{"gene":"KNG1","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2020,"finding":"Overexpression of KNG1 in alveolar epithelial type II cells stimulated with LPS activated NF-κB signaling and suppressed Nrf2/HO-1 expression, promoting inflammation and oxidative stress; conversely, KNG1 downregulation (by sufentanil treatment) reduced NF-κB and increased Nrf2/HO-1, attenuating lung injury.","method":"Western blot of NF-κB, Nrf2, and HO-1 protein levels following KNG1 overexpression in LPS-stimulated alveolar epithelial type II cells (AEC II); ELISA for inflammatory cytokines; in vivo rat sepsis model with KNG1 protein expression measured by western blot","journal":"Molecular medicine reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single overexpression experiment in cell line with no mutagenesis or binding assay; no pathway epistasis confirmed beyond correlation of KNG1 level with NF-κB/Nrf2 signaling changes","pmids":["33000200"],"is_preprint":false}],"current_model":"Based on the available literature corpus, KNG1 (kininogen-1) overexpression in lung epithelial cells has been associated with activation of NF-κB and suppression of Nrf2/HO-1 signaling to promote inflammation and oxidative stress, though the corpus contains very few mechanistic studies of the KNG1 protein itself, with most retrieved papers concerning the unrelated BK polyomavirus, BK potassium channels (KCNMA1), or BCKDK."},"narrative":{"mechanistic_narrative":"KNG1 (kininogen-1) has been linked to the regulation of inflammatory and oxidative-stress signaling in lung epithelium, where its overexpression in LPS-stimulated alveolar epithelial type II cells activates NF-κB while suppressing Nrf2/HO-1 expression, promoting inflammation and oxidative stress; reducing KNG1 reverses these changes and attenuates lung injury [PMID:33000200]. Beyond this single low-confidence association in a cell and rat sepsis model [PMID:33000200], no further mechanistic detail of the KNG1 protein — its binding partners, molecular activity, or the route by which it modulates these pathways — has been characterized in the available corpus.","teleology":[{"year":2020,"claim":"Whether KNG1 levels influence inflammatory and antioxidant signaling in lung epithelium was unknown; manipulating KNG1 abundance showed it tracks with NF-κB activation and Nrf2/HO-1 suppression, establishing a correlative role in epithelial inflammation and oxidative stress.","evidence":"Western blot of NF-κB, Nrf2, HO-1 after KNG1 overexpression in LPS-stimulated AEC II cells, cytokine ELISA, and an in vivo rat sepsis model","pmids":["33000200"],"confidence":"Low","gaps":["Single lab, single overexpression experiment with no mutagenesis or binding assay; no pathway epistasis confirmed beyond correlation","No direct molecular partner or substrate of KNG1 identified","Mechanism by which KNG1 modulates NF-κB and Nrf2/HO-1 is unresolved"]},{"year":null,"claim":"The biochemical activity of KNG1, its direct interactors, and the causal mechanism connecting it to NF-κB and Nrf2/HO-1 signaling remain undefined.","evidence":"No further mechanistic studies present in the corpus","pmids":[],"confidence":"Low","gaps":["No structural or biochemical characterization of the protein","No direct physical partners established","No demonstration of a direct versus indirect effect on the implicated pathways"]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P01042","full_name":"Kininogen-1","aliases":["Alpha-2-thiol proteinase inhibitor","Fitzgerald factor","High molecular weight kininogen","HMWK","Williams-Fitzgerald-Flaujeac factor"],"length_aa":644,"mass_kda":72.0,"function":"Kininogens are inhibitors of thiol proteases. HMW-kininogen plays an important role in blood coagulation by helping to position optimally prekallikrein and factor XI next to factor XII; HMW-kininogen inhibits the thrombin- and plasmin-induced aggregation of thrombocytes. LMW-kininogen inhibits the aggregation of thrombocytes. LMW-kininogen is in contrast to HMW-kininogen not involved in blood clotting The active peptide bradykinin is a potent vasodilatator that is released from HMW-kininogen shows a variety of physiological effects: (A) influence in smooth muscle contraction, (B) induction of hypotension, (C) natriuresis and diuresis, (D) decrease in blood glucose level, (E) it is a mediator of inflammation and causes (E1) increase in vascular permeability, (E2) stimulation of nociceptors (4E3) release of other mediators of inflammation (e.g. prostaglandins), (F) it has a cardioprotective effect (directly via bradykinin action, indirectly via endothelium-derived relaxing factor action)","subcellular_location":"Secreted, extracellular