",
-          "Smet C",
-          "Verdier Y",
-          "Vingtdeux V",
-          "Vinh J"
+          "D'Adamio L",
+          "Del Prete D",
+          "Rajadhyaksha AM",
+          "Rice RC"
         ],
-        "date": "2013-03-01",
-        "first": "Ando K",
-        "last": "Buée L",
-        "name": "Neurobiology of aging",
-        "pages": "757-69",
-        "reference": "22926167",
-        "title": "Tau pathology modulates Pin1 post-translational modifications and may be relevant as biomarker.",
+        "date": "2016-08-12",
+        "first": "Del Prete D",
+        "last": "D'Adamio L",
+        "name": "The Journal of biological chemistry",
+        "pages": "17209-27",
+        "reference": "27325702",
+        "title": "Amyloid Precursor Protein (APP) May Act as a Substrate and a Recognition Unit for CRL4CRBN and Stub1 E3 Ligases Facilitating Ubiquitination of Proteins Involved in Presynaptic Functions and Neurodegeneration.",
         "type": "PubMed",
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-      "evidence": "In fact, phosphorylation of Pin1 at Ser16 inhibits its nuclear localization possibly through inhibition of Pin1 substrate-binding property (Lu et al., 2002) while phosphorylation at Ser65 does not change activity of localization but stabilizes Pin1 by preventing its ubiquitination",
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     {
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       "citation": {
         "authors": [
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-          "Blum D",
-          "Bretteville A",
-          "Buée L",
-          "Bégard S",
-          "Bélarbi K",
-          "Caillet-Boudin ML",
+          "D'Adamio L",
+          "Del Prete D",
+          "Rajadhyaksha AM",
+          "Rice RC"
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+        "date": "2016-08-12",
+        "first": "Del Prete D",
+        "last": "D'Adamio L",
+        "name": "The Journal of biological chemistry",
+        "pages": "17209-27",
+        "reference": "27325702",
+        "title": "Amyloid Precursor Protein (APP) May Act as a Substrate and a Recognition Unit for CRL4CRBN and Stub1 E3 Ligases Facilitating Ubiquitination of Proteins Involved in Presynaptic Functions and Neurodegeneration.",
+        "type": "PubMed",
+        "volume": "291"
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+      "evidence": "As reported in Table 6, several brain-derived proteins associated with the ACR bait were ubiquitinated. These proteins can be separated into four groups as follows: (a) group 1, proteins of the ubiquitin-conjugating system; (b) group 2, presynaptic proteins; (c) group 3, other proteins implicated in AD; and (d) group 4, phosphorylation-dependent ACR interactors.",
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+        "first": "Del Prete D",
+        "last": "D'Adamio L",
+        "name": "The Journal of biological chemistry",
+        "pages": "17209-27",
+        "reference": "27325702",
+        "title": "Amyloid Precursor Protein (APP) May Act as a Substrate and a Recognition Unit for CRL4CRBN and Stub1 E3 Ligases Facilitating Ubiquitination of Proteins Involved in Presynaptic Functions and Neurodegeneration.",
+        "type": "PubMed",
+        "volume": "291"
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+      "evidence": "As reported in Table 6, several brain-derived proteins associated with the ACR bait were ubiquitinated. These proteins can be separated into four groups as follows: (a) group 1, proteins of the ubiquitin-conjugating system; (b) group 2, presynaptic proteins; (c) group 3, other proteins implicated in AD; and (d) group 4, phosphorylation-dependent ACR interactors.",
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+        "first": "Del Prete D",
+        "last": "D'Adamio L",
+        "name": "The Journal of biological chemistry",
+        "pages": "17209-27",
+        "reference": "27325702",
+        "title": "Amyloid Precursor Protein (APP) May Act as a Substrate and a Recognition Unit for CRL4CRBN and Stub1 E3 Ligases Facilitating Ubiquitination of Proteins Involved in Presynaptic Functions and Neurodegeneration.",
+        "type": "PubMed",
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+      "evidence": "As reported in Table 6, several brain-derived proteins associated with the ACR bait were ubiquitinated. These proteins can be separated into four groups as follows: (a) group 1, proteins of the ubiquitin-conjugating system; (b) group 2, presynaptic proteins; (c) group 3, other proteins implicated in AD; and (d) group 4, phosphorylation-dependent ACR interactors.",
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+        "last": "D'Adamio L",
+        "name": "The Journal of biological chemistry",
+        "pages": "17209-27",
+        "reference": "27325702",
+        "title": "Amyloid Precursor Protein (APP) May Act as a Substrate and a Recognition Unit for CRL4CRBN and Stub1 E3 Ligases Facilitating Ubiquitination of Proteins Involved in Presynaptic Functions and Neurodegeneration.",
+        "type": "PubMed",
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+      "evidence": "As reported in Table 6, several brain-derived proteins associated with the ACR bait were ubiquitinated. These proteins can be separated into four groups as follows: (a) group 1, proteins of the ubiquitin-conjugating system; (b) group 2, presynaptic proteins; (c) group 3, other proteins implicated in AD; and (d) group 4, phosphorylation-dependent ACR interactors.",
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+        "first": "Del Prete D",
+        "last": "D'Adamio L",
+        "name": "The Journal of biological chemistry",
+        "pages": "17209-27",
+        "reference": "27325702",
+        "title": "Amyloid Precursor Protein (APP) May Act as a Substrate and a Recognition Unit for CRL4CRBN and Stub1 E3 Ligases Facilitating Ubiquitination of Proteins Involved in Presynaptic Functions and Neurodegeneration.",
+        "type": "PubMed",
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+      "evidence": "As reported in Table 6, several brain-derived proteins associated with the ACR bait were ubiquitinated. These proteins can be separated into four groups as follows: (a) group 1, proteins of the ubiquitin-conjugating system; (b) group 2, presynaptic proteins; (c) group 3, other proteins implicated in AD; and (d) group 4, phosphorylation-dependent ACR interactors.",
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+        "date": "2016-08-12",
+        "first": "Del Prete D",
+        "last": "D'Adamio L",
+        "name": "The Journal of biological chemistry",
+        "pages": "17209-27",
+        "reference": "27325702",
+        "title": "Amyloid Precursor Protein (APP) May Act as a Substrate and a Recognition Unit for CRL4CRBN and Stub1 E3 Ligases Facilitating Ubiquitination of Proteins Involved in Presynaptic Functions and Neurodegeneration.",
+        "type": "PubMed",
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+      "evidence": "As reported in Table 6, several brain-derived proteins associated with the ACR bait were ubiquitinated. These proteins can be separated into four groups as follows: (a) group 1, proteins of the ubiquitin-conjugating system; (b) group 2, presynaptic proteins; (c) group 3, other proteins implicated in AD; and (d) group 4, phosphorylation-dependent ACR interactors.",
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+          "D'Adamio L",
+          "Del Prete D",
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+        "date": "2016-08-12",
+        "first": "Del Prete D",
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+        "title": "SUMOylation at K340 inhibits tau degradation through deregulating its phosphorylation and ubiquitination.",
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+          "Albrecht F",
+          "Arendt T",
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+          "Flach K",
+          "Goedert M",
+          "Herrmann L",
+          "Hilbrich I",
+          "Holzer M",
+          "Ramminger E"
+        ],
+        "date": "2014-09-01",
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+        "last": "Holzer M",
+        "name": "Biochimica et biophysica acta",
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+        "title": "Axotrophin/MARCH7 acts as an E3 ubiquitin ligase and ubiquitinates tau protein in vitro impairing microtubule binding.",
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+      "evidence": "We show that axotrophin/MARCH7, a RING-variant domain containing protein with similarity to E3 ubiquitin ligases interacts with tau. We find here that tau becomes mono-ubiquitinated by recombinant tau-interacting RING-variant domain, which diminishes its microtubule-binding. Tau becomes mono-ubiquitinated by recombinant tau-interacting RING-variant domain reducing microtubule-binding.",
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+          "Alzheimer Disease": true
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+        "authors": [
+          "Feng Y",
+          "Jiang J",
+          "Liu XH",
+          "Liu ZC",
+          "Luo HB",
+          "Shu XJ",
+          "Wang JZ",
+          "Wang XC",
+          "Xia YY",
+          "Xiong YS",
+          "Ye K",
+          "Yin G",
+          "Yu G",
+          "Zeng K"
+        ],
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+        "first": "Luo HB",
+        "last": "Wang JZ",
+        "name": "Proceedings of the National Academy of Sciences of the United States of America",
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+        "reference": "25378699",
+        "title": "SUMOylation at K340 inhibits tau degradation through deregulating its phosphorylation and ubiquitination.",
+        "type": "PubMed",
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+      "evidence": "Furthermore, the enhanced SUMO-immunoreactivity, costained with the hyperphosphorylated tau, is detected in cerebral cortex of the AD brains, and β-amyloid exposure of rat primary hippocampal neurons induces a dose-dependent SUMOylation of the hyperphosphorylated tau. Our findings suggest that tau SUMOylation reciprocally stimulates its phosphorylation and inhibits the ubiquitination-mediated tau degradation, which provides a new insight into the AD-like tau accumulation.",
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+          "Feng Y",
+          "Jiang J",
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+          "Liu ZC",
+          "Luo HB",
+          "Shu XJ",
+          "Wang JZ",
+          "Wang XC",
+          "Xia YY",
+          "Xiong YS",
+          "Ye K",
+          "Yin G",
+          "Yu G",
+          "Zeng K"
+        ],
+        "date": "2014-11-18",
+        "first": "Luo HB",
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+        "name": "Proceedings of the National Academy of Sciences of the United States of America",
+        "pages": "16586-91",
+        "reference": "25378699",
+        "title": "SUMOylation at K340 inhibits tau degradation through deregulating its phosphorylation and ubiquitination.",
+        "type": "PubMed",
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+      },
+      "evidence": "Furthermore, the enhanced SUMO-immunoreactivity, costained with the hyperphosphorylated tau, is detected in cerebral cortex of the AD brains, and β-amyloid exposure of rat primary hippocampal neurons induces a dose-dependent SUMOylation of the hyperphosphorylated tau. Our findings suggest that tau SUMOylation reciprocally stimulates its phosphorylation and inhibits the ubiquitination-mediated tau degradation, which provides a new insight into the AD-like tau accumulation.",
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+        "authors": [
+          "Clelland CL",
+          "Duff KE",
+          "Emrani S",
+          "Goldberg AL",
+          "Kukushkin NV",
+          "Myeku N",
+          "Yu WH"
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+        "date": "2016-01-01",
+        "first": "Myeku N",
+        "last": "Duff KE",
+        "name": "Nature medicine",
+        "pages": "46-53",
+        "reference": "26692334",
+        "title": "Tau-driven 26S proteasome impairment and cognitive dysfunction can be prevented early in disease by activating cAMP-PKA signaling.",
+        "type": "PubMed",
+        "volume": "22"
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+      "evidence": "Rolipram is a specific phosphodiesterase type 4 (PDE4) inhibitor that increases cAMP levels in multiple tissues in vivo. The chymotrypsin-like activity of the 26S proteasomes in crude extracts was elevated after administration of db-cAMP or rolipram but was blocked by epoxomicin Exposure of slices from the early-stage mice to rolipram or db-cAMP for 8 h reduced amounts of total and insoluble tau (Fig. 3a), including phosphorylated tau (Supplementary Fig. 4a,b). In contrast, epoxomicin treatment increased levels of phosphorylated tau (Supplementary Fig. 4), although the amount of total tau remained unchanged (Fig. 3a). PKA is known to phosphorylate tau at Ser214 (pS214)29. We therefore monitored the amount of pS214 tau to determine whether rolipram and db-cAMP activated PKA. The amount of pS214 tau was higher in db-cAMP– and rolipram-treated samples than in control (DMSO) and epoxomicin-treated slices (Fig. 3a).",
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+          "Duff KE",
+          "Emrani S",
+          "Goldberg AL",
+          "Kukushkin NV",
+          "Myeku N",
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+        "first": "Myeku N",
+        "last": "Duff KE",
+        "name": "Nature medicine",
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+        "title": "Tau-driven 26S proteasome impairment and cognitive dysfunction can be prevented early in disease by activating cAMP-PKA signaling.",
+        "type": "PubMed",
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+      "evidence": "Rolipram is a specific phosphodiesterase type 4 (PDE4) inhibitor that increases cAMP levels in multiple tissues in vivo. The chymotrypsin-like activity of the 26S proteasomes in crude extracts was elevated after administration of db-cAMP or rolipram but was blocked by epoxomicin Exposure of slices from the early-stage mice to rolipram or db-cAMP for 8 h reduced amounts of total and insoluble tau (Fig. 3a), including phosphorylated tau (Supplementary Fig. 4a,b). In contrast, epoxomicin treatment increased levels of phosphorylated tau (Supplementary Fig. 4), although the amount of total tau remained unchanged (Fig. 3a). PKA is known to phosphorylate tau at Ser214 (pS214)29. We therefore monitored the amount of pS214 tau to determine whether rolipram and db-cAMP activated PKA. The amount of pS214 tau was higher in db-cAMP– and rolipram-treated samples than in control (DMSO) and epoxomicin-treated slices (Fig. 3a).",
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+          "Myeku N",
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+        "first": "Myeku N",
+        "last": "Duff KE",
+        "name": "Nature medicine",
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+        "reference": "26692334",
+        "title": "Tau-driven 26S proteasome impairment and cognitive dysfunction can be prevented early in disease by activating cAMP-PKA signaling.",
+        "type": "PubMed",
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+      "evidence": "Rolipram is a specific phosphodiesterase type 4 (PDE4) inhibitor that increases cAMP levels in multiple tissues in vivo. The chymotrypsin-like activity of the 26S proteasomes in crude extracts was elevated after administration of db-cAMP or rolipram but was blocked by epoxomicin Exposure of slices from the early-stage mice to rolipram or db-cAMP for 8 h reduced amounts of total and insoluble tau (Fig. 3a), including phosphorylated tau (Supplementary Fig. 4a,b). In contrast, epoxomicin treatment increased levels of phosphorylated tau (Supplementary Fig. 4), although the amount of total tau remained unchanged (Fig. 3a). PKA is known to phosphorylate tau at Ser214 (pS214)29. We therefore monitored the amount of pS214 tau to determine whether rolipram and db-cAMP activated PKA. The amount of pS214 tau was higher in db-cAMP– and rolipram-treated samples than in control (DMSO) and epoxomicin-treated slices (Fig. 3a).",
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+        "reference": "26692334",
+        "title": "Tau-driven 26S proteasome impairment and cognitive dysfunction can be prevented early in disease by activating cAMP-PKA signaling.",
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+      "evidence": "Rolipram is a specific phosphodiesterase type 4 (PDE4) inhibitor that increases cAMP levels in multiple tissues in vivo. The chymotrypsin-like activity of the 26S proteasomes in crude extracts was elevated after administration of db-cAMP or rolipram but was blocked by epoxomicin Exposure of slices from the early-stage mice to rolipram or db-cAMP for 8 h reduced amounts of total and insoluble tau (Fig. 3a), including phosphorylated tau (Supplementary Fig. 4a,b). In contrast, epoxomicin treatment increased levels of phosphorylated tau (Supplementary Fig. 4), although the amount of total tau remained unchanged (Fig. 3a). PKA is known to phosphorylate tau at Ser214 (pS214)29. We therefore monitored the amount of pS214 tau to determine whether rolipram and db-cAMP activated PKA. The amount of pS214 tau was higher in db-cAMP– and rolipram-treated samples than in control (DMSO) and epoxomicin-treated slices (Fig. 3a).",
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+        "first": "Myeku N",
+        "last": "Duff KE",
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+        "title": "Tau-driven 26S proteasome impairment and cognitive dysfunction can be prevented early in disease by activating cAMP-PKA signaling.",
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+      "evidence": "Rolipram is a specific phosphodiesterase type 4 (PDE4) inhibitor that increases cAMP levels in multiple tissues in vivo. The chymotrypsin-like activity of the 26S proteasomes in crude extracts was elevated after administration of db-cAMP or rolipram but was blocked by epoxomicin Exposure of slices from the early-stage mice to rolipram or db-cAMP for 8 h reduced amounts of total and insoluble tau (Fig. 3a), including phosphorylated tau (Supplementary Fig. 4a,b). In contrast, epoxomicin treatment increased levels of phosphorylated tau (Supplementary Fig. 4), although the amount of total tau remained unchanged (Fig. 3a). PKA is known to phosphorylate tau at Ser214 (pS214)29. We therefore monitored the amount of pS214 tau to determine whether rolipram and db-cAMP activated PKA. The amount of pS214 tau was higher in db-cAMP– and rolipram-treated samples than in control (DMSO) and epoxomicin-treated slices (Fig. 3a).",
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+          "Duff KE",
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+          "Goldberg AL",
+          "Kukushkin NV",
+          "Myeku N",
+          "Yu WH"
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+        "first": "Myeku N",
+        "last": "Duff KE",
+        "name": "Nature medicine",
+        "pages": "46-53",
+        "reference": "26692334",
+        "title": "Tau-driven 26S proteasome impairment and cognitive dysfunction can be prevented early in disease by activating cAMP-PKA signaling.",
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+      "evidence": "Rolipram is a specific phosphodiesterase type 4 (PDE4) inhibitor that increases cAMP levels in multiple tissues in vivo. The chymotrypsin-like activity of the 26S proteasomes in crude extracts was elevated after administration of db-cAMP or rolipram but was blocked by epoxomicin Exposure of slices from the early-stage mice to rolipram or db-cAMP for 8 h reduced amounts of total and insoluble tau (Fig. 3a), including phosphorylated tau (Supplementary Fig. 4a,b). In contrast, epoxomicin treatment increased levels of phosphorylated tau (Supplementary Fig. 4), although the amount of total tau remained unchanged (Fig. 3a). PKA is known to phosphorylate tau at Ser214 (pS214)29. We therefore monitored the amount of pS214 tau to determine whether rolipram and db-cAMP activated PKA. The amount of pS214 tau was higher in db-cAMP– and rolipram-treated samples than in control (DMSO) and epoxomicin-treated slices (Fig. 3a).",
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+          "Albrecht F",
+          "Arendt T",
+          "Arsalan-Werner A",
+          "Flach K",
+          "Goedert M",
+          "Herrmann L",
+          "Hilbrich I",
+          "Holzer M",
+          "Ramminger E"
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+        "first": "Flach K",
+        "last": "Holzer M",
+        "name": "Biochimica et biophysica acta",
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+        "title": "Axotrophin/MARCH7 acts as an E3 ubiquitin ligase and ubiquitinates tau protein in vitro impairing microtubule binding.",
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+      "evidence": "We show that axotrophin/MARCH7, a RING-variant domain containing protein with similarity to E3 ubiquitin ligases interacts with tau. We find here that tau becomes mono-ubiquitinated by recombinant tau-interacting RING-variant domain, which diminishes its microtubule-binding. Tau becomes mono-ubiquitinated by recombinant tau-interacting RING-variant domain reducing microtubule-binding.",
