From 8e634e086f706bd96455f2341aa3f1a3bd24528f Mon Sep 17 00:00:00 2001 From: GitHub Action Date: Tue, 19 Nov 2024 01:14:05 +0000 Subject: [PATCH] Updated service open landscape data --- model.json | 9 + open.ttl | 513 ++++++++++++++++++++++++++++++++++------------------- 2 files changed, 342 insertions(+), 180 deletions(-) diff --git a/model.json b/model.json index 1347c9d..08702d1 100644 --- a/model.json +++ b/model.json @@ -233,6 +233,10 @@ "class": "https://identifiers.org/aop/436", "status": "conformant" }, + { + "class": "https://identifiers.org/aop/545", + "status": "conformant" + }, { "class": "https://identifiers.org/aop/303", "status": "conformant" @@ -1112,6 +1116,11 @@ "status": "nonconformant", "reason": "Cardinality violation (max=1): 2" }, + { + "class": "https://identifiers.org/aop/546", + "status": "nonconformant", + "reason": "Cardinality violation (max=1): 2" + }, { "class": "https://identifiers.org/aop/219", "status": "nonconformant", diff --git a/open.ttl b/open.ttl index 5678fda..d073cad 100644 --- a/open.ttl +++ b/open.ttl @@ -36825,6 +36825,13 @@ kb:CausalAssertion_91 a sbd:CausalAssertion, pav:createdBy ; dcterms:license . + a sbd:Model ; + rdfs:label "Activation, Pregnane-X receptor, NR1l2 leads to Increased, plasma low-density lipoprotein (LDL) cholesterol"@en ; + dc:source ; + dc:description "This Adverse Outcome Pathway (AOP) was developed as part of an Environmental Protection Agency effort to represent putative AOPs from peer-reviewed literature which were heretofore unrepresented in the AOP-Wiki.  The originating work for this AOP was: Itkonen, A., Hakkola, J., and Rysa, J.  2023.  Adverse outcome pathway for pregnane X receptor‑induced Hypercholesterolemia.  Archives of Toxicology 97: 2861–2877.   This publication, and the work cited within, were used create and support this AOP and its respective KE and KER pages.  The focus of the originating work was to use an AOP framework to investigate the mechanisms linking Pregnane X receptor (PXR) activation to increased plasma low-density lipoprotein (LDL) cholesterol.  Itkonen et al. (2023) provided network analysis from a literature search to assess the empirical evidence, biological plausibility and domain of applicability for each developed key event and key event relationship.   Available evidence provided support of mechanisms for increased plasma low-density lipoprotein (LDL) cholesterol through 3 pathways: 1. Increased, cholesterol synthesis enzymes; 2. Increased, protein expression of proprotein convertase subtilisin/kexin type 9 (PCSK9); 3. Increased, squalene epoxidase (SQLE) protein expression.  In this AOP, we focus on the pathway through Increased, cholesterol synthesis enzymes.  Empirical studies were primarily from laboratory rodents and humans.  "@en ; + foaf:page ; + dcterms:license . + a sbd:Model ; rdfs:label "Binding to the picrotoxin site of ionotropic GABA receptors leading to epileptic seizures in adult brain"@en ; dc:source ; @@ -41005,14 +41012,14 @@ kb:CausalAssertion_91 a sbd:CausalAssertion, dcterms:license . a sbd:Model ; - rdfs:label "Succinate dehydrogenase inactivation leading to cancer"@en ; + rdfs:label "Succinate dehydrogenase inactivation leads to cancer by promoting EMT"@en ; dc:source ; dc:description "Cancer is a critical endpoint in human health risk assessment.   It is embedded in regulatory frameworks for human health protection in many countries (see OSHA 2023 for examples of US regulations and European Parliament 2022 for examples of regulations in Europe)."@en ; foaf:page ; dcterms:license . a sbd:Model ; - rdfs:label "Succinate dehydrogenase inactivation leading to cancer"@en ; + rdfs:label "Succinate dehydrogenase inactivation leads to cancer by promoting EMT"@en ; dc:source ; dc:description "Succinate dehydrogenase (SDH) is a key enzyme of mitochondria, organelles that play a crucial role in the production of energy, the metabolic and calcium homeostasis, the control of apoptosis, and the production of reactive oxygen species. SDH is involved in two interconnected metabolic processes for energy production: 1) cellular respiration, where it allows the transfer of electrons to ubiquinone as complex II of the mitochondrial respiratory chain, and 2) the Krebs cycle, where it catalyzes the oxidation of succinate to fumarate. Numerous studies show that a complete inactivation of SDH caused by a first constitutional mutation associated with a second somatic mutation, leads to cancerous pathologies in young adults, including particularly aggressive forms of cancer such as paragangliomas (neuroendocrine tumors of the head and neck, thorax, abdomen and pelvis), pheochromocytomas (tumors of the adrenal medulla), renal cancers and gastrointestinal stromal tumors. The cellular and molecular mechanisms related to the genetic inactivation of SDH have been well described in neuroendocrine tumors, where it induces an oxidative stress, a pseudohypoxia phenotype, a metabolic, epigenetic