{"gene":"KNG1","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":1975,"finding":"High molecular weight kininogen (HMWK) was identified as the critical plasma factor (Williams factor) required for surface-activated intrinsic coagulation, fibrinolysis, and kinin generation. Williams trait plasma, deficient in kininogen antigen, failed to convert prekallikrein to kallikrein or release kinin upon kaolin contact activation; correction was achieved by purified HMWK and a subfraction of low molecular weight kininogen, establishing KNG1-encoded proteins as obligate cofactors in Hageman factor (factor XII)-dependent pathways.","method":"Plasma fractionation (ion exchange chromatography, gel filtration, disc gel electrophoresis, immunoadsorbent), functional reconstitution assays (partial thromboplastin time, fibrinolytic assay, kinin-generating assay) in kininogen-deficient patient plasma","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1 — reconstitution of function with purified protein in deficient plasma, replicated across multiple orthogonal assays","pmids":["1202089"],"is_preprint":false},{"year":1979,"finding":"Human high molecular weight kininogen (HMW kininogen) is a single-chain plasma protein (Mr ~108,000) cleaved by plasma kallikrein to release bradykinin and yield a two-chain disulfide-linked molecule composed of a heavy chain (~65 kDa) and a histidine-rich light chain (~44 kDa). The isolated light chain retains full procoagulant activity and has high affinity for negatively charged surfaces. Cleavage of HMW kininogen also occurs in plasma during contact activation and requires prekallikrein and factor XII.","method":"Protein purification, SDS-PAGE, sedimentation equilibrium, in vitro kallikrein cleavage assay, 125I-radiolabeling and plasma contact activation with kaolin, procoagulant activity assay of isolated light chain","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — reconstitution with purified proteins, multiple orthogonal biochemical methods, direct functional readout","pmids":["500690"],"is_preprint":false},{"year":1984,"finding":"Alpha-2-thiol proteinase inhibitor (a cysteine proteinase inhibitor isolated from human plasma) is identical to low molecular weight (LMW) kininogen, establishing that KNG1 encodes a dual-function protein: a kinin precursor and a cysteine proteinase inhibitor. The cDNA contained 1,281 bp encoding the pre-protein including the bradykinin nonapeptide sequence, and showed 74% amino acid homology to bovine LMW kininogen.","method":"lambda gt11 cDNA library screening with antibody to alpha-2-thiol proteinase inhibitor, cDNA sequencing, partial N-terminal amino acid sequencing of light chain, immunological cross-reactivity","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 — cDNA cloning and sequencing with protein sequence confirmation, establishing molecular identity","pmids":["6441591"],"is_preprint":false},{"year":1985,"finding":"Human HMW and LMW prekininogens are produced from a single gene (KNG1) by alternative RNA processing. The two mRNAs share identical sequence through the heavy chain and bradykinin-coding regions but completely diverge thereafter, yielding light chains of 255 (HMW) and 38 (LMW) amino acids respectively. The heavy chain contains 17 cysteines conserved with bovine kininogen, supporting eight disulfide-bonded loop structures.","method":"cDNA cloning and sequence analysis, S1 nuclease mapping, Northern blot hybridization, comparison with bovine sequence","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — complete cDNA sequence determination confirmed by S1 mapping and Northern blot, establishing alternative splicing mechanism","pmids":["2989293"],"is_preprint":false},{"year":1985,"finding":"The KNG1 gene spans ~27 kb and contains 11 exons. The nine 5'-terminal exons encode the signal peptide and heavy chain common to both HMW and LMW kininogens. Exon 10 encodes bradykinin plus the HMW-specific sequence continuation; exon 11 encodes the LMW-unique sequence. This structure demonstrates that the gene underwent two successive domain duplications (exons 3–5 and 6–8 are most closely related), generating the triply repeated cystatin-like domain structure of the heavy chain.","method":"Genomic DNA cloning, restriction enzyme mapping, nucleotide sequence determination of all 11 exons and exon-intron boundaries","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — complete gene structure determination with sequence evidence, evolutionary model supported by sequence comparison","pmids":["2989294"],"is_preprint":false},{"year":1986,"finding":"LMW kininogen (a KNG1 product) functions as a cysteine proteinase inhibitor in biological fluids. Purified LMW kininogen inhibits papain and human cathepsin B; combined enzyme kinetic and concentration measurements showed that kininogen has the capacity to play physiologically important roles as a cysteine proteinase inhibitor in blood plasma, synovial fluid, and amniotic fluid, where it is the most abundant cysteine proteinase inhibitor.","method":"Affinity chromatography on immobilized carboxymethylpapain, ion exchange chromatography, immunosorption; inhibition and rate constant measurements with papain and cathepsin B; immunochemical concentration determinations in biological fluids","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro enzyme kinetic assays with purified protein, quantitative inhibition constants determined","pmids":["3488317"],"is_preprint":false},{"year":1988,"finding":"Human umbilical vein endothelial cells (HUVEC) both synthesize HMW kininogen (a 120 kDa protein detected by 35S-methionine labeling and anti-kininogen immunoisolation, with a 3,500-nt mRNA on Northern blot) and express specific zinc-dependent cell-surface binding sites for HMWK (~9.3×10^5 sites/cell, Kd ~52 nM). Binding is reversible, saturable at 4°C, and not competed by kallikrein, factor XII, fibrinogen, fibronectin, or thrombin, establishing HUVEC as a site for contact activation and cysteine protease regulation.","method":"35S-methionine metabolic labeling