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+          "Suzuki M",
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+        "title": "Ubiquitin is conjugated with amino-terminally processed tau in paired helical filaments.",
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+          "Suzuki M",
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+          "Titani K"
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+        "reference": "8391280",
+        "title": "Ubiquitin is conjugated with amino-terminally processed tau in paired helical filaments.",
+        "type": "PubMed",
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+      "evidence": "Ubiquitination occurs at lysines (K254, K257 K311) in repeat domain; participates in triage process",
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+          "Suzuki M",
+          "Takio K",
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+        "date": "1993-06-01",
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+        "title": "Ubiquitin is conjugated with amino-terminally processed tau in paired helical filaments.",
+        "type": "PubMed",
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+      "evidence": "Ubiquitination occurs at lysines (K254, K257 K311) in repeat domain; participates in triage process",
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+          "Hamel C",
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+        "date": "2016-10-01",
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+        "title": "Pathological conformations involving the amino terminus of tau occur early in Alzheimer's disease and are differentially detected by monoclonal antibodies.",
+        "type": "PubMed",
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+      "evidence": "Previously, we have shown that TNT1 is a marker of PAD exposure and that this event occurs early in the progression of Alzheimer’s disease. Establishing whether this was true for all N-terminal antibodies was important for understanding more about PAD exposure in Alzheimer’s disease. We significantly extend these findings with TNT1 and show that TNT2 behaves similarly as a marker of PAD exposure. In contrast, other N-terminal antibodies, with slightly different epitopes, do not function as pathological, PAD exposure-specific markers and recognize all forms of tau similarly. Here, we found that TNT1 and TNT2 appear in Braak I–II stages and do not colocalize with ThR in the diffuse, granular pre-tangle pathology conclusively demonstrating that PAD exposure is an early event.",
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+        "authors": [
+          "Akaike T",
+          "Ida T",
+          "Matsushita K",
+          "Soeda Y",
+          "Sumioka A",
+          "Takashima A",
+          "Yoshikawa M",
+          "Yoshitake J"
+        ],
+        "date": "2016-10-21",
+        "first": "Yoshitake J",
+        "last": "Takashima A",
+        "name": "The Journal of biological chemistry",
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+          "Kanaan NM",
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+          "Nilson AN",
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+      "evidence": "Tau Oligomers co-localize with astrocytes, microglia, and HMGB1, a pro-inflammatory cytokine, are present in the retina and are associated with inflammatory cells.",
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+        "name": "The Journal of biological chemistry",
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+          "Brew BJ",
+          "Cullen KM",
+          "Guillemin GJ",
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+        "title": "The excitotoxin quinolinic acid induces tau phosphorylation in human neurons.",
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+      "evidence": "Kynurenic pathway is overactive in AD. QA is co-localized with hyperphosphorylated tau within cortical neurons in AD brain. In primary cultures of human neurons, QA treatment increased tau phosphorylation at serine 199/202, threonine 231 and serine 396/404 in a dose dependent manner. This increase in tau phosphorylation was paralleled by a substantial decrease in the total protein phosphatase activity, mostly in PP2A expression and modest in PP1.",
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+          "Braidy N",
+          "Brew BJ",
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+          "Guillemin GJ",
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+        "name": "PloS one",
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+          "Braidy N",
+          "Brew BJ",
+          "Cullen KM",
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+        "title": "The excitotoxin quinolinic acid induces tau phosphorylation in human neurons.",
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+      "evidence": "Kynurenic pathway is overactive in AD. QA is co-localized with hyperphosphorylated tau within cortical neurons in AD brain. In primary cultures of human neurons, QA treatment increased tau phosphorylation at serine 199/202, threonine 231 and serine 396/404 in a dose dependent manner. This increase in tau phosphorylation was paralleled by a substantial decrease in the total protein phosphatase activity, mostly in PP2A expression and modest in PP1.",
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+          "Braidy N",
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+        "name": "PloS one",
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+          "Brew BJ",
+          "Cullen KM",
+          "Guillemin GJ",
+          "Rahman A",
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+      "evidence": "Western blot analyses showed a decrease of methyl-PP2A and an increase of demethyl-PP2A with a concomitant reduction in the methyl/demethyl PP2A ratio in both PSP (74%) and AD (76%) brains, associated with an LCMT-1 decrease and a demethylating enzyme increase, protein phosphatase methylesterase (PME-1), in both diseases.",
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+          "Arendt T",
+          "Brückner MK",
+          "Gruschka H",
+          "Hilbrich I",
+          "Holzer M",
+          "Rohn S",
+          "Ueberham E",
+          "Ueberham U",
+          "Wodischeck S"
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+        "title": "Pin1 promotes degradation of Smad proteins and their interaction with phosphorylated tau in Alzheimer's disease.",
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+        "MeSHAnatomy": {
+          "Cell Nucleus": true
+        }
+      },
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+          "Arendt T",
+          "Brückner MK",
+          "Gruschka H",
+          "Hilbrich I",
+          "Holzer M",
+          "Rohn S",
+          "Ueberham E",
+          "Ueberham U",
+          "Wodischeck S"
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+        "date": "2014-12-01",
+        "first": "Ueberham U",
+        "last": "Arendt T",
+        "name": "Neuropathology and applied neurobiology",
+        "pages": "815-32",
+        "reference": "24964035",
+        "title": "Pin1 promotes degradation of Smad proteins and their interaction with phosphorylated tau in Alzheimer's disease.",
+        "type": "PubMed",
+        "volume": "40"
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+      "evidence": "Alltogether, this provides evidence for a negative feed-back regulation of Pin1 by Smad. A similar mechanism might be instrumental in AD, where nuclear Smad concentrations are significantly reduced , which potentially contributes to increased levels of Pin1 [16]",
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+      "citation": {
+        "authors": [
+          "Lu KP",
+          "Nakamura K",
+          "Zhou XZ"
+        ],
+        "date": "2013-08-01",
+        "first": "Nakamura K",
+        "last": "Lu KP",
+        "name": "Current molecular medicine",
+        "pages": "1098-109",
+        "reference": "23157676",
+        "title": "Distinct functions of cis and trans phosphorylated tau in Alzheimer's disease and their therapeutic implications.",
+        "type": "PubMed",
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+      "evidence": "Pin1 accelerates cis to trans conversion to prevent accumulation of pathogenic cis p-tau conformation in AD, providing the first structural evidence for how Pin1 protects against AD.",
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+      "citation": {
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+          "Lu KP",
+          "Nakamura K",
+          "Zhou XZ"
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+        "date": "2013-08-01",
+        "first": "Nakamura K",
+        "last": "Lu KP",
+        "name": "Current molecular medicine",
+        "pages": "1098-109",
+        "reference": "23157676",
+        "title": "Distinct functions of cis and trans phosphorylated tau in Alzheimer's disease and their therapeutic implications.",
+        "type": "PubMed",
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+      "evidence": "Pin1 accelerates cis to trans conversion to prevent accumulation of pathogenic cis p-tau conformation in AD, providing the first structural evidence for how Pin1 protects against AD.",
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+          "High": true
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+        "authors": [
+          "Baulieu EE",
+          "Byrne C",
+          "Cantrelle FX",
+          "Chambraud B",
+          "Giustiniani J",
+          "Guillemeau K",
+          "Huvent I",
+          "Jacquot Y",
+          "Kamah A",
+          "Landrieu I",
+          "Lippens G",
+          "Smet C"
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+        "date": "2016-03-27",
+        "first": "Kamah A",
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+        "name": "Journal of molecular biology",
+        "pages": "1080-1090",
+        "reference": "26903089",
+        "title": "Isomerization and Oligomerization of Truncated and Mutated Tau Forms by FKBP52 are Independent Processes.",
+        "type": "PubMed",
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+      "evidence": "We identified a novel molecular interaction implying the PHF6 peptide of Tau and the FK1/FK2 domains of FKBP52 independent of FK506 binding; suggesting a non-catalytic molecular interaction that might govern the effect of FKBP52 on Tau.",
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+        "authors": [
+          "Ikura T",
+          "Ito N"
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+        "date": "2013-09-01",
+        "first": "Ikura T",
+        "last": "Ito N",
+        "name": "Protein engineering, design &amp; selection : PEDS",
+        "pages": "539-46",
+        "reference": "23832849",
+        "title": "Peptidyl-prolyl isomerase activity of FK506 binding protein 12 prevents tau peptide from aggregating.",
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+        "volume": "26"
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+      "evidence": "We then investigated the function of FK506-binding protein (FKBP) 12, which is known to accumulate in neurofibrillary tangles in vivo, on aggregation of the R3 peptide and found that FKBP12 completely prevented the peptide from aggregating at a concentration ratio of 1 : 4 (peptide:FKBP12). FKBP12 also restored the oligomer of the peptide to its monomeric status. Mutational studies on the catalytic center of FKBP12 indicated that peptidyl-prolyl isomerase activity of FKBP12 was essential for prevention of aggregation. Assuming that the propensity of aggregation of the peptide is different in each cis-/trans-isomer, we propose that the aggregation behavior of the R3 peptide can be theoretically described with a simple kinetic scheme, in which only the cis-isomer can aggregate and FKBP12 catalyzes isomerization of the peptide in both the monomeric and aggregative states.",
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+        "pages": "539-46",
+        "reference": "23832849",
+        "title": "Peptidyl-prolyl isomerase activity of FK506 binding protein 12 prevents tau peptide from aggregating.",
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+        "volume": "26"
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+      "evidence": "We then investigated the function of FK506-binding protein (FKBP) 12, which is known to accumulate in neurofibrillary tangles in vivo, on aggregation of the R3 peptide and found that FKBP12 completely prevented the peptide from aggregating at a concentration ratio of 1 : 4 (peptide:FKBP12). FKBP12 also restored the oligomer of the peptide to its monomeric status. Mutational studies on the catalytic center of FKBP12 indicated that peptidyl-prolyl isomerase activity of FKBP12 was essential for prevention of aggregation. Assuming that the propensity of aggregation of the peptide is different in each cis-/trans-isomer, we propose that the aggregation behavior of the R3 peptide can be theoretically described with a simple kinetic scheme, in which only the cis-isomer can aggregate and FKBP12 catalyzes isomerization of the peptide in both the monomeric and aggregative states.",
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+        "last": "Ito N",
+        "name": "Protein engineering, design &amp; selection : PEDS",
+        "pages": "539-46",
+        "reference": "23832849",
+        "title": "Peptidyl-prolyl isomerase activity of FK506 binding protein 12 prevents tau peptide from aggregating.",
+        "type": "PubMed",
+        "volume": "26"
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+      "evidence": "We then investigated the function of FK506-binding protein (FKBP) 12, which is known to accumulate in neurofibrillary tangles in vivo, on aggregation of the R3 peptide and found that FKBP12 completely prevented the peptide from aggregating at a concentration ratio of 1 : 4 (peptide:FKBP12). FKBP12 also restored the oligomer of the peptide to its monomeric status. Mutational studies on the catalytic center of FKBP12 indicated that peptidyl-prolyl isomerase activity of FKBP12 was essential for prevention of aggregation. Assuming that the propensity of aggregation of the peptide is different in each cis-/trans-isomer, we propose that the aggregation behavior of the R3 peptide can be theoretically described with a simple kinetic scheme, in which only the cis-isomer can aggregate and FKBP12 catalyzes isomerization of the peptide in both the monomeric and aggregative states.",
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+          "Ando K",
+          "Blum D",
+          "Bretteville A",
+          "Buée L",
+          "Bégard S",
+          "Bélarbi K",
+          "Caillet-Boudin ML",
+          "Demey-Thomas E",
+          "Dourlen P",
+          "Drobecq H",
+          "Eddarkaoui S",
+          "Galas MC",
+          "Ghestem A",
+          "Hamdane M",
+          "Landrieu I",
+          "Lippens G",
+          "Maurage CA",
+          "Melnyk P",
+          "Sambo AV",
+          "Sergeant N",
+          "Smet C",
+          "Verdier Y",
+          "Vingtdeux V",
+          "Vinh J"
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+        "date": "2013-03-01",
+        "first": "Ando K",
+        "last": "Buée L",
+        "name": "Neurobiology of aging",
+        "pages": "757-69",
+        "reference": "22926167",
+        "title": "Tau pathology modulates Pin1 post-translational modifications and may be relevant as biomarker.",
+        "type": "PubMed",
+        "volume": "34"
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+      "evidence": "Because Pin1 has at least 4 major isovariants in addition to the native polypeptide, this means that Pin1 has 4 (possibly more) posttranslational modifications including phosphorylation at 3 sites (Ser16 and Ser65/Ser71), N-acetylation (amino-terminus and Lys46) and oxidation (Met130 and 146). In all experimental conditions, including tau-overexpressing cells, tau transgenic mice and AD brains, global levels of Pin1 posttranslational modifications were decreased compared with control conditions.",
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+          "Buée L",
+          "Bégard S",
+          "Bélarbi K",
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+          "Dourlen P",
+          "Drobecq H",
+          "Eddarkaoui S",
+          "Galas MC",
+          "Ghestem A",
+          "Hamdane M",
+          "Landrieu I",
+          "Lippens G",
+          "Maurage CA",
+          "Melnyk P",
+          "Sambo AV",
+          "Sergeant N",
+          "Smet C",
+          "Verdier Y",
+          "Vingtdeux V",
+          "Vinh J"
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+        "date": "2013-03-01",
+        "first": "Ando K",
+        "last": "Buée L",
+        "name": "Neurobiology of aging",
+        "pages": "757-69",
+        "reference": "22926167",
+        "title": "Tau pathology modulates Pin1 post-translational modifications and may be relevant as biomarker.",
+        "type": "PubMed",
+        "volume": "34"
+      },
+      "evidence": "In fact, phosphorylation of Pin1 at Ser16 inhibits its nuclear localization possibly through inhibition of Pin1 substrate-binding property (Lu et al., 2002) while phosphorylation at Ser65 does not change activity of localization but stabilizes Pin1 by preventing its ubiquitination",
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+      "relation": "decreases",
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+    {
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+          "Ando K",
+          "Blum D",
+          "Bretteville A",
+          "Buée L",
+          "Bégard S",
+          "Bélarbi K",
+          "Caillet-Boudin ML",
           "Demey-Thomas E",
           "Dourlen P",
           "Drobecq H",
@@ -74047,42 +89698,282 @@
         "volume": "34"
       },
       "evidence": "Because Pin1 has at least 4 major isovariants in addition to the native polypeptide, this means that Pin1 has 4 (possibly more) posttranslational modifications including phosphorylation at 3 sites (Ser16 and Ser65/Ser71), N-acetylation (amino-terminus and Lys46) and oxidation (Met130 and 146). In all experimental conditions, including tau-overexpressing cells, tau transgenic mice and AD brains, global levels of Pin1 posttranslational modifications were decreased compared with control conditions.",
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-      "relation": "negativeCorrelation",
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     },
     {
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       "citation": {
         "authors": [
-          "Asada A",
-          "Hasegawa M",
-          "Hisanaga S",
-          "Ishiguro K",
-          "Kimura T",
-          "Oikawa T",
-          "Saito T",
-          "Uchida C",
-          "Uchida T",
-          "Yotsumoto K"
+          "Ando K",
+          "Blum D",
+          "Bretteville A",
+          "Buée L",
+          "Bégard S",
+          "Bélarbi K",
+          "Caillet-Boudin ML",
+          "Demey-Thomas E",
+          "Dourlen P",
+          "Drobecq H",
+          "Eddarkaoui S",
+          "Galas MC",
+          "Ghestem A",
+          "Hamdane M",
+          "Landrieu I",
+          "Lippens G",
+          "Maurage CA",
+          "Melnyk P",
+          "Sambo AV",
+          "Sergeant N",
+          "Smet C",
+          "Verdier Y",
+          "Vingtdeux V",
+          "Vinh J"
         ],
-        "date": "2009-06-19",
-        "first": "Yotsumoto K",
-        "last": "Hisanaga S",
-        "name": "The Journal of biological chemistry",
-        "pages": "16840-7",
-        "reference": "19401603",
-        "title": "Effect of Pin1 or microtubule binding on dephosphorylation of FTDP-17 mutant Tau.",
+        "date": "2013-03-01",
+        "first": "Ando K",
+        "last": "Buée L",
+        "name": "Neurobiology of aging",
+        "pages": "757-69",
+        "reference": "22926167",
+        "title": "Tau pathology modulates Pin1 post-translational modifications and may be relevant as biomarker.",
         "type": "PubMed",
-        "volume": "284"
+        "volume": "34"
       },
-      "evidence": "Taken together, these results indicate that the binding of P-Tau to microtubules suppresses its dephosphorylation.",
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-      "relation": "positiveCorrelation",
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-      "target": 538
+      "evidence": "In fact, phosphorylation of Pin1 at Ser16 inhibits its nuclear localization possibly through inhibition of Pin1 substrate-binding property (Lu et al., 2002) while phosphorylation at Ser65 does not change activity of localization but stabilizes Pin1 by preventing its ubiquitination",
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+          "Blum D",
+          "Bretteville A",
+          "Buée L",
+          "Bégard S",
+          "Bélarbi K",
+          "Caillet-Boudin ML",
+          "Demey-Thomas E",
+          "Dourlen P",
+          "Drobecq H",
+          "Eddarkaoui S",
+          "Galas MC",
+          "Ghestem A",
+          "Hamdane M",
+          "Landrieu I",