and transcriptional remodeling, and alterations in tumor cell migration and invasion capacities, in connection with the accumulation of succinate, the substrate of SDH. The succinate dehydrogenase inhibitors (SDHi) are fungicides used to control the proliferation of pathogenic fungi in cereal, fruit and vegetable crops, with a mode of action based on blocking the activity of SDH. The analysis of literature data shows that the impact of SDHi on health remains largely unexplored to date, despite a growing number of studies reporting toxic effects in non-target organisms. This is supported by our recent work highlighting 1) the high degree of conservation of the SDH catalytic site (i.e. the SDHi binding site) during the evolution and 2) the ability of SDHi to inhibit SDH in the mitochondria of non-target species, including humans (PMID: 31697708). These observations show that SDHi are not specific to fungal SDH and that their use may present a risk to human health, particularly in the context of chronic exposure through the diet. Moreover, the analysis of regulatory assessment reports shows that most SDHi induce tumors in animals without evidence of genotoxicity. Thus, for these substances, the mechanisms of carcinogenicity are, to date, not clearly established.  Our hypothesis is that, if SDHi fungicides are able to alter SDH activity in humans, the consequences of SDHi exposure on cellular and mitochondrial functions may resemble those observed in SDH-mutated tumors and SDH-deficient cells. We assume that the development of an AOP deciphering the different steps leading to cancer following a genetically-SDH inactivation could help to propose the exploration of relevant key events and adverse effects upon chronic exposure to SDHi fungicides.  "@en ; foaf:page ; @@ -41028,14 +41035,14 @@ kb:CausalAssertion_91 a sbd:CausalAssertion, a sbd:Model ; rdfs:label "Binding of chemicals to ionotropic glutamate receptors leads to impairment of learning and memory via loss of drebrin from dendritic spines of neurons"@en ; dc:source ; - dc:description "We discovered drebrin in 1985 and have investigated drebrin for many years (Shirao and Sekino, 2017)."@en ; + dc:description "A prime example of impairments in learning and memory as the adverse outcome for regulatory action is developmental lead exposure and IQ function in children (Bellinger, 2012). Most methods are well established in the published literature and many have been engaged to evaluate the effects of developmental thyroid disruption. The US EPA and OECD Developmental Neurotoxicity (DNT) Guidelines (OCSPP 870.6300 or OECD TG 426) as well as OECD TG 443 (OECD, 2018) both require testing of learning and memory (USEPA, 1998; OECD, 2007) advising to use the following tests passive avoidance, delayed-matching-to-position for the adult rat and for the infant rat, olfactory conditioning, Morris water maze, Biel or Cincinnati maze, radial arm maze, T-maze, and acquisition and retention of schedule-controlled behavior. These DNT Guidelines have been deemed valid to identify developmental neurotoxicity and adverse neurodevelopmental outcomes (Makris et al., 2009).  Also, in the frame of the OECD GD 43 (2008) on reproductive toxicity, learning and memory testing may have potential to be applied in the context of developmental neurotoxicity studies. However, many of the learning and memory tasks used in guideline studies may not readily detect subtle impairments in cognitive function associated with modest degrees of developmental thyroid disruption (Gilbert et al., 2012).   "@en ; foaf:page ; dcterms:license . a sbd:Model ; rdfs:label "Binding of chemicals to ionotropic glutamate receptors leads to impairment of learning and memory via loss of drebrin from dendritic spines of neurons"@en ; dc:source ; - dc:description "A prime example of impairments in learning and memory as the adverse outcome for regulatory action is developmental lead exposure and IQ function in children (Bellinger, 2012). Most methods are well established in the published literature and many have been engaged to evaluate the effects of developmental thyroid disruption. The US EPA and OECD Developmental Neurotoxicity (DNT) Guidelines (OCSPP 870.6300 or OECD TG 426) as well as OECD TG 443 (OECD, 2018) both require testing of learning and memory (USEPA, 1998; OECD, 2007) advising to use the following tests passive avoidance, delayed-matching-to-position for the adult rat and for the infant rat, olfactory conditioning, Morris water maze, Biel or Cincinnati maze, radial arm maze, T-maze, and acquisition and retention of schedule-controlled behavior. These DNT Guidelines have been deemed valid to identify developmental neurotoxicity and adverse neurodevelopmental outcomes (Makris et al., 2009).  