and immunoprecipitation, Northern blot, 125I-HMWK binding assays, saturation/competition binding analysis, SDS-PAGE","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — direct binding assay with purified radiolabeled protein, biosynthesis confirmed by metabolic labeling; multiple methods","pmids":["2460446"],"is_preprint":false},{"year":1996,"finding":"The zinc-dependent endothelial cell receptor for HMW kininogen (and factor XII) on HUVECs was identified as gC1q-R, a 33-kDa membrane glycoprotein. Using HK-affinity chromatography of solubilized HUVEC membranes in the presence of ZnCl2, a single major 33-kDa protein was eluted and identified by partial N-terminal sequencing and anti-gC1q-R monoclonal antibodies. Recombinant gC1q-R binds biotinylated HK and factor XII in a zinc-dependent manner. Anti-gC1q-R antibodies block 125I-HK binding to HUVEC. The HK-binding site on gC1q-R is distinct from the C1q-binding site.","method":"HK-affinity chromatography of HUVEC membranes ± ZnCl2, SDS-PAGE and silver staining, N-terminal partial sequencing, Western blot with anti-gC1q-R monoclonal antibodies, ligand blot and dot blot with biotinylated HK and factor XII, 125I-HK competition binding assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — receptor identification by affinity purification with sequence confirmation, functional validation by competition binding and antibody blocking, multiple orthogonal methods","pmids":["8710908"],"is_preprint":false},{"year":2005,"finding":"Cleaved HMW kininogen (HKa, the two-chain form generated after kallikrein-mediated bradykinin release) inhibits angiogenesis, while intact HMW kininogen (HK) promotes angiogenesis through its released bradykinin moiety. These represent opposing functions of the KNG1 protein before and after kallikrein cleavage: HK serves as a proangiogenic bradykinin precursor, while HKa is an antiangiogenic molecule acting on endothelial cells.","method":"Review synthesizing experimental data including endothelial cell binding studies, in vitro angiogenesis assays, and molecular mechanism studies of HKa antiangiogenic activity","journal":"Journal of thrombosis and haemostasis : JTH","confidence":"Medium","confidence_rationale":"Tier 3 — review of prior experimental findings; mechanistic basis established in underlying primary studies cited","pmids":["15733059"],"is_preprint":false}],"current_model":"KNG1 encodes a single-gene precursor processed by alternative splicing into high molecular weight (HMW) and low molecular weight (LMW) kininogens; both isoforms share a heavy chain with three cystatin-like domains that inhibit cysteine proteases (papain, cathepsin B), contain the bradykinin nonapeptide, and differ in their light chains. Plasma kallikrein cleaves HMW kininogen (HK) at two sites to release bradykinin, generating the two-chain disulfide-linked HKa whose histidine-rich light chain binds negatively charged surfaces and retains full procoagulant cofactor activity; HK binds to endothelial cells via the zinc-dependent receptor gC1q-R (~9.3×10^5 sites/cell, Kd ~52 nM), positioning it as an obligate cofactor for contact activation of factor XII and prekallikrein, while the intact HK promotes angiogenesis (via bradykinin) and the cleaved form HKa is antiangiogenic."},"narrative":{"teleology":[{"year":1975,"claim":"Identification of HMW kininogen as the missing plasma factor (Williams factor) resolved how surface-dependent contact activation of coagulation, fibrinolysis, and kinin generation are coupled through a single cofactor.","evidence":"Reconstitution of contact activation in kininogen-deficient patient plasma with purified HMWK across coagulation, fibrinolytic, and kinin-generating assays","pmids":["1202089"],"confidence":"High","gaps":["Molecular structure of the cofactor not yet known","Mechanism by which kininogen promotes factor XII activation on surfaces undefined"]},{"year":1979,"claim":"Elucidation of the kallikrein cleavage products of HMW kininogen — a heavy chain, bradykinin, and a histidine-rich light chain retaining procoagulant activity — established the molecular architecture underlying the bifunctional (kinin precursor + coagulation cofactor) nature of KNG1.","evidence":"In vitro kallikrein cleavage, SDS-PAGE, radiolabeled plasma contact activation, isolated light chain procoagulant assay","pmids":["500690"],"confidence":"High","gaps":["Complete amino acid sequence not determined","Basis for light chain surface binding not characterized"]},{"year":1984,"claim":"Demonstrating that LMW kininogen is identical to alpha-2-thiol proteinase inhibitor unified two research fields and revealed that KNG1 encodes a dual-function protein — both a kinin precursor and a cysteine proteinase inhibitor.","evidence":"cDNA cloning with antibody screening, sequencing confirming bradykinin-containing reading frame, immunological cross-reactivity with LMW kininogen","pmids":["6441591"],"confidence":"High","gaps":["Full-length HMW kininogen cDNA not yet cloned","Inhibitory domains not mapped"]},{"year":1985,"claim":"Complete gene structure determination showed that KNG1 spans 11 exons (~27 kb) and that HMW and LMW kininogens arise by alternative RNA splicing at the bradykinin-encoding exon boundary, with the heavy chain containing triply repeated cystatin-like domains generated by successive gene duplications.","evidence":"cDNA cloning and sequencing of both isoforms, S1 nuclease mapping, genomic sequencing of all 11 exons and splice junctions","pmids":["2989293","2989294"],"confidence":"High","gaps":["Regulatory elements controlling alternative splicing not identified","Functional contribution of individual cystatin-like domains not dissected"]},{"year":1986,"claim":"Quantitative enzyme kinetic studies established LMW kininogen as the most abundant cysteine proteinase inhibitor in plasma, synovial fluid, and amniotic fluid, defining its physiological protease-regulatory role.","evidence":"Purification by carboxymethylpapain affinity chromatography, inhibition kinetics against papain and cathepsin B, immunochemical