space","url":"https://www.uniprot.org/uniprotkb/P01042/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KNG1","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/KNG1","total_profiled":1310},"omim":[{"mim_id":"619363","title":"ANGIOEDEMA, HEREDITARY, 6; HAE6","url":"https://www.omim.org/entry/619363"},{"mim_id":"612358","title":"KININOGEN 1; KNG1","url":"https://www.omim.org/entry/612358"},{"mim_id":"610619","title":"COAGULATION FACTOR XII; F12","url":"https://www.omim.org/entry/610619"},{"mim_id":"600337","title":"BRADYKININ RECEPTOR B1; BDKRB1","url":"https://www.omim.org/entry/600337"},{"mim_id":"228960","title":"HIGH MOLECULAR WEIGHT KININOGEN DEFICIENCY","url":"https://www.omim.org/entry/228960"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"liver","ntpm":2986.1}],"url":"https://www.proteinatlas.org/search/KNG1"},"hgnc":{"alias_symbol":["BK","HMWK"],"prev_symbol":["KNG","BDK","HK"]},"alphafold":{"accession":"P01042","domains":[{"cath_id":"3.10.450.10","chopping":"24-130","consensus_level":"high","plddt":86.0317,"start":24,"end":130},{"cath_id":"3.10.450.10","chopping":"147-256","consensus_level":"high","plddt":89.926,"start":147,"end":256},{"cath_id":"3.10.450.10","chopping":"270-373","consensus_level":"high","plddt":90.1062,"start":270,"end":373}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P01042","model_url":"https://alphafold.ebi.ac.uk/files/AF-P01042-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P01042-F1-predicted_aligned_error_v6.png","plddt_mean":65.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KNG1","jax_strain_url":"https://www.jax.org/strain/search?query=KNG1"},"sequence":{"accession":"P01042","fasta_url":"https://rest.uniprot.org/uniprotkb/P01042.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P01042/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P01042"}},"corpus_meta":[{"pmid":"1314587","id":"PMC_1314587","title":"Cloning and pharmacological characterization of a human bradykinin (BK-2) receptor.","date":"1992","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/1314587","citation_count":440,"is_preprint":false},{"pmid":"27807200","id":"PMC_27807200","title":"Molecular Determinants of BK Channel Functional Diversity and Functioning.","date":"2017","source":"Physiological reviews","url":"https://pubmed.ncbi.nlm.nih.gov/27807200","citation_count":207,"is_preprint":false},{"pmid":"28298471","id":"PMC_28298471","title":"BK Polyomavirus: Clinical Aspects, Immune Regulation, and Emerging Therapies.","date":"2017","source":"Clinical microbiology reviews","url":"https://pubmed.ncbi.nlm.nih.gov/28298471","citation_count":178,"is_preprint":false},{"pmid":"24025517","id":"PMC_24025517","title":"A BK (Slo1) channel journey from molecule to physiology.","date":"2013","source":"Channels (Austin, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/24025517","citation_count":142,"is_preprint":false},{"pmid":"16771813","id":"PMC_16771813","title":"BK virus infection in transplant recipients: an overview and update.","date":"2006","source":"American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons","url":"https://pubmed.ncbi.nlm.nih.gov/16771813","citation_count":138,"is_preprint":false},{"pmid":"11880513","id":"PMC_11880513","title":"Cloning and characterization of glioma BK, a novel BK channel isoform highly expressed in human glioma cells.","date":"2002","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/11880513","citation_count":136,"is_preprint":false},{"pmid":"24119828","id":"PMC_24119828","title":"BK and JC virus: a review.","date":"2013","source":"The Journal of infection","url":"https://pubmed.ncbi.nlm.nih.gov/24119828","citation_count":127,"is_preprint":false},{"pmid":"18759010","id":"PMC_18759010","title":"Regulation of synaptic transmission by presynaptic CaMKII and BK channels.","date":"2008","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/18759010","citation_count":112,"is_preprint":false},{"pmid":"30742788","id":"PMC_30742788","title":"Regulation of BK Channels by Beta and Gamma Subunits.","date":"2019","source":"Annual review of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/30742788","citation_count":109,"is_preprint":false},{"pmid":"17208484","id":"PMC_17208484","title":"Relationships between BK virus lineages and human populations.","date":"2006","source":"Microbes and infection","url":"https://pubmed.ncbi.nlm.nih.gov/17208484","citation_count":108,"is_preprint":false},{"pmid":"22930268","id":"PMC_22930268","title":"Intracellular BK(Ca) (iBK(Ca)) channels.","date":"2012","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/22930268","citation_count":107,"is_preprint":false},{"pmid":"25705194","id":"PMC_25705194","title":"BK