Also, in the frame of the OECD GD 43 (2008) on reproductive toxicity, learning and memory testing may have potential to be applied in the context of developmental neurotoxicity studies. However, many of the learning and memory tasks used in guideline studies may not readily detect subtle impairments in cognitive function associated with modest degrees of developmental thyroid disruption (Gilbert et al., 2012).   "@en ; + dc:description "We discovered drebrin in 1985 and have studied it extensively over many years. In 2017, we published a book as the culmination of our research, Drebrin: From Structure and Function to Physiological and Pathological Roles, as part of the Advances in Experimental Medicine and Biology series by Springer. We originally started to develope this AOP with a three-years research funfing from the Japan Chemical Industry Association (JCIA) Long-range Research Initiative (LRI) to YS from 2020 to 2022 for the research entitled "Proposal of a new AOP for the neurotoxicity and developmental neurotoxicity assessment of glutamate receptor binding agonists that cause learning and memory impairment".  The new adverse outcome (AO),  the learning and memory impairment, has new key events including loss of drebrin from the dendritic spines and the concsequent thin and slender shape of dendritic spines that causes synaptic dysfunction. Drebrin is an actin-binding protein that governs dendritic spine formation of CNS neurons and is responsible for the morphological plasticity of dendritic spines associated with learning and memory. The subcellular localization of drebrin is determined by glutamate receptor activity.  We have improved Banker's method for low density neuronal culture system and established  an immunocytochemical evaluation system of drebrin clusters cultured hippocampal neurons in 96 well plate using frozen hippocampal neurons prepared from rat embryo. We have developed an image processing algorithm for quantitative analysis of neuron count, dendrite length, and drebrin clusters from high-content image data using a confocal image cytometer. In particular, the brightness distribution analysis of drebrin clusters is highly sensitive. We have started to develop a machine learning platform for AI. From the images of immunocytochemical staining, we will clarify the indices for quantitatively evaluating the structural changes of neurons, and provide SOPs for culture techniques and analysis methods. In the future, we are planning to build an experimental system using neurons derived from human iPS cells."@en ; foaf:page ; dcterms:license . @@ -41749,7 +41756,7 @@ kb:CausalAssertion_91 a sbd:CausalAssertion, a sbd:Model ; rdfs:label "Decreased Sodium/Potassium ATPase activity leads to Heart failure"@en ; dc:source ; - dc:description "This Adverse Outcome Pathway (AOP) was developed as part of an Environmental Protection Agency effort to represent putative AOPs from peer-reviewed literature which were heretofore unrepresented in the AOP-Wiki.  The originating work for this AOP was: Brix, K.V., De Boeck, G., Baken, S., and Forte, D.J.  2022.  Adverse Outcome Pathways for Chronic Copper Toxicity to Fish and Amphibians.  Environmental Toxicology and Chemistry 41(12): 2911-2927.   This publication, and the work cited within, were used create and support this AOP and its respective KE and KER pages.  The focus of the originating work was to use an AOP framework to integrate lines of evidence from multiple disciplines based on evolving guidance developed by the Organization for Economic Cooperation and Development (OECD).   Brix et al. (2022) provided network analysis focused on mechanisms of action for copper toxicity in aquatic vertebrates through literature searches.  Literature searches provided the following mechanisms of copper toxicity: disruption of ion regulation; oxidative stress; effects on liver metabolism; effects on bioenergetics leading to impaired growth and reproduction; effects on sensory systems; effects on amphibian metabolism.  These mechanisms were the basis for examining empirical studies for development of key events and key event relationships within an adverse outcome pathway framework.  Freshwater organisms are hypertonic (higher ion concentration) compared to the aquatic environment while salt-water organisms are hypotonic (lower ion concentration) compared to the aquatic environment; therefore osmoregulation in freshwater organisms versus salt-water organisms regulate ion concentrations and fluid volumes in opposite directions.  Decrease in Sodium/Potassium ATPase activity and the resulting adverse outcome pathway were observed in freshwater vertebrates, primarily fish (Brix et al. 2022). The authors of AOP 539 focused on disruption of ion regulation as the priority adverse outcome pathway to develop, because of the strength of  evidence linking the various key event relationships and the eventual adverse outcome.  "@en ; + dc:description "This Adverse Outcome Pathway (AOP) was developed as part of an Environmental Protection Agency effort to represent putative AOPs from peer-reviewed literature which were heretofore unrepresented in the AOP-Wiki.  