concentration measurements in biological fluids","pmids":["3488317"],"confidence":"High","gaps":["In vivo significance of kininogen-mediated cysteine protease inhibition not tested","Relative contributions of HMW vs. LMW kininogen to protease inhibition in tissues unknown"]},{"year":1988,"claim":"Discovery that endothelial cells both synthesize HMW kininogen and express specific zinc-dependent surface binding sites placed KNG1 at the interface of contact activation and vascular biology.","evidence":"35S-methionine metabolic labeling and immunoprecipitation in HUVEC, 125I-HMWK saturation binding yielding Kd ~52 nM and ~9.3×10^5 sites/cell","pmids":["2460446"],"confidence":"High","gaps":["Molecular identity of the endothelial receptor unknown","Physiological consequence of endothelial kininogen synthesis not established"]},{"year":1996,"claim":"Identification of gC1q-R as the zinc-dependent endothelial receptor for HMW kininogen and factor XII resolved the molecular basis for assembly of the contact activation complex on endothelial surfaces.","evidence":"HK-affinity chromatography of HUVEC membranes with zinc, N-terminal sequencing, anti-gC1q-R antibody blocking of 125I-HK binding, recombinant gC1q-R ligand binding","pmids":["8710908"],"confidence":"High","gaps":["Structural basis of HK–gC1q-R interaction not resolved","Role of cytokeratin 1 and uPAR as co-receptors described elsewhere not yet integrated","In vivo validation of gC1q-R as contact activation platform lacking"]},{"year":2005,"claim":"Recognition that intact HMW kininogen (proangiogenic via bradykinin) and cleaved HKa (antiangiogenic) exert opposing vascular functions revealed that kallikrein processing acts as a molecular switch on KNG1-dependent angiogenic regulation.","evidence":"Review synthesizing endothelial cell binding, in vitro angiogenesis, and molecular mechanism studies","pmids":["15733059"],"confidence":"Medium","gaps":["Antiangiogenic receptor and signaling pathway for HKa on endothelial cells incompletely defined","In vivo relevance of HKa antiangiogenesis in tumor models not independently confirmed in this source"]},{"year":null,"claim":"The structural basis for kallikrein cleavage-dependent conformational changes in HKa that convert it from proangiogenic cofactor to antiangiogenic effector, and the in vivo physiological significance of endothelial kininogen synthesis, remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal structure of full-length HMW kininogen or HKa available","Endothelial autocrine/paracrine role of locally synthesized kininogen untested in vivo","Relative contributions of gC1q-R versus other candidate receptors (cytokeratin 1, uPAR) to HK-mediated contact activation in vivo undetermined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,5,8]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[1,8]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,1,5,6]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[6,7]}],"pathway":[{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[0,1,7]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[5,8]}],"complexes":[],"partners":["F12","KLKB1","C1QBP"],"other_free_text":[]},"mechanistic_narrative":"KNG1 encodes a single-gene precursor that is alternatively spliced to produce high molecular weight (HMW) and low molecular weight (LMW) kininogens, both sharing a heavy chain with three cystatin-like domains that inhibit cysteine proteases such as papain and cathepsin B [PMID:3488317, PMID:6441591]. HMW kininogen serves as an obligate cofactor for contact activation of factor XII and prekallikrein on negatively charged surfaces; its histidine-rich light chain, generated by plasma kallikrein cleavage that simultaneously releases bradykinin, retains full procoagulant activity and binds the endothelial receptor gC1q-R in a zinc-dependent manner [PMID:1202089, PMID:500690, PMID:8710908]. KNG1 deficiency (Williams trait) abolishes surface-activated coagulation, fibrinolysis, and kinin generation [PMID:1202089]. Intact HMW kininogen is proangiogenic through bradykinin release, whereas the cleaved two-chain form (HKa) is antiangiogenic, establishing opposing vascular functions governed by kallikrein processing [PMID:15733059]."},"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":439,"is_preprint":false,"source_track":"pubmed_title"},{"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":202,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23836898","id":"PMC_23836898","title":"Akt phosphorylates HK-II at Thr-473 and increases mitochondrial HK-II association to protect cardiomyocytes.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23836898","citation_count":199,"is_preprint":false,"source_track":"pubmed_title"},{"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":174,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18536934","id":"PMC_18536934","title":"The gastric HK-ATPase: structure, function, and inhibition.","date":"2008","source":"Pflugers Archiv : European journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/18536934","citation_count":162,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"6314501","id":"PMC_6314501","title":"BK viral enhancer element and a human cellular homolog.","date":"1983","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/6314501","citation_count":149,"is_preprint":false,"source_track":"pubmed_title"},{"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,"source_track":"pubmed_title"},{"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":126,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12910256","id":"PMC_12910256","title":"Oncogenic transformation by BK virus and association with human tumors.","date":"2003","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/12910256","citation_count":124,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"2820135","id":"PMC_2820135","title":"Association of polyomaviruses JC, SV40, and BK with human brain