channels: multiple sensors, one activation gate.","date":"2015","source":"Frontiers in physiology","url":"https://pubmed.ncbi.nlm.nih.gov/25705194","citation_count":106,"is_preprint":false},{"pmid":"11160513","id":"PMC_11160513","title":"BK channels in human glioma cells.","date":"2001","source":"Journal of neurophysiology","url":"https://pubmed.ncbi.nlm.nih.gov/11160513","citation_count":103,"is_preprint":false},{"pmid":"12490781","id":"PMC_12490781","title":"BK virus and SV40 co-infection in polyomavirus nephropathy.","date":"2002","source":"Transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/12490781","citation_count":100,"is_preprint":false},{"pmid":"17266458","id":"PMC_17266458","title":"Antivirals for the treatment of polyomavirus BK replication.","date":"2007","source":"Expert review of anti-infective therapy","url":"https://pubmed.ncbi.nlm.nih.gov/17266458","citation_count":93,"is_preprint":false},{"pmid":"22402031","id":"PMC_22402031","title":"BK polyomavirus: emerging pathogen.","date":"2012","source":"Microbes and infection","url":"https://pubmed.ncbi.nlm.nih.gov/22402031","citation_count":88,"is_preprint":false},{"pmid":"26731714","id":"PMC_26731714","title":"BK Polyomavirus Infection and Renourinary Tumorigenesis.","date":"2016","source":"American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons","url":"https://pubmed.ncbi.nlm.nih.gov/26731714","citation_count":79,"is_preprint":false},{"pmid":"25027630","id":"PMC_25027630","title":"Big Potassium (BK) ion channels in biology, disease and possible targets for cancer immunotherapy.","date":"2014","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/25027630","citation_count":79,"is_preprint":false},{"pmid":"19781792","id":"PMC_19781792","title":"BK Channels: mediators and models for alcohol tolerance.","date":"2009","source":"Trends in neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/19781792","citation_count":79,"is_preprint":false},{"pmid":"17890268","id":"PMC_17890268","title":"Cytomegalovirus and polyomavirus BK posttransplant.","date":"2007","source":"Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association","url":"https://pubmed.ncbi.nlm.nih.gov/17890268","citation_count":74,"is_preprint":false},{"pmid":"23782063","id":"PMC_23782063","title":"The human polyomavirus BK (BKPyV): virological background and clinical implications.","date":"2013","source":"APMIS : acta pathologica, microbiologica, et immunologica Scandinavica","url":"https://pubmed.ncbi.nlm.nih.gov/23782063","citation_count":72,"is_preprint":false},{"pmid":"9829644","id":"PMC_9829644","title":"Transplacental transmission of human polyomavirus BK.","date":"1998","source":"Journal of medical virology","url":"https://pubmed.ncbi.nlm.nih.gov/9829644","citation_count":71,"is_preprint":false},{"pmid":"24130487","id":"PMC_24130487","title":"A structure-guided mutation in the major capsid protein retargets BK polyomavirus.","date":"2013","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/24130487","citation_count":70,"is_preprint":false},{"pmid":"188048","id":"PMC_188048","title":"Occurrence of BK virus DNA in DNA obtained from certain human tumors.","date":"1976","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/188048","citation_count":70,"is_preprint":false},{"pmid":"22584144","id":"PMC_22584144","title":"Large conductance, calcium- and voltage-gated potassium (BK) channels: regulation by cholesterol.","date":"2012","source":"Pharmacology & therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/22584144","citation_count":66,"is_preprint":false},{"pmid":"16626031","id":"PMC_16626031","title":"Human polyomavirus JC and BK persistent infection.","date":"2006","source":"Advances in experimental medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/16626031","citation_count":63,"is_preprint":false},{"pmid":"25360119","id":"PMC_25360119","title":"Regulation of BK channels by auxiliary γ subunits.","date":"2014","source":"Frontiers in physiology","url":"https://pubmed.ncbi.nlm.nih.gov/25360119","citation_count":63,"is_preprint":false},{"pmid":"19060544","id":"PMC_19060544","title":"Cellular immune responses to BK virus.","date":"2008","source":"Current opinion in organ transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/19060544","citation_count":63,"is_preprint":false},{"pmid":"22860078","id":"PMC_22860078","title":"Entry tropism of BK and Merkel cell polyomaviruses in cell culture.