+          "Lippens G",
+          "Maurage CA",
+          "Melnyk P",
+          "Sambo AV",
+          "Sergeant N",
+          "Smet C",
+          "Verdier Y",
+          "Vingtdeux V",
+          "Vinh J"
+        ],
+        "date": "2013-03-01",
+        "first": "Ando K",
+        "last": "Buée L",
+        "name": "Neurobiology of aging",
+        "pages": "757-69",
+        "reference": "22926167",
+        "title": "Tau pathology modulates Pin1 post-translational modifications and may be relevant as biomarker.",
+        "type": "PubMed",
+        "volume": "34"
+      },
+      "evidence": "In fact, phosphorylation of Pin1 at Ser16 inhibits its nuclear localization possibly through inhibition of Pin1 substrate-binding property (Lu et al., 2002) while phosphorylation at Ser65 does not change activity of localization but stabilizes Pin1 by preventing its ubiquitination",
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+          "Ando K",
+          "Blum D",
+          "Bretteville A",
+          "Buée L",
+          "Bégard S",
+          "Bélarbi K",
+          "Caillet-Boudin ML",
+          "Demey-Thomas E",
+          "Dourlen P",
+          "Drobecq H",
+          "Eddarkaoui S",
+          "Galas MC",
+          "Ghestem A",
+          "Hamdane M",
+          "Landrieu I",
+          "Lippens G",
+          "Maurage CA",
+          "Melnyk P",
+          "Sambo AV",
+          "Sergeant N",
+          "Smet C",
+          "Verdier Y",
+          "Vingtdeux V",
+          "Vinh J"
+        ],
+        "date": "2013-03-01",
+        "first": "Ando K",
+        "last": "Buée L",
+        "name": "Neurobiology of aging",
+        "pages": "757-69",
+        "reference": "22926167",
+        "title": "Tau pathology modulates Pin1 post-translational modifications and may be relevant as biomarker.",
+        "type": "PubMed",
+        "volume": "34"
+      },
+      "evidence": "Because Pin1 has at least 4 major isovariants in addition to the native polypeptide, this means that Pin1 has 4 (possibly more) posttranslational modifications including phosphorylation at 3 sites (Ser16 and Ser65/Ser71), N-acetylation (amino-terminus and Lys46) and oxidation (Met130 and 146). In all experimental conditions, including tau-overexpressing cells, tau transgenic mice and AD brains, global levels of Pin1 posttranslational modifications were decreased compared with control conditions.",
+      "key": "279712e0aabbac871d63565b884cd2cce2162f8b811ff5278f73fd67fcb32193898299d3b4fda40865e01b22778faaeae7d928b8a25f9cc9ce199812235fbf25",
+      "line": 4968,
+      "relation": "decreases",
+      "source": 735,
+      "target": 734
+    },
+    {
+      "key": "504c86acdae0f210e50e180197b182402f58f520e5e3eb58587736e9798cc50831c0d17d1cc774a41d0243d3e0cdb357578d3895233d56ce5967cf038de03c27",
+      "relation": "hasComponent",
+      "source": 301,
+      "target": 667
+    },
+    {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Ando K",
+          "Blum D",
+          "Bretteville A",
+          "Buée L",
+          "Bégard S",
+          "Bélarbi K",
+          "Caillet-Boudin ML",
+          "Demey-Thomas E",
+          "Dourlen P",
+          "Drobecq H",
+          "Eddarkaoui S",
+          "Galas MC",
+          "Ghestem A",
+          "Hamdane M",
+          "Landrieu I",
+          "Lippens G",
+          "Maurage CA",
+          "Melnyk P",
+          "Sambo AV",
+          "Sergeant N",
+          "Smet C",
+          "Verdier Y",
+          "Vingtdeux V",
+          "Vinh J"
+        ],
+        "date": "2013-03-01",
+        "first": "Ando K",
+        "last": "Buée L",
+        "name": "Neurobiology of aging",
+        "pages": "757-69",
+        "reference": "22926167",
+        "title": "Tau pathology modulates Pin1 post-translational modifications and may be relevant as biomarker.",
+        "type": "PubMed",
+        "volume": "34"
+      },
+      "evidence": "Pin1 binds to phosphorylated Thr231 of tau and facilitates the dephosphorylation of phosphoThr231 through isomerization (Galas et al., 2006; Hamdane et al., 2006; Lu et al., 1999a). Phosphorylation at Thr231 on tau is associated with the early events of tau aggregation and NFT (Augustinack et al., 2002). Pin1 binds and isomerizes the proline imidic peptide bond following the phosphothreonine 231",
+      "key": "b088917b9426905415f64d80c13169ea3345831832a437b5c53204e49c913b42902f7b4fdd5c4082623cbc958b7047414393ea826eebd73cfad499311b2596f5",
+      "line": 4976,
+      "relation": "decreases",
+      "source": 301,
+      "target": 667
+    },
+    {
+      "key": "8a8797e875c0852e19e69032141dd252a9a7f20edb285dd4bec3204f4b50b69b2428fcf0680636190f1629798cc6dea9f54788a574c73d28e0fd1b9728aa6826",
+      "relation": "hasComponent",
+      "source": 301,
+      "target": 734
+    },
+    {
+      "annotations": {
+        "Confidence": {
+          "Medium": true
+        }
+      },
+      "citation": {
+        "authors": [
+          "Ando K",
+          "Blum D",
+          "Bretteville A",
+          "Buée L",
+          "Bégard S",
+          "Bélarbi K",
+          "Caillet-Boudin ML",
+          "Demey-Thomas E",
+          "Dourlen P",
+          "Drobecq H",
+          "Eddarkaoui S",
+          "Galas MC",
+          "Ghestem A",
+          "Hamdane M",
+          "Landrieu I",
+          "Lippens G",
+          "Maurage CA",
+          "Melnyk P",
+          "Sambo AV",
+          "Sergeant N",
+          "Smet C",
+          "Verdier Y",
+          "Vingtdeux V",
+          "Vinh J"
+        ],
+        "date": "2013-03-01",
+        "first": "Ando K",
+        "last": "Buée L",
+        "name": "Neurobiology of aging",
+        "pages": "757-69",
+        "reference": "22926167",
+        "title": "Tau pathology modulates Pin1 post-translational modifications and may be relevant as biomarker.",
+        "type": "PubMed",
+        "volume": "34"
+      },
+      "evidence": "In fact, phosphorylation of Pin1 at Ser16 inhibits its nuclear localization possibly through inhibition of Pin1 substrate-binding property (Lu et al., 2002) while phosphorylation at Ser65 does not change activity of localization but stabilizes Pin1 by preventing its ubiquitination",
+      "key": "800086546f683ea6eddb9e92ecca2445503cb04c921e0da3a21a8493619650e66aaf04d5adfca5bc54e8abbe06bc14f5cf0fb58b5b652b667168b84355f5e0df",
+      "line": 4987,
+      "object": {
+        "modifier": "Degradation"
+      },
+      "relation": "increases",
+      "source": 739,
+      "target": 734
     }
   ],
   "multigraph": true,
@@ -74108,6 +89999,13 @@
       "name": "1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate",
       "namespace": "CHEBI"
     },
+    {
+      "bel": "a(CHEBI:\"3',5'-cyclic AMP\")",
+      "function": "Abundance",
+      "id": "e634e1d295920557f5cf0c1b3fd2bf18d082b00fb983d6632b989552d1ba51e14a88952b3abfc55d7ab65f035c7e90d951497cfa11719f0492edab0ddb91813a",
+      "name": "3',5'-cyclic AMP",
+      "namespace": "CHEBI"
+    },
     {
       "bel": "a(CHEBI:\"D-glyceraldehyde 3-phosphate\")",
       "function": "Abundance",
@@ -74157,6 +90055,13 @@
       "name": "all-trans-retinoic acid",
       "namespace": "CHEBI"
     },
+    {
+      "bel": "a(CHEBI:\"amyloid-beta polypeptide 42\")",
+      "function": "Abundance",
+      "id": "c2da54109c90719396dfdfb558be74582b8522863849a50f3f5029b7d60f4d53df3cfa1a97b787e760a2f74ea1f74012eb49273beeded42a2873d788953b4a13",
+      "name": "amyloid-beta polypeptide 42",
+      "namespace": "CHEBI"
+    },
     {
       "bel": "a(CHEBI:\"amyloid-beta\")",
       "function": "Abundance",
@@ -74200,10 +90105,10 @@
       "namespace": "CHEBI"
     },
     {
-      "bel": "a(CHEBI:\"folate(2-)\")",
+      "bel": "a(CHEBI:\"exendin-4\")",
       "function": "Abundance",
-      "id": "9aec6d047b8226fc629be25461498fadf3709b99f223a6b8f53004b1f579180f2f9245467e1ee5814a44a1d5505cb96c09a86e10c989709a4eb54a08b8b50406",
-      "name": "folate(2-)",
+      "id": "b8b0cf187ed430c95b271fae8e1900ad04b10e9a0e29bce1ace98341eb53d106b98b43299108c7a74cbf10a79b4038d608f18da9148c38c1ab465ab44eb7838d",
+      "name": "exendin-4",
       "namespace": "CHEBI"
     },
     {
@@ -74304,6 +90209,20 @@
       "name": "quinolinic acid",
       "namespace": "CHEBI"
     },
+    {
+      "bel": "a(CHEBI:\"reactive nitrogen species\")",
+      "function": "Abundance",
+      "id": "e4bd29cc8cc5e2507af94944842f6b880c05f2ea4505aabea01fe8b012132bcfef36110b8b76497d9ed51a2c2ffa3cce3fd3fec654527a9ebe167a27db37438b",
+      "name": "reactive nitrogen species",
+      "namespace": "CHEBI"
+    },
+    {
+      "bel": "a(CHEBI:\"reactive oxygen species\")",
+      "function": "Abundance",
+      "id": "5da7879846ec42231f9176e97a7f14c4b573807576fa75be6e3acb71f391f25971e33d2f7fb886003ebd8020ab592e1424e2fc106f91213d546078dd09fabb65",
+      "name": "reactive oxygen species",
+      "namespace": "CHEBI"
+    },
     {
       "bel": "a(CHEBI:\"sodium azide\")",
       "function": "Abundance",
@@ -74339,6 +90258,27 @@
       "name": "trichostatin A",
       "namespace": "CHEBI"
     },
+    {
+      "bel": "a(CHEBI:\"uric acid\")",
+      "function": "Abundance",
+      "id": "0a0a711d49d83c8f7f0f9ea40413d31d5c44de9c4317006cd090862393e05f65c06f961f7bd0541f7c9b847f7373c72de7cdaaaa05af70aa175669dc888fddf5",
+      "name": "uric acid",
+      "namespace": "CHEBI"
+    },
+    {
+      "bel": "a(CHEBI:ATP)",
+      "function": "Abundance",
+      "id": "dbc5553fb6213ed82215c03a89950a37045e23683ffa96b44532f3e75d204cc547a974025c2799c6a189ad0c5045d96b16d1f5f7ac9296473ba1c647499bb3b2",
+      "name": "ATP",
+      "namespace": "CHEBI"
+    },
+    {
+      "bel": "a(CHEBI:C646)",
+      "function": "Abundance",
+      "id": "2a82f325bc0dae19113c618c1b68a58ed5ee340e9f0536cac18dca8664dd6c79bf3e03881b170639717926fa59d9a6f4482ebe76d5d9823b4230aa88cd4306f3",
+      "name": "C646",
+      "namespace": "CHEBI"
+    },
     {
       "bel": "a(CHEBI:Iproniazid)",
       "function": "Abundance",
@@ -74367,6 +90307,13 @@
       "name": "Trolox",
       "namespace": "CHEBI"
     },
+    {
+      "bel": "a(CHEBI:acetylcholine)",
+      "function": "Abundance",
+      "id": "bae5841bb74f1e9eb73cd433cda657927031217c24e17f21bb2975128d1d9be4dc899448ede71d9aa18224145a1681b90b33287454eabf938f405bc1b8894b62",
+      "name": "acetylcholine",
+      "namespace": "CHEBI"
+    },
     {
       "bel": "a(CHEBI:acrolein)",
       "function": "Abundance",
@@ -74389,10 +90336,17 @@
       "namespace": "CHEBI"
     },
     {
-      "bel": "a(CHEBI:cinnamaldehyde)",
+      "bel": "a(CHEBI:antioxidant)",
+      "function": "Abundance",
+      "id": "532cca355e793f00fffa1df608d6c7b2ae16ca1cf9a8b72199fe64d52e06718ccdfb7bc76e319c6612692e80f7f07e2935ebf085cb0194c6e267a6253a886170",
+      "name": "antioxidant",
+      "namespace": "CHEBI"
+    },
+    {
+      "bel": "a(CHEBI:cinnamaldehydes)",
       "function": "Abundance",
-      "id": "849588a349f9c8b549d94900c2d451370c0bd6170d3daa9bd9d877b83c347e4088ac221ce3e572205c4699dde1528325c3efd65cf256423a1ff148126d9b79fe",
-      "name": "cinnamaldehyde",
+      "id": "c976ab63c3e96e58af8eeda1e3939631b8641b02cf8f1cd6edbfdf3bedabd9b3b081e53d6e4445ce73cea4259f0e6f4ffbe7bd7c0b88c68445ed202f12853c9c",
+      "name": "cinnamaldehydes",
       "namespace": "CHEBI"
     },
     {
@@ -74451,6 +90405,13 @@
       "name": "glyceraldehyde",
       "namespace": "CHEBI"
     },
+    {
+      "bel": "a(CHEBI:glyoxal)",
+      "function": "Abundance",
+      "id": "23977b88adf90321ea346aa42c1cc0be1b5c6aac80286e314ddae0010ad7ce432e90e21081e65ca7780083c6b6212160490740557356ead316112481ce25441d",
+      "name": "glyoxal",
+      "namespace": "CHEBI"
+    },
     {
       "bel": "a(CHEBI:harmine)",
       "function": "Abundance",
@@ -74500,6 +90461,20 @@
       "name": "linsidomine",
       "namespace": "CHEBI"
     },
+    {
+      "bel": "a(CHEBI:lipopolysaccharide)",
+      "function": "Abundance",
+      "id": "66bc1a5b41c832a7d7b4b61aa44aae11a4bb778b350f17f7386e2f2a86365ef3007d5e07af494b32cae117170398c1fe5b5ee0e0e95bcef83eede21157e23d04",
+      "name": "lipopolysaccharide",
+      "namespace": "CHEBI"
+    },
+    {
+      "bel": "a(CHEBI:malonaldehyde)",
+      "function": "Abundance",
+      "id": "739f31faea80a4346f93d88fb322844d4a48cedd3887e50968fbf26d7666f2cec39be3aadacf4e570e76340d40b2e860ed74d5181306d84b7ca1c26ab4443bba",
+      "name": "malonaldehyde",
+      "namespace": "CHEBI"
+    },
     {
       "bel": "a(CHEBI:memantine)",
       "function": "Abundance",
@@ -74549,6 +90524,13 @@
       "name": "phosphatidylinositol",
       "namespace": "CHEBI"
     },
+    {
+      "bel": "a(CHEBI:pyruvate)",
+      "function": "Abundance",
+      "id": "eebc992abdd52a2d985528c46d28c30167dff7dc7c2ec6650eb512da88b0df4bdfeb60e3c6c6c4cf3d232ed6e38022be6336304bbd138fc67792054a07aaee9b",
+      "name": "pyruvate",
+      "namespace": "CHEBI"
+    },
     {
       "bel": "a(CHEBI:quinalizarin)",
       "function": "Abundance",
@@ -74577,6 +90559,13 @@
       "name": "rolipram",
       "namespace": "CHEBI"
     },
+    {
+      "bel": "a(CHEBI:salicylate)",
+      "function": "Abundance",
+      "id": "525fe39e75a2726a4bf8536eabaed93fa266384823cbe38c38165144291cbe90a95e750df1fbf225c0e284fc70eef2ae7759616bf402e5bb50bbe49693a7578f",
+      "name": "salicylate",
+      "namespace": "CHEBI"
+    },
     {
       "bel": "a(CHEBI:salsalate)",
       "function": "Abundance",
@@ -74612,13 +90601,6 @@
       "name": "thiostrepton",
       "namespace": "CHEBI"
     },
-    {
-      "bel": "a(CHEBI:vorinostat)",
-      "function": "Abundance",
-      "id": "82ccdbc25f13c4670b6e495c550f1851ac164c1c40ac430c58704e70806ad970973e429c1de9a57b146424cade364ecc3beeb739af263e2b23f21875478fb0ab",
-      "name": "vorinostat",
-      "namespace": "CHEBI"
-    },
     {
       "bel": "a(CL:0000127)",
       "function": "Abundance",
@@ -74647,6 +90629,13 @@
       "name": "dendritic spine",
       "namespace": "GO"
     },
+    {
+      "bel": "a(GO:\"filamentous actin\")",
+      "function": "Abundance",
+      "id": "5527d5652cdac735338ae3e1099fe49deb61ba7d536b6bf3ad06d1052de4d85c2f0f267cab9603e3143db3c9dbb98e7e0a2a87118800eef92a0a292691f1aa7b",
+      "name": "filamentous actin",
+      "namespace": "GO"
+    },
     {
       "bel": "a(GO:\"neurofibrillary tangle\")",
       "function": "Abundance",
@@ -74661,13 +90650,6 @@
       "name": "neuron spine",
       "namespace": "GO"
     },
-    {
-      "bel": "a(GO:\"neuron to neuron synapse\")",
-      "function": "Abundance",
-      "id": "bec0f76a3d8df706d52b5fea2d7e18845ba61e6d9b092b2072dfdbffd4478c76ee173ff323a0d8dd5bcb2b39391258417c8a97ed4b52cd32a7d99678094818ab",
-      "name": "neuron to neuron synapse",
-      "namespace": "GO"
-    },
     {
       "bel": "a(GO:\"synaptic vesicle\")",
       "function": "Abundance",
@@ -74711,31 +90693,17 @@
       "namespace": "GO"
     },
     {
-      "bel": "a(HBP:\"8-nitro-cGMP\")",
-      "function": "Abundance",
-      "id": "ac338737f9f81197ff6f9fe356098bc21ed52af7088dc1d89321f526eb1345256064b9ac5feeab04b1a37cb5db7804c1a4a16be999f35854fb2b37a8696f72ca",
-      "name": "8-nitro-cGMP",
-      "namespace": "HBP"
-    },
-    {
-      "bel": "a(HBP:\"ACY-1215\")",
-      "function": "Abundance",
-      "id": "814981465d066613e710f54c561570ec98bcabfdfd0d9cbc1d25fa32c4568d1d855cbe5a8ffae27e1b6add2fbfc629afe196c41202bfc93af10b4c8abc1a5cff",
-      "name": "ACY-1215",
-      "namespace": "HBP"
-    },
-    {
-      "bel": "a(HBP:\"APP processing\")",
+      "bel": "a(HBP:\"3-3 dityrosine cross-linking\")",
       "function": "Abundance",
-      "id": "618e2b77c0381f30990a9efd718b9486d8714967d58d1b4cdf496d085b74e85bb4692cd7332f7e73af7d56d1bd2c1b9442e3975968605646051e4840f5a37034",
-      "name": "APP processing",
+      "id": "bff34c5fa15ffc37084075100b408bce64ba965316585ecbe13d78f354db87779cda856fa35f6c6e3e8774a42c318e285cc4576e2885706e44a29d21ee08f741",
+      "name": "3-3 dityrosine cross-linking",
       "namespace": "HBP"
     },
     {
-      "bel": "a(HBP:\"BAY61-3606\")",
+      "bel": "a(HBP:\"8-nitro-cGMP\")",
       "function": "Abundance",
-      "id": "6192a982f1f295dbc29e02e93c096027f9fcc5b2ddc5ba1018026e9689c8b141d45c946851634945888722e6a2c1ac2dfe908f3f9662f1bf1bb1549c26e341f1",
-      "name": "BAY61-3606",
+      "id": "ac338737f9f81197ff6f9fe356098bc21ed52af7088dc1d89321f526eb1345256064b9ac5feeab04b1a37cb5db7804c1a4a16be999f35854fb2b37a8696f72ca",
+      "name": "8-nitro-cGMP",
       "namespace": "HBP"
     },
     {
@@ -74773,20 +90741,6 @@
       "name": "C-30-27",
       "namespace": "HBP"
     },
-    {
-      "bel": "a(HBP:\"CM-414\")",
-      "function": "Abundance",
-      "id": "cb2daa66f71b2a2396dd9339d1dc8401b1054e9607c42631949ee929f5d3f4dd821a69424e142d07653a794fbd523e7cb4c5c60a6a95ad30fc9594fcf573c9b3",
-      "name": "CM-414",
-      "namespace": "HBP"
-    },
-    {
-      "bel": "a(HBP:\"Chronic cerebral hypoperfusion\")",
-      "function": "Abundance",
-      "id": "ee655f2b9d1cfedf05a384f6df468e1ad49cf468dc46a70a7153357d7ded4dbe683457b3237a3adcb2802e69d3650d3a5b9aefa06548958ce45ff9a7a7d318c6",
-      "name": "Chronic cerebral hypoperfusion",
-      "namespace": "HBP"
-    },
     {
       "bel": "a(HBP:\"GA-AGE\")",
       "function": "Abundance",
@@ -74808,13 +90762,6 @@
       "name": "ID-8",
       "namespace": "HBP"
     },
-    {
-      "bel": "a(HBP:\"LDN-193594\")",
-      "function": "Abundance",
-      "id": "b1a6132b65312900bd089c0ef62499f12ad790b39b2e0e9a31a061415099703d17dcd05e0f64a1fae5ea610b68df3b25ca0557a62d7f814bd4fdb6dc69e2f592",
-      "name": "LDN-193594",
-      "namespace": "HBP"
-    },
     {
       "bel": "a(HBP:\"LDN-193665\")",
       "function": "Abundance",
@@ -74829,249 +90776,102 @@
       "name": "LDN-213843",
       "namespace": "HBP"
     },
-    {
-      "bel": "a(HBP:\"O-GlcNAcylation\")",
-      "function": "Abundance",
-      "id": "259eed3210338b4a65e77722930b276c00317c9e6a9775f218cc4eca3be39f4bb9066fc917c48e987a8d2f22605a492cbdcd683fb708ca6bc189ff8b33e810db",
-      "name": "O-GlcNAcylation",
-      "namespace": "HBP"
-    },
-    {
-      "bel": "a(HBP:\"Pathological Tau Spreading\")",
-      "function": "Abundance",
-      "id": "0a7d36c6924fa5dff54bd509cc96d2407f060d70f052204a340d4ecd728dd4643265aa3cccb31439ee2bb8d0656ebd0699117b65fdbe820493f221963a03dc17",
-      "name": "Pathological Tau Spreading",
-      "namespace": "HBP"
-    },
     {
       "bel": "a(HBP:\"Purkinje cell layer of cerebellar cortex\")",
       "function": "Abundance",
-      "id": "91e4444d1df41034d993fd07ed9881e83d00d5b66ca7e54c4bbe769ad7069d5ffb58480c6d66a1521231f7d26454d9eab1316b4e38a790b420816632ac1a03d9",
-      "name": "Purkinje cell layer of cerebellar cortex",
-      "namespace": "HBP"
-    },
-    {
-      "bel": "a(HBP:\"SL-327\")",
-      "function": "Abundance",
-      "id": "03f36edda63dd7cc9822fd17fb54cf54e1c1dd27c01ee98b14e7b1d1c0b5293bf666ea4ca9594b85696a2d5d00bb908931fe91a84992ba6876471b493de12027",
-      "name": "SL-327",
-      "namespace": "HBP"
-    },
-    {
-      "bel": "a(HBP:\"Tau Protein Secondary Structure, Turn\")",
-      "function": "Abundance",
-      "id": "7d89c1e535e9fa2cde5b013604ec41c497023cf2a3ecc20026f668df5d02dc041836007094b47a40c4e5b6c85c548bce14241f16d8832e8df19cdeb8ad16835f",
-      "name": "Tau Protein Secondary Structure, Turn",
-      "namespace": "HBP"
-    },
-    {
-      "bel": "a(HBP:\"Tau aggregates\")",
-      "function": "Abundance",
-      "id": "2f93b798e33773ea9681389870bbee41f6fa7ee04c087bda4bd1492520385f58d089a7261b1353e15c31d3e29a96ff31884886e6ab9fa477ef8f63f19cf154f7",
-      "name": "Tau aggregates",
-      "namespace": "HBP"
-    },
-    {
-      "bel": "a(HBP:\"Tau epitope, 12E8\")",
-      "function": "Abundance",
-      "id": "c34be6135c1bcd4e691269a37f289417ef6eedb6703788075919639ed0c6acb23ba43df0be54976b5421f588702fdbbf831494230c26c570783d44d889d4a1aa",
-      "name": "Tau epitope, 12E8",
-      "namespace": "HBP"
-    },
-    {
-      "bel": "a(HBP:\"Tau epitope, AT100\")",
-      "function": "Abundance",
-      "id": "29f2657150f230902d81e137b4206783c60d5e671218dbf4a5720234551eca983539a9a71a08b5af48d26493d0db101dbccf850ff2db0016f9266d69a00911ea",
-      "name": "Tau epitope, AT100",
-      "namespace": "HBP"
-    },
-    {
-      "bel": "a(HBP:\"Tau epitope, AT180\")",
-      "function": "Abundance",
-      "id": "b0b8cf64217d1ea9b2008e088c9190a538f9500a5238b79b7b7cd9c21003676daf0558c7665e06bd43d8390679ea61b08cafe4c0b6c9f997603dd3e5ee84fda7",
-      "name": "Tau epitope, AT180",
-      "namespace": "HBP"
-    },
-    {
-      "bel": "a(HBP:\"Tau epitope, CP13\")",
-      "function": "Abundance",
-      "id": "b265db51adfba5abdc9e0d401f21f82fa16dac7ae7b814311cfeb6e07bc5a9b5a348ba99b8eec10d87c3e3edf1dad111f32026d30dd93ea36983c6c22653836a",
-      "name": "Tau epitope, CP13",
-      "namespace": "HBP"
-    },
-    {
-      "bel": "a(HBP:\"Tau epitope, PHF1\")",
-      "function": "Abundance",
-      "id": "c133b6c209011d4109489ea5c061c0e42f0d3de18c0fed8add35868a1e7b4e855ef0807c5408696433a43e16957e93313e67d611f53a51cb81089f561d7069a7",
-      "name": "Tau epitope, PHF1",
-      "namespace": "HBP"
-    },
-    {
-      "bel": "a(HBP:\"Tau oligomers\")",
-      "function": "Abundance",
-      "id": "d4ceff8aa5a5d05770aaa29b828d003b85d64e7e5337c6624b7c5a84111845897462b589e7b259b0eed6bcfc63f34cdaf1f9b988c788804799aea026d8731d98",
-      "name": "Tau oligomers",
-      "namespace": "HBP"
-    },
-    {
-      "bel": "a(HBP:\"Thiamet G\")",
-      "function": "Abundance",