tumors.","date":"1987","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/2820135","citation_count":113,"is_preprint":false,"source_track":"pubmed_title"},{"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,"source_track":"pubmed_title"},{"pmid":"21831150","id":"PMC_21831150","title":"BK virus-specific immunity kinetics: a predictor of recovery from polyomavirus BK-associated nephropathy.","date":"2011","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/21831150","citation_count":109,"is_preprint":false,"source_track":"pubmed_title"},{"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":106,"is_preprint":false,"source_track":"pubmed_title"},{"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":106,"is_preprint":false,"source_track":"pubmed_title"},{"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,"source_track":"pubmed_title"},{"pmid":"20876611","id":"PMC_20876611","title":"Genome-wide association study for adiponectin levels in Filipino women identifies CDH13 and a novel uncommon haplotype at KNG1-ADIPOQ.","date":"2010","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20876611","citation_count":90,"is_preprint":false,"source_track":"pubmed_title"},{"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,"source_track":"pubmed_title"},{"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,"source_track":"pubmed_title"},{"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":77,"is_preprint":false,"source_track":"pubmed_title"},{"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,"source_track":"pubmed_title"},{"pmid":"2159787","id":"PMC_2159787","title":"Location of the carbohydrates present in the HK-ATPase vesicles isolated from hog gastric mucosa.","date":"1990","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/2159787","citation_count":71,"is_preprint":false,"source_track":"pubmed_title"},{"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,"source_track":"pubmed_title"},{"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,"source_track":"pubmed_title"},{"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":70,"is_preprint":false,"source_track":"pubmed_title"},{"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":65,"is_preprint":false,"source_track":"pubmed_title"},{"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,"source_track":"pubmed_title"},{"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,"source_track":"pubmed_title"},{"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,"source_track":"pubmed_title"},{"pmid":"38494080","id":"PMC_38494080","title":"GLUT and HK: Two primary and essential key players in tumor glycolysis.","date":"2024","source":"Seminars in cancer biology","url":"https://pubmed.ncbi.nlm.nih.gov/38494080","citation_count":61,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18617563","id":"PMC_18617563","title":"Aldosterone increases KCa1.1 (BK) channel-mediated colonic K+ secretion.","date":"2008","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/18617563","citation_count":58,"is_preprint":false,"source_track":"pubmed_title"},{"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":56,"is_preprint":false,"source_track":"pubmed_title"},{"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":52,"is_preprint":false,"source_track":"pubmed_title"},{"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,"source_track":"pubmed_title"},{"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,"source_track":"pubmed_title"},{"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,"source_track":"pubmed_title"},{"pmid":"29252987","id":"PMC_29252987","title":"Roles of claudin-2, ZO-1 and occludin in leaky HK-2 cells.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/29252987","citation_count":46,"is_preprint":false,"source_track":"pubmed_title"},{"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 proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/28344541","citation_count":45,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8990088","id":"PMC_8990088","title":"Human polyomavirus BK and immunogenicity of mammalian DNA: a conceptual framework.","date":"1997","source":"Methods (San Diego, Calif.)","url":"https://pubmed.ncbi.nlm.nih.gov/8990088","citation_count":45,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15690396","id":"PMC_15690396","title":"The human polyomavirus BK: Potential role in cancer.","date":"2005","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/15690396","citation_count":44,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22099377","id":"PMC_22099377","title":"Efficient propagation of archetype BK and JC polyomaviruses.","date":"2011","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/22099377","citation_count":44,"is_preprint":false,"source_track":"pubmed_title"},{"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":43,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28151406","id":"PMC_28151406","title":"A Simple and Reliable Strategy for BK Virus Subtyping and Subgrouping.","date":"2017","source":"Journal of clinical microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/28151406","citation_count":43,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31570704","id":"PMC_31570704","title":"Dissociation of mitochondrial HK-II elicits mitophagy and confers cardioprotection against ischemia.","date":"2019","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/31570704","citation_count":43,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22090511","id":"PMC_22090511","title":"Fast-activating voltage- and calcium-dependent potassium (BK) conductance promotes bursting in pituitary cells: a dynamic clamp study.","date":"2011","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/22090511","citation_count":41,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15733059","id":"PMC_15733059","title":"Two faces of high-molecular-weight kininogen (HK) in angiogenesis: bradykinin turns it on and cleaved HK (HKa) turns it off.","date":"2005","source":"Journal of thrombosis and haemostasis : JTH","url":"https://pubmed.ncbi.nlm.nih.gov/15733059","citation_count":41,"is_preprint":false,"source_track":"pubmed_title"},{"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,"source_track":"pubmed_title"},{"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":39,"is_preprint":false,"source_track":"pubmed_title"},{"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,"source_track":"pubmed_title"},{"pmid":"31336246","id":"PMC_31336246","title":"The case for BK polyomavirus as a cause of bladder cancer.","date":"2019","source":"Current opinion in virology","url":"https://pubmed.ncbi.nlm.nih.gov/31336246","citation_count":37,"is_preprint":false,"source_track":"pubmed_title"},{"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":37,"is_preprint":false,"source_track":"pubmed_title"},{"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":36,"is_preprint":false,"source_track":"pubmed_title"},{"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,"source_track":"pubmed_title"},{"pmid":"30498444","id":"PMC_30498444","title":"Celastrol Alleviates Chronic Obstructive Pulmonary Disease by Inhibiting Cellular Inflammation Induced by Cigarette Smoke via the Ednrb/Kng1 Signaling Pathway.","date":"2018","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/30498444","citation_count":36,"is_preprint":false,"source_track":"pubmed_title"},{"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,"source_track":"pubmed_title"},{"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":35,"is_preprint":false,"source_track":"pubmed_title"},{"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":34,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12595498","id":"PMC_12595498","title":"TGF-beta1-mediated inhibition of HK-2 cell migration.","date":"2003","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/12595498","citation_count":34,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29562663","id":"PMC_29562663","title":"Agnoprotein Is an Essential Egress Factor during BK Polyomavirus Infection.","date":"2018","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/29562663","citation_count":34,"is_preprint":false,"source_track":"pubmed_title"},{"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,"source_track":"pubmed_title"},{"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":33,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"4258145","id":"PMC_4258145","title":"Changes from high potassium (hk) to low potassium (lk) in bovine red cells.","date":"1972","source":"The Journal of general physiology","url":"https://pubmed.ncbi.nlm.nih.gov/4258145","citation_count":33,"is_preprint":false,"source_track":"pubmed_title"},{"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":33,"is_preprint":false,"source_track":"pubmed_title"},{"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,"source_track":"pubmed_title"},{"pmid":"24446243","id":"PMC_24446243","title":"Mitochondrial but not plasmalemmal BK channels are hypoxia-sensitive in human glioma.","date":"2014","source":"Glia","url":"https://pubmed.ncbi.nlm.nih.gov/24446243","citation_count":33,"is_preprint":false,"source_track":"pubmed_title"},{"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":31,"is_preprint":false,"source_track":"pubmed_title"},{"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":31,"is_preprint":false,"source_track":"pubmed_title"},{"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,"source_track":"pubmed_title"},{"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,"source_track":"pubmed_title"},{"pmid":"29751615","id":"PMC_29751615","title":"The Maxi-K (BK) Channel Antagonist Penitrem A as a Novel Breast Cancer-Targeted Therapeutic.","date":"2018","source":"Marine drugs","url":"https://pubmed.ncbi.nlm.nih.gov/29751615","citation_count":30,"is_preprint":false,"source_track":"pubmed_title"},{"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":29,"is_preprint":false,"source_track":"pubmed_title"},{"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":28,"is_preprint":false,"source_track":"pubmed_title"},{"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,"source_track":"pubmed_title"},{"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,"source_track":"pubmed_title"},{"pmid":"24174048","id":"PMC_24174048","title":"The M-antigen in HK and LK sheep red cell membranes.","date":"1969","source":"The Journal of membrane biology","url":"https://pubmed.ncbi.nlm.nih.gov/24174048","citation_count":27,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29556720","id":"PMC_29556720","title":"Polymyxin B causes DNA damage in HK-2 cells and mice.","date":"2018","source":"Archives of toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/29556720","citation_count":26,"is_preprint":false,"source_track":"pubmed_title"},{"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":25,"is_preprint":false,"source_track":"pubmed_title"},{"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,"source_track":"pubmed_title"},{"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,"source_track":"pubmed_title"},{"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":24,"is_preprint":false,"source_track":"pubmed_title"},{"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,"source_track":"pubmed_title"},{"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":24,"is_preprint":false,"source_track":"pubmed_title"},{"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,"source_track":"pubmed_title"},{"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,"source_track":"pubmed_title"},{"pmid":"25448808","id":"PMC_25448808","title":"Involvement of PPARγ in emodin-induced HK-2 cell apoptosis.","date":"2015","source":"Toxicology in vitro : an international journal published in association with BIBRA","url":"https://pubmed.ncbi.nlm.nih.gov/25448808","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25594022","id":"PMC_25594022","title":"Polyomavirus BK and prostate cancer: an unworthy scientific effort?","date":"2014","source":"Oncoscience","url":"https://pubmed.ncbi.nlm.nih.gov/25594022","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21445248","id":"PMC_21445248","title":"Enhancement effects of martentoxin on glioma BK channel and BK channel (α+β1) subtypes.