The originating work for this AOP was: Brix, K.V., De Boeck, G., Baken, S., and Fort, D.J.  2022.  Adverse Outcome Pathways for Chronic Copper Toxicity to Fish and Amphibians.  Environmental Toxicology and Chemistry 41(12): 2911-2927.   This publication, and the work cited within, were used create and support this AOP and its respective KE and KER pages.  The focus of the originating work was to use an AOP framework to integrate lines of evidence from multiple disciplines based on evolving guidance developed by the Organization for Economic Cooperation and Development (OECD).   Brix et al. (2022) provided network analysis focused on mechanisms of action for copper toxicity in aquatic vertebrates through literature searches.  Literature searches provided the following mechanisms of copper toxicity: disruption of ion regulation; oxidative stress; effects on liver metabolism; effects on bioenergetics leading to impaired growth and reproduction; effects on sensory systems; effects on amphibian metabolism.  These mechanisms were the basis for examining empirical studies for development of key events and key event relationships within an adverse outcome pathway framework.  Freshwater organisms are hypertonic (higher ion concentration) compared to the aquatic environment while salt-water organisms are hypotonic (lower ion concentration) compared to the aquatic environment; therefore osmoregulation in freshwater organisms versus salt-water organisms regulate ion concentrations and fluid volumes in opposite directions.  Decrease in Sodium/Potassium ATPase activity and the resulting adverse outcome pathway were observed in freshwater vertebrates, primarily fish (Brix et al. 2022). The authors of AOP 539 focused on disruption of ion regulation as the priority adverse outcome pathway to develop, because of the strength of  evidence linking the various key event relationships and the eventual adverse outcome.  "@en ; foaf:page ; dcterms:license . @@ -41802,6 +41809,20 @@ kb:CausalAssertion_91 a sbd:CausalAssertion, foaf:page ; dcterms:license . + a sbd:Model ; + rdfs:label "Succinate dehydrogenase inactivation leads to cancer through hypoxic-like mechanisms"@en ; + dc:source ; + dc:description "Cancer is a critical endpoint in human health risk assessment.   It is embedded in regulatory frameworks for human health protection in many countries (see OSHA 2023 for examples of US regulations and European Parliament 2022 for examples of regulations in Europe)."@en ; + foaf:page ; + dcterms:license . + + a sbd:Model ; + rdfs:label "Succinate dehydrogenase inactivation leads to cancer through hypoxic-like mechanisms"@en ; + dc:source ; + dc:description "Succinate dehydrogenase (SDH) is a key enzyme of mitochondria, organelles that play a crucial role in the production of energy, the metabolic and calcium homeostasis, the control of apoptosis, and the production of reactive oxygen species. SDH is involved in two interconnected metabolic processes for energy production: 1) cellular respiration, where it allows the transfer of electrons to ubiquinone as complex II of the mitochondrial respiratory chain, and 2) the Krebs cycle, where it catalyzes the oxidation of succinate to fumarate. Numerous studies show that a complete inactivation of SDH caused by a first constitutional mutation associated with a second somatic mutation, leads to cancerous pathologies in young adults, including particularly aggressive forms of cancer such as paragangliomas (neuroendocrine tumors of the head and neck, thorax, abdomen and pelvis), pheochromocytomas (tumors of the adrenal medulla), renal cancers and gastrointestinal stromal tumors. The cellular and molecular mechanisms related to the genetic inactivation of SDH have been well described in neuroendocrine tumors, where it induces an oxidative stress, a pseudohypoxia phenotype, a metabolic, epigenetic and transcriptional remodeling, and alterations in tumor cell migration and invasion capacities, in connection with the accumulation of succinate, the substrate of SDH. The succinate dehydrogenase inhibitors (SDHi) are fungicides used to control the proliferation of pathogenic fungi in cereal, fruit and vegetable crops, with a mode of action based on blocking the activity of SDH. The analysis of literature data shows that the impact of SDHi on health remains largely unexplored to date, despite a growing number of studies reporting toxic effects in non-target organisms. This is supported by our recent work highlighting 1) the high degree of conservation of the SDH catalytic site (i.e. the SDHi binding site) during the evolution and 2) the ability of SDHi to inhibit SDH in the mitochondria of non-target species, including humans (PMID: 31697708). These observations show that SDHi are not specific to fungal SDH and that their use may present a risk to human health, particularly in the context of chronic exposure through the diet. Moreover, the analysis of regulatory assessment reports shows that most SDHi induce tumors in animals without evidence of genotoxicity. Thus, for these substances, the mechanisms of carcinogenicity are, to date, not clearly established.  