-      "id": "9c87bcd9a5b64973866cab9379e486e08a063e7672ad3600431330dccaa9f168c0cad2dc07255ce823f6abcff145d2ac8ac9b18f6340c9b876b99d8adee54106",
-      "name": "Thiamet G",
-      "namespace": "HBP"
-    },
-    {
-      "bel": "a(HBP:\"Thioflavin S\")",
-      "function": "Abundance",
-      "id": "d318d56679b51903566a06b7241f1663b9122a694795d9cdb2e0a31215a24b2c4856584ce2ad7f8b8f83bd1ea3f44cdecab722f6da291ee4c2bc79d02fe4460b",
-      "name": "Thioflavin S",
-      "namespace": "HBP"
-    },
-    {
-      "bel": "a(HBP:\"Tubastatin A\")",
-      "function": "Abundance",
-      "id": "543d83ed00654be5a30b1189970df285c3a3dbbc5e4a9b7f8ed08986e84aa64aa6dca0804cad71b9bfef8f9ce23e468fd9b2f3e8dc8f2d61fce603243c374e11",
-      "name": "Tubastatin A",
-      "namespace": "HBP"
-    },
-    {
-      "bel": "a(HBP:\"USP14 Aptamer\")",
-      "function": "Abundance",
-      "id": "2e26db861e30249f39f0b2cbd862a6738a2f246625f73d25175025a98371d29e485bd180aec356281bb3b577c7885c4bf361ccb7f4ef5adf5707ae06b4d8029d",
-      "name": "USP14 Aptamer",
-      "namespace": "HBP"
-    },
-    {
-      "bel": "a(HBP:\"advanced glycation end product\")",
-      "function": "Abundance",
-      "id": "b606da9926a6aedd95a3e3bc39323e5326a30baae889e95c54f504370752dfb683372116ca5fa32d4145709a3ee24347cacc159cb1f2d3462a7e3a1b0fe18ed3",
-      "name": "advanced glycation end product",
-      "namespace": "HBP"
-    },
-    {
-      "bel": "a(HBP:\"amyloid-beta oligomers\")",
-      "function": "Abundance",
-      "id": "a0fc661406161db12bdd89333a13d0ee89b3aa089d5eb16676962cae3efd25d4d3dd6e593dbcaebf5fc0c26f9c8c070a98f2ff0fb94a0d52412c0fa0bf6c5b3b",
-      "name": "amyloid-beta oligomers",
-      "namespace": "HBP"
-    },
-    {
-      "bel": "a(HBP:\"cholinergic neuron\")",
-      "function": "Abundance",
-      "id": "222e8baa384f196d88fa9367bc972387df34f9cadf56c3733d8ac55d2d2ba31f9fca6bd4517d95045cac9f2c5a9f2d92879d1df7ababae05f708fe9bccd541f8",
-      "name": "cholinergic neuron",
-      "namespace": "HBP"
-    },
-    {
-      "bel": "a(HBP:\"cystein-dependent auto-acetylation\")",
-      "function": "Abundance",
-      "id": "00ed3d399dca2a1ae08fcc6a0b03496fd11344857eaf3d952bfb5ae75c2ea4210d908ef34c7983754458bff3601c89ebe74de40b76f1c165fa627038f67051aa",
-      "name": "cystein-dependent auto-acetylation",
-      "namespace": "HBP"
-    },
-    {
-      "bel": "a(HBP:\"dystrophic neurite\")",
-      "function": "Abundance",
-      "id": "fefc1fd142102e9ec451f3defbfa09282680ba961ca9d6eda0211708b220ab75feecdeacefdd380dabe553134605ff79003d247ebd3c4420bc0a98959cfe38e7",
-      "name": "dystrophic neurite",
-      "namespace": "HBP"
-    },
-    {
-      "bel": "a(HBP:\"granular layer of cerebellar cortex\")",
-      "function": "Abundance",
-      "id": "394cae54c24c281590878facbf46895d1fbdbe53e1915f522fbc9e33a18d78d817c651e01395a86d677f5426ca4a77208252ec52523d57e17b4c7eb692309231",
-      "name": "granular layer of cerebellar cortex",
+      "id": "91e4444d1df41034d993fd07ed9881e83d00d5b66ca7e54c4bbe769ad7069d5ffb58480c6d66a1521231f7d26454d9eab1316b4e38a790b420816632ac1a03d9",
+      "name": "Purkinje cell layer of cerebellar cortex",
       "namespace": "HBP"
     },
     {
-      "bel": "a(HBP:\"granulovacuolar degeneration\")",
+      "bel": "a(HBP:\"Tau Protein Secondary Structure, Turn\")",
       "function": "Abundance",
-      "id": "54b3df161c7ebc26f946c45b1ae5ca5b615f2be1fa76d947ef8072095dc05e7bf8be6f8b752b892d7440ec2fc1dde20db7c94c0717767859053d266cdd2616d8",
-      "name": "granulovacuolar degeneration",
+      "id": "7d89c1e535e9fa2cde5b013604ec41c497023cf2a3ecc20026f668df5d02dc041836007094b47a40c4e5b6c85c548bce14241f16d8832e8df19cdeb8ad16835f",
+      "name": "Tau Protein Secondary Structure, Turn",
       "namespace": "HBP"
     },
     {
-      "bel": "a(HBP:\"microtubule-binding region\")",
+      "bel": "a(HBP:\"Tau aggregates\")",
       "function": "Abundance",
-      "id": "284e708151d3cdbad19b4883cd8b646d2cc4aca4e6b25b4267105e4c9dfe435cae86b0db038162e48956fb2de06ded489d92170df9e0c06d0d16a3b3376903c6",
-      "name": "microtubule-binding region",
+      "id": "2f93b798e33773ea9681389870bbee41f6fa7ee04c087bda4bd1492520385f58d089a7261b1353e15c31d3e29a96ff31884886e6ab9fa477ef8f63f19cf154f7",
+      "name": "Tau aggregates",
       "namespace": "HBP"
     },
     {
-      "bel": "a(HBP:\"molecular layer of cerebellar cortex\")",
+      "bel": "a(HBP:\"Tau fibrils\")",
       "function": "Abundance",
-      "id": "f809e7785f6b94b3b5815a9a92df5e592c84af5e9f1cdd700a85b4fe8cec7a57d326ab70b814fdf25d76fc9e1a814993bf6a95732ffd526f7bb67f456bb3025a",
-      "name": "molecular layer of cerebellar cortex",
+      "id": "cd2dab27f628336ca0ed44605c7cd92f2fd119b914305cba845b06c61ab768ecf96cc32e4679b8ca5361f3e5cd3bd2418c91526348cc067d58282b812be1310a",
+      "name": "Tau fibrils",
       "namespace": "HBP"
     },
     {
-      "bel": "a(HBP:\"paired helical filaments\")",
+      "bel": "a(HBP:\"Tau oligomers\")",
       "function": "Abundance",
-      "id": "8d87710f8ebf7593b6b0020396d36a868362a39b367908774a967b0efb7397212d51216da225ac3218af26e6abb0338cdd1d676c9db11cf8e6c16c127fd2305b",
-      "name": "paired helical filaments",
+      "id": "d4ceff8aa5a5d05770aaa29b828d003b85d64e7e5337c6624b7c5a84111845897462b589e7b259b0eed6bcfc63f34cdaf1f9b988c788804799aea026d8731d98",
+      "name": "Tau oligomers",
       "namespace": "HBP"
     },
     {
-      "bel": "a(HBP:\"peripheral nervous system injury\")",
+      "bel": "a(HBP:\"Thiamet G\")",
       "function": "Abundance",
-      "id": "32fb786aa36a893e7971c7db42a4450fd90b4fa0c1e53bd8e926e096cade4b4acd69512177b252c2d5ae8698a9bc958c6fbc77f272b76ed722da95e380e2baec",
-      "name": "peripheral nervous system injury",
+      "id": "9c87bcd9a5b64973866cab9379e486e08a063e7672ad3600431330dccaa9f168c0cad2dc07255ce823f6abcff145d2ac8ac9b18f6340c9b876b99d8adee54106",
+      "name": "Thiamet G",
       "namespace": "HBP"
     },
     {
-      "bel": "a(HBP:\"projection domain\")",
+      "bel": "a(HBP:\"Thioflavin S\")",
       "function": "Abundance",
-      "id": "31a22a4945740607c37eaffffee69204a782bb99d194666c1e1dfcedddecd16ea5e29806adcd3582432a92c7ff14f16209c61e6625d79a128be75e3e83339e7d",
-      "name": "projection domain",
+      "id": "d318d56679b51903566a06b7241f1663b9122a694795d9cdb2e0a31215a24b2c4856584ce2ad7f8b8f83bd1ea3f44cdecab722f6da291ee4c2bc79d02fe4460b",
+      "name": "Thioflavin S",
       "namespace": "HBP"
     },
     {
-      "bel": "a(HBP:\"proline-rich domain\")",
+      "bel": "a(HBP:\"USP14 Aptamer\")",
       "function": "Abundance",
-      "id": "fa9f3c0d9b8afb90cac43e07d09daa57c9dc083ca98d8e49a6453f44d2d59c447910942a96e06d6cff58a40082f7e1cdcd33b3538954bf3553e15f7aca51f15e",
-      "name": "proline-rich domain",
+      "id": "2e26db861e30249f39f0b2cbd862a6738a2f246625f73d25175025a98371d29e485bd180aec356281bb3b577c7885c4bf361ccb7f4ef5adf5707ae06b4d8029d",
+      "name": "USP14 Aptamer",
       "namespace": "HBP"
     },
     {
-      "bel": "a(HBP:Astrogliosis)",
+      "bel": "a(HBP:\"advanced glycation end product\")",
       "function": "Abundance",
-      "id": "47c0ace975f6894865a2ab85c0ef2adf6663bac2f00f2d2316ec1da1886f9c507393915fc150cc7ea060f4f8eb559a8409eef92d8b5728e0984f4c0acad995f8",
-      "name": "Astrogliosis",
+      "id": "b606da9926a6aedd95a3e3bc39323e5326a30baae889e95c54f504370752dfb683372116ca5fa32d4145709a3ee24347cacc159cb1f2d3462a7e3a1b0fe18ed3",
+      "name": "advanced glycation end product",
       "namespace": "HBP"
     },
     {
-      "bel": "a(HBP:C646)",
+      "bel": "a(HBP:\"amyloid-beta oligomers\")",
       "function": "Abundance",
-      "id": "07dc705c39483d5077f038aeb34262e11d5c7e30166f8c555aff7e3af00f9c06f4b9fec85b554e2b5bc0607eee111da80db060006b0af350fe8d21755cc0a672",
-      "name": "C646",
+      "id": "a0fc661406161db12bdd89333a13d0ee89b3aa089d5eb16676962cae3efd25d4d3dd6e593dbcaebf5fc0c26f9c8c070a98f2ff0fb94a0d52412c0fa0bf6c5b3b",
+      "name": "amyloid-beta oligomers",
       "namespace": "HBP"
     },
     {
-      "bel": "a(HBP:CGP3466B)",
+      "bel": "a(HBP:\"dystrophic neurite\")",
       "function": "Abundance",
-      "id": "6356c831ff870fc99b3358f85910da4f563f5ab179690f7e6d43759118d012455af0466459db07cd5c9bec95d4077db79c015db6f7635c5876c63b3251366071",
-      "name": "CGP3466B",
+      "id": "fefc1fd142102e9ec451f3defbfa09282680ba961ca9d6eda0211708b220ab75feecdeacefdd380dabe553134605ff79003d247ebd3c4420bc0a98959cfe38e7",
+      "name": "dystrophic neurite",
       "namespace": "HBP"
     },
     {
-      "bel": "a(HBP:Excitotoxicity)",
+      "bel": "a(HBP:\"granular layer of cerebellar cortex\")",
       "function": "Abundance",
-      "id": "80f0fe9786f726038f985feb4dc24c6add06927628a431fd67220bcc4eee6f64d44b062beb6925b2e5d96998987c03cbc272ea5e23197ce62e58cf17fa7517b7",
-      "name": "Excitotoxicity",
+      "id": "394cae54c24c281590878facbf46895d1fbdbe53e1915f522fbc9e33a18d78d817c651e01395a86d677f5426ca4a77208252ec52523d57e17b4c7eb692309231",
+      "name": "granular layer of cerebellar cortex",
       "namespace": "HBP"
     },
     {
-      "bel": "a(HBP:MPT0G211)",
+      "bel": "a(HBP:\"molecular layer of cerebellar cortex\")",
       "function": "Abundance",
-      "id": "6d3500e4fd41afa1436b3dcbc82c09c9c9db4d376179493bf80bfb418709f0b69cacef45c1481ef683b3c9b3ebb2f05dea9370c2845f5fdd81ab02bd0cbbd000",
-      "name": "MPT0G211",
+      "id": "f809e7785f6b94b3b5815a9a92df5e592c84af5e9f1cdd700a85b4fe8cec7a57d326ab70b814fdf25d76fc9e1a814993bf6a95732ffd526f7bb67f456bb3025a",
+      "name": "molecular layer of cerebellar cortex",
       "namespace": "HBP"
     },
     {
-      "bel": "a(HBP:Microgliosis)",
+      "bel": "a(HBP:\"paired helical filaments\")",
       "function": "Abundance",
-      "id": "8cbd75925314cb55243c71a01132bde1090f5f7a882d6cd6e54c45af4a0fb659aefde98beada6563ae3ddc9bf7073903b6c3de8e582f694a4a09b3f4069f1a95",
-      "name": "Microgliosis",
+      "id": "8d87710f8ebf7593b6b0020396d36a868362a39b367908774a967b0efb7397212d51216da225ac3218af26e6abb0338cdd1d676c9db11cf8e6c16c127fd2305b",
+      "name": "paired helical filaments",
       "namespace": "HBP"
     },
     {
@@ -75081,13 +90881,6 @@
       "name": "Neurites",
       "namespace": "HBP"
     },
-    {
-      "bel": "a(HBP:Neurodegeneration)",
-      "function": "Abundance",
-      "id": "52fac4ee7f9b3b0fbfcb98add48ce6b5926d97ec8d5b2d7be5e26abd9856e9a5fb4751523d7874eb2444348b726fedf3c0e18a99cf5383b69f3380c3be2f91ff",
-      "name": "Neurodegeneration",
-      "namespace": "HBP"
-    },
     {
       "bel": "a(HBP:RGFP966)",
       "function": "Abundance",
@@ -75109,20 +90902,6 @@
       "name": "Trithiocarbonates",
       "namespace": "HBP"
     },
-    {
-      "bel": "a(HBP:Tubacin)",
-      "function": "Abundance",
-      "id": "dedc7e2e81e2f3f52ebb15e15196a8293a376a1c28fd1a6a3d5c3d427e91d4a14decf57c27d714a83e286a5f815cc1da700bc8c735b50305fc0b103248938299",
-      "name": "Tubacin",
-      "namespace": "HBP"
-    },
-    {
-      "bel": "a(HBP:crebinostat)",
-      "function": "Abundance",
-      "id": "a094b41982d856e0db569ae9306394b542dc773d18e9b7e152c79af639d3727865041e2545a39c01e2f79cea3ba7a6afb921154d1f9def86e3b63a4b87f569f0",
-      "name": "crebinostat",
-      "namespace": "HBP"
-    },
     {
       "bel": "a(HBP:diaminothiazole)",
       "function": "Abundance",
@@ -75158,20 +90937,6 @@
       "name": "maitotoxin",
       "namespace": "HBP"
     },
-    {
-      "bel": "a(HBP:neuroinflammation)",
-      "function": "Abundance",
-      "id": "81fb27d30ab96c3501b38fdf7671e85423e8e196d875c6c367e2f54a3c95df7bf044cdbcb87a67091de83cbb4dc42e68cc385bd5e955f18d77c4082b02409b26",
-      "name": "neuroinflammation",
-      "namespace": "HBP"
-    },
-    {
-      "bel": "a(HBP:neurotoxicity)",
-      "function": "Abundance",
-      "id": "6b7106f4208714e93b995a2819bc36b00466f0ca04b7037093197acad869ef56ae1f9e6b2ceb0b83e8a93a28decaf6a762f8bf2b782d9c7afc649a3317516d37",
-      "name": "neurotoxicity",
-      "namespace": "HBP"
-    },
     {
       "bel": "a(HBP:olomoucine)",
       "function": "Abundance",
@@ -75228,6 +90993,20 @@
       "name": "Dendritic Spines",
       "namespace": "MESH"
     },
+    {
+      "bel": "a(MESH:\"Microtubule-Associated Proteins\")",
+      "function": "Abundance",
+      "id": "69adeb9d2710e22e164b6fd819d921c0428f015fc26f58a3729172f48b8d79eafa9485cb1f87e566fa9a897a3343c04e2b8c84a83b644d3f4361d25e833729e2",
+      "name": "Microtubule-Associated Proteins",
+      "namespace": "MESH"
+    },
+    {
+      "bel": "a(MESH:\"Motor Neurons\")",
+      "function": "Abundance",
+      "id": "bb5722c6fe091afe7a756b250e791caced9dd243596a7c32f1f3fb9f155cc10be16bc028cc0afc928b36a2ba5f8617b89593f670f15052461f81252dc15973d7",
+      "name": "Motor Neurons",
+      "namespace": "MESH"
+    },
     {
       "bel": "a(MESH:\"Neuropil Threads\")",
       "function": "Abundance",
@@ -75249,6 +91028,13 @@
       "name": "Astrocytes",
       "namespace": "MESH"
     },
+    {
+      "bel": "a(MESH:Axons)",
+      "function": "Abundance",
+      "id": "b9459adb8419b819171fa893fdd95e86a7d9cdbb11543e8943c7ec71529965bbe7910a1282a8ad0d70eb070e87ce7a58c09dc3de9c63ef260809af3bb5dc5ba9",
+      "name": "Axons",
+      "namespace": "MESH"
+    },
     {
       "bel": "a(MESH:Brain)",
       "function": "Abundance",
@@ -75257,10 +91043,10 @@
       "namespace": "MESH"
     },
     {
-      "bel": "a(MESH:Hippocampus)",
+      "bel": "a(MESH:Microtubules)",
       "function": "Abundance",
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+      "name": "Microtubules",
       "namespace": "MESH"
     },
     {
@@ -75277,6 +91063,90 @@
       "name": "Neuropil",
       "namespace": "MESH"
     },
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+      "name": "Synapses",
+      "namespace": "MESH"
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+      "namespace": "PUBCHEM"
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       "bel": "bp(GO:\"Wnt signaling pathway\")",
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@@ -75285,538 +91155,1837 @@
       "namespace": "GO"
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     {
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     {
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     {
-      "bel": "complex(GO:\"tubulin complex\")",
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-          "namespace": "HGNC"
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           "namespace": "HGNC"
         },
         {
-          "bel": "p(HGNC:NFE2L2, pmod(Ph))",
+          "bel": "p(INTERPRO:\"Triosephosphate isomerase\", pmod(NO))",
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+          "namespace": "INTERPRO",
           "variants": [
             {
               "identifier": {
-                "name": "Ph",
+                "name": "NO",
                 "namespace": "bel"
               },
               "kind": "pmod"
@@ -75826,42 +92995,44 @@
       ]
     },
     {
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+      "bel": "complex(p(HGNC:MAPT, pmod(Ph)), p(HGNC:SMAD2))",
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+                "namespace": "bel"
+              },
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+            }
+          ]
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         {
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-        },
-        {
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+          "bel": "p(HGNC:MAPT, pmod(Ph, Ser, 262))",
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@@ -75872,28 +93043,37 @@
                 "namespace": "bel"
               },
               "kind": "pmod",
-              "pos": 202
+              "pos": 262
+            }
+          ]
+        },
+        {
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+          "name": "MARK4",
+          "namespace": "HGNC",
+          "variants": [
+            {
+              "identifier": {
+                "name": "Ph",
+                "namespace": "bel"
+              },
+              "kind": "pmod"
             }
           ]
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       ]
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@@ -75904,28 +93084,28 @@
                 "namespace": "bel"
               },
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-              "pos": 396
+              "pos": 262
             }
           ]
+        },
+        {
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-        {
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@@ -75936,171 +93116,189 @@
                 "namespace": "bel"
               },
               "kind": "pmod",
-              "pos": 404
+              "pos": 356
             }
           ]
+        },
+        {
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           "namespace": "HGNC",
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+              "code": "Ser",
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                 "name": "Ph",
                 "namespace": "bel"
               },
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+              "pos": 396
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                 "namespace": "bel"
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+              "pos": 404
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+                "namespace": "bel"
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+      "bel": "complex(p(HGNC:SV2A), p(HGNC:SYT1))",
+      "function": "Complex",
+      "id": "86575c7e52c3f56912705a2c2104bae81f25ff3b6871265e6197e45d39af63a4273cfc95abc9699f103b902f08e33de69734828cc3cd3802d2ac810a5ec488d6",
+      "members": [
         {
-          "bel": "p(HGNC:CUL4B)",
+          "bel": "p(HGNC:SV2A)",
           "function": "Protein",
-          "id": "e3e857fd5c5ba254530870be70727cb3f3c028a4c889ed39e10048dc17eae355ca7f02fd9bd5f9d5ca2a35fc8226c94a8fffb1e82bedc7e8e2a8601847a9a0f9",
-          "name": "CUL4B",
+          "id": "5e365e2af11cf5457b19a378393a9709a08ed8ded54bc5f1abbfd3af850f3f8b2ebad61645bd80fe755b146c1c3449df6b2f35cc4c4bb9d4d76abc67852ad632",
+          "name": "SV2A",
           "namespace": "HGNC"
         },
         {
-          "bel": "p(HGNC:DDB1)",
+          "bel": "p(HGNC:SYT1)",
           "function": "Protein",
-          "id": "b755eecfaa18cb1aec8341ad003eafe0adcbdfc9d6c453ca7da453b3ddb965aa2a575f7af1ddf94e7ba89fa967a413d1699c99f40e8c5305c34acee4657a3817",
-          "name": "DDB1",
+          "id": "b7a278b3abaab03d628ac2d176cf130b82a94485774ec548d33cdf51aa40065b2d08e06bc61c76aa9766c8ffa3ae713882da16f875fcee6ce2e24ce3b8df647b",
+          "name": "SYT1",
           "namespace": "HGNC"
         }
       ]
     },
     {
-      "bel": "complex(p(HGNC:CUL3), p(HGNC:KEAP1), p(HGNC:NFE2L2))",
+      "bel": "complex(p(MGI:Cdk5), p(MGI:Cdk5r1))",
       "function": "Complex",
-      "id": "03d19f6488df91cf4dabce821dbdb91f38bf3f871268b5803430547d7b2e4bb57159e5658d5259f973111f277c752a42af846595e537f67f93d3f29c09e895dc",
+      "id": "3e328c7cd733917d16e4971a3b767f98ad662e8ccc28c78488e70d6df65c934b4bbc76541c63a5bba27338eef448696fb4040f2cb6c7957050bebd96a4794d76",
       "members": [
         {
-          "bel": "p(HGNC:CUL3)",
-          "function": "Protein",
-          "id": "e3c87e99847e4fbcfcf4437274ab159f5ff2cc75c4cc22b660f5cbee86b20c08cee308b6fe8590788acf25c50a7dc0bd82927798d06746fa2f6fac8ba63bd9b8",
-          "name": "CUL3",
-          "namespace": "HGNC"
-        },
-        {
-          "bel": "p(HGNC:KEAP1)",
+          "bel": "p(MGI:Cdk5)",
           "function": "Protein",
-          "id": "ac5b90f683c70d7c98852200b82d97e1b9c6dadc08a979341fb205cb99aa201796fb24c5c1c2e69b24015d83c9aa6da9f6e2f257aadde2ba87accdb9f5366e7b",
-          "name": "KEAP1",
-          "namespace": "HGNC"
+          "id": "2242415e42a04751fb07681acad9f9769f79233a0a87835fe653ed5eee7c77c637074541986216571a96f3ce1b3c69824b051ac84147deb6ef24b12f4bda30f6",
+          "name": "Cdk5",
+          "namespace": "MGI"
         },
         {
-          "bel": "p(HGNC:NFE2L2)",
+          "bel": "p(MGI:Cdk5r1)",
           "function": "Protein",
-          "id": "f707e81d79f55da8c33a4f0fad8eda52a2960c3256f2cd831a5d51542d824e4ed26a18f97cebba93ca1b75239d492efaa0acefa07f5cb15dd98f75c9078ac249",
-          "name": "NFE2L2",
-          "namespace": "HGNC"
+          "id": "3d50e67a9f3663145ba6a1f0e6d443bba4283d6d0095a685abe8f8e624799511b4f796da0fac59b04f20c1a9af9f65ba68a216dc4abc5f91c4fa44b00229ed39",
+          "name": "Cdk5r1",
+          "namespace": "MGI"
         }
       ]
     },
     {
-      "bel": "complex(p(HGNC:FYN), p(MGI:Mapt))",
+      "bel": "complex(p(MGI:Dapk1), p(MGI:Mapt))",
       "function": "Complex",
-      "id": "cacae42bfccf6660720843f0734ae3891ee8ebe856ae166892c3d712cf854ee968dd105316b11b47589df20e2bb23ef2fa1c3212be7db781e65863fb60569860",
+      "id": "b3cd9fc59b35a3421d647b4b85265a5600c65dbc17d18a921f6ce6e62ead416a3991b0418128d72fe41682fbae14d96ad503bff5425babbc08ab320f91a84b1a",
       "members": [
         {
-          "bel": "p(HGNC:FYN)",
+          "bel": "p(MGI:Dapk1)",
           "function": "Protein",
-          "id": "ecffd0427f2e321c9ed5143ca2510464c2fef5432457c332ee991bda79dbdd12ace6375208ee66760cc5b9b7990248651b41a370f16eb9459d2b8682cb0da86b",
-          "name": "FYN",
-          "namespace": "HGNC"
+          "id": "9f6471994bf7d5037d53141c3bf0bd5c257b0a513a0a5f0431d5db8ddcb6320c8f4638359a1a00b58f9ffaafcd1b17649a8e454a1c4c9f4d079dd31478f55e3f",
+          "name": "Dapk1",
+          "namespace": "MGI"
         },
         {