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21445248","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"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,"source_track":"pubmed_title"},{"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":21,"is_preprint":false,"source_track":"pubmed_title"},{"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,"source_track":"pubmed_title"},{"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":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20846459","id":"PMC_20846459","title":"A study of association between expression of hOGG1, VDAC1, HK-2 and cervical carcinoma.","date":"2010","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/20846459","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"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,"source_track":"pubmed_title"},{"pmid":"33525649","id":"PMC_33525649","title":"Effect of Increased IL-1β on Expression of HK in Alzheimer's Disease.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33525649","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"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,"source_track":"pubmed_title"},{"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,"source_track":"pubmed_title"},{"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":18,"is_preprint":false,"source_track":"pubmed_title"},{"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,"source_track":"pubmed_title"},{"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,"source_track":"pubmed_title"},{"pmid":"24727949","id":"PMC_24727949","title":"Intrinsic disorder in the BK channel and its interactome.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24727949","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"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,"source_track":"pubmed_title"},{"pmid":"10969042","id":"PMC_10969042","title":"A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9.","date":"2000","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/10969042","citation_count":2338,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12477932","id":"PMC_12477932","title":"Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12477932","citation_count":1479,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"24816252","id":"PMC_24816252","title":"An atlas of genetic influences on human blood metabolites.","date":"2014","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24816252","citation_count":1209,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12754519","id":"PMC_12754519","title":"Identification and quantification of N-linked glycoproteins using hydrazide chemistry, stable isotope labeling and mass spectrometry.","date":"2003","source":"Nature biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/12754519","citation_count":1176,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"11815627","id":"PMC_11815627","title":"Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11815627","citation_count":1146,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26186194","id":"PMC_26186194","title":"The BioPlex Network: A Systematic Exploration of the Human Interactome.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26186194","citation_count":1118,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28514442","id":"PMC_28514442","title":"Architecture of the human interactome defines protein communities and disease networks.","date":"2017","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/28514442","citation_count":1085,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33961781","id":"PMC_33961781","title":"Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.","date":"2021","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/33961781","citation_count":705,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14718574","id":"PMC_14718574","title":"The human plasma proteome: a nonredundant list developed by combination of four separate sources.","date":"2004","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/14718574","citation_count":658,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"1652157","id":"PMC_1652157","title":"Factor XI activation in a revised model of blood coagulation.","date":"1991","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/1652157","citation_count":656,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21873635","id":"PMC_21873635","title":"Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium.","date":"2011","source":"Briefings in bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/21873635","citation_count":656,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19056867","id":"PMC_19056867","title":"Large-scale proteomics and phosphoproteomics of urinary exosomes.","date":"2008","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/19056867","citation_count":607,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"4322742","id":"PMC_4322742","title":"A dipeptidyl carboxypeptidase that converts angiotensin I and inactivates bradykinin.","date":"1970","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/4322742","citation_count":539,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"8125298","id":"PMC_8125298","title":"Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides.","date":"1994","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/8125298","citation_count":492,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"3488317","id":"PMC_3488317","title":"Isolation of six cysteine proteinase inhibitors from human urine. Their physicochemical and enzyme kinetic properties and concentrations in biological fluids.","date":"1986","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/3488317","citation_count":434,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16344560","id":"PMC_16344560","title":"Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes.","date":"2005","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/16344560","citation_count":409,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16335952","id":"PMC_16335952","title":"Human