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22860078","citation_count":61,"is_preprint":false},{"pmid":"33809472","id":"PMC_33809472","title":"BK Polyomavirus Nephropathy in Kidney Transplantation: Balancing Rejection and Infection.","date":"2021","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/33809472","citation_count":60,"is_preprint":false},{"pmid":"19530118","id":"PMC_19530118","title":"Evolution of the BK polyomavirus: epidemiological, anthropological and clinical implications.","date":"2009","source":"Reviews in medical virology","url":"https://pubmed.ncbi.nlm.nih.gov/19530118","citation_count":53,"is_preprint":false},{"pmid":"20603335","id":"PMC_20603335","title":"Allosteric interactions and the modular nature of the voltage- and Ca2+-activated (BK) channel.","date":"2010","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/20603335","citation_count":51,"is_preprint":false},{"pmid":"15995966","id":"PMC_15995966","title":"Quantitation of DNA of polyomaviruses BK and JC in human kidneys.","date":"2005","source":"The Journal of infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/15995966","citation_count":47,"is_preprint":false},{"pmid":"26287261","id":"PMC_26287261","title":"Oxidative Stress and Maxi Calcium-Activated Potassium (BK) Channels.","date":"2015","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/26287261","citation_count":46,"is_preprint":false},{"pmid":"28344541","id":"PMC_28344541","title":"OLFM4, KNG1 and Sec24C identified by proteomics and immunohistochemistry as potential markers of early colorectal cancer stages.","date":"2017","source":"Clinical 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framework.","date":"1997","source":"Methods (San Diego, Calif.)","url":"https://pubmed.ncbi.nlm.nih.gov/8990088","citation_count":45,"is_preprint":false},{"pmid":"32824463","id":"PMC_32824463","title":"BKCa Channels as Targets for Cardioprotection.","date":"2020","source":"Antioxidants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/32824463","citation_count":44,"is_preprint":false},{"pmid":"27238262","id":"PMC_27238262","title":"Posttranscriptional and Posttranslational Regulation of BK Channels.","date":"2016","source":"International review of neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/27238262","citation_count":44,"is_preprint":false},{"pmid":"34452367","id":"PMC_34452367","title":"BK Polyomavirus-Biology, Genomic Variation and Diagnosis.","date":"2021","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/34452367","citation_count":43,"is_preprint":false},{"pmid":"27391197","id":"PMC_27391197","title":"Increased Frequency of BK Virus-Specific Polyfunctional CD8+ T Cells Predict Successful Control of BK Viremia After Kidney Transplantation.","date":"2017","source":"Transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/27391197","citation_count":43,"is_preprint":false},{"pmid":"20720523","id":"PMC_20720523","title":"BK channels and a new form of hypertension.","date":"2010","source":"Kidney international","url":"https://pubmed.ncbi.nlm.nih.gov/20720523","citation_count":41,"is_preprint":false},{"pmid":"26663765","id":"PMC_26663765","title":"Characterization of Immunodominant BK Polyomavirus 9mer Epitope T Cell Responses.","date":"2016","source":"American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons","url":"https://pubmed.ncbi.nlm.nih.gov/26663765","citation_count":40,"is_preprint":false},{"pmid":"31896595","id":"PMC_31896595","title":"BK Polyomavirus Hijacks Extracellular Vesicles for En Bloc Transmission.","date":"2020","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/31896595","citation_count":39,"is_preprint":false},{"pmid":"29530986","id":"PMC_29530986","title":"Cereblon Maintains Synaptic and Cognitive Function by Regulating BK Channel.","date":"2018","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/29530986","citation_count":39,"is_preprint":false},{"pmid":"25202277","id":"PMC_25202277","title":"Lipid regulation of BK channel function.","date":"2014","source":"Frontiers in physiology","url":"https://pubmed.ncbi.nlm.nih.gov/25202277","citation_count":38,"is_preprint":false},{"pmid":"33000200","id":"PMC_33000200","title":"Sufentanil attenuates inflammation and oxidative stress in sepsis-induced acute lung injury by downregulating KNG1 expression.","date":"2020","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/33000200","citation_count":38,"is_preprint":false},{"pmid":"17693758","id":"PMC_17693758","title":"BK channels in the kidney.","date":"2007","source":"Current opinion in nephrology and hypertension","url":"https://pubmed.ncbi.nlm.nih.gov/17693758","citation_count":38,"is_preprint":false},{"pmid":"32128960","id":"PMC_32128960","title":"BK polyomavirus diversity-Why viral variation matters.","date":"2020","source":"Reviews in medical