           "bel": "p(MGI:Mapt)",
@@ -76112,48 +93310,73 @@
       ]
     },
     {
-      "bel": "complex(p(HGNC:MAPT), p(HGNC:TGM2))",
+      "bel": "complex(p(MGI:Dcaf1), p(MGI:Dyrk1a))",
       "function": "Complex",
-      "id": "f597b3fc1120f5aaa9233b42cec3e17ed1bd3027785249c65c954d9d9435e4e687965bb0d3faaf9bb9a270aeb8837e12169df586e446c49369028dafe7cdf93a",
+      "id": "0e4e393c6c2d1da9d0d848402b26c663bd5ae2d9cfed46500ea80a59b85742ab1c3c6f050edca1a1af60c829c8425c1bacbd1773811f9616765cb4c853accbfe",
       "members": [
         {
-          "bel": "p(HGNC:MAPT)",
+          "bel": "p(MGI:Dcaf1)",
           "function": "Protein",
-          "id": "ad82d360f02888e890bb2d1f91d1dc020c21cebed2b4eed0193a58e6b396b5f0797d607568dea382c05ffe2a003537d10190b020739af8d51c8d7dbc19bf5ab1",
-          "name": "MAPT",
-          "namespace": "HGNC"
+          "id": "59b84bc42074f8bb1e399325b748b4615f4b4fdf12e2dfbfcdf217f1076a9eb3ad8d06c4a0538ce828bf96fb6282c3776eb9411f88ed77f1028b0727a9e4a775",
+          "name": "Dcaf1",
+          "namespace": "MGI"
         },
         {
-          "bel": "p(HGNC:TGM2)",
+          "bel": "p(MGI:Dyrk1a)",
           "function": "Protein",
-          "id": "954461bfca0f13db007c13a48240c616213276a3e047bbdb8830adef53040c76c0b0d21fcfab6420d59481c73e2b1766cb737abf75aa921354d5d7a8830d17d8",
-          "name": "TGM2",
-          "namespace": "HGNC"
+          "id": "2e7b2037076194038fbe01ac55b538f712182e5d06da9877c6d3f8e6d1e8db2e03bc2bb55d1bc1fc6c5431ad46716ad6fd44e090c9d09ae0552da0297a4447b0",
+          "name": "Dyrk1a",
+          "namespace": "MGI"
         }
       ]
     },
     {
-      "bel": "complex(p(HGNC:MAPT), p(INTERPRO:\"Triosephosphate isomerase\", pmod(NO)))",
+      "bel": "complex(p(MGI:Dpysl2, pmod(Ph)), p(MGI:Mapt, pmod(HBP:hyperphosphorylation)), p(MGI:Wasf1, pmod(Ph)))",
       "function": "Complex",
-      "id": "1a822cb1a15d34c2a22914b6bdf4f99702e91e314a140ea3fee9372ed245c7e7d6ec7f7aa21fd90a31462277b615f265fe6592e6f6a14c1f735618f55119130d",
+      "id": "82ca25e7fb32f08f21f7e8921113b383302a632be6724ec48fa87f060e56682899831c82d51c07c079d224dbd5d3ae8dfc160d88f1bf2d088288eeecd7f2c0cc",
       "members": [
         {
-          "bel": "p(HGNC:MAPT)",
+          "bel": "p(MGI:Dpysl2, pmod(Ph))",
           "function": "Protein",
-          "id": "ad82d360f02888e890bb2d1f91d1dc020c21cebed2b4eed0193a58e6b396b5f0797d607568dea382c05ffe2a003537d10190b020739af8d51c8d7dbc19bf5ab1",
-          "name": "MAPT",
-          "namespace": "HGNC"
+          "id": "6a0c7b3a61d4846bbeae7c93eafeac42a6e3138c2966c8f4b236efecf20f4732c927ee70b5a543480f5fb91c18faf1fa177544066647e711a47ee42b3f63d45a",
+          "name": "Dpysl2",
+          "namespace": "MGI",
+          "variants": [
+            {
+              "identifier": {
+                "name": "Ph",
+                "namespace": "bel"
+              },
+              "kind": "pmod"
+            }
+          ]
         },
         {
-          "bel": "p(INTERPRO:\"Triosephosphate isomerase\", pmod(NO))",
+          "bel": "p(MGI:Mapt, pmod(HBP:hyperphosphorylation))",
           "function": "Protein",
-          "id": "9084a52d47969f6c4df607304cf072f93519825b10368eb8bfe860aafa8043a2e485e74549fb86f806ca96d24cf7e7069e1037de2990dcc7fe9663c5b47b9f88",
-          "name": "Triosephosphate isomerase",
-          "namespace": "INTERPRO",
+          "id": "288a16bac682506988ebfa8afae90f04174b60844d23b90b45b4b0c9707eec496ff8c6b60c60d12b5b6519bfd5c1ea73cc7cf89166b95b0e1cb01b21e3d3ed0c",
+          "name": "Mapt",
+          "namespace": "MGI",
           "variants": [
             {
               "identifier": {
-                "name": "NO",
+                "name": "hyperphosphorylation",
+                "namespace": "HBP"
+              },
+              "kind": "pmod"
+            }
+          ]
+        },
+        {
+          "bel": "p(MGI:Wasf1, pmod(Ph))",
+          "function": "Protein",
+          "id": "bd366fffd010b0efe59dc9f90a4a38b9448441d17a0dd08c4b9ea8f1be66445e387eec5817adf9947dba1111d2e16868c118f4f2e47879b7b1c52f6ebbe86bcf",
+          "name": "Wasf1",
+          "namespace": "MGI",
+          "variants": [
+            {
+              "identifier": {
+                "name": "Ph",
                 "namespace": "bel"
               },
               "kind": "pmod"
@@ -76163,16 +93386,16 @@
       ]
     },
     {
-      "bel": "complex(p(HGNC:MAPT, pmod(Ph)), p(HGNC:SMAD2))",
+      "bel": "complex(p(MGI:Dpysl2, pmod(Ph)), p(MGI:Mapt, pmod(Ph)), p(MGI:Wasf1, pmod(Ph)))",
       "function": "Complex",
-      "id": "9f8cced36ab45dc2bfa8ecaa02959b96f098e7aeb605feddb69ef831880304adef3daa41fcabca971b3915c51e7835e727b34caf97f04a2e7dab3d0e181210d6",
+      "id": "269621fd15d3fae84074f94b44b41be82b0bc35131d307a3eaebe84572a7446f27a243b7c96519d77391631827c95e6afaad7e78387d09704d82e55e2463f9da",
       "members": [
         {
-          "bel": "p(HGNC:MAPT, pmod(Ph))",
+          "bel": "p(MGI:Dpysl2, pmod(Ph))",
           "function": "Protein",
-          "id": "526bae251987f8c4f55f6e2451662fa55e087c57585beae7c389b020d73487c739834e9b8ec841783de6a5b5fb9df8b138e9eff4406a9ec5e606766575dcac0e",
-          "name": "MAPT",
-          "namespace": "HGNC",
+          "id": "6a0c7b3a61d4846bbeae7c93eafeac42a6e3138c2966c8f4b236efecf20f4732c927ee70b5a543480f5fb91c18faf1fa177544066647e711a47ee42b3f63d45a",
+          "name": "Dpysl2",
+          "namespace": "MGI",
           "variants": [
             {
               "identifier": {
@@ -76184,67 +93407,64 @@
           ]
         },
         {
-          "bel": "p(HGNC:SMAD2)",
-          "function": "Protein",
-          "id": "ac9eb6340da114bccc3be554fb1b60e05ad8a2d5ea0ed8e6071fca40d08c35057421eb77165117ab24cd8b2d03f168ccd7ab57f9c60e050758f697c37fea433e",
-          "name": "SMAD2",
-          "namespace": "HGNC"
-        }
-      ]
-    },
-    {
-      "bel": "complex(p(MGI:Dapk1), p(MGI:Mapt))",
-      "function": "Complex",
-      "id": "b3cd9fc59b35a3421d647b4b85265a5600c65dbc17d18a921f6ce6e62ead416a3991b0418128d72fe41682fbae14d96ad503bff5425babbc08ab320f91a84b1a",
-      "members": [
-        {
-          "bel": "p(MGI:Dapk1)",
+          "bel": "p(MGI:Mapt, pmod(Ph))",
           "function": "Protein",
-          "id": "9f6471994bf7d5037d53141c3bf0bd5c257b0a513a0a5f0431d5db8ddcb6320c8f4638359a1a00b58f9ffaafcd1b17649a8e454a1c4c9f4d079dd31478f55e3f",
-          "name": "Dapk1",
-          "namespace": "MGI"
+          "id": "866eb2548d3ebb8c575db22b2dbbed794da750619a04d31b30c8ffbd59b1562d89d2191f4ea30cc09874d9d44f251a203918593f4cc4e29a12eb1d52d0f58bd4",
+          "name": "Mapt",
+          "namespace": "MGI",
+          "variants": [
+            {
+              "identifier": {
+                "name": "Ph",
+                "namespace": "bel"
+              },
+              "kind": "pmod"
+            }
+          ]
         },
         {
-          "bel": "p(MGI:Mapt)",
+          "bel": "p(MGI:Wasf1, pmod(Ph))",
           "function": "Protein",
-          "id": "7d94454106658b1e4190b417a419f7ccbab4b525157cd679cbb4da8a006b08c3819b0a360b692358b3f80ea2648890248be2aa7c97e1d59962dc6aa097560f2d",
-          "name": "Mapt",
-          "namespace": "MGI"
+          "id": "bd366fffd010b0efe59dc9f90a4a38b9448441d17a0dd08c4b9ea8f1be66445e387eec5817adf9947dba1111d2e16868c118f4f2e47879b7b1c52f6ebbe86bcf",
+          "name": "Wasf1",
+          "namespace": "MGI",
+          "variants": [
+            {
+              "identifier": {
+                "name": "Ph",
+                "namespace": "bel"
+              },
+              "kind": "pmod"
+            }
+          ]
         }
       ]
     },
     {
-      "bel": "complex(p(MGI:Dcaf1), p(MGI:Dyrk1a))",
+      "bel": "complex(p(RGD:Hdac4), p(RGD:Nr1h3), p(RGD:Stat1, pmod(Ph)))",
       "function": "Complex",
-      "id": "0e4e393c6c2d1da9d0d848402b26c663bd5ae2d9cfed46500ea80a59b85742ab1c3c6f050edca1a1af60c829c8425c1bacbd1773811f9616765cb4c853accbfe",
+      "id": "2ae20e8450363e10831c27db6a78751cec955158b197ac1972191006220ffe942d404d18a84a00a3b541c18b1e78f27ea34b15e752468b2110ea958cd01ee6a8",
       "members": [
         {
-          "bel": "p(MGI:Dcaf1)",
+          "bel": "p(RGD:Hdac4)",
           "function": "Protein",
-          "id": "59b84bc42074f8bb1e399325b748b4615f4b4fdf12e2dfbfcdf217f1076a9eb3ad8d06c4a0538ce828bf96fb6282c3776eb9411f88ed77f1028b0727a9e4a775",
-          "name": "Dcaf1",
-          "namespace": "MGI"
+          "id": "66222eb5a3d4303e7ac5f25c6296c68385271561aa2dcbfa0ff38cd49e5bfff8234baeb9f4a5a61d5a3d8e31ddac95f9702776281160ddf2e1d48c0647e320e8",
+          "name": "Hdac4",
+          "namespace": "RGD"
         },
         {
-          "bel": "p(MGI:Dyrk1a)",
+          "bel": "p(RGD:Nr1h3)",
           "function": "Protein",
-          "id": "2e7b2037076194038fbe01ac55b538f712182e5d06da9877c6d3f8e6d1e8db2e03bc2bb55d1bc1fc6c5431ad46716ad6fd44e090c9d09ae0552da0297a4447b0",
-          "name": "Dyrk1a",
-          "namespace": "MGI"
-        }
-      ]
-    },
-    {
-      "bel": "complex(p(MGI:Dpysl2, pmod(Ph)), p(MGI:Mapt), p(MGI:Wasf1, pmod(Ph)))",
-      "function": "Complex",
-      "id": "ad38a9d554620597a95a7a7d19846fa12598d2df694695258c690d2ce947fbe384791927468541b9de9cb96f3f0ec8c38929513d37143873d729275b6a9bc6db",
-      "members": [
+          "id": "39177fb2df29eb03ef6ab639cb22bbe3fa40c78a8f4b261ecf300de4d2caa505edda81acbfdb084a6ebc7cbe5ddff8555a67faf6805919a023e1b7c1bbf8a3a3",
+          "name": "Nr1h3",
+          "namespace": "RGD"
+        },
         {
-          "bel": "p(MGI:Dpysl2, pmod(Ph))",
+          "bel": "p(RGD:Stat1, pmod(Ph))",
           "function": "Protein",
-          "id": "6a0c7b3a61d4846bbeae7c93eafeac42a6e3138c2966c8f4b236efecf20f4732c927ee70b5a543480f5fb91c18faf1fa177544066647e711a47ee42b3f63d45a",
-          "name": "Dpysl2",
-          "namespace": "MGI",
+          "id": "3fe94eeef7d00318a427d61a08c81453aed3688d482a843359f12c053a3364a7eb777693f2594676e3280bef47e7bce3075db9617f251ee9657422886fee49c6",
+          "name": "Stat1",
+          "namespace": "RGD",
           "variants": [
             {
               "identifier": {
@@ -76254,20 +93474,34 @@
               "kind": "pmod"
             }
           ]
+        }
+      ]
+    },
+    {
+      "bel": "complex(p(RGD:Nr1h2), p(RGD:Pias1), p(RGD:Stat1, pmod(Ph)))",
+      "function": "Complex",
+      "id": "fd37a544ac3954f47637a51c8f29d7bfe05e523b4efdb76bd2629139d4b433784e9171f572a39baa1b0abef24a32edf8bcee92298882958f0f755948a696b214",
+      "members": [
+        {
+          "bel": "p(RGD:Nr1h2)",
+          "function": "Protein",
+          "id": "de5761ae9f1142f5efde9eb091376274ea721c39602ae9f7e018cd28576d7ec7ebab67426a9cb7cae284a346b627973d074e3b0a25af6b26e903148c8bf45ab1",
+          "name": "Nr1h2",
+          "namespace": "RGD"
         },
         {
-          "bel": "p(MGI:Mapt)",
+          "bel": "p(RGD:Pias1)",
           "function": "Protein",
-          "id": "7d94454106658b1e4190b417a419f7ccbab4b525157cd679cbb4da8a006b08c3819b0a360b692358b3f80ea2648890248be2aa7c97e1d59962dc6aa097560f2d",
-          "name": "Mapt",
-          "namespace": "MGI"
+          "id": "4f454438de4b4eee5328db37d8ae5f12cd582d1d532d033341ac0f1b4733a9a1c8f0b2a4daf55e28fe97472ddd6e8c3e65125b177b3d3b67580684002a001365",
+          "name": "Pias1",
+          "namespace": "RGD"
         },
         {
-          "bel": "p(MGI:Wasf1, pmod(Ph))",
+          "bel": "p(RGD:Stat1, pmod(Ph))",
           "function": "Protein",
-          "id": "bd366fffd010b0efe59dc9f90a4a38b9448441d17a0dd08c4b9ea8f1be66445e387eec5817adf9947dba1111d2e16868c118f4f2e47879b7b1c52f6ebbe86bcf",
-          "name": "Wasf1",
-          "namespace": "MGI",
+          "id": "3fe94eeef7d00318a427d61a08c81453aed3688d482a843359f12c053a3364a7eb777693f2594676e3280bef47e7bce3075db9617f251ee9657422886fee49c6",
+          "name": "Stat1",
+          "namespace": "RGD",
           "variants": [
             {
               "identifier": {
@@ -76329,6 +93563,48 @@
         }
       ]
     },
+    {
+      "bel": "composite(a(CHEBI:cinnamaldehydes), p(HGNC:MAPT))",
+      "function": "Composite",
+      "id": "9aa80a74f9ce83ab184fb7ed36efed4eb99f11e7919fd16720fd0d99fd2f0b845bddcee0e77d5e3a2b6f5c99475abc5821cc08265a44c2eef24a4265d1e11b3f",
+      "members": [
+        {
+          "bel": "a(CHEBI:cinnamaldehydes)",
+          "function": "Abundance",
+          "id": "c976ab63c3e96e58af8eeda1e3939631b8641b02cf8f1cd6edbfdf3bedabd9b3b081e53d6e4445ce73cea4259f0e6f4ffbe7bd7c0b88c68445ed202f12853c9c",
+          "name": "cinnamaldehydes",
+          "namespace": "CHEBI"
+        },
+        {
+          "bel": "p(HGNC:MAPT)",
+          "function": "Protein",
+          "id": "ad82d360f02888e890bb2d1f91d1dc020c21cebed2b4eed0193a58e6b396b5f0797d607568dea382c05ffe2a003537d10190b020739af8d51c8d7dbc19bf5ab1",
+          "name": "MAPT",
+          "namespace": "HGNC"
+        }
+      ]
+    },
+    {
+      "bel": "composite(a(CHEBI:glucose), a(PUBCHEM:16132389))",
+      "function": "Composite",
+      "id": "b1d79bbc097c49570f58124ef6661b42f1a692f2359b3281c59004586b245a7ad58a6cdc9caa480438cfa4c863e3f359b0f40e02e572f39b1a9c2b007f75a6a0",
+      "members": [
+        {
+          "bel": "a(CHEBI:glucose)",
+          "function": "Abundance",
+          "id": "ad228f723834a0438254651fae75410bfa5cb8ee6d9baa98af0240115b1e5ec55edb5d001429c764d8785ec034b6b90edc76a4b83d14572cae3624feacf85491",
+          "name": "glucose",
+          "namespace": "CHEBI"
+        },
+        {
+          "bel": "a(PUBCHEM:16132389)",
+          "function": "Abundance",
+          "id": "f2f5a9840b00a638d570d85c9b744dfdf1cdc24370c729b6c4fe30b13c141462ad3b532b064363ebefe36ef5fed46d2e90f701990e39aaa892857c4db6fc44f0",
+          "name": "16132389",
+          "namespace": "PUBCHEM"
+        }
+      ]
+    },
     {
       "bel": "composite(a(CHEBI:homocysteine), p(HGNC:BDNF), p(HGNC:DYRK1A))",
       "function": "Composite",
@@ -76357,85 +93633,6 @@
         }
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-        {
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-        {
-          "bel": "p(HGNC:MAPT, pmod(Ac, Lys, 369))",
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-                "namespace": "bel"
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-              "kind": "pmod",
-              "pos": 369
-            }
-          ]
-        }
-      ]
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       "bel": "g(DBSNP:rs10807287)",
       "function": "Gene",
@@ -76471,13 +93668,6 @@
       "name": "rs63750688",
       "namespace": "DBSNP"
     },
-    {
-      "bel": "g(DBSNP:rs63751438)",
-      "function": "Gene",
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-      "name": "rs63751438",
-      "namespace": "DBSNP"
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     {
       "bel": "g(DBSNP:rs761059)",
       "function": "Gene",
@@ -76506,6 +93696,20 @@
       "name": "rs8063",
       "namespace": "DBSNP"
     },
+    {
+      "bel": "g(HBP:\"APOE e3\")",
+      "function": "Gene",
+      "id": "1f7180ecd91e4bdae4d29d7baf2aa2206dc0d7d64f9ead8d736e39a21926e0b50e88dcab7219d6e5066035e360696d84f78b29e1ca3c931259295038820e3734",
+      "name": "APOE e3",
+      "namespace": "HBP"
+    },
+    {
+      "bel": "g(HBP:\"APOE e4\")",
+      "function": "Gene",
+      "id": "04016d02eb722dd432653575a2fdb39cb6e4abd7f368a02ecf500f45d1b4425cc1d6bc18e60417e0e0cded5967e9c097527bd3898ae21d2292f411b6d3240ae9",
+      "name": "APOE e4",
+      "namespace": "HBP"
+    },
     {
       "bel": "g(HGNC:DYRK1A)",
       "function": "Gene",
@@ -76514,12 +93718,25 @@
       "namespace": "HGNC"
     },
     {
-      "bel": "g(HGNC:OGT)",
+      "bel": "g(HGNC:OGA)",
       "function": "Gene",
-      "id": "0c459c82d4d92f1a7a19163cac8968e491e6ab32a0401441dfa38b45854d71603e7fb2e9fb98c0648076a78daae9a2a7a97f6e23f71150e687970b8fbd44ab5f",
-      "name": "OGT",
+      "id": "9d80d6606a9698fdcc090073ce66d8d2c93ea49535d9081aa511feb4bdcdee698e355050d446c257a2c8b8cd1d1622561a2cca05570985764f1ec14ec3cae6ba",
+      "name": "OGA",
       "namespace": "HGNC"
     },
+    {
+      "bel": "g(HGNC:OGA, var(\"?\"))",
+      "function": "Gene",
+      "id": "5a532d6067475636dd5031e492fb799959c493f55c06af586aa90fe3c30d9d5d4edeb8145af47bd88c9a46ee44d04a7a5e1428b989ad8a4bbd7551231dc26b23",
+      "name": "OGA",
+      "namespace": "HGNC",
+      "variants": [
+        {
+          "identifier": "?",
+          "kind": "hgvs"
+        }
+      ]
+    },
     {
       "bel": "g(HGNC:TTBK1)",
       "function": "Gene",
@@ -76597,13 +93814,6 @@
       "name": "2.7.11.26",
       "namespace": "ECCODE"
     },
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-      "function": "Protein",
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-      "namespace": "ECCODE"
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       "bel": "p(ECCODE:\"3.2.1.169\")",
       "function": "Protein",
@@ -76618,13 +93828,6 @@
       "name": "3.4.22.52",
       "namespace": "ECCODE"
     },
-    {
-      "bel": "p(ECCODE:\"3.5.1.98\")",
-      "function": "Protein",
-      "id": "a1d6bf6362aa5a68fb0ba838680ea1b0a63195c18b7eb2f8dc41ee51838bd4144141c3cb2bcf5dfa770ec9f41e63d312f7f41821f99fd4829ea9f3b4a464ca43",
-      "name": "3.5.1.98",
-      "namespace": "ECCODE"
-    },
     {
       "bel": "p(FPLX:\"CAMK2_complex\")",
       "function": "Protein",
@@ -76680,6 +93883,13 @@
         }
       ]
     },
+    {
+      "bel": "p(FPLX:AMPK)",
+      "function": "Protein",
+      "id": "131d91a9caa5cdbc7b28605571e134fa945e7705a05cb7d6e238dbb6268ca89c9ea06d040b41f3d5dc7803109910aa78cc4504a4e5408bfe08c5b1a32300a499",
+      "name": "AMPK",
+      "namespace": "FPLX"
+    },
     {
       "bel": "p(FPLX:AP1)",
       "function": "Protein",
@@ -76701,6 +93911,13 @@
       "name": "CALM",
       "namespace": "FPLX"
     },
+    {
+      "bel": "p(FPLX:CAPN)",
+      "function": "Protein",
+      "id": "6f506e5acb6237d0e34184acfe8d2efae60b5a8768be39aef77eb7aafa275c04b84363c108a4c2c63f97ed37ef223374197448c83ece6ed541ec79f4b6d8bf69",
+      "name": "CAPN",
+      "namespace": "FPLX"
+    },
     {
       "bel": "p(FPLX:CEBP)",
       "function": "Protein",
@@ -76775,6 +93992,29 @@
       "name": "HDAC",
       "namespace": "FPLX"
     },
+    {
+      "bel": "p(FPLX:Histone)",
+      "function": "Protein",
+      "id": "f25ce0befe6c8c6f6b62f94bb45d9d7e3a0a8c141e1a80d297af8e440fc3c93c8fd2cc92b17efdd2a4a7fe383916dbadb524a23991638daebd1448c87b5a5670",
+      "name": "Histone",
+      "namespace": "FPLX"
+    },
+    {
+      "bel": "p(FPLX:Histone, pmod(Ac))",
+      "function": "Protein",
+      "id": "20ba61fb982dd73b6d020d80e494bd0e1948b1c3c0b9df6a297f9a299cd8ffba10ac88010edc1c88a85c3044e2608b5bb291e2281e86edd60216caa90ac075c8",
+      "name": "Histone",
+      "namespace": "FPLX",
+      "variants": [
+        {
+          "identifier": {
+            "name": "Ac",
+            "namespace": "bel"
+          },
+          "kind": "pmod"
+        }
+      ]
+    },
     {
       "bel": "p(FPLX:JNK)",
       "function": "Protein",
@@ -76798,6 +94038,24 @@
         }
       ]
     },
+    {
+      "bel": "p(FPLX:JNK, pmod(Ph, Ser, 404))",
+      "function": "Protein",
+      "id": "a72dd1491ff7f84de8d1f93fd964db278ba7f191917f0fd8110f249cc8d4ce33bcd5bb601385fdf9a353f0422c0f7d4b3a51a43e796058202560564968cdbe3a",
+      "name": "JNK",
+      "namespace": "FPLX",
+      "variants": [
+        {
+          "code": "Ser",
+          "identifier": {
+            "name": "Ph",
+            "namespace": "bel"
+          },
+          "kind": "pmod",
+          "pos": 404
+        }
+      ]
+    },
     {
       "bel": "p(FPLX:MAPK)",
       "function": "Protein",
@@ -76874,6 +94132,29 @@
       "name": "PLC",
       "namespace": "FPLX"
     },
+    {
+      "bel": "p(FPLX:PPP1)",
+      "function": "Protein",
+      "id": "988419e86b60ec5d3089171f7ee147a5508044bd5e1f8fea8bf4c0fa388359ecda28e3df00821a28c84199c166df2f863b5396accdf0835c02a484c1a5ddf3d3",
+      "name": "PPP1",
+      "namespace": "FPLX"
+    },
+    {
+      "bel": "p(FPLX:PPP1, pmod(Ph))",
+      "function": "Protein",
+      "id": "80355d49d43fa140ed0500914f9913794198aaef048805a70629bd6073abe780e3b8e6c88fefe5827173b65d680c7cf5c40adb1cc562fabe50832fee593ee770",
+      "name": "PPP1",
+      "namespace": "FPLX",
+      "variants": [
+        {
+          "identifier": {
+            "name": "Ph",
+            "namespace": "bel"
+          },
+          "kind": "pmod"
+        }
+      ]
+    },
     {
       "bel": "p(FPLX:PPP2)",
       "function": "Protein",
@@ -76881,6 +94162,36 @@
       "name": "PPP2",
       "namespace": "FPLX"
     },
+    {
+      "bel": "p(FPLX:PPP2, pmod(Me))",
+      "function": "Protein",
+      "id": "e2cfa32e4a576164a82bc105d31e17ce8d8bf4bf49329be63f01a601dde3c4c43d5fff1e5ae80bc3b1a2a8fd4657f08937aea05ff902a895db639028d3cca59b",
+      "name": "PPP2",
+      "namespace": "FPLX",
+      "variants": [
+        {
+          "identifier": {
+            "name": "Me",
+            "namespace": "bel"
+          },
+          "kind": "pmod"
+        }
+      ]
+    },
+    {
+      "bel": "p(FPLX:Proteasome)",
+      "function": "Protein",
+      "id": "645bfb1e8fc6c1ec119c660999773cfddcb4cf0f2f8f8c0e07af96aceec91f6e5218098423451401e3da7ba628a36a7437a426ca75f5ca004f97d56d7bbfd541",
+      "name": "Proteasome",
+      "namespace": "FPLX"
+    },
+    {
+      "bel": "p(FPLX:SMAD)",
+      "function": "Protein",
+      "id": "6d32e2b8c3b6c514afbe1ca60638f0c99ddf47dbf88ff5d4c666611443fc20ca25fa2a9be2f5160463f2c013dd703d2a08aea3244e4f3dafff8528960150c66c",