plasma N-glycoproteome analysis by immunoaffinity subtraction, hydrazide chemistry, and mass spectrometry.","date":"2005","source":"Journal of proteome research","url":"https://pubmed.ncbi.nlm.nih.gov/16335952","citation_count":350,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"1202089","id":"PMC_1202089","title":"Williams trait. Human kininogen deficiency with diminished levels of plasminogen proactivator and prekallikrein associated with abnormalities of the Hageman factor-dependent pathways.","date":"1975","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/1202089","citation_count":347,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21145461","id":"PMC_21145461","title":"Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics.","date":"2010","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/21145461","citation_count":318,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"2834384","id":"PMC_2834384","title":"Presence of three distinct molecular species of Gi protein alpha subunit. Structure of rat cDNAs and human genomic DNAs.","date":"1988","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/2834384","citation_count":256,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"500690","id":"PMC_500690","title":"Human high molecular weight kininogen. Studies of structure-function relationships and of proteolysis of the molecule occurring during contact activation of plasma.","date":"1979","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/500690","citation_count":226,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"6441591","id":"PMC_6441591","title":"Isolation of a human cDNA for alpha 2-thiol proteinase inhibitor and its identity with low molecular weight kininogen.","date":"1984","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/6441591","citation_count":225,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25037231","id":"PMC_25037231","title":"Extracellular matrix signatures of human primary metastatic colon cancers and their metastases to liver.","date":"2014","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/25037231","citation_count":203,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"8710908","id":"PMC_8710908","title":"Identification of the zinc-dependent endothelial cell binding protein for high molecular weight kininogen and factor XII: identity with the receptor that binds to the globular \"heads\" of C1q (gC1q-R).","date":"1996","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/8710908","citation_count":202,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"6055465","id":"PMC_6055465","title":"Second kininase in human blood plasma.","date":"1967","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/6055465","citation_count":198,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12173","id":"PMC_12173","title":"Post-proline cleaving enzyme. Purification of this endopeptidase by affinity chromatography.","date":"1976","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12173","citation_count":197,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28675934","id":"PMC_28675934","title":"Characterization of the Extracellular Matrix of Normal and Diseased Tissues Using Proteomics.","date":"2017","source":"Journal of proteome research","url":"https://pubmed.ncbi.nlm.nih.gov/28675934","citation_count":185,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"2989294","id":"PMC_2989294","title":"Structural organization of the human kininogen gene and a model for its evolution.","date":"1985","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/2989294","citation_count":184,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"2460446","id":"PMC_2460446","title":"The expression of high molecular weight kininogen on human umbilical vein endothelial cells.","date":"1988","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/2460446","citation_count":174,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"2989293","id":"PMC_2989293","title":"Cloning and sequence analysis of cDNAs for human high molecular weight and low molecular weight prekininogens. Primary structures of two human prekininogens.","date":"1985","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/2989293","citation_count":171,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":43451,"output_tokens":1277,"usd":0.074754},"stage2":{"model":"claude-opus-4-6","input_tokens":4499,"output_tokens":1974,"usd":0.107768},"total_usd":0.427337,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":56130,"output_tokens":3581,"usd":0.111052},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":6450,"output_tokens":2277,"usd":0.133763}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"High-molecular-weight kininogen (HK/KNG1) binds to endothelial cells where it is cleaved by plasma kallikrein to release bradykinin (BK); the remaining cleaved HK (HKa) inhibits angiogenesis while the released bradykinin promotes angiogenesis, demonstrating opposing roles for intact vs. cleaved KNG1 in vascular biology.\",\n      \"method\": \"Biochemical cleavage assays, endothelial cell binding studies, angiogenesis assays\",\n      \"journal\": \"Journal of thrombosis and haemostasis : JTH\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional characterization with multiple assays in a single review synthesizing experimental work, but relies on prior experimental literature rather than a single fully controlled study\",\n      \"pmids\": [\"15733059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KNG1 overexpression in alveolar epithelial type II cells (AEC II) attenuated the inhibitory effects of sufentanil on LPS-induced inflammation and oxidative stress, and KNG1 was found to regulate NF-κB and Nrf2/HO-1 signaling pathways; sufentanil protected against sepsis-induced acute lung injury in part by downregulating KNG1 expression.