virology","url":"https://pubmed.ncbi.nlm.nih.gov/32128960","citation_count":36,"is_preprint":false},{"pmid":"36220546","id":"PMC_36220546","title":"BDK inhibition acts as a catabolic switch to mimic fasting and improve metabolism in mice.","date":"2022","source":"Molecular metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/36220546","citation_count":36,"is_preprint":false},{"pmid":"16734628","id":"PMC_16734628","title":"Update on BK virus entry and intracellular trafficking.","date":"2006","source":"Transplant infectious disease : an official journal of the Transplantation Society","url":"https://pubmed.ncbi.nlm.nih.gov/16734628","citation_count":36,"is_preprint":false},{"pmid":"29632550","id":"PMC_29632550","title":"Role of BK human polyomavirus in cancer.","date":"2018","source":"Infectious agents and cancer","url":"https://pubmed.ncbi.nlm.nih.gov/29632550","citation_count":35,"is_preprint":false},{"pmid":"30181277","id":"PMC_30181277","title":"Glutamate-activated BK channel complexes formed with NMDA receptors.","date":"2018","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/30181277","citation_count":35,"is_preprint":false},{"pmid":"31879339","id":"PMC_31879339","title":"The functionally relevant site for paxilline inhibition of BK channels.","date":"2019","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/31879339","citation_count":34,"is_preprint":false},{"pmid":"27238270","id":"PMC_27238270","title":"BK Channels in the Vascular System.","date":"2016","source":"International review of neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/27238270","citation_count":33,"is_preprint":false},{"pmid":"31486669","id":"PMC_31486669","title":"The Role of KCNMB1 and BK Channels in Myofibroblast Differentiation and Pulmonary Fibrosis.","date":"2020","source":"American journal of respiratory cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/31486669","citation_count":33,"is_preprint":false},{"pmid":"19956720","id":"PMC_19956720","title":"BK channels control cerebellar Purkinje and Golgi cell rhythmicity in vivo.","date":"2009","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/19956720","citation_count":33,"is_preprint":false},{"pmid":"36834817","id":"PMC_36834817","title":"Ca2+- and Voltage-Activated K+ (BK) Channels in the Nervous System: One Gene, a Myriad of Physiological Functions.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36834817","citation_count":32,"is_preprint":false},{"pmid":"16626029","id":"PMC_16626029","title":"Molecular genetics of the BK virus.","date":"2006","source":"Advances in experimental medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/16626029","citation_count":32,"is_preprint":false},{"pmid":"37558654","id":"PMC_37558654","title":"Small molecule branched-chain ketoacid dehydrogenase kinase (BDK) inhibitors with opposing effects on BDK protein levels.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/37558654","citation_count":31,"is_preprint":false},{"pmid":"31043526","id":"PMC_31043526","title":"BK Polyomavirus Activates the DNA Damage Response To Prolong S Phase.","date":"2019","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/31043526","citation_count":31,"is_preprint":false},{"pmid":"24735545","id":"PMC_24735545","title":"Polyomavirus BK-encoded microRNA suppresses autoregulation of viral replication.","date":"2014","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/24735545","citation_count":31,"is_preprint":false},{"pmid":"19074007","id":"PMC_19074007","title":"BK channels in innate immune functions of neutrophils and macrophages.","date":"2008","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/19074007","citation_count":31,"is_preprint":false},{"pmid":"27238266","id":"PMC_27238266","title":"Modulation of BK Channels by Ethanol.","date":"2016","source":"International review of neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/27238266","citation_count":30,"is_preprint":false},{"pmid":"32395331","id":"PMC_32395331","title":"Pathogenicity of BK virus on the urinary system.","date":"2020","source":"Central European journal of urology","url":"https://pubmed.ncbi.nlm.nih.gov/32395331","citation_count":30,"is_preprint":false},{"pmid":"12538331","id":"PMC_12538331","title":"BK virus DNA in CSF of immunocompetent and immunocompromised patients.","date":"2003","source":"Archives of disease in childhood","url":"https://pubmed.ncbi.nlm.nih.gov/12538331","citation_count":30,"is_preprint":false},{"pmid":"38584598","id":"PMC_38584598","title":"Large conductance voltage-and calcium-activated K+ (BK) channel in health and disease.","date":"2024","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/38584598","citation_count":29,"is_preprint":false},{"pmid":"24934303","id":"PMC_24934303","title":"Cellular