+      "name": "SMAD",
+      "namespace": "FPLX"
+    },
     {
       "bel": "p(FPLX:Tubulin)",
       "function": "Protein",
@@ -76911,6 +94222,22 @@
       "name": "p38",
       "namespace": "FPLX"
     },
+    {
+      "bel": "p(FPLX:p38, pmod(Ph))",
+      "function": "Protein",
+      "id": "0473896c39547c78f048fe2b1bbb93a48851ef0e10d3f51c860e81d1c24b120ab756c0ba52e3b3fb7a3be3925ab0e4d067edd620e7320b7b429de58b73964425",
+      "name": "p38",
+      "namespace": "FPLX",
+      "variants": [
+        {
+          "identifier": {
+            "name": "Ph",
+            "namespace": "bel"
+          },
+          "kind": "pmod"
+        }
+      ]
+    },
     {
       "bel": "p(HBP:\"20 S Proteasome\")",
       "function": "Protein",
@@ -76932,20 +94259,6 @@
       "name": "4R tau",
       "namespace": "HBP"
     },
-    {
-      "bel": "p(HBP:\"APOE e3\")",
-      "function": "Protein",
-      "id": "bd29e2f2b9549d7957c20a8b0512e802b1dea89fca770d8861b46b8f6b4010603b52c8d92bac289df54d44cd60bd6cea17fecf8b4896587fa6fac997d1c6809d",
-      "name": "APOE e3",
-      "namespace": "HBP"
-    },
-    {
-      "bel": "p(HBP:\"APOE e4\")",
-      "function": "Protein",
-      "id": "a519d6630bc8e246f2e2604c283b9bad94ea08e43b589ba0c7b579cd4dd7776fd102b8bb0f102104720c312573c9bbadcf691c420a26bcaf53f05359810784c3",
-      "name": "APOE e4",
-      "namespace": "HBP"
-    },
     {
       "bel": "p(HBP:\"APP, ACR\")",
       "function": "Protein",
@@ -77020,6 +94333,22 @@
       "name": "KXGS motif",
       "namespace": "HBP"
     },
+    {
+      "bel": "p(HBP:\"KXGS motif\", pmod(Ph))",
+      "function": "Protein",
+      "id": "0af871cc15cb1b180b5fe7652e4b5d20c09e38e2b6c952b6aae5e6a352bed132b4acad34c8d1c01073b176bea09d9e6d7a762db695b990f062afeda0c92defce",
+      "name": "KXGS motif",
+      "namespace": "HBP",
+      "variants": [
+        {
+          "identifier": {
+            "name": "Ph",
+            "namespace": "bel"
+          },
+          "kind": "pmod"
+        }
+      ]
+    },
     {
       "bel": "p(HBP:\"Kalirin 7\")",
       "function": "Protein",
@@ -77053,24 +94382,17 @@
       "namespace": "HBP"
     },
     {
-      "bel": "p(HBP:\"NP_001387.2:p.Arg205del\")",
-      "function": "Protein",
-      "id": "af7b5a49201f6bd4f568445754a8f42be099b1569b66dd48f30ad2a1eda7c92e1941c15fdada36dc64167123d9f61a6d8fee9fbeb994ef6996110b98f40486c9",
-      "name": "NP_001387.2:p.Arg205del",
-      "namespace": "HBP"
-    },
-    {
-      "bel": "p(HBP:\"NP_001387.2:p.Glu239del\")",
+      "bel": "p(HBP:\"PrP106-126\")",
       "function": "Protein",
-      "id": "d04cb74265d5ca80f24da47f43be5f29b4ea6b215d6b929cbf85b5d8848e2027b01bcec47aad269ffa8d34a6b2ea1f329f27f3746aa29fab29a42d658c70d134",
-      "name": "NP_001387.2:p.Glu239del",
+      "id": "19168ec84399fd45c2295c1dfc1f714156122dac79e7e28b26c462df1ba3f560712458ab698c89ca76620b1331df09cbe60e592e4f19ebcb57d626c47cbe7a0f",
+      "name": "PrP106-126",
       "namespace": "HBP"
     },
     {
-      "bel": "p(HBP:\"PrP106-126\")",
+      "bel": "p(HBP:\"TGM2 Isoform 3 (349 aa)\")",
       "function": "Protein",
-      "id": "19168ec84399fd45c2295c1dfc1f714156122dac79e7e28b26c462df1ba3f560712458ab698c89ca76620b1331df09cbe60e592e4f19ebcb57d626c47cbe7a0f",
-      "name": "PrP106-126",
+      "id": "d80c01716bc5ee8a327234e63058f1656508362b300acaef709ceea4caa3120eb7ce1e0492fdb9b362b874b14c137523935c81b2259f6a7b62223d2e30d2bbe1",
+      "name": "TGM2 Isoform 3 (349 aa)",
       "namespace": "HBP"
     },
     {
@@ -77122,6 +94444,13 @@
       "name": "Tau dimers",
       "namespace": "HBP"
     },
+    {
+      "bel": "p(HBP:\"Tau epitope, 12E8\")",
+      "function": "Protein",
+      "id": "72de20126b65e85da2d43dd825ecd26ae58ba64abba5a6120af65879c6e282d12c94e9f03f98b39c647e76aec99887c3c2813a7bb606a7761bcf8428360682e9",
+      "name": "Tau epitope, 12E8",
+      "namespace": "HBP"
+    },
     {
       "bel": "p(HBP:\"Tau epitope, AD2\")",
       "function": "Protein",
@@ -77136,6 +94465,13 @@
       "name": "Tau epitope, AP422",
       "namespace": "HBP"
     },
+    {
+      "bel": "p(HBP:\"Tau epitope, AT100\")",
+      "function": "Protein",
+      "id": "fff95986904271a3e8bbfe9473380ebcf27d82daf7c7f407692398b036f9629d5182bb614c1da43d497696ef369bd427d2d9f7ebc24751f13bdb14b604146da7",
+      "name": "Tau epitope, AT100",
+      "namespace": "HBP"
+    },
     {
       "bel": "p(HBP:\"Tau epitope, AT180\")",
       "function": "Protein",
@@ -77171,6 +94507,22 @@
       "name": "Tau epitope, PHF1",
       "namespace": "HBP"
     },
+    {
+      "bel": "p(HBP:\"Tau epitope, PHF1\", pmod(Ph))",
+      "function": "Protein",
+      "id": "2e1b047b5bff2b44b7b197bba51f9a3971fdcf93654fbc4941a06327a2d12ea4fe1c19164a6cd7aa93276e0681ec631d20fd5b9bfad6c022c5e048525050693f",
+      "name": "Tau epitope, PHF1",
+      "namespace": "HBP",
+      "variants": [
+        {
+          "identifier": {
+            "name": "Ph",
+            "namespace": "bel"
+          },
+          "kind": "pmod"
+        }
+      ]
+    },
     {
       "bel": "p(HBP:\"Tau isoform B (381 aa)\")",
       "function": "Protein",
@@ -77351,28 +94703,12 @@
       ]
     },
     {
-      "bel": "p(HBP:\"Tau isoform Fetal-tau (352 aa)\")",
+      "bel": "p(HBP:\"Tau oligomers\")",
       "function": "Protein",
-      "id": "34a61591a27bd14ba018bae24717ce7a3da5e791ace8bb1b3524b04e8300872f2fc834ccb43fbf8a4f8cc1293bced6f707cd0b6de7e3cf14b54a6415c642629d",
-      "name": "Tau isoform Fetal-tau (352 aa)",
+      "id": "ed6d04df9a0e3006de2d946bb0b33df722f4f72254d8fef8f09063aeccdf1b2eb9f0f64aadce581d4a37361e6b788845eaac017c9e3337a4dd2b98531f1d67b6",
+      "name": "Tau oligomers",
       "namespace": "HBP"
     },
-    {
-      "bel": "p(HBP:\"Tau isoform Fetal-tau (352 aa)\", pmod(HBP:glycation))",
-      "function": "Protein",
-      "id": "75608ded0ed93e9382e1bfd6ab1bfa7f31b865716fd3c1cbbdea82e5d0b2d38b909632f41d7e91c369fbb9043cb2209c131c9b8823c1e09c3c55067117da3440",
-      "name": "Tau isoform Fetal-tau (352 aa)",
-      "namespace": "HBP",
-      "variants": [
-        {
-          "identifier": {
-            "name": "glycation",
-            "namespace": "HBP"
-          },
-          "kind": "pmod"
-        }
-      ]
-    },
     {
       "bel": "p(HBP:\"VQIINK motif\")",
       "function": "Protein",
@@ -77394,6 +94730,13 @@
       "name": "cis p-tau",
       "namespace": "HBP"
     },
+    {
+      "bel": "p(HBP:\"microtubule-binding region\")",
+      "function": "Protein",
+      "id": "99043577ba012bab6beaa261af4af0794f0bbf7ec841805dcdc7c837d54ed8ba6ee159ed8f3749148f589a7f75faa8a15068d82c4ead932464ee78fd704732b9",
+      "name": "microtubule-binding region",
+      "namespace": "HBP"
+    },
     {
       "bel": "p(HBP:\"paired helical filaments\")",
       "function": "Protein",
@@ -77408,6 +94751,20 @@
       "name": "phosphatase-activating domain",
       "namespace": "HBP"
     },
+    {
+      "bel": "p(HBP:\"projection domain\")",
+      "function": "Protein",
+      "id": "385650dd621a10fc5da2ecfb6697742fb09c8f30832981ba0b7dc317aeb874754f17c5198f2bd0727f9c0b294e47dfe46bd0191d6432010ef40db087b3d9f253",
+      "name": "projection domain",
+      "namespace": "HBP"
+    },
+    {
+      "bel": "p(HBP:\"proline-rich domain\")",
+      "function": "Protein",
+      "id": "5cefaca4e5e21345587ca7dde8672c232adc78c6490528795ee4db664694e8797ecab83a98fba3c2093225c5f01a9e8dcc4b10865d72a7ce6c09c6e0f04927ab",
+      "name": "proline-rich domain",
+      "namespace": "HBP"
+    },
     {
       "bel": "p(HBP:\"proline-rich region 2\")",
       "function": "Protein",
@@ -77445,13 +94802,6 @@
       "name": "tubulin-binding repeat 2",
       "namespace": "HBP"
     },
-    {
-      "bel": "p(HBP:\"tubulin-binding repeat 3\")",
-      "function": "Protein",
-      "id": "5aa28093ea3fef93baf2663bbf46aa247e003e90a4266213ee0ab34c6e0e30e6aa237ff9ba0e5b2431b549689faa0c4427e31879b1c83f67cde526af0ea6067b",
-      "name": "tubulin-binding repeat 3",
-      "namespace": "HBP"
-    },
     {
       "bel": "p(HBP:\"tubulin-binding repeat 4\")",
       "function": "Protein",
@@ -77473,20 +94823,6 @@
       "name": "RAC1b",
       "namespace": "HBP"
     },
-    {
-      "bel": "p(HBP:neurotoxicity)",
-      "function": "Protein",
-      "id": "f2d9b66956de8515be99744da047f00b49b5e488a151577ddb497a96a7cb374e2739e49cee7c66d00ef9b907f4a795fe0c2da90658e6021b637dfc878a529cc8",
-      "name": "neurotoxicity",
-      "namespace": "HBP"
-    },
-    {
-      "bel": "p(HBP:pretangles)",
-      "function": "Protein",
-      "id": "50984dc5930c47498d2dad119831a7b54a55a99d3896337f6c83e66d61d12613e7be31e9fa0a19d6c5701270555b91ba964e25fa891314f5299b49d0af7b6d6e",
-      "name": "pretangles",
-      "namespace": "HBP"
-    },
     {
       "bel": "p(HGNC:ABL1)",
       "function": "Protein",
@@ -77774,13 +95110,6 @@
         }
       ]
     },
-    {
-      "bel": "p(HGNC:CASP1)",
-      "function": "Protein",
-      "id": "573c1f59f79260b0e8231f27d98abeece26f3766396d321ebfa7b7b383c97b58b352e2a1d09292a03153a23832e0349cde21b58fd43b5609c74bbfdabf271d9c",
-      "name": "CASP1",
-      "namespace": "HGNC"
-    },
     {
       "bel": "p(HGNC:CASP3)",
       "function": "Protein",
@@ -77890,6 +95219,13 @@
       "name": "CRBN",
       "namespace": "HGNC"
     },
+    {
+      "bel": "p(HGNC:CSK)",
+      "function": "Protein",
+      "id": "edf06aa27cb34744956716e36b8303f799dacfaa79680f93d34d1dda249f4c1282439b9b4da61d709a64dfa0d994fe119eb1bd62ae5d8a6e42511e60e64c963b",
+      "name": "CSK",
+      "namespace": "HGNC"
+    },
     {
       "bel": "p(HGNC:CSN3)",
       "function": "Protein",
@@ -78029,9 +95365,9 @@
       ]
     },
     {
-      "bel": "p(HGNC:CTNNB1, pmod(Ph, Ser, 35))",
+      "bel": "p(HGNC:CTNNB1, pmod(Ph, Ser, 37))",
       "function": "Protein",
-      "id": "72212638f1c403d2421411850e87bb1ee608222da4f9d3f1f931b1a0505a7c8af25f20ba5760cf8665b3beba0c6f23c50c4eab906e024fe29268d4a8bbea66d7",
+      "id": "f0137fa33e2af27d7578b5b6eb18c49b10ee69295e1f98f0e1746a006128f9084530530d07a59414591c15c346c1e684a02dc065423672f83f960a342209c3d8",
       "name": "CTNNB1",
       "namespace": "HGNC",
       "variants": [
@@ -78042,14 +95378,14 @@
             "namespace": "bel"
           },
           "kind": "pmod",
-          "pos": 35
+          "pos": 37
         }
       ]
     },
     {
-      "bel": "p(HGNC:CTNNB1, pmod(Ph, Ser, 37))",
+      "bel": "p(HGNC:CTNNB1, pmod(Ph, Ser, 45))",
       "function": "Protein",
-      "id": "f0137fa33e2af27d7578b5b6eb18c49b10ee69295e1f98f0e1746a006128f9084530530d07a59414591c15c346c1e684a02dc065423672f83f960a342209c3d8",
+      "id": "84fc2a6a3e81ce4d027bed0a13500cb555b4f90aaf885493bdabd2a7bf60acc1345584db2348c5f42acb13b7904360f237455b89bde457ce4506db642dc1a34e",
       "name": "CTNNB1",
       "namespace": "HGNC",
       "variants": [
@@ -78060,7 +95396,7 @@
             "namespace": "bel"
           },
           "kind": "pmod",
-          "pos": 37
+          "pos": 45
         }
       ]
     },
@@ -78175,6 +95511,22 @@
         }
       ]
     },
+    {
+      "bel": "p(HGNC:DAPK1, pmod(Ph))",
+      "function": "Protein",
+      "id": "2e472e45e16521be87886399a052e9d62b77bcf92c01ef051bc434c26025a76990d25b8226e59022992cc53995a41290bbefbbe393e266f5c7542bae5e31dee9",
+      "name": "DAPK1",
+      "namespace": "HGNC",
+      "variants": [
+        {
+          "identifier": {
+            "name": "Ph",
+            "namespace": "bel"
+          },
+          "kind": "pmod"
+        }
+      ]
+    },
     {
       "bel": "p(HGNC:DAPK2)",
       "function": "Protein",
@@ -78203,29 +95555,6 @@
       "name": "DLG4",
       "namespace": "HGNC"
     },
-    {
-      "bel": "p(HGNC:DPYSL2)",
-      "function": "Protein",
-      "id": "f9d6de9d3af67f9e9378efaee963b6652f2603f0efda63e78455ab4ed0595c13f9ae30ed7cb747083e17dc5c890a345c1f387bec3be06d7f4b80c064fc9d3502",
-      "name": "DPYSL2",
-      "namespace": "HGNC"
-    },
-    {
-      "bel": "p(HGNC:DPYSL2, pmod(Ph))",
-      "function": "Protein",
-      "id": "c0b4a5e92a2fc66c0fd003bb1110e1e7e8c19b61cf5d1d71e8eab1c685bdc4522b32cd3ee712872dd0946444bd23542949042de6e510aeca67b13d39fdc860aa",
-      "name": "DPYSL2",
-      "namespace": "HGNC",
-      "variants": [
-        {
-          "identifier": {
-            "name": "Ph",
-            "namespace": "bel"
-          },
-          "kind": "pmod"
-        }
-      ]
-    },
     {
       "bel": "p(HGNC:DUSP6)",
       "function": "Protein",
@@ -78247,6 +95576,32 @@
       "name": "DYRK1A",
       "namespace": "HGNC"
     },
+    {
+      "bel": "p(HGNC:DYRK1A, var(\"p.Arg205del\"))",
+      "function": "Protein",
+      "id": "e16f2e8fbf614b8875a183a8763ae6deeb4dcabacba812318d269ff26b8960484f0239fd365ca0682fe85fe8cf2a0cd432eadf143277911309f2c3037b21ea5f",
+      "name": "DYRK1A",
+      "namespace": "HGNC",
+      "variants": [
+        {
+          "identifier": "p.Arg205del",
+          "kind": "hgvs"
+        }
+      ]
+    },
+    {
+      "bel": "p(HGNC:DYRK1A, var(\"p.Glu239del\"))",
+      "function": "Protein",
+      "id": "46bdac5cd42642beeab7509e5e08181dadab19ef3407f8012f9ef5dcf26bf849b93dae93a6a159c45d12d2dcd0031c1dabb3244aee737e3dafb31d1bd549c2a7",
+      "name": "DYRK1A",
+      "namespace": "HGNC",
+      "variants": [
+        {
+          "identifier": "p.Glu239del",
+          "kind": "hgvs"
+        }
+      ]
+    },
     {
       "bel": "p(HGNC:DYRK1B)",
       "function": "Protein",
@@ -78291,6 +95646,13 @@
       "name": "FGR",
       "namespace": "HGNC"
     },
+    {
+      "bel": "p(HGNC:FKBP1A)",
+      "function": "Protein",
+      "id": "5d459428cba61445afcbcff9f74aee2fa9a7d2693c853075ae9abcb46149a6277cd5f2de3eece57b9529bdbad094243894b73c2734ef5a2437348d567af8e4d6",
+      "name": "FKBP1A",
+      "namespace": "HGNC"
+    },
     {
       "bel": "p(HGNC:FKBP4)",
       "function": "Protein",
@@ -78305,6 +95667,29 @@
       "name": "FYN",
       "namespace": "HGNC"
     },
+    {
+      "bel": "p(HGNC:GAPDH)",
+      "function": "Protein",
+      "id": "ebf0bfd2c6d35ba188b282517c5fe7b22dfa293d342c939063396abd6ddcf5e4c9f2e3ddd125a0024a364f84dd609edf7c9bdb6876ccfdaf165caf4935608ac7",
+      "name": "GAPDH",
+      "namespace": "HGNC"
+    },
+    {
+      "bel": "p(HGNC:GAPDH, pmod(NO))",
+      "function": "Protein",
+      "id": "3b4047fb3c98b4b65c868539ca623aece491714794d8f781dec7e1903337cef8771cceaf3437369fbb8e5dc8c5847c798d7da75e6056cbc54f9381a5f5ecb76a",
+      "name": "GAPDH",
+      "namespace": "HGNC",
+      "variants": [
+        {
+          "identifier": {
+            "name": "NO",
+            "namespace": "bel"
+          },
+          "kind": "pmod"
+        }
+      ]
+    },
     {
       "bel": "p(HGNC:GLP1R)",
       "function": "Protein",
@@ -78326,20 +95711,6 @@
       "name": "GRIK2",
       "namespace": "HGNC"
     },
-    {
-      "bel": "p(HGNC:GRIN2B)",
-      "function": "Protein",
-      "id": "dd9815c83f93be031a07df6d80146f91f55b3ad8850ccdd967007048fd2354c2bc2fec0dd0a8f428c9c411568fced227500db81dfea20193b9138af7008527a0",
-      "name": "GRIN2B",
-      "namespace": "HGNC"
-    },
-    {
-      "bel": "p(HGNC:GRIN2D)",
-      "function": "Protein",
-      "id": "bab96f9039cecdea17efc38fd53b0cc231e88d46dc6d97369a326f7e508748b6426eb664e1aff81cf5c0b2de0631f26c1c846e40e594e875403a272362c435a0",
-      "name": "GRIN2D",
-      "namespace": "HGNC"
-    },
     {
       "bel": "p(HGNC:GSK3B)",
       "function": "Protein",
@@ -78586,22 +95957,6 @@
       "name": "MAPK8",
       "namespace": "HGNC"
     },
-    {
-      "bel": "p(HGNC:MAPK8, pmod(Ph))",
-      "function": "Protein",
-      "id": "3849bd36f846d2af74d548d1bf778631ca8e438313e8f5e66ab87f8dea83ed7423fe02708dc0d7de4a32420270f10e281186c69502ae776afc8185c4ca64f431",
-      "name": "MAPK8",
-      "namespace": "HGNC",
-      "variants": [
-        {
-          "identifier": {
-            "name": "Ph",
-            "namespace": "bel"
-          },
-          "kind": "pmod"
-        }
-      ]
-    },
     {
       "bel": "p(HGNC:MAPRE1)",
       "function": "Protein",
@@ -78609,6 +95964,13 @@
       "name": "MAPRE1",
       "namespace": "HGNC"
     },
+    {
+      "bel": "p(HGNC:MAPRE3)",
+      "function": "Protein",
+      "id": "9ff95cb16ffd4ebba9a7b41151ae500a582a46f2bef194262f814fae8d2a7cfb56628dd1dd0a2a9de60d51b2731f455e64920df9040a466a6702eec0d1862525",
+      "name": "MAPRE3",
+      "namespace": "HGNC"
+    },
     {
       "bel": "p(HGNC:MAPT)",
       "function": "Protein",
@@ -78692,6 +96054,51 @@
         }
       ]
     },
+    {
+      "bel": "p(HGNC:MAPT, pmod(Ac, Lys, 163), pmod(Ac, Lys, 280), pmod(Ac, Lys, 281), pmod(Ac, Lys, 369))",
+      "function": "Protein",
+      "id": "c0899a0ca86e6446da11c2ce4b47f13e6b25ae7971984dc0a51150c2a5135d6e41ef7bafb37ec90bdf0eadefa48035b42bbb2f4b06e9342edcfc85598d56f01f",
+      "name": "MAPT",
+      "namespace": "HGNC",
+      "variants": [
+        {
+          "code": "Lys",
+          "identifier": {
+            "name": "Ac",
+            "namespace": "bel"
+          },
+          "kind": "pmod",
+          "pos": 163
+        },
+        {
+          "code": "Lys",
+          "identifier": {
+            "name": "Ac",
+            "namespace": "bel"
+          },
+          "kind": "pmod",
+          "pos": 280
+        },
+        {
+          "code": "Lys",
+          "identifier": {
+            "name": "Ac",
+            "namespace": "bel"
+          },
+          "kind": "pmod",
+          "pos": 281
+        },
+        {
+          "code": "Lys",
+          "identifier": {
+            "name": "Ac",
+            "namespace": "bel"
+          },
+          "kind": "pmod",
+          "pos": 369
+        }
+      ]
+    },
     {
       "bel": "p(HGNC:MAPT, pmod(Ac, Lys, 174))",
       "function": "Protein",
@@ -78818,6 +96225,33 @@
         }
       ]
     },
+    {
+      "bel": "p(HGNC:MAPT, pmod(Ac, Lys, 280), pmod(Ac, Lys, 281))",
+      "function": "Protein",
+      "id": "d825c5f73936ae09e63a38f627a6ddcef0111a175f076110e93a299f032ac0ccb2e9821843cd2d8d2ab112df4eb7aaa6622fa17e3a959d30bc94fcae9efdc32d",
+      "name": "MAPT",
+      "namespace": "HGNC",
+      "variants": [
+        {
+          "code": "Lys",
+          "identifier": {
+            "name": "Ac",
+            "namespace": "bel"
+          },
+          "kind": "pmod",
+          "pos": 280
+        },
+        {
+          "code": "Lys",
+          "identifier": {
+            "name": "Ac",
+            "namespace": "bel"
+          },
+          "kind": "pmod",
+          "pos": 281
+        }
+      ]
+    },
     {
       "bel": "p(HGNC:MAPT, pmod(Ac, Lys, 281))",
       "function": "Protein",
@@ -79135,6 +96569,22 @@
         }
       ]
     },
+    {
+      "bel": "p(HGNC:MAPT, pmod(HBP:misfolded))",
+      "function": "Protein",
+      "id": "ecfcb63ffa4e25322a36f440d3724bb450fc6d9ec496f8cd7c66f53a282dbffac579d5bca7b6e04df3ee3d7e3449e11776da8bfb6b14907fe46211e64326a6ff",
+      "name": "MAPT",
+      "namespace": "HGNC",
+      "variants": [
+        {
+          "identifier": {
+            "name": "misfolded",
+            "namespace": "HBP"
+          },
+          "kind": "pmod"
+        }
+      ]
+    },
     {
       "bel": "p(HGNC:MAPT, pmod(HBP:nitration))",
       "function": "Protein",
@@ -79421,9 +96871,9 @@
       ]
     },
     {
-      "bel": "p(HGNC:MAPT, pmod(Me, Lys, 353))",
+      "bel": "p(HGNC:MAPT, pmod(Me, Lys, 311))",
       "function": "Protein",
-      "id": "582b76e84d0c2b5cffd2a6e4e5cc5948f4809a3260775da4927f94939b7046578c435f14e8ab852b285c6b9770fdd2cba34a18ce5247c5061b3317dd88aa6308",
+      "id": "7ef49088d0e6a246fdba3c92499a33a057111b84087a7fd0bb8406b4107f748aee8bbd8103976aeffc4e4653b6965ea212c6747467f22237df73559b09b14145",
       "name": "MAPT",
       "namespace": "HGNC",
       "variants": [
@@ -79434,14 +96884,14 @@
             "namespace": "bel"
           },
           "kind": "pmod",
-          "pos": 353
+          "pos": 311
         }
       ]
     },
     {
-      "bel": "p(HGNC:MAPT, pmod(Me, Lys, 44))",
+      "bel": "p(HGNC:MAPT, pmod(Me, Lys, 353))",
       "function": "Protein",
-      "id": "5895e3e228f0c9083ea7e3336955e7f5139c3e032f48720a4cfab17cc9065bf005ff9078511b800f3de6dbcdc188c31527a9e5b89d9228bf409d16bd2aa2fddc",
+      "id": "582b76e84d0c2b5cffd2a6e4e5cc5948f4809a3260775da4927f94939b7046578c435f14e8ab852b285c6b9770fdd2cba34a18ce5247c5061b3317dd88aa6308",
       "name": "MAPT",
       "namespace": "HGNC",
       "variants": [
@@ -79452,14 +96902,14 @@
             "namespace": "bel"
           },
           "kind": "pmod",
-          "pos": 44
+          "pos": 353
         }
       ]
     },
     {
-      "bel": "p(HGNC:MAPT, pmod(Me, Lys, 67))",
+      "bel": "p(HGNC:MAPT, pmod(Me, Lys, 44))",
       "function": "Protein",
-      "id": "0c388c958cf017384386bcd493d76cd92215ef06a042c6af0474ae469114afd9f86218300b5936ca88fed3b62ca2515fc781961b2ada907a0c4844c62a1652e4",
+      "id": "5895e3e228f0c9083ea7e3336955e7f5139c3e032f48720a4cfab17cc9065bf005ff9078511b800f3de6dbcdc188c31527a9e5b89d9228bf409d16bd2aa2fddc",
       "name": "MAPT",
       "namespace": "HGNC",
       "variants": [
@@ -79470,25 +96920,25 @@
             "namespace": "bel"
           },
           "kind": "pmod",
-          "pos": 67
+          "pos": 44
         }
       ]
     },
     {
-      "bel": "p(HGNC:MAPT, pmod(Me2, Lys, 311))",
+      "bel": "p(HGNC:MAPT, pmod(Me, Lys, 67))",
       "function": "Protein",
-      "id": "42d96f245721dad3e244a0f1e9049ba2be04f05e387021dc8a010675e2cbd5c95f3f9f1dac42f0b4b9f39a238efad2032d11084fcf85c5b9f8e773f92b5dde35",