Our hypothesis is that, if SDHi fungicides are able to alter SDH activity in humans, the consequences of SDHi exposure on cellular and mitochondrial functions may resemble those observed in SDH-mutated tumors and SDH-deficient cells. We assume that the development of an AOP deciphering the different steps leading to cancer following a genetically-SDH inactivation could help to propose the exploration of relevant key events and adverse effects upon chronic exposure to SDHi fungicides."@en ; + foaf:page ; + dcterms:license . + a sbd:Model ; rdfs:label "Retinoic acid receptor agonism during neurodevelopment leading to impaired learning and memory"@en ; dc:source ; @@ -41907,6 +41928,39 @@ kb:CausalAssertion_91 a sbd:CausalAssertion, pav:createdBy ; dcterms:license . + a sbdbel:CausalAssertion ; + rdfs:label "KER 3366"@en ; + dc:source ; + sbdbel:cause ; + sbdbel:relationship ; + sbdbel:outcome ; + dcterms:license . + + rdfs:label "Decreased, insulin-induced gene 1 (INSIG1) protein activity"@en . + rdfs:label "Increased, Sterol Regulatory Element Binding Protein 2 (SREBP2) protein expression "@en . + + a sbdbel:CausalAssertion ; + rdfs:label "KER 3367"@en ; + dc:source ; + sbdbel:cause ; + sbdbel:relationship ; + sbdbel:outcome ; + dcterms:license . + + rdfs:label "Increased, Sterol Regulatory Element Binding Protein 2 (SREBP2) protein expression "@en . + rdfs:label "Increased, cholesterol synthesis enzymes "@en . + + a sbdbel:CausalAssertion ; + rdfs:label "KER 3368"@en ; + dc:source ; + sbdbel:cause ; + sbdbel:relationship ; + sbdbel:outcome ; + dcterms:license . + + rdfs:label "Increased, cholesterol synthesis enzymes "@en . + rdfs:label "Increased, plasma low-density lipoprotein (LDL) cholesterol "@en . + a sbdbel:CausalAssertion ; rdfs:label "KER 1024"@en ; dc:source ; @@ -48518,28 +48572,6 @@ kb:CausalAssertion_91 a sbd:CausalAssertion, rdfs:label "Trigeminal nerve activation"@en . rdfs:label "SP (Substance P) release, Local increase of SP"@en . - a sbdbel:CausalAssertion ; - rdfs:label "KER 1578"@en ; - dc:source ; - sbdbel:cause ; - sbdbel:relationship ; - sbdbel:outcome ; - dcterms:license . - - rdfs:label "Trigeminal nerve activation"@en . - rdfs:label "Increased CGRP, neuronal release of CGRP"@en . - - a sbdbel:CausalAssertion ; - rdfs:label "KER 1582"@en ; - dc:source ; - sbdbel:cause ; - sbdbel:relationship ; - sbdbel:outcome ; - dcterms:license . - - rdfs:label "Trigeminal nerve activation"@en . - rdfs:label "Irritation of nasal mucosa inducing sneeze reflex"@en . - a sbdbel:CausalAssertion ; rdfs:label "KER 1772"@en ; dc:source ; @@ -50223,17 +50255,6 @@ kb:CausalAssertion_91 a sbd:CausalAssertion, rdfs:label "Release of G Proteins"@en . rdfs:label "Inhibition of N-type Ca ion channels"@en . - a sbdbel:CausalAssertion ; - rdfs:label "KER 1569"@en ; - dc:source ; - sbdbel:cause ; - sbdbel:relationship ; - sbdbel:outcome ; - dcterms:license . - - rdfs:label "Inhibition of N-type Ca ion channels"@en . - rdfs:label "Inhibition of neurotransmitter vesicle release"@en . - a sbdbel:CausalAssertion ; rdfs:label "KER 1570"@en ; dc:source ; @@ -50245,17 +50266,6 @@ kb:CausalAssertion_91 a sbd:CausalAssertion, rdfs:label "Inhibition of neurotransmitter vesicle release"@en . rdfs:label "Analgesia"@en . - a sbdbel:CausalAssertion ; - rdfs:label "KER 1573"@en ; - dc:source ; - sbdbel:cause ; - sbdbel:relationship ; - sbdbel:outcome ; - dcterms:license . - - rdfs:label "Inhibition of neurotransmitter vesicle release"@en . - rdfs:label "Anti-depressant Activity"@en . - a sbdbel:CausalAssertion ; rdfs:label "KER 1571"@en ; dc:source ; @@ -51895,6 +51905,17 @@ kb:CausalAssertion_91 a sbd:CausalAssertion, rdfs:label "Decreased, PPAR-beta activation"@en . rdfs:label "Decreased, HSD17B10 expression"@en . + a sbdbel:CausalAssertion ; + rdfs:label "KER 3365"@en ; + dc:source ; + sbdbel:cause ; + sbdbel:relationship ; + sbdbel:outcome ; + dcterms:license . + + rdfs:label "Activation, Pregnane-X receptor, NR1l2"@en . + rdfs:label "Decreased, insulin-induced gene 1 (INSIG1) protein activity"@en . + a sbdbel:CausalAssertion ; rdfs:label "KER 3100"@en ; dc:source ; @@ -51972,16 +51993,16 @@ kb:CausalAssertion_91 a sbd:CausalAssertion, rdfs:label "Increase, Reactive Oxygen Species"@en . rdfs:label "Increase, Oxidative DNA damage"@en . - a sbdbel:CausalAssertion ; - rdfs:label "KER 3235"@en ; + a sbdbel:CausalAssertion ; + rdfs:label "KER 2998"@en ; dc:source ; sbdbel:cause ; sbdbel:relationship ; - sbdbel:outcome ; + sbdbel:outcome ; dcterms:license . rdfs:label "Increase, Reactive Oxygen Species"@en . - rdfs:label "Increased, Oxidative Stress"@en . + rdfs:label "Increase, Oxidative Stress"@en . a sbdbel:CausalAssertion ; rdfs:label "KER 3238"@en ; @@ -52335,17 +52356,6 @@ kb:CausalAssertion_91 a