immunotherapy for patients with reactivation of JC and BK polyomaviruses after transplantation.","date":"2014","source":"Cytotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/24934303","citation_count":29,"is_preprint":false},{"pmid":"18819837","id":"PMC_18819837","title":"Polyomaviruses BK- And JC-DNA quantitation in kidney allograft biopsies.","date":"2008","source":"Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology","url":"https://pubmed.ncbi.nlm.nih.gov/18819837","citation_count":28,"is_preprint":false},{"pmid":"37771695","id":"PMC_37771695","title":"BK polyomavirus: latency, reactivation, diseases and tumorigenesis.","date":"2023","source":"Frontiers in cellular and infection microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/37771695","citation_count":27,"is_preprint":false},{"pmid":"209454","id":"PMC_209454","title":"BK virus DNA: cleavage map and sequence analysis.","date":"1978","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/209454","citation_count":27,"is_preprint":false},{"pmid":"15001555","id":"PMC_15001555","title":"Interactions between bradykinin (BK) and cell adhesion molecule (CAM) expression in peptidoglycan-polysaccharide (PG-PS)-induced arthritis.","date":"2004","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/15001555","citation_count":27,"is_preprint":false},{"pmid":"24310299","id":"PMC_24310299","title":"Genomics of BK viremia in kidney transplant recipients.","date":"2014","source":"Transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/24310299","citation_count":26,"is_preprint":false},{"pmid":"23673010","id":"PMC_23673010","title":"WNK4 inhibits Ca(2+)-activated big-conductance potassium channels (BK) via mitogen-activated protein kinase-dependent pathway.","date":"2013","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/23673010","citation_count":26,"is_preprint":false},{"pmid":"32958651","id":"PMC_32958651","title":"Melatonin promotes sleep by activating the BK channel in C. elegans.","date":"2020","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/32958651","citation_count":26,"is_preprint":false},{"pmid":"22108781","id":"PMC_22108781","title":"Investigation of human JC and BK polyomaviruses in breast carcinomas.","date":"2011","source":"Breast cancer research and treatment","url":"https://pubmed.ncbi.nlm.nih.gov/22108781","citation_count":25,"is_preprint":false},{"pmid":"32060729","id":"PMC_32060729","title":"Targeting BKCa Channels in Migraine: Rationale and Perspectives.","date":"2020","source":"CNS drugs","url":"https://pubmed.ncbi.nlm.nih.gov/32060729","citation_count":24,"is_preprint":false},{"pmid":"15915669","id":"PMC_15915669","title":"Dissociation of branched-chain alpha-keto acid dehydrogenase kinase (BDK) from branched-chain alpha-keto acid dehydrogenase complex (BCKDC) by BDK inhibitors.","date":"2005","source":"Journal of nutritional science and vitaminology","url":"https://pubmed.ncbi.nlm.nih.gov/15915669","citation_count":24,"is_preprint":false},{"pmid":"28051178","id":"PMC_28051178","title":"Muscle-specific deletion of BDK amplifies loss of myofibrillar protein during protein undernutrition.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28051178","citation_count":23,"is_preprint":false},{"pmid":"29623857","id":"PMC_29623857","title":"The Large Conductance Calcium- and Voltage-activated Potassium Channel (BK) and Epilepsy.","date":"2018","source":"CNS & neurological disorders drug targets","url":"https://pubmed.ncbi.nlm.nih.gov/29623857","citation_count":22,"is_preprint":false},{"pmid":"27238265","id":"PMC_27238265","title":"Modulation of BK Channels by Small Endogenous Molecules and Pharmaceutical Channel Openers.","date":"2016","source":"International review of neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/27238265","citation_count":22,"is_preprint":false},{"pmid":"30126198","id":"PMC_30126198","title":"Cell Cycle Regulation by Ca2+-Activated K⁺ (BK) Channels Modulators in SH-SY5Y Neuroblastoma Cells.","date":"2018","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30126198","citation_count":22,"is_preprint":false},{"pmid":"32821148","id":"PMC_32821148","title":"BK Virus Nephropathy: Prevalence, Impact and Management Strategies.","date":"2020","source":"International journal of nephrology and renovascular disease","url":"https://pubmed.ncbi.nlm.nih.gov/32821148","citation_count":21,"is_preprint":false},{"pmid":"32928222","id":"PMC_32928222","title":"BK polyomavirus infection promotes growth and aggressiveness in bladder cancer.","date":"2020","source":"Virology journal","url":"https://pubmed.ncbi.nlm.nih.gov/32928222","citation_count":21,"is_preprint":false},{"pmid":"35014034","id":"PMC_35014034","title":"The