+      "id": "0c388c958cf017384386bcd493d76cd92215ef06a042c6af0474ae469114afd9f86218300b5936ca88fed3b62ca2515fc781961b2ada907a0c4844c62a1652e4",
       "name": "MAPT",
       "namespace": "HGNC",
       "variants": [
         {
           "code": "Lys",
           "identifier": {
-            "name": "Me2",
+            "name": "Me",
             "namespace": "bel"
           },
           "kind": "pmod",
-          "pos": 311
+          "pos": 67
         }
       ]
     },
@@ -79526,6 +96976,29 @@
         }
       ]
     },
+    {
+      "bel": "p(HGNC:MAPT, pmod(Ph), pmod(Ub))",
+      "function": "Protein",
+      "id": "fb30b0398726466ad51e8bac571c86a54cdb260083d02234fa74b9a8a7b36e2db52cdb0e39ffaba6b242bc5aa90a230cb07499e0bd0d87d3faa99abdea1f56f1",
+      "name": "MAPT",
+      "namespace": "HGNC",
+      "variants": [
+        {
+          "identifier": {
+            "name": "Ph",
+            "namespace": "bel"
+          },
+          "kind": "pmod"
+        },
+        {
+          "identifier": {
+            "name": "Ub",
+            "namespace": "bel"
+          },
+          "kind": "pmod"
+        }
+      ]
+    },
     {
       "bel": "p(HGNC:MAPT, pmod(Ph, Ser, 113))",
       "function": "Protein",
@@ -80201,24 +97674,6 @@
         }
       ]
     },
-    {
-      "bel": "p(HGNC:MAPT, pmod(Ph, Thr, 17))",
-      "function": "Protein",
-      "id": "7213323bda2e267bff101987d39a3cf3714667748cbeee0ae3758842c5b46ef622f95aa7b7b608364d4b6db4bb58a2bcbb21bff0f0ef18a0ea795f3f54e3f953",
-      "name": "MAPT",
-      "namespace": "HGNC",
-      "variants": [
-        {
-          "code": "Thr",
-          "identifier": {
-            "name": "Ph",
-            "namespace": "bel"
-          },
-          "kind": "pmod",
-          "pos": 17
-        }
-      ]
-    },
     {
       "bel": "p(HGNC:MAPT, pmod(Ph, Thr, 175))",
       "function": "Protein",
@@ -80489,6 +97944,24 @@
         }
       ]
     },
+    {
+      "bel": "p(HGNC:MAPT, pmod(Ph, Tyr, 29))",
+      "function": "Protein",
+      "id": "4f9907b76c1b0bcd3417202611c9d68ea4af590c8030bccc2c97314fe432659db575558619b0dd46010eeb10c40e969bef899fd9f6ae115042ba8226f7b79922",
+      "name": "MAPT",
+      "namespace": "HGNC",
+      "variants": [
+        {
+          "code": "Tyr",
+          "identifier": {
+            "name": "Ph",
+            "namespace": "bel"
+          },
+          "kind": "pmod",
+          "pos": 29
+        }
+      ]
+    },
     {
       "bel": "p(HGNC:MAPT, pmod(Ph, Tyr, 363))",
       "function": "Protein",
@@ -80860,6 +98333,19 @@
         }
       ]
     },
+    {
+      "bel": "p(HGNC:MAPT, var(\"p.Lys280*\"))",
+      "function": "Protein",
+      "id": "dfcd38dbb0e3225602d2642d25caa63773b827ad09b97375d161dce9f42f6c57d0a18d2d47dea27849464a130a3bdd24180274b87c6f20d40e28b6ed765e7ff8",
+      "name": "MAPT",
+      "namespace": "HGNC",
+      "variants": [
+        {
+          "identifier": "p.Lys280*",
+          "kind": "hgvs"
+        }
+      ]
+    },
     {
       "bel": "p(HGNC:MAPT, var(\"p.Lys280Gln\"))",
       "function": "Protein",
@@ -81076,6 +98562,13 @@
       "name": "MARK2",
       "namespace": "HGNC"
     },
+    {
+      "bel": "p(HGNC:MARK3)",
+      "function": "Protein",
+      "id": "c6a7a64107fc70fb1b2de0aa596a033d42f57d98fed0f955f597ea6bab1023c81754cd83150a9a8fb58b36bfb8dc16e3525972fdd6c0c6a13a5bf574e6b9ece4",
+      "name": "MARK3",
+      "namespace": "HGNC"
+    },
     {
       "bel": "p(HGNC:MARK4)",
       "function": "Protein",
@@ -81160,15 +98653,15 @@
       ]
     },
     {
-      "bel": "p(HGNC:NFE2L2, pmod(UbPoly))",
+      "bel": "p(HGNC:NFE2L2, pmod(Ub))",
       "function": "Protein",
-      "id": "a57f172cde497b89a2937d56501afd2cddf3c0c4a457b1b6be90ffe7e7b57f55f2e7dc249d8036d369518a8cc41d131e3755e378574405e0464ba5bb14f42e59",
+      "id": "14acb331101a61f17d10bf309314f931fc10b8ef305aaeba94d2652c4f3563f476e2d51aa3d072d120cb80514059c1020dc910f7e13b4ad2d5b9b87b72548f67",
       "name": "NFE2L2",
       "namespace": "HGNC",
       "variants": [
         {
           "identifier": {
-            "name": "UbPoly",
+            "name": "Ub",
             "namespace": "bel"
           },
           "kind": "pmod"
@@ -81176,10 +98669,10 @@
       ]
     },
     {
-      "bel": "p(HGNC:NGF)",
+      "bel": "p(HGNC:NFKBIA)",
       "function": "Protein",
-      "id": "6280e1263996aa31e327521e5975bd06ec1fcc254924ed2e22ada8044eaafa6aeb9242e083f65427b4461e8f6a7d39b80be9b9a35d3509d266e3ced9c2b7afe4",
-      "name": "NGF",
+      "id": "9b4bb952ac56939715566b2be0e9e32837d1688e51c453a2e2d00d51fb4efd6b25a3e42654c40166b33acc42b405f24eeb2dacff3aac84d496bae22778f98e45",
+      "name": "NFKBIA",
       "namespace": "HGNC"
     },
     {
@@ -81275,6 +98768,36 @@
         }
       ]
     },
+    {
+      "bel": "p(HGNC:PIN1, pmod(Ub))",
+      "function": "Protein",
+      "id": "b60710c9a805e9b86388cab902eb8e4c40655e0f6741b5a1651bf49665f7ab8df2eaf9d95551264f543394854165b674b9a998e785289d4afc3769df7d6c2806",
+      "name": "PIN1",
+      "namespace": "HGNC",
+      "variants": [
+        {
+          "identifier": {
+            "name": "Ub",
+            "namespace": "bel"
+          },
+          "kind": "pmod"
+        }
+      ]
+    },
+    {
+      "bel": "p(HGNC:PLCG1)",
+      "function": "Protein",
+      "id": "1512790a6177cbcb3e1fa3670ab32a1e96cb66ceb251a6717153f95adb12b12bc42d7a8b96a468e6b27fb7365da5f4c302ebb64b5bb611fec1d9c50a25d334f1",
+      "name": "PLCG1",
+      "namespace": "HGNC"
+    },
+    {
+      "bel": "p(HGNC:PPME1)",
+      "function": "Protein",
+      "id": "80273eb097478aa5cecf67bcddbaebe183225b2e8b064d8c2cc7b67ecf7ff6dbe118d4e45d10e7fafd1d11971ed597982cec5f76275fd2bf4607ac5d1756fde1",
+      "name": "PPME1",
+      "namespace": "HGNC"
+    },
     {
       "bel": "p(HGNC:PPP1CA)",
       "function": "Protein",
@@ -81360,6 +98883,13 @@
         }
       ]
     },
+    {
+      "bel": "p(HGNC:PPP2CB)",
+      "function": "Protein",
+      "id": "67732a285b15db2be42c869cc075162c0c34f334f4c3985bdf7bbcd89ea83f5142cd2cb6462bcc4e80aa48dc653786e9426fe315643b3b49b79797231f33d02f",
+      "name": "PPP2CB",
+      "namespace": "HGNC"
+    },
     {
       "bel": "p(HGNC:PPP2R5E)",
       "function": "Protein",
@@ -81468,13 +98998,6 @@
       "name": "RHOA",
       "namespace": "HGNC"
     },
-    {
-      "bel": "p(HGNC:RHOT1)",
-      "function": "Protein",
-      "id": "1e80553c912815d51ee6947bc4301107007a2b8f23a8bbab692379227f6fe5f6ce19f3e052789a0c3b0e8b940e52a4f2e5a004e9d423f08eaed1b2eae306f240",
-      "name": "RHOT1",
-      "namespace": "HGNC"
-    },
     {
       "bel": "p(HGNC:S100B)",
       "function": "Protein",
@@ -81563,13 +99086,6 @@
       "name": "SMAD2",
       "namespace": "HGNC"
     },
-    {
-      "bel": "p(HGNC:SMAD3)",
-      "function": "Protein",
-      "id": "f1df97604661ba3fb80211b8bce03e38d1a54a645379df8d662a585129a7fde66297e9f4fe99c9d3af6b799df93ac7898204b802ca5aa736ca1f6bb3484cc66a",
-      "name": "SMAD3",
-      "namespace": "HGNC"
-    },
     {
       "bel": "p(HGNC:SNAP25)",
       "function": "Protein",
@@ -81676,6 +99192,19 @@
       "name": "SUMO3",
       "namespace": "HGNC"
     },
+    {
+      "bel": "p(HGNC:SUMO3, var(\"p.Lys11Arg\"))",
+      "function": "Protein",
+      "id": "3c25f62d351e9894b818bc47f47d107f4eeda3eeb411836021067335d6f9dfa5b2c7487b79bdc5b3f84aff80eaec68cd3590d52d065fb05cfc93bf53c28d3b1a",
+      "name": "SUMO3",
+      "namespace": "HGNC",
+      "variants": [
+        {
+          "identifier": "p.Lys11Arg",
+          "kind": "hgvs"
+        }
+      ]
+    },
     {
       "bel": "p(HGNC:SV2A)",
       "function": "Protein",
@@ -82362,11 +99891,25 @@
       "namespace": "HGNC"
     },
     {
-      "bel": "p(INTERPRO:\"14-3-3 domain\")",
+      "bel": "p(HGNC:YWHAZ)",
       "function": "Protein",
-      "id": "d0a251fc97189b6b4d9b4c6bd813845f13f5ba9188437860beb6c0cf651bf9404a1fbb658a8ba34896becba9c97f86aecc87333c1c9c7c57391fd420341eba65",
-      "name": "14-3-3 domain",
-      "namespace": "INTERPRO"
+      "id": "e34d659c6722333f4f7db72f276727f6aaadd83e08eaa6e3f32cdc113b6a73bb927f8f66b88eda74697be02655279bb1b7ced720d1a34e97156cde5ae615974a",
+      "name": "YWHAZ",
+      "namespace": "HGNC"
+    },
+    {
+      "bel": "p(HGNCGENEFAMILY:\"Src family tyrosine kinases\")",
+      "function": "Protein",
+      "id": "3b5404723dc21176ec3576192ada4e7ab24e87e29ddd333ad9f0f98412222a04570eb40e4b00d4b36dd5ff1665ef3e4465cd8e6156ade3a0a1ec7918ca7092d3",
+      "name": "Src family tyrosine kinases",
+      "namespace": "HGNCGENEFAMILY"
+    },
+    {
+      "bel": "p(HGNCGENEFAMILY:Transglutaminases)",
+      "function": "Protein",
+      "id": "8eab92cc1d286c2120d67c2679d49e3068c21178c02a30cc03511b93da75ee636a02a7b6e3855b55caea8e7fe4fe9b6c45ebf335342330661bc33ee6f02e8908",
+      "name": "Transglutaminases",
+      "namespace": "HGNCGENEFAMILY"
     },
     {
       "bel": "p(INTERPRO:\"Alpha tubulin\")",
@@ -82398,13 +99941,6 @@
       "name": "Death domain",
       "namespace": "INTERPRO"
     },
-    {
-      "bel": "p(INTERPRO:\"FKBP-type peptidyl-prolyl cis-trans isomerase domain\")",
-      "function": "Protein",
-      "id": "6630b88e950c2725f22cf2ba8e0b2e1afc884c1b5d9b403e6db6ba769906c57b7ab776f23982a1d2e0aaddc6497e95e8275c504202efe3fa13d8793e88bfe6b3",
-      "name": "FKBP-type peptidyl-prolyl cis-trans isomerase domain",
-      "namespace": "INTERPRO"
-    },
     {
       "bel": "p(INTERPRO:\"Heat shock protein Hsp90 family\")",
       "function": "Protein",
@@ -82413,18 +99949,20 @@
       "namespace": "INTERPRO"
     },
     {
-      "bel": "p(INTERPRO:\"Kinase associated domain 1 (KA1)\")",
-      "function": "Protein",
-      "id": "f985a7a001f12251daca2e3a0010feedd29fb50a2233a1e2bd87e7a5d563f67a5fa0e89df6fd6c167661c2f634029ac3dde0e148c413fdae15f6799dd95f887b",
-      "name": "Kinase associated domain 1 (KA1)",
-      "namespace": "INTERPRO"
-    },
-    {
-      "bel": "p(INTERPRO:\"Peptidase C2, calpain, catalytic domain\")",
+      "bel": "p(INTERPRO:\"Heat shock protein Hsp90 family\", pmod(Ac))",
       "function": "Protein",
-      "id": "8a8d228e8be4ea2d2ddeae2f0d4818c02a6bcc74833d78a9fbe652882e7442070050d99ae48493d71df331f31a5cd0c1808041d1bf23ab54c54ab9caf688a83f",
-      "name": "Peptidase C2, calpain, catalytic domain",
-      "namespace": "INTERPRO"
+      "id": "14a345b0f0863287f0e830ea9f1ef4282ae1412b6b09a2deb66de28f158b0e676a04919d1c0372fe59ba026dead3ef5ea3b0c6728c8e850aec4494e85fb63729",
+      "name": "Heat shock protein Hsp90 family",
+      "namespace": "INTERPRO",
+      "variants": [
+        {
+          "identifier": {
+            "name": "Ac",
+            "namespace": "bel"
+          },
+          "kind": "pmod"
+        }
+      ]
     },
     {
       "bel": "p(INTERPRO:\"SH3 domain\")",
@@ -82500,35 +100038,35 @@
       ]
     },
     {
-      "bel": "p(INTERPRO:\"Tubulin/FtsZ, GTPase domain\")",
+      "bel": "p(MESH:\"Receptors, N-Methyl-D-Aspartate\")",
       "function": "Protein",
-      "id": "b52f674125417153c9471426864622a5f7505626edf3bc9a0a5fc7228ebb3ead701e49cb80b4e6bb4c86386fd0e812bb3ef690ed9955c0b322c828550543507d",
-      "name": "Tubulin/FtsZ, GTPase domain",
-      "namespace": "INTERPRO"
+      "id": "ab91a476fe132c4c83d7b29153f974577ea615b5e5d8b9bf9e0fa9837b4c78ab8faeb90157fee0678d87fae0d5d4a5ceed372d81c6cf0b12f81ea0faf35d858d",
+      "name": "Receptors, N-Methyl-D-Aspartate",
+      "namespace": "MESH"
     },
     {
-      "bel": "p(INTERPRO:\"Tubulin/FtsZ, GTPase domain\", pmod(Ac))",
+      "bel": "p(MESH:Proteins)",
       "function": "Protein",
-      "id": "28f7da3cf4bfd332ccb8d92d39cef783caa0f7fac86341057f925a91e885beca762e6d20d16e7e14a07f107ce7a155d61d384ef590025f651031b941e657b41d",
-      "name": "Tubulin/FtsZ, GTPase domain",
-      "namespace": "INTERPRO",
+      "id": "20fec9748aca569e46ee2703620f548aece50dde1dd6518d2833a58da6a5fc28e70918b127d515943ad659b626fa533df7854b4887e2cab8d3a7af00dea602d0",
+      "name": "Proteins",
+      "namespace": "MESH"
+    },
+    {
+      "bel": "p(MESH:Proteins, pmod(HBP:\"O-GlcNAcylation\"))",
+      "function": "Protein",
+      "id": "ebea203e53c77c1f06d577c839ba21f7705fdcbd5995ba399d2aaad5e9cc3daa8f0a0a0a9a4ba49842cad6de5fbeebb9b49b1752b2185328eddb4c1352ae53dc",
+      "name": "Proteins",
+      "namespace": "MESH",
       "variants": [
         {
           "identifier": {
-            "name": "Ac",
-            "namespace": "bel"
+            "name": "O-GlcNAcylation",
+            "namespace": "HBP"
           },
           "kind": "pmod"
         }
       ]
     },
-    {
-      "bel": "p(MESH:\"Receptors, N-Methyl-D-Aspartate\")",
-      "function": "Protein",
-      "id": "ab91a476fe132c4c83d7b29153f974577ea615b5e5d8b9bf9e0fa9837b4c78ab8faeb90157fee0678d87fae0d5d4a5ceed372d81c6cf0b12f81ea0faf35d858d",
-      "name": "Receptors, N-Methyl-D-Aspartate",
-      "namespace": "MESH"
-    },
     {
       "bel": "p(MGI:App)",
       "function": "Protein",
@@ -82551,12 +100089,21 @@
       "namespace": "MGI"
     },
     {
-      "bel": "p(MGI:Camk2b, pmod(Ph, Thr, 287))",
+      "bel": "p(MGI:Camk2b, pmod(Ph, Thr, 286), pmod(Ph, Thr, 287))",
       "function": "Protein",
-      "id": "41ae26d28d58e04017a2c0e88f77da91328aabe4e8893c5566cbc0fe7d5ccdd3020662a7942587f84e5fa5ebf067e6e645a707857c96ba869f414d2b09c28141",
+      "id": "770fec059e41c4e63a386afa31f98ce4cb27c8d0ce6bf69233566057b9ccb44a9826d0dde84c60b6278d696a73cea57c76932739e1b4bfa2381617f7fdc141c6",
       "name": "Camk2b",
       "namespace": "MGI",
       "variants": [
+        {
+          "code": "Thr",
+          "identifier": {
+            "name": "Ph",
+            "namespace": "bel"
+          },
+          "kind": "pmod",
+          "pos": 286
+        },
         {
           "code": "Thr",
           "identifier": {
@@ -82569,12 +100116,21 @@
       ]
     },
     {
-      "bel": "p(MGI:Camk2b, pmod(Ph, Thr, 306))",
+      "bel": "p(MGI:Camk2b, pmod(Ph, Thr, 305), pmod(Ph, Thr, 306))",
       "function": "Protein",
-      "id": "85ae42060e46dbf4da7c668112cd52e6a171a7b79b135d362a6d8f3d62216af2ede07225da448936522aa30cb93a3f27df6aa08b3efbc4a675737fc3efa580a8",
+      "id": "815b2d0e7ac0d3b76b40760e0afd15115487b0308c60ac1544f7e99f199e84d5173ae50d5d148640a64cc4e7a6207e0a01e6729a24d667e9a8e1ad6a60a0d6b8",
       "name": "Camk2b",
       "namespace": "MGI",
       "variants": [
+        {
+          "code": "Thr",
+          "identifier": {
+            "name": "Ph",
+            "namespace": "bel"
+          },
+          "kind": "pmod",
+          "pos": 305
+        },
         {
           "code": "Thr",
           "identifier": {
@@ -82621,13 +100177,6 @@
       "name": "Crh",
       "namespace": "MGI"
     },
-    {
-      "bel": "p(MGI:Crhr1)",
-      "function": "Protein",
-      "id": "7c572ed2b3f5325df2083d26dcbf2f697ed311544b299d1b3ea3dd77de10f3c3fd9a554877ad7aec6231da0514b4ac26c06cf979b460f8af5ade5f9f54a304fb",
-      "name": "Crhr1",
-      "namespace": "MGI"
-    },
     {
       "bel": "p(MGI:Dapk1)",
       "function": "Protein",
@@ -82642,13 +100191,6 @@
       "name": "Dcaf1",
       "namespace": "MGI"
     },
-    {
-      "bel": "p(MGI:Dnmt1)",
-      "function": "Protein",
-      "id": "0d96591f5ea61a07ee213d18cd4112e046de567a32f541cec48f7bb6727aa00b3b6f5dc4e1e241efc8ef9914578772eed1875250ee8ef3c5fb880d3a01337b38",
-      "name": "Dnmt1",
-      "namespace": "MGI"
-    },
     {
       "bel": "p(MGI:Dpysl2)",
       "function": "Protein",
@@ -82686,6 +100228,22 @@
       "name": "Ep300",
       "namespace": "MGI"
     },
+    {
+      "bel": "p(MGI:Ep300, pmod(Ac))",
+      "function": "Protein",
+      "id": "bab88efa0abcf3b704ed3fa720bade08315fdec90aaa1e9c65f099fe71f3e02cacbf3faa3db3deba702b9fe671803da5cc973e69fddf4a3224c7b1754ce211ff",
+      "name": "Ep300",
+      "namespace": "MGI",
+      "variants": [
+        {
+          "identifier": {
+            "name": "Ac",
+            "namespace": "bel"
+          },
+          "kind": "pmod"
+        }
+      ]
+    },
     {
       "bel": "p(MGI:Fyn)",
       "function": "Protein",
@@ -82748,6 +100306,13 @@
         }
       ]
     },
+    {
+      "bel": "p(MGI:Grin2d)",
+      "function": "Protein",
+      "id": "cd27771c2f6d6b436129e39e2d8fca4c76c8445ff02e1868682a560e6a47569a732b94674fbe4250e9b15dc247cc1bffda868e0982b7b098c965ef854c0edb7d",
+      "name": "Grin2d",
+      "namespace": "MGI"
+    },
     {
       "bel": "p(MGI:Gsk3b)",
       "function": "Protein",
@@ -82755,6 +100320,24 @@
       "name": "Gsk3b",
       "namespace": "MGI"
     },
+    {
+      "bel": "p(MGI:Gsk3b, pmod(Ph, Ser, 9))",
+      "function": "Protein",
+      "id": "4d90780b3f316d2414103b665105ca43ff5f125cb292b23e5dcb20ce6ce992e4f4e171cd3f050a88488a343cd93a9c947e2e6260fd5f5f5944c2cc5537fbb3d8",
+      "name": "Gsk3b",
+      "namespace": "MGI",
+      "variants": [
+        {
+          "code": "Ser",
+          "identifier": {
+            "name": "Ph",
+            "namespace": "bel"
+          },
+          "kind": "pmod",
+          "pos": 9
+        }
+      ]
+    },
     {
       "bel": "p(MGI:Gsk3b, pmod(Ph, Tyr, 216))",
       "function": "Protein",
@@ -82826,13 +100409,6 @@
       "name": "Mapk14",
       "namespace": "MGI"
     },
-    {
-      "bel": "p(MGI:Mapk8)",
-      "function": "Protein",
-      "id": "180370fe7647f0ed8873ea850caa7ecf749570fd473d7cc3323b70c27da7f06294077ae0914137ef66e09793571ce1a24d88d5e9aa35d98dc52998ce14d2b81a",
-      "name": "Mapk8",
-      "namespace": "MGI"
-    },
     {
       "bel": "p(MGI:Mapt)",
       "function": "Protein",
@@ -82841,25 +100417,27 @@
       "namespace": "MGI"
     },
     {
-      "bel": "p(MGI:Mapt, pmod(Ac))",
+      "bel": "p(MGI:Mapt, pmod(Ac, Lys, 174))",
       "function": "Protein",
-      "id": "f7f88373eefe8e35dbdd45235c15a3f973cc5b4ae594df8bbdb74b855432a11c17268b97df9fc604af82e9c11ae131a497e279734efa1f8f8458ad4cd3e747a4",
+      "id": "f342d33f0bcbb4f3e2dba58e6532d4d105668417a6d00b309d7ccfccc75688a1d6b5fa9be196035da5bc54ff5d5019f948a727deb23e919e6e2023a240b4ff23",
       "name": "Mapt",
       "namespace": "MGI",
       "variants": [
         {
+          "code": "Lys",
           "identifier": {
             "name": "Ac",
             "namespace": "bel"
           },
-          "kind": "pmod"
+          "kind": "pmod",
+          "pos": 174
         }
       ]
     },
     {
-      "bel": "p(MGI:Mapt, pmod(Ac, Lys, 174))",
+      "bel": "p(MGI:Mapt, pmod(Ac, Lys, 274))",
       "function": "Protein",
-      "id": "f342d33f0bcbb4f3e2dba58e6532d4d105668417a6d00b309d7ccfccc75688a1d6b5fa9be196035da5bc54ff5d5019f948a727deb23e919e6e2023a240b4ff23",
+      "id": "09818aef7a68bd3867e4869a5165be2ca50397e4809054d6acb0252f81cc9e7ed5cbe935b1cecaeb407d48b7b5ebc846b23d6997a96b1e4a75b33e46848c534f",
       "name": "Mapt",
       "namespace": "MGI",
       "variants": [
@@ -82870,7 +100448,7 @@
             "namespace": "bel"
           },
           "kind": "pmod",
-          "pos": 174
+          "pos": 274
         }
       ]
     },
@@ -82893,31 +100471,33 @@
       ]
     },
     {
-      "bel": "p(MGI:Mapt, pmod(HBP:\"O-GlcNAcylation\"))",
+      "bel": "p(MGI:Mapt, pmod(Ac, Lys, 281))",
       "function": "Protein",
-      "id": "bbcb2df365693602eaf0dc8146b0e49b0c110fa73bbb3aec3b0e60e613d232072ee14723f18b985e7a5c44a10c0cec38d179fd55bd32eb13050c72c6e1fe3c01",
+      "id": "90c009a6dbe7299553b7fb595a9d2fc986e26d03e5cc98169a02d6db80ef236fea20065551e07b6033a54985bb1e5baa10c7ebe93973bc40df1cc8f9f1653873",
       "name": "Mapt",
       "namespace": "MGI",
       "variants": [
         {
+          "code": "Lys",
           "identifier": {
-            "name": "O-GlcNAcylation",
-            "namespace": "HBP"
+            "name": "Ac",
+            "namespace": "bel"
           },
-          "kind": "pmod"
+          "kind": "pmod",
+          "pos": 281
         }
       ]
     },
     {
-      "bel": "p(MGI:Mapt, pmod(HBP:hyperphosphorylation))",
+      "bel": "p(MGI:Mapt, pmod(HBP:\"O-GlcNAcylation\"))",
       "function": "Protein",
-      "id": "288a16bac682506988ebfa8afae90f04174b60844d23b90b45b4b0c9707eec496ff8c6b60c60d12b5b6519bfd5c1ea73cc7cf89166b95b0e1cb01b21e3d3ed0c",
+      "id": "bbcb2df365693602eaf0dc8146b0e49b0c110fa73bbb3aec3b0e60e613d232072ee14723f18b985e7a5c44a10c0cec38d179fd55bd32eb13050c72c6e1fe3c01",
       "name": "Mapt",
       "namespace": "MGI",
       "variants": [
         {
           "identifier": {
-            "name": "hyperphosphorylation",
+            "name": "O-GlcNAcylation",
             "namespace": "HBP"
           },
           "kind": "pmod"
@@ -82925,38 +100505,18 @@
       ]
     },
     {
-      "bel": "p(MGI:Mapt, pmod(HBP:nitration, Tyr, 488))",
-      "function": "Protein",
-      "id": "760d36cb789a5c3bc36780eb17dc8db8899681d770b38a895ebc15282c278b8a48806639de0e12f5d0ed2d8541cfef2eec4ccb640e1e3fb8b6d9c5290104a555",
-      "name": "Mapt",
-      "namespace": "MGI",
-      "variants": [
-        {
-          "code": "Tyr",
-          "identifier": {
-            "name": "nitration",
-            "namespace": "HBP"
-          },
-          "kind": "pmod",
-          "pos": 488
-        }
-      ]
-    },
-    {
-      "bel": "p(MGI:Mapt, pmod(HBP:nitration, Tyr, 507))",
+      "bel": "p(MGI:Mapt, pmod(HBP:hyperphosphorylation))",
       "function": "Protein",
-      "id": "97bc64754cc13c14fc88fc57bc7d8f51cc9a3c529b7473d7676ef2e6912497448b1640f34c2cee4d90c62799d8f37612508a14afcb9ce3ea3f2669948065c435",