sbd:CausalAssertion, rdfs:label "Proliferation, Cell proliferation in the absence of cytotoxicity"@en . rdfs:label "Hyperplasia, Hyperplasia"@en . - a sbdbel:CausalAssertion ; - rdfs:label "KER 3307"@en ; - dc:source ; - sbdbel:cause ; - sbdbel:relationship ; - sbdbel:outcome ; - dcterms:license . - - rdfs:label "N/A, hypoxia"@en . - rdfs:label "Increase, angiogenesis"@en . - a sbdbel:CausalAssertion ; rdfs:label "KER 1321"@en ; dc:source ; @@ -52533,17 +52543,6 @@ kb:CausalAssertion_91 a sbd:CausalAssertion, rdfs:label "hyperpolarisation, neuron"@en . rdfs:label "Analgesia"@en . - a sbdbel:CausalAssertion ; - rdfs:label "KER 1572"@en ; - dc:source ; - sbdbel:cause ; - sbdbel:relationship ; - sbdbel:outcome ; - dcterms:license . - - rdfs:label "hyperpolarisation, neuron"@en . - rdfs:label "Anti-depressant Activity"@en . - a sbdbel:CausalAssertion ; rdfs:label "KER 763"@en ; dc:source ; @@ -52797,6 +52796,17 @@ kb:CausalAssertion_91 a sbd:CausalAssertion, rdfs:label "Altered Cell Differentiation Signaling"@en . rdfs:label "Altered Bone Cell Homeostasis"@en . + a sbdbel:CausalAssertion ; + rdfs:label "KER 3374"@en ; + dc:source ; + sbdbel:cause ; + sbdbel:relationship ; + sbdbel:outcome ; + dcterms:license . + + rdfs:label "Infiltration, Inflammatory cells"@en . + rdfs:label "Activation, Macrophages"@en . + a sbdbel:CausalAssertion ; rdfs:label "KER 3114"@en ; dc:source ; @@ -52907,6 +52917,17 @@ kb:CausalAssertion_91 a sbd:CausalAssertion, rdfs:label "Gluten-reactive CD4+ T cells, activation and proliferation"@en . rdfs:label "Human leukocyte antigen DQ2/8-gluten complexes, formation"@en . + a sbdbel:CausalAssertion ; + rdfs:label "KER 3379"@en ; + dc:source ; + sbdbel:cause ; + sbdbel:relationship ; + sbdbel:outcome ; + dcterms:license . + + rdfs:label "Androgen receptor activation, increased"@en . + rdfs:label "Altered, Transcription of genes by the androgen receptor"@en . + a sbdbel:CausalAssertion ; rdfs:label "KER 3333"@en ; dc:source ; @@ -53292,28 +53313,6 @@ kb:CausalAssertion_91 a sbd:CausalAssertion, rdfs:label "Oxidative Stress "@en . rdfs:label "Proteasomal dysfunction"@en . - a sbdbel:CausalAssertion ; - rdfs:label "KER 3293"@en ; - dc:source ; - sbdbel:cause ; - sbdbel:relationship ; - sbdbel:outcome ; - dcterms:license . - - rdfs:label "Oxidative Stress "@en . - rdfs:label "The NO synthase pathway activation"@en . - - a sbdbel:CausalAssertion ; - rdfs:label "KER 3294"@en ; - dc:source ; - sbdbel:cause ; - sbdbel:relationship ; - sbdbel:outcome ; - dcterms:license . - - rdfs:label "Oxidative Stress "@en . - rdfs:label "Ferroptosis related pathways activation"@en . - a sbdbel:CausalAssertion ; rdfs:label "KER 3310"@en ; dc:source ; @@ -53325,28 +53324,6 @@ kb:CausalAssertion_91 a sbd:CausalAssertion, rdfs:label "Oxidative Stress "@en . rdfs:label "Lipid Peroxidation"@en . - a sbdbel:CausalAssertion ; - rdfs:label "KER 3316"@en ; - dc:source ; - sbdbel:cause ; - sbdbel:relationship ; - sbdbel:outcome ; - dcterms:license . - - rdfs:label "Oxidative Stress "@en . - rdfs:label "Altered Stress Response Signaling"@en . - - a sbdbel:CausalAssertion ; - rdfs:label "KER 3319"@en ; - dc:source ; - sbdbel:cause ; - sbdbel:relationship ; - sbdbel:outcome ; - dcterms:license . - - rdfs:label "Oxidative Stress "@en . - rdfs:label "Altered Cell Differentiation Signaling"@en . - a sbdbel:CausalAssertion ; rdfs:label "KER 3325"@en ; dc:source ; @@ -54051,17 +54028,6 @@ kb:CausalAssertion_91 a sbd:CausalAssertion, rdfs:label "Increase, DNA strand breaks"@en . rdfs:label "Increase, Oocyte apoptosis"@en . - a sbdbel:CausalAssertion ; - rdfs:label "KER 3315"@en ; - dc:source ; - sbdbel:cause ; - sbdbel:relationship ; - sbdbel:outcome ; - dcterms:license . - - rdfs:label "Increase, DNA strand breaks"@en . - rdfs:label "Altered Stress Response Signaling"@en . - a sbdbel:CausalAssertion ; rdfs:label "KER 2375"@en ; dc:source ; @@ -54799,6 +54765,28 @@ kb:CausalAssertion_91 a sbd:CausalAssertion, rdfs:label "FOXJ1 Protein, Decreased"@en . rdfs:label "Motile Cilia Number/Length, Decreased"@en . + a sbdbel:CausalAssertion ; + rdfs:label "KER 3372"@en ; + dc:source ; + sbdbel:cause ; + sbdbel:relationship ; + sbdbel:outcome ; + dcterms:license . + + rdfs:label "Increase, Oxidative Stress"@en . + rdfs:label "Increase, Endothelial Dysfunction"@en . + + a sbdbel:CausalAssertion ; + rdfs:label "KER 3375"@en ; + dc:source ; + sbdbel:cause ; + sbdbel:relationship ; + sbdbel:outcome ; + dcterms:license . + + rdfs:label "Increase, Oxidative Stress"@en . + rdfs:label "Lipid Peroxidation"@en . + a sbdbel:CausalAssertion ; rdfs:label "KER 2606"@en ; dc:source ; @@ -56526,6 +56514,28 @@ kb:CausalAssertion_91 a sbd:CausalAssertion, rdfs:label "Increased, Male offspring"@en . rdfs:label "Decline, Population"@en . + a sbdbel:CausalAssertion ; + rdfs:label "KER 1578"@en ; + dc:source ; + sbdbel:cause ; + sbdbel:relationship ; + sbdbel:outcome ; + dcterms:license . + + rdfs:label "Trigeminal nerve activation"@en . + rdfs:label "Increased CGRP, neuronal release of CGRP"@en . + + a sbdbel:CausalAssertion ; + rdfs:label "KER 1582"@en ; + dc:source ; + sbdbel:cause ; + sbdbel:relationship ; + sbdbel:outcome ; + dcterms:license . + + rdfs:label "Trigeminal nerve activation"@en . + rdfs:label "Irritation of nasal mucosa inducing sneeze reflex"@en . + a sbdbel:CausalAssertion ; rdfs:label "KER 1583"@en ; dc:source ; @@ -56746,17 +56756,6 @@ kb:CausalAssertion_91 a sbd:CausalAssertion, rdfs:label "Decrease, Oogenesis"@en . rdfs:label "Reduction, Cumulative fecundity and spawning"@en . - a sbdbel:CausalAssertion ; - rdfs:label "KER 3308"@en ; - dc:source ; - sbdbel:cause ; - sbdbel:relationship ; - sbdbel:outcome ; - dcterms:license . - - rdfs:label "Increase, angiogenesis"@en . - rdfs:label "Increase, Cancer"@en . - a sbdbel:CausalAssertion ; rdfs:label "KER 154"@en ; dc:source ; @@ -56823,6 +56822,28 @@ kb:CausalAssertion_91 a sbd:CausalAssertion, rdfs:label "Opening of G protein gated inward rectifying K channels"@en . rdfs:label "hyperpolarisation, neuron"@en . + a sbdbel:CausalAssertion ; + rdfs:label "KER 1569"@en ; + dc:source ; + sbdbel:cause ; + sbdbel:relationship ; + sbdbel:outcome ; + dcterms:license . + + rdfs:label "Inhibition of N-type Ca ion channels"@en . + rdfs:label "Inhibition of neurotransmitter vesicle release"@en . + + a sbdbel:CausalAssertion ; + rdfs:label "KER 1573"@en ; + dc:source ; + sbdbel:cause ; + sbdbel:relationship ; + sbdbel:outcome ; + dcterms:license . + + rdfs:label "Inhibition of neurotransmitter vesicle release"@en . + rdfs:label "Anti-depressant Activity"@en . + a sbdbel:CausalAssertion ; rdfs:label "KER 2879"@en ; dc:source ; @@ -61828,6 +61849,17 @@ kb:CausalAssertion_91 a sbd:CausalAssertion, rdfs:label "N/A, hypoxia"@en . rdfs:label "Increased, amputations"@en . + a sbdbel:CausalAssertion ; + rdfs:label "KER 3370"@en ; + dc:source ; + sbdbel:cause ; + sbdbel:relationship ; + sbdbel:outcome ; + dcterms:license . + + rdfs:label "N/A, hypoxia"@en . + rdfs:label "Increase, Cancer"@en . + a sbdbel:CausalAssertion ; rdfs:label "KER 603"@en ; dc:source ; @@ -62631,6 +62663,17 @@ kb:CausalAssertion_91 a sbd:CausalAssertion, rdfs:label "Activation, ionotropic GABA Receptor chloride channel"@en . rdfs:label "Increased, Chloride conductance"@en . + a sbdbel:CausalAssertion ; + rdfs:label "KER 1572"@en ; + dc:source ; + sbdbel:cause ; + sbdbel:relationship ; + sbdbel:outcome ; + dcterms:license . + + rdfs:label "hyperpolarisation, neuron"@en . + rdfs:label "Anti-depressant Activity"@en . + a sbdbel:CausalAssertion ; rdfs:label "KER 755"@en ; dc:source ; @@ -63005,6 +63048,17 @@ kb:CausalAssertion_91 a sbd:CausalAssertion, rdfs:label "Inhibition, Prolyl hydroxylases"@en . rdfs:label "Increased, HIF-1 heterodimer"@en . + a sbdbel:CausalAssertion ; + rdfs:label "KER 3369"@en ; + dc:source ; + sbdbel:cause ; + sbdbel:relationship ; + sbdbel:outcome ; + dcterms:license . + + rdfs:label "Inhibition, Prolyl hydroxylases"@en . + rdfs:label "N/A, hypoxia"@en . + a sbdbel:CausalAssertion ; rdfs:label "KER 800"@en ; dc:source ; @@ -63610,28 +63664,6 @@ kb:CausalAssertion_91 a sbd:CausalAssertion, rdfs:label "Decrease, Digestion of old cuticle"@en . rdfs:label "Increase, Premature molting"@en . - a sbdbel:CausalAssertion ; - rdfs:label "KER 3288"@en ; - dc:source ; - sbdbel:cause ; - sbdbel:relationship ; - sbdbel:outcome ; - dcterms:license . - - rdfs:label "Decreased, Sodium uptake in gills"@en . - rdfs:label "Decreased, Plasma sodium concentrations"@en . - - a sbdbel:CausalAssertion ; - rdfs:label "KER 3291"@en ; - dc:source ; - sbdbel:cause ; - sbdbel:relationship ; - sbdbel:outcome ; - dcterms:license . - - rdfs:label "Increased, Blood viscosity"@en . - rdfs:label "Increased, Cardiac stress"@en . - a sbdbel:CausalAssertion ; rdfs:label "KER 3292"@en ; dc:source ; @@ -63896,17 +63928,6 @@ kb:CausalAssertion_91 a sbd:CausalAssertion, rdfs:label "Gluten-reactive CD4+ T cells, activation and proliferation"@en . rdfs:label "Intestinal barrier, disruption"@en . - a sbdbel:CausalAssertion ; - rdfs:label "KER 3347"@en ; - dc:source ; - sbdbel:cause ; - sbdbel:relationship ; - sbdbel:outcome ; - dcterms:license . - - rdfs:label "Decreased, blood plasma volume"@en . - rdfs:label "Increased, Blood viscosity"@en . - a sbdbel:CausalAssertion ; rdfs:label "KER 3338"@en ; dc:source ; @@ -63995,6 +64016,61 @@ kb:CausalAssertion_91 a sbd:CausalAssertion, rdfs:label "Apoptosis"@en . rdfs:label "Aberrant, synaptic formation and plasticity"@en . + a sbdbel:CausalAssertion ; + rdfs:label "KER 3293"@en ; + dc:source ; + sbdbel:cause ; + sbdbel:relationship ; + sbdbel:outcome ; + dcterms:license . + + rdfs:label "Oxidative Stress "@en . + rdfs:label "The NO synthase pathway activation"@en . + + a sbdbel:CausalAssertion ; + rdfs:label "KER 3294"@en ; + dc:source ; + sbdbel:cause ; + sbdbel:relationship ; + sbdbel:outcome ; + dcterms:license . + + rdfs:label "Oxidative Stress "@en . + rdfs:label "Ferroptosis