LRRC family of BK channel regulatory subunits: potential roles in health and disease.","date":"2022","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/35014034","citation_count":21,"is_preprint":false},{"pmid":"33346797","id":"PMC_33346797","title":"Upregulated LRRC55 promotes BK channel activation and aggravates cell injury in podocytes.","date":"2021","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33346797","citation_count":20,"is_preprint":false},{"pmid":"7736783","id":"PMC_7736783","title":"Three members of the human cystatin gene superfamily, AHSG, HRG, and KNG, map within one megabase of genomic DNA at 3q27.","date":"1995","source":"Cytogenetics and cell genetics","url":"https://pubmed.ncbi.nlm.nih.gov/7736783","citation_count":20,"is_preprint":false},{"pmid":"31570694","id":"PMC_31570694","title":"BK ablation attenuates osteoblast bone formation via integrin pathway.","date":"2019","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/31570694","citation_count":19,"is_preprint":false},{"pmid":"24721651","id":"PMC_24721651","title":"Interacting influence of diuretics and diet on BK channel-regulated K homeostasis.","date":"2013","source":"Current opinion in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/24721651","citation_count":19,"is_preprint":false},{"pmid":"22027587","id":"PMC_22027587","title":"BK viral disease in renal transplantation.","date":"2011","source":"Current opinion in organ transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/22027587","citation_count":19,"is_preprint":false},{"pmid":"27238260","id":"PMC_27238260","title":"Biophysics of BK Channel Gating.","date":"2016","source":"International review of neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/27238260","citation_count":18,"is_preprint":false},{"pmid":"27238264","id":"PMC_27238264","title":"Functional Role of Mitochondrial and Nuclear BK Channels.","date":"2016","source":"International review of neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/27238264","citation_count":18,"is_preprint":false},{"pmid":"34764886","id":"PMC_34764886","title":"BK in Double-Membrane Organelles: A Biophysical, Pharmacological, and Functional Survey.","date":"2021","source":"Frontiers in physiology","url":"https://pubmed.ncbi.nlm.nih.gov/34764886","citation_count":18,"is_preprint":false},{"pmid":"33112543","id":"PMC_33112543","title":"Prevalence of Human Polyomavirus JC and BK in Normal Population.","date":"2020","source":"Asian Pacific journal of cancer prevention : APJCP","url":"https://pubmed.ncbi.nlm.nih.gov/33112543","citation_count":18,"is_preprint":false},{"pmid":"27733613","id":"PMC_27733613","title":"Alcohol Regulates BK Surface Expression via Wnt/β-Catenin Signaling.","date":"2016","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/27733613","citation_count":18,"is_preprint":false},{"pmid":"30649755","id":"PMC_30649755","title":"Regulation of BK Channel Activity by Cholesterol and Its Derivatives.","date":"2019","source":"Advances in experimental medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/30649755","citation_count":18,"is_preprint":false},{"pmid":"28954487","id":"PMC_28954487","title":"Occurrence of BK Virus and Human Papilloma Virus in colorectal cancer.","date":"2017","source":"Annals of agricultural and environmental medicine : AAEM","url":"https://pubmed.ncbi.nlm.nih.gov/28954487","citation_count":18,"is_preprint":false},{"pmid":"29464200","id":"PMC_29464200","title":"Polyomavirus BK Nephropathy-Associated Transcriptomic Signatures: A Critical Reevaluation.","date":"2018","source":"Transplantation direct","url":"https://pubmed.ncbi.nlm.nih.gov/29464200","citation_count":18,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":87938,"output_tokens":1526,"usd":0.216773,"retried_sync":true,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6727,"output_tokens":907,"usd":0.028155,"stage2_stop_reason":"end_turn"},"total_usd":0.244928,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to identify papers about the canonical KNG1 protein (kininogen-1, also known as HMWK, KNG, BDK in the context of bradykinin/kinin system). \n\nThe vast majority of papers in this corpus are about:\n- BK polyomavirus (BKPyV) — a virus, NOT the KNG1 protein\n- BK channels (KCNMA1/Slo1) — a potassium channel gene, NOT KNG1\n- BDK = BCKDK (branched-chain ketoacid dehydrogenase kinase) — a different gene\n\nI need to find papers specifically about KNG1 (kininogen-1), which encodes the precursor of bradykinin and is a member of the cystatin superfamily.\n\nReviewing each paper:\n- Paper [89] (PMID: 7736783): Maps KNG1 gene to chromosome 3q27 — this is about the KNG1 gene locus, a chromosomal mapping study. This is a genomic/cytogenetic paper, not mechanistic.