+      "id": "288a16bac682506988ebfa8afae90f04174b60844d23b90b45b4b0c9707eec496ff8c6b60c60d12b5b6519bfd5c1ea73cc7cf89166b95b0e1cb01b21e3d3ed0c",
       "name": "Mapt",
       "namespace": "MGI",
       "variants": [
         {
-          "code": "Tyr",
           "identifier": {
-            "name": "nitration",
+            "name": "hyperphosphorylation",
             "namespace": "HBP"
           },
-          "kind": "pmod",
-          "pos": 507
+          "kind": "pmod"
         }
       ]
     },
@@ -83165,24 +100725,6 @@
         }
       ]
     },
-    {
-      "bel": "p(MGI:Mapt, pmod(Ph, Ser, 301))",
-      "function": "Protein",
-      "id": "f54a2e2adf5b91142b482d19eba652e35566cacca79f1539f513eaf95f1a66a332b4ad63148ca6666c4df2858fbb8afc9184aa1474803ade16c41e3024bdd76d",
-      "name": "Mapt",
-      "namespace": "MGI",
-      "variants": [
-        {
-          "code": "Ser",
-          "identifier": {
-            "name": "Ph",
-            "namespace": "bel"
-          },
-          "kind": "pmod",
-          "pos": 301
-        }
-      ]
-    },
     {
       "bel": "p(MGI:Mapt, pmod(Ph, Ser, 396))",
       "function": "Protein",
@@ -83327,6 +100869,24 @@
         }
       ]
     },
+    {
+      "bel": "p(MGI:Mapt, pmod(Ph, Thr, 204))",
+      "function": "Protein",
+      "id": "b8e0825c7a9d3c88b8b9fb279c5f5552136001dfb443487a5fb902c96b3cec63a4b59e628ebc529945ef525fc26cca8cdde74495987316ef0ad0a47c14fc54df",
+      "name": "Mapt",
+      "namespace": "MGI",
+      "variants": [
+        {
+          "code": "Thr",
+          "identifier": {
+            "name": "Ph",
+            "namespace": "bel"
+          },
+          "kind": "pmod",
+          "pos": 204
+        }
+      ]
+    },
     {
       "bel": "p(MGI:Mapt, pmod(Ph, Thr, 205))",
       "function": "Protein",
@@ -83435,6 +100995,19 @@
         }
       ]
     },
+    {
+      "bel": "p(MGI:Mapt, var(\"p.Pro301Leu\"))",
+      "function": "Protein",
+      "id": "cb4d9e7ada2a1bebe9b2b0560001e3ca48bac98b19a5c12e5b38e302e33c15460e501c72d6d3fb6c2e82afcbbeaf2403f0d65f6925bceedc1d78737845c147cb",
+      "name": "Mapt",
+      "namespace": "MGI",
+      "variants": [
+        {
+          "identifier": "p.Pro301Leu",
+          "kind": "hgvs"
+        }
+      ]
+    },
     {
       "bel": "p(MGI:Mef2d)",
       "function": "Protein",
@@ -83442,6 +101015,13 @@
       "name": "Mef2d",
       "namespace": "MGI"
     },
+    {
+      "bel": "p(MGI:Nfe2l2)",
+      "function": "Protein",
+      "id": "ca5db172043ef01a28448899ca79737eaba71966fd12f33a2ac47b7a96a80b0818798fa4693d9517f0e4cc1ec2847ebd3fedeb6a92fd6a7a8fc9e5b2d9767439",
+      "name": "Nfe2l2",
+      "namespace": "MGI"
+    },
     {
       "bel": "p(MGI:Pde5a)",
       "function": "Protein",
@@ -83456,6 +101036,13 @@
       "name": "Ppargc1a",
       "namespace": "MGI"
     },
+    {
+      "bel": "p(MGI:Ppme1)",
+      "function": "Protein",
+      "id": "2593791445e3a7c17083d7afa6bb1c8c5125c8a728193fc06f82d424a226a956c94829df296808bbc8e29de062db8a166e2d64f91b85eb73f2d3326a630d5dc8",
+      "name": "Ppme1",
+      "namespace": "MGI"
+    },
     {
       "bel": "p(MGI:Ppp1ca)",
       "function": "Protein",
@@ -83516,24 +101103,6 @@
         }
       ]
     },
-    {
-      "bel": "p(MGI:Ppp2ca, pmod(Me, Leu, 309))",
-      "function": "Protein",
-      "id": "388ea51fa6444a3500bf41c7f9671fa03bb3f27fb36364fe7f33448d02de364e5541cb5120226e6baf1ffa9e531693a331099c05d81505f1d4187b5b8e048f0d",
-      "name": "Ppp2ca",
-      "namespace": "MGI",
-      "variants": [
-        {
-          "code": "Leu",
-          "identifier": {
-            "name": "Me",
-            "namespace": "bel"
-          },
-          "kind": "pmod",
-          "pos": 309
-        }
-      ]
-    },
     {
       "bel": "p(MGI:Sirt1)",
       "function": "Protein",
@@ -83624,6 +101193,13 @@
         }
       ]
     },
+    {
+      "bel": "p(MGI:Wwc1)",
+      "function": "Protein",
+      "id": "7873e4144454e87149f49475c3e6acf3c688ff4a67d3f2249c59fd2b735cbfec766153a5f206f30d54067f6073868cde1fff0a5b7de3b19193f62c7a0fda2684",
+      "name": "Wwc1",
+      "namespace": "MGI"
+    },
     {
       "bel": "p(RGD:Akt1)",
       "function": "Protein",
@@ -83791,6 +101367,45 @@
       "name": "Mapt",
       "namespace": "RGD"
     },
+    {
+      "bel": "p(RGD:Mapt, pmod(HBP:hyperphosphorylation))",
+      "function": "Protein",
+      "id": "a08b50d5f982e033ae12cbb16002a13a4fb9e25284c14c0e899f0cd06f39401fd76ea8a0717258fe4396d8be0e30ce51ce0d5f0d37ae31bb37addb085f7a4e8b",
+      "name": "Mapt",
+      "namespace": "RGD",
+      "variants": [
+        {
+          "identifier": {
+            "name": "hyperphosphorylation",
+            "namespace": "HBP"
+          },
+          "kind": "pmod"
+        }
+      ]
+    },
+    {
+      "bel": "p(RGD:Mapt, pmod(HBP:hyperphosphorylation), pmod(Sumo))",
+      "function": "Protein",
+      "id": "ce7246aa0d36e3f9e8b28001aefea879c067ccfb136e5451f5de6d05ed8953d43d0f4e26f20e094f3227b7da182ccb06d56e3844d9d2baf604dab86a081a649b",
+      "name": "Mapt",
+      "namespace": "RGD",
+      "variants": [
+        {
+          "identifier": {
+            "name": "hyperphosphorylation",
+            "namespace": "HBP"
+          },
+          "kind": "pmod"
+        },
+        {
+          "identifier": {
+            "name": "Sumo",
+            "namespace": "bel"
+          },
+          "kind": "pmod"
+        }
+      ]
+    },
     {
       "bel": "p(RGD:Mapt, pmod(HBP:nitration))",
       "function": "Protein",
@@ -83807,6 +101422,24 @@
         }
       ]
     },
+    {
+      "bel": "p(RGD:Mapt, pmod(HBP:nitration, Tyr, 507))",
+      "function": "Protein",
+      "id": "fad61e1b1cf35996d72310bb3f049a523901ac9631521fa3f48f32373565c5ced5a907a16396e1d186c24a73b17e67172e725516d4ff5d208638c0f1714bb898",
+      "name": "Mapt",
+      "namespace": "RGD",
+      "variants": [
+        {
+          "code": "Tyr",
+          "identifier": {
+            "name": "nitration",
+            "namespace": "HBP"
+          },
+          "kind": "pmod",
+          "pos": 507
+        }
+      ]
+    },
     {
       "bel": "p(RGD:Mapt, pmod(Ph))",
       "function": "Protein",
@@ -83859,6 +101492,24 @@
         }
       ]
     },
+    {
+      "bel": "p(RGD:Mapt, pmod(Ph, Ser, 356))",
+      "function": "Protein",
+      "id": "52753f4872998446c99ee1db0f08ff34eca2493c5863875a3259790c07ad4ee47f8e3c8d4d32f8b5dd356cbed1b66d8706d9b2654367892f576f85405aa4588a",
+      "name": "Mapt",
+      "namespace": "RGD",
+      "variants": [
+        {
+          "code": "Ser",
+          "identifier": {
+            "name": "Ph",
+            "namespace": "bel"
+          },
+          "kind": "pmod",
+          "pos": 356
+        }
+      ]
+    },
     {
       "bel": "p(RGD:Mapt, pmod(Ph, Ser, 396))",
       "function": "Protein",
@@ -83967,22 +101618,6 @@
         }
       ]
     },
-    {
-      "bel": "p(RGD:Mapt, pmod(Sumo))",
-      "function": "Protein",
-      "id": "de7a2aea1a431a0260c33894ac73a51a1244c87a3b17193950b40c5ba290a3928dd95bb700d398afeb1a30e43051c014639439b1f231b3c8d58743402e105637",
-      "name": "Mapt",
-      "namespace": "RGD",
-      "variants": [
-        {
-          "identifier": {
-            "name": "Sumo",
-            "namespace": "bel"
-          },
-          "kind": "pmod"
-        }
-      ]
-    },
     {
       "bel": "p(RGD:Mtor)",
       "function": "Protein",
@@ -84117,6 +101752,22 @@
       "name": "Stat1",
       "namespace": "RGD"
     },
+    {
+      "bel": "p(RGD:Stat1, pmod(Ph))",
+      "function": "Protein",
+      "id": "3fe94eeef7d00318a427d61a08c81453aed3688d482a843359f12c053a3364a7eb777693f2594676e3280bef47e7bce3075db9617f251ee9657422886fee49c6",
+      "name": "Stat1",
+      "namespace": "RGD",
+      "variants": [
+        {
+          "identifier": {
+            "name": "Ph",
+            "namespace": "bel"
+          },
+          "kind": "pmod"
+        }
+      ]
+    },
     {
       "bel": "p(RGD:Syk)",
       "function": "Protein",
@@ -84145,6 +101796,13 @@
       "name": "Argyrophilic Grain Disease",
       "namespace": "HBP"
     },
+    {
+      "bel": "path(HBP:\"Chronic cerebral hypoperfusion\")",
+      "function": "Pathology",
+      "id": "7c4efd01598345b35a3ba6d42a3403dafa0a976bcf0f569dc3ed439c0b04dc144fac0cbbe218960e28fca4dcaf4bdc33ce4f04949b38838eae138a2d17df85c9",
+      "name": "Chronic cerebral hypoperfusion",
+      "namespace": "HBP"
+    },
     {
       "bel": "path(HBP:\"Corticobasal Degeneration\")",
       "function": "Pathology",
@@ -84152,6 +101810,20 @@
       "name": "Corticobasal Degeneration",
       "namespace": "HBP"
     },
+    {
+      "bel": "path(HBP:\"Long-Term Depression\")",
+      "function": "Pathology",
+      "id": "cf78997836b56dfdfbf3889d4b4591ea6698479708da5d74f185cd0163802158f5bc2059f559fbfa94038c5d1e0e0a341e177d532593af1c0b2b5de422783191",
+      "name": "Long-Term Depression",
+      "namespace": "HBP"
+    },
+    {
+      "bel": "path(HBP:\"Pathological Tau Spreading\")",
+      "function": "Pathology",
+      "id": "09d81acd9ebeea96be2f04196ca9bcc34c8943b83a5cde98e4d5250c138a926cae41ac40acbacb046987542bb70a1afa00e22cad64a49dea7efd769891251b96",
+      "name": "Pathological Tau Spreading",
+      "namespace": "HBP"
+    },
     {
       "bel": "path(HBP:\"Spinocerebellar Ataxia 11\")",
       "function": "Pathology",
@@ -84159,6 +101831,76 @@
       "name": "Spinocerebellar Ataxia 11",
       "namespace": "HBP"
     },
+    {
+      "bel": "path(HBP:\"granulovacuolar degeneration\")",
+      "function": "Pathology",
+      "id": "00a4bb7df2476d3e892a5ce08bd72e7ff07e60d7a798e334aea9636c8432a91fa997a86adeb7c9d6f93ce95f7074bd5c781ba63fbf02c05b32db97137c51a181",
+      "name": "granulovacuolar degeneration",
+      "namespace": "HBP"
+    },
+    {
+      "bel": "path(HBP:\"mitochondrial dysfunction\")",
+      "function": "Pathology",
+      "id": "290f620a8ca62af5c329ceed61c52205bedef0b2ba17347a57e3e26dec8a12aac110be32f0fda6061476b9745f37c4e21a45fe75b71d678f32dc6ccdf5362edd",
+      "name": "mitochondrial dysfunction",
+      "namespace": "HBP"
+    },
+    {
+      "bel": "path(HBP:\"peripheral nervous system injury\")",
+      "function": "Pathology",
+      "id": "a4d367364f5a461a27d3c3a02f9e8e095aec038fac08fb4a1db04721d87221212834d1c7547efccf46077416635b115ec53e1b177289c3ed6b6a5126c344bafa",
+      "name": "peripheral nervous system injury",
+      "namespace": "HBP"
+    },
+    {
+      "bel": "path(HBP:Astrogliosis)",
+      "function": "Pathology",
+      "id": "725adf66cc2e0e619b684e19c06f9ae5b0cbe69757338edb5d79c436324b9872dfb11c137ed19527876bbb1b23994f9f963be861b99e5b33a3310e9520469c6c",
+      "name": "Astrogliosis",
+      "namespace": "HBP"
+    },
+    {
+      "bel": "path(HBP:Excitotoxicity)",
+      "function": "Pathology",
+      "id": "a05c050bca725d20db7b6ec5e13953fdae42d759e81cdf3a7da295d0aa2627850ab52a6005cad1a67d57f1b478c352e14c4939cdb970f17e5f753392924eef02",
+      "name": "Excitotoxicity",
+      "namespace": "HBP"
+    },
+    {
+      "bel": "path(HBP:Microgliosis)",
+      "function": "Pathology",
+      "id": "a18feb59f8f1222551cb9eb2a4baa16eba4b543576d650414f42054d1e1ddeaa2eec0065864b77b12c2aee2c9a24600934e1d243d4845a29f4604ae474652c41",
+      "name": "Microgliosis",
+      "namespace": "HBP"
+    },
+    {
+      "bel": "path(HBP:Neurodegeneration)",
+      "function": "Pathology",
+      "id": "1e32e61de82d42fab0a4abcd15d32d3fa5b2f65883b2d99c828d4019591a465f11cd017eefe918bc5d066b7f3cef9d21f4e0988e5c23cc2c135313815478263a",
+      "name": "Neurodegeneration",
+      "namespace": "HBP"
+    },
+    {
+      "bel": "path(HBP:neuroinflammation)",
+      "function": "Pathology",
+      "id": "7da4c1851d405ae42ceb2b655ea0797603e3aa6c4089b285a29d55e2214268f89b7afe29df156ba327787e919db0c9d9e8a2acfca1b410a71e9283f021b55b23",
+      "name": "neuroinflammation",
+      "namespace": "HBP"
+    },
+    {
+      "bel": "path(HBP:neurotoxicity)",
+      "function": "Pathology",
+      "id": "1f25791dbb09af20ea60156b4ab96950653396306bd4059d680a6baeb4a0872d1d483dc8a80de8c3be1b693c2254b41aad6b88fa1726ae383fe80d3069b3dd3b",
+      "name": "neurotoxicity",
+      "namespace": "HBP"
+    },
+    {
+      "bel": "path(HP:Neurodegeneration)",
+      "function": "Pathology",
+      "id": "147561abc7f6701abebffd45f44916b712f900d63acea6c80bb945bee3908e728bbe60dd1b63ce6c6833ee03a88f0537ad03e5da7f67e71176d2f91aad08f8ac",
+      "name": "Neurodegeneration",
+      "namespace": "HP"
+    },
     {
       "bel": "path(MESH:\"Acidosis, Lactic\")",
       "function": "Pathology",
@@ -84174,10 +101916,10 @@
       "namespace": "MESH"
     },
     {
-      "bel": "path(MESH:\"Autism Spectrum Disorder\")",
+      "bel": "path(MESH:\"Cardiovascular Diseases\")",
       "function": "Pathology",
-      "id": "eab0bca058fefb09abf999426de449dbe235835fe60dcffc6a4e257471c42379a43eb7ca411959680409c348a44cd52d0530c2dc16e6e3781f64a446ba59627a",
-      "name": "Autism Spectrum Disorder",
+      "id": "6b78a50fee2c5ce47c0ffa42f440a233340ac685cc3efa7b2c06bdcbdbfa4a530b1c0c9dbbf219fafec8fb740f76f6df1420f681741f05cbfb0fc544877b1d67",
+      "name": "Cardiovascular Diseases",
       "namespace": "MESH"
     },
     {
@@ -84201,6 +101943,13 @@
       "name": "Diabetes Mellitus, Type 2",
       "namespace": "MESH"
     },
+    {
+      "bel": "path(MESH:\"Down Syndrome\")",
+      "function": "Pathology",
+      "id": "3c70bf952a4a541caab3c832e97814c7d87b5c568cc2225ad985dab51802bf5d41c75c20298514df6338380b564189e309d158ae0b7d7729e949a13e9d0f024c",
+      "name": "Down Syndrome",
+      "namespace": "MESH"
+    },
     {
       "bel": "path(MESH:\"Frontotemporal Dementia\")",
       "function": "Pathology",
@@ -84236,6 +101985,13 @@
       "name": "Plaque, Amyloid",
       "namespace": "MESH"
     },
+    {
+      "bel": "path(MESH:\"Spatial Learning\")",
+      "function": "Pathology",
+      "id": "211fd251c25349853a592b788437a1aa0fe1602f377e94c9e69815a2a9f82bb978e86febde798f0201920212b625fdde1919ddc54014881c2255cb8c56ba7057",
+      "name": "Spatial Learning",
+      "namespace": "MESH"
+    },
     {
       "bel": "path(MESH:\"Supranuclear Palsy, Progressive\")",
       "function": "Pathology",
@@ -84265,24 +102021,24 @@
       "namespace": "MESH"
     },
     {
-      "bel": "r(HBP:\"TGM2 Isoform 3 (349 aa)\")",
-      "function": "RNA",
-      "id": "25a0cd7b3e5a85c298708851f06eb60b4df698f1fc55688ea5ba24ea965704f105ab877fe3f2dcef142ca7e9434e5d0ea8ff64871250522d9482ea150d6914fa",
-      "name": "TGM2 Isoform 3 (349 aa)",
-      "namespace": "HBP"
+      "bel": "path(MESH:Tauopathies)",
+      "function": "Pathology",
+      "id": "d2087b32a76c528191af8305652f4664cbeb31b3f4e3f9627aaf61259e271f83a7d1be65f83e9178ccf3811482ece65b940fe4ce9a714b2281f705c0d499502b",
+      "name": "Tauopathies",
+      "namespace": "MESH"
     },
     {
-      "bel": "r(HGNC:BDNF)",
+      "bel": "r(HGNC:BRCA1)",
       "function": "RNA",
-      "id": "0716d15a357b13aac3835d0a2ebf6523d6c878a1bc6f29defea119a74c9b1ee017c1a7d31b31dcfed4b4329c85f46fdf746dfdf6ad2234ec6be6ae17d0454a67",
-      "name": "BDNF",
+      "id": "7174833f8cfcafb551b7dab8799d73dd743f78e688c69b6bd4c9009a444b2d5e0d4ada2bba1d31e724d2bc3c242a51d49d4ea139ea8bcc02d7a575504a65c39e",
+      "name": "BRCA1",
       "namespace": "HGNC"
     },
     {
-      "bel": "r(HGNC:BRCA1)",
+      "bel": "r(HGNC:CCN4)",
       "function": "RNA",
-      "id": "7174833f8cfcafb551b7dab8799d73dd743f78e688c69b6bd4c9009a444b2d5e0d4ada2bba1d31e724d2bc3c242a51d49d4ea139ea8bcc02d7a575504a65c39e",
-      "name": "BRCA1",
+      "id": "039e8a300f0e853690c5ca45d7391e1cb3832ad93217c627adf398122f73fd65fa1b3fb093ee777cd496252ede1c81ef4787c0e5529d406a353c6d6079dd491f",
+      "name": "CCN4",
       "namespace": "HGNC"
     },
     {
@@ -84307,24 +102063,17 @@
       "namespace": "HGNC"
     },
     {
-      "bel": "r(HGNC:GAL)",
-      "function": "RNA",
-      "id": "faeb530e3ec8332e527c5d052de6826102774a7111de4a95b88ad53de3cd1f02843627c916c4fee4bae37384c88dd25558b7bd9411c3d04bf545562d13353284",
-      "name": "GAL",
-      "namespace": "HGNC"
-    },
-    {
-      "bel": "r(HGNC:GAP43)",
+      "bel": "r(HGNC:GAPDH)",
       "function": "RNA",
-      "id": "700b280791036d5863d44b1a281557d2195f4e4b7853bb6e3fe84e7a57405785d1c098dbe755ecde338966c3472e4e65d49a201bab44c6a01c083cfae9824414",
-      "name": "GAP43",
+      "id": "642cebc93aa006da87d20648125f6f7d655e7068b121ccd788938f3c8ef965ff562602c8af20e049d6278380b13143361143a80c1e6de6dfc44720a575c45dc8",
+      "name": "GAPDH",
       "namespace": "HGNC"
     },
     {
-      "bel": "r(HGNC:GAPDH)",
+      "bel": "r(HGNC:GSK3B)",
       "function": "RNA",
-      "id": "642cebc93aa006da87d20648125f6f7d655e7068b121ccd788938f3c8ef965ff562602c8af20e049d6278380b13143361143a80c1e6de6dfc44720a575c45dc8",
-      "name": "GAPDH",
+      "id": "d19d75d0ebd1faebbb84c97d5153b12b61680456833ff8a8e0d4d85da0030a7c76e304b19e4ab6f59275e8f01318d1dfe582ca5ab22368c7378dc7201ce3bf3b",
+      "name": "GSK3B",
       "namespace": "HGNC"
     },
     {
@@ -84376,13 +102125,6 @@
       "name": "TGM2",
       "namespace": "HGNC"
     },
-    {
-      "bel": "r(HGNC:WISP1)",
-      "function": "RNA",
-      "id": "aee7314cfb17be9a310f95caaa7f33c530d1b9a66fc35443ceace5f0e2fca0bb4016b2926b95a1b310b61a57607d0a753a3619425ea7550ce7d626ce3dca8ca6",
-      "name": "WISP1",
-      "namespace": "HGNC"
-    },
     {
       "bel": "r(HGNC:WNT1)",
       "function": "RNA",
@@ -84390,6 +102132,13 @@
       "name": "WNT1",
       "namespace": "HGNC"
     },
+    {
+      "bel": "r(MGI:Dnmt1)",
+      "function": "RNA",
+      "id": "1749d9d8a8de1ffaa053fa4bcb70e13daab88263f85209a21b8112fef8b80d81dea1d2b7a1672fe11919ae366d900f5150df3bd5cfb5b49f90c14cfc9a498cd3",
+      "name": "Dnmt1",
+      "namespace": "MGI"
+    },
     {
       "bel": "r(MGI:Dyrk1a)",
       "function": "RNA",
@@ -84447,19 +102196,26 @@
       "namespace": "RGD"
     },
     {
-      "bel": "rxn(reactants(a(CHEBI:\"dihydroxyacetone phosphate\")), products(a(CHEBI:\"D-glyceraldehyde 3-phosphate\")))",
+      "bel": "rxn(reactants(a(CHEBI:\"D-glyceraldehyde 3-phosphate\"), a(CHEBI:\"dihydroxyacetone phosphate\")), products(a(CHEBI:ATP)))",
       "function": "Reaction",
-      "id": "74ca98a81a66f88b64d8feb86c47d418e2c3ed0441796244644c1aa6539b47497696f7712815a7e96e8241859814de8097649bbf6619f8e24fce8449fab4f158",
+      "id": "7b3ebf0c002bfc21452fc459e07ef79a04b88db084597d94b37e58111a92bca1ed6c8cbc13379e4b0c43df6c13bacaf8f69fb07db0e2f7c31e79f663f594a77d",
       "products": [
         {
-          "bel": "a(CHEBI:\"D-glyceraldehyde 3-phosphate\")",
+          "bel": "a(CHEBI:ATP)",
           "function": "Abundance",
-          "id": "e6622cdbeb459d4543f81a75975e918be4c38fcf918e1f26675304ed5b08fdf2b8aa6d4a83bb0994bf3d86a59909f8b477cc2ebc6f0c1e9f3c6d9de73c33d858",
-          "name": "D-glyceraldehyde 3-phosphate",
+          "id": "dbc5553fb6213ed82215c03a89950a37045e23683ffa96b44532f3e75d204cc547a974025c2799c6a189ad0c5045d96b16d1f5f7ac9296473ba1c647499bb3b2",
+          "name": "ATP",
           "namespace": "CHEBI"
         }
       ],
       "reactants": [
+        {
+          "bel": "a(CHEBI:\"D-glyceraldehyde 3-phosphate\")",
+          "function": "Abundance",
+          "id": "e6622cdbeb459d4543f81a75975e918be4c38fcf918e1f26675304ed5b08fdf2b8aa6d4a83bb0994bf3d86a59909f8b477cc2ebc6f0c1e9f3c6d9de73c33d858",
+          "name": "D-glyceraldehyde 3-phosphate",
+          "namespace": "CHEBI"
+        },
         {
           "bel": "a(CHEBI:\"dihydroxyacetone phosphate\")",
           "function": "Abundance",
@@ -84468,6 +102224,52 @@
           "namespace": "CHEBI"
         }
       ]
+    },
+    {
+      "bel": "rxn(reactants(a(CHEBI:pyruvate)), products(a(CHEBI:\"acetyl-CoA\")))",
+      "function": "Reaction",
+      "id": "fe25a8a2a43f8c8e4ec0865f245ceb58aa65840ba1f4b7b0fad5ade4bb66e30bec27d71cc482edc2f2daf8024944a9d963703d9eeb3d8960433defc800e8ea1e",
+      "products": [
+        {
+          "bel": "a(CHEBI:\"acetyl-CoA\")",
+          "function": "Abundance",
+          "id": "a5fa305d2e2001d715f893ae6c2d622f7e9190eff20a4c42d6ac7af0177896d9464cdd5304827d22ac2fce8b653837ad54d0a95422b99f8fbf8e348571b0e739",
+          "name": "acetyl-CoA",
+          "namespace": "CHEBI"
+        }
+      ],
+      "reactants": [
+        {
+          "bel": "a(CHEBI:pyruvate)",
+          "function": "Abundance",
+          "id": "eebc992abdd52a2d985528c46d28c30167dff7dc7c2ec6650eb512da88b0df4bdfeb60e3c6c6c4cf3d232ed6e38022be6336304bbd138fc67792054a07aaee9b",
+          "name": "pyruvate",
+          "namespace": "CHEBI"
+        }
+      ]
+    },
+    {
+      "bel": "rxn(reactants(p(RGD:Cdk5r1)), products(p(HBP:\"CDK5R1 p25\")))",
+      "function": "Reaction",
+      "id": "4e8cbedc277c951441fc09f9f9d985f4483b6431ac750bf14b2dc344fd3281a5e2823fee7faa0fc9be4c979ef2088145f322ba59515755b46f16f2e73ce45e75",
+      "products": [
+        {
+          "bel": "p(HBP:\"CDK5R1 p25\")",
+          "function": "Protein",
+          "id": "b9acb485fabc1c7883aa9ac67f71d55dff4e5c27418b7943228400bb500f3375ac4f4a4b270f27b62607362f97486edd6684f70ae85d0ca803fae12c9b21d2c9",
+          "name": "CDK5R1 p25",
+          "namespace": "HBP"
+        }
+      ],
+      "reactants": [
+        {
+          "bel": "p(RGD:Cdk5r1)",
+          "function": "Protein",
+          "id": "0a31d9ef412caa7b86375c05ed1eaf67708897d7a340009d33e494764f0c5b38f11ec671ea93937b3100ebab3a111a671e5a8c62b040515c11b1eab56a50c380",
+          "name": "Cdk5r1",
+          "namespace": "RGD"
+        }
+      ]
     }
   ]
 }
\ No newline at end of file