related pathways activation"@en . + + a sbdbel:CausalAssertion ; + rdfs:label "KER 3316"@en ; + dc:source ; + sbdbel:cause ; + sbdbel:relationship ; + sbdbel:outcome ; + dcterms:license . + + rdfs:label "Oxidative Stress "@en . + rdfs:label "Altered Stress Response Signaling"@en . + + a sbdbel:CausalAssertion ; + rdfs:label "KER 3319"@en ; + dc:source ; + sbdbel:cause ; + sbdbel:relationship ; + sbdbel:outcome ; + dcterms:license . + + rdfs:label "Oxidative Stress "@en . + rdfs:label "Altered Cell Differentiation Signaling"@en . + + a sbdbel:CausalAssertion ; + rdfs:label "KER 3382"@en ; + dc:source ; + sbdbel:cause ; + sbdbel:relationship ; + sbdbel:outcome ; + dcterms:license . + + rdfs:label "Oxidative Stress "@en . + rdfs:label "Increase mutations"@en . + a sbdbel:CausalAssertion ; rdfs:label "KER 3172"@en ; dc:source ; @@ -64006,6 +64082,17 @@ kb:CausalAssertion_91 a sbd:CausalAssertion, rdfs:label "Decrease, dihydrotestosterone (DHT) level"@en . rdfs:label "Impaired, urethral tube closure "@en . + a sbdbel:CausalAssertion ; + rdfs:label "KER 3315"@en ; + dc:source ; + sbdbel:cause ; + sbdbel:relationship ; + sbdbel:outcome ; + dcterms:license . + + rdfs:label "Increase, DNA strand breaks"@en . + rdfs:label "Altered Stress Response Signaling"@en . + a sbdbel:CausalAssertion ; rdfs:label "KER 3186"@en ; dc:source ; @@ -64050,6 +64137,17 @@ kb:CausalAssertion_91 a sbd:CausalAssertion, rdfs:label "Succinate dehydrogenase, inhibited"@en . rdfs:label "Succinate Accumulation"@en . + a sbdbel:CausalAssertion ; + rdfs:label "KER 3378"@en ; + dc:source ; + sbdbel:cause ; + sbdbel:relationship ; + sbdbel:outcome ; + dcterms:license . + + rdfs:label "Agonism, Androgen receptor"@en . + rdfs:label "Androgen receptor activation, increased"@en . + a sbdbel:CausalAssertion ; rdfs:label "KER 3123"@en ; dc:source ; @@ -64061,16 +64159,16 @@ kb:CausalAssertion_91 a sbd:CausalAssertion, rdfs:label "Decrease of neuronal network function"@en . rdfs:label "autism-like behavior"@en . - a sbdbel:CausalAssertion ; - rdfs:label "KER 3236"@en ; + a sbdbel:CausalAssertion ; + rdfs:label "KER 3376"@en ; dc:source ; - sbdbel:cause ; + sbdbel:cause ; sbdbel:relationship ; - sbdbel:outcome ; + sbdbel:outcome ; dcterms:license . - rdfs:label "Increased, Oxidative Stress"@en . - rdfs:label "Increase mutations"@en . + rdfs:label "Activation, Macrophages"@en . + rdfs:label "Foam cell formation"@en . a sbdbel:CausalAssertion ; rdfs:label "KER 3117"@en ; @@ -64105,6 +64203,17 @@ kb:CausalAssertion_91 a sbd:CausalAssertion, rdfs:label "Increase, Inflammation"@en . rdfs:label "Demyelination, increased"@en . + a sbdbel:CausalAssertion ; + rdfs:label "KER 3377"@en ; + dc:source ; + sbdbel:cause ; + sbdbel:relationship ; + sbdbel:outcome ; + dcterms:license . + + rdfs:label "Lipid Peroxidation"@en . + rdfs:label "Foam cell formation"@en . + a sbdbel:CausalAssertion ; rdfs:label "KER 3176"@en ; dc:source ; @@ -64149,6 +64258,17 @@ kb:CausalAssertion_91 a sbd:CausalAssertion, rdfs:label "protein-coupled estrogen receptor 1 (GPER) activation"@en . rdfs:label "Decreased, ERαβ heterodimers"@en . + a sbdbel:CausalAssertion ; + rdfs:label "KER 3373"@en ; + dc:source ; + sbdbel:cause ; + sbdbel:relationship ; + sbdbel:outcome ; + dcterms:license . + + rdfs:label "Increase, Endothelial Dysfunction"@en . + rdfs:label "Infiltration, Inflammatory cells"@en . + a sbdbel:CausalAssertion ; rdfs:label "KER 3298"@en ; dc:source ; @@ -64193,6 +64313,17 @@ kb:CausalAssertion_91 a sbd:CausalAssertion, rdfs:label "Altered, cholesterol metabolism"@en . rdfs:label "Altered Liver X receptor activity"@en . + a sbdbel:CausalAssertion ; + rdfs:label "KER 3288"@en ; + dc:source ; + sbdbel:cause ; + sbdbel:relationship ; + sbdbel:outcome ; + dcterms:license . + + rdfs:label "Decreased, Sodium uptake in gills"@en . + rdfs:label "Decreased, Plasma sodium concentrations"@en . + a sbdbel:CausalAssertion ; rdfs:label "KER 3346"@en ; dc:source ; @@ -64204,6 +64335,17 @@ kb:CausalAssertion_91 a sbd:CausalAssertion, rdfs:label "Decreased, Plasma sodium concentrations"@en . rdfs:label "Decreased, blood plasma volume"@en . + a sbdbel:CausalAssertion ; + rdfs:label "KER 3291"@en ; + dc:source ; + sbdbel:cause ; + sbdbel:relationship ; + sbdbel:outcome ; + dcterms:license . + + rdfs:label "Increased, Blood viscosity"@en . + rdfs:label "Increased, Cardiac stress"@en . + a sbdbel:CausalAssertion ; rdfs:label "KER 3351"@en ; dc:source ; @@ -64413,6 +64555,17 @@ kb:CausalAssertion_91 a sbd:CausalAssertion, rdfs:label "Disrupted PPAR isoform nuclear signaling"@en . rdfs:label "Dysregulation of transcriptional expression within PPAR signaling network"@en . + a sbdbel:CausalAssertion ; + rdfs:label "KER 3347"@en ; + dc:source ; + sbdbel:cause ; + sbdbel:relationship ; + sbdbel:outcome ; + dcterms:license . + + rdfs:label "Decreased, blood plasma volume"@en . + rdfs:label "Increased, Blood viscosity"@en . + #771 triples detected in the JSON-LD @prefix dc: . @prefix dct: .