\n- Paper [74] (PMID: 15001555): About bradykinin (BK) and cell adhesion molecules in arthritis — this is about bradykinin receptors (B1R, B2R), not about KNG1 protein mechanism directly.\n- Paper [1] (PMID: 1314587): About BK-2 bradykinin receptor cloning — this is about the receptor, not KNG1.\n- Paper [49] (PMID: 33000200): About KNG1 in sepsis-induced ALI — this directly mentions KNG1 protein expression and its role in NF-κB and Nrf2/HO-1 signaling.\n- Paper [35] (PMID: 28344541): Identifies KNG1 as a proteomics marker in colorectal cancer — expression study, not mechanistic.\n\nOnly paper [49] and [89] and [74] are potentially relevant to KNG1 the protein. Paper [49] has some mechanistic content (overexpression of KNG1 activates NF-κB, inhibits Nrf2/HO-1). Paper [89] is chromosomal mapping only.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2020,\n      \"finding\": \"Overexpression of KNG1 in alveolar epithelial type II cells stimulated with LPS activated NF-κB signaling and suppressed Nrf2/HO-1 expression, promoting inflammation and oxidative stress; conversely, KNG1 downregulation (by sufentanil treatment) reduced NF-κB and increased Nrf2/HO-1, attenuating lung injury.\",\n      \"method\": \"Western blot of NF-κB, Nrf2, and HO-1 protein levels following KNG1 overexpression in LPS-stimulated alveolar epithelial type II cells (AEC II); ELISA for inflammatory cytokines; in vivo rat sepsis model with KNG1 protein expression measured by western blot\",\n      \"journal\": \"Molecular medicine reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single overexpression experiment in cell line with no mutagenesis or binding assay; no pathway epistasis confirmed beyond correlation of KNG1 level with NF-κB/Nrf2 signaling changes\",\n      \"pmids\": [\"33000200\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Based on the available literature corpus, KNG1 (kininogen-1) overexpression in lung epithelial cells has been associated with activation of NF-κB and suppression of Nrf2/HO-1 signaling to promote inflammation and oxidative stress, though the corpus contains very few mechanistic studies of the KNG1 protein itself, with most retrieved papers concerning the unrelated BK polyomavirus, BK potassium channels (KCNMA1), or BCKDK.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KNG1 (kininogen-1) has been linked to the regulation of inflammatory and oxidative-stress signaling in lung epithelium, where its overexpression in LPS-stimulated alveolar epithelial type II cells activates NF-\\u03baB while suppressing Nrf2/HO-1 expression, promoting inflammation and oxidative stress; reducing KNG1 reverses these changes and attenuates lung injury [#0]. Beyond this single low-confidence association in a cell and rat sepsis model [#0], no further mechanistic detail of the KNG1 protein \\u2014 its binding partners, molecular activity, or the route by which it modulates these pathways \\u2014 has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2020,\n      \"claim\": \"Whether KNG1 levels influence inflammatory and antioxidant signaling in lung epithelium was unknown; manipulating KNG1 abundance showed it tracks with NF-\\u03baB activation and Nrf2/HO-1 suppression, establishing a correlative role in epithelial inflammation and oxidative stress.\",\n      \"evidence\": \"Western blot of NF-\\u03baB, Nrf2, HO-1 after KNG1 overexpression in LPS-stimulated AEC II cells, cytokine ELISA, and an in vivo rat sepsis model\",\n      \"pmids\": [\"33000200\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single lab, single overexpression experiment with no mutagenesis or binding assay; no pathway epistasis confirmed beyond correlation\",\n        \"No direct molecular partner or substrate of KNG1 identified\",\n        \"Mechanism by which KNG1 modulates NF-\\u03baB and Nrf2/HO-1 is unresolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The biochemical activity of KNG1, its direct interactors, and the causal mechanism connecting it to NF-\\u03baB and Nrf2/HO-1 signaling remain undefined.\",\n      \"evidence\": \"No further mechanistic studies present in the corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural or biochemical characterization of the protein\",\n        \"No direct physical partners established\",\n        \"No demonstration of a direct versus indirect effect on the implicated pathways\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [],\n    \"pathway\": [],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"loss","faith_supported":1,"faith_total":2,"faith_pct":50.0}}