\",\n      \"method\": \"Western blot, ELISA, KNG1 overexpression in AEC II cells, rat sepsis model, pathway analysis\",\n      \"journal\": \"Molecular medicine reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — in vitro overexpression with functional readouts and in vivo model, but single lab, limited mechanistic depth on KNG1's direct molecular action\",\n      \"pmids\": [\"33000200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Celastrol alleviates COPD-associated cellular inflammation by suppressing the Ednrb/Kng1 signaling pathway; Kng1 expression was elevated in COPD models and its reduction by celastrol corresponded to decreased inflammatory cytokines and reduced apoptosis in both cell and animal models.\",\n      \"method\": \"Bioinformatics, quantitative PCR, western blotting, ELISA, flow cytometry, TUNEL staining in Beas-2B cells and C57BL/6 mice\",\n      \"journal\": \"Frontiers in pharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — correlative pathway assignment based on expression changes; no direct KNG1 loss-of-function or reconstitution experiment to establish causal mechanism\",\n      \"pmids\": [\"30498444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"A novel uncommon haplotype at the KNG1-ADIPOQ locus (rs11924390 near KNG1 combined with rs864265 near ADIPOQ) was strongly associated with lower plasma adiponectin levels in Filipino women, suggesting a regulatory role for KNG1 genomic region on adiponectin expression.\",\n      \"method\": \"Genome-wide association study with imputation, haplotype analysis, replicated in two independent cohorts\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — GWAS/genetic association; no direct functional experiment on KNG1 protein mechanism\",\n      \"pmids\": [\"20876611\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KNG1 protein was identified by label-free proteomics as differentially distributed in early colorectal cancer stages compared to normal and preneoplastic tissues, and validated by immunohistochemistry, implicating KNG1 in early colorectal carcinogenesis.\",\n      \"method\": \"Label-free proteomics on 76 colorectal tissue samples, immunohistochemistry validation\",\n      \"journal\": \"Clinical proteomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3/4 — protein identification by proteomics and IHC; no mechanistic experiment on KNG1 function\",\n      \"pmids\": [\"28344541\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KNG1 (high-molecular-weight kininogen) functions as a plasma protein that binds to endothelial cells and is cleaved by plasma kallikrein to release bradykinin, with intact KNG1 and its cleaved form (HKa) exerting opposing effects on angiogenesis (HKa inhibitory, bradykinin stimulatory); KNG1 also participates in NF-κB and Nrf2/HO-1 inflammatory signaling in lung epithelial cells, and its genomic locus is associated with adiponectin regulation, though many of these mechanistic details remain incompletely characterized.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nLooking at the corpus, I need to identify papers actually about KNG1 (kininogen-1, high molecular weight kininogen/HMWK, the plasma protein precursor of bradykinin involved in the contact activation/kallikrein-kinin system).\n\nThe vast majority of papers in the main retrieved corpus are about:\n- BK polyomavirus (alias collision with \"BK virus\")\n- BK channels (KCNMA1/KCa1.1, alias collision with \"Big K\" potassium channels)\n- HK-2 (a human kidney cell line, not KNG1)\n- HK-ATPase (gastric pump, not KNG1)\n- HK hexokinase (not KNG1)\n- BDK (branched-chain ketoacid dehydrogenase kinase, not KNG1)\n\nPapers to KEEP from the main corpus:\n- [45] PMID:15733059 — high-molecular-weight kininogen (HK/HKa) and angiogenesis — directly about KNG1\n\nPapers to KEEP from the gene2pubmed corpus:\n- [10] PMID:1202089 — Williams trait, kininogen deficiency\n- [18] PMID:500690 — HMW kininogen structure-function\n- [22] PMID:6441591 — cDNA for alpha2-thiol proteinase inhibitor = LMW kininogen\n- [24] PMID:8710908 — zinc-dependent endothelial cell binding of HK, receptor = gC1q-R\n- [28] PMID:2989294 — kininogen gene structure\n- [29] PMID:2460446 — HMWK expression on endothelial cells\n- [30] PMID:2989293 — cDNA for HMW and LMW prekininogens\n\nAlso from gene2pubmed:\n- [13] PMID:4322742 — ACE inactivates bradykinin (relevant to KNG1 product)\n- [15] PMID:3488317 — kininogen as cysteine proteinase inhibitor\n\nOther gene2pubmed papers that mention KNG1/kininogen tangentially but are not mechanistic about KNG1 specifically: [1],[2],[3],[4],[5],[6],[7],[8],[9],[11],[12],[14],[16],[17],[19],[20],[21],[23],[25],[26],[27] — these are proteomics/interactome/methodology papers where KNG1 appears as a data point.\n\nFrom main corpus [37] PMID:28344541 and [51] PMID:33000200 and [53] PMID:30498444 — these mention KNG1 protein but provide no mechanistic findings about how KNG1 works.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1975,\n      \"finding\": \"High molecular weight kininogen (HMWK) was identified as the critical plasma factor (Williams factor) required for surface-activated intrinsic coagulation, fibrinolysis, and kinin generation. Williams trait plasma, deficient in kininogen antigen, failed to convert prekallikrein to kallikrein or release kinin upon kaolin contact activation; correction was achieved by purified HMWK and a subfraction of low molecular weight kininogen, establishing KNG1-encoded proteins as obligate cofactors in Hageman factor (factor XII)-dependent pathways.\",\n      \"method\": \"Plasma fractionation (ion exchange chromatography, gel filtration, disc gel electrophoresis, immunoadsorbent), functional reconstitution assays (partial thromboplastin time, fibrinolytic assay, kinin-generating assay) in kininogen-deficient patient plasma\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution of function with purified protein in deficient plasma, replicated across multiple orthogonal assays\",\n      \"pmids\": [\"1202089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1979,\n      \"finding\": \"Human high molecular weight kininogen (HMW kininogen) is a single-chain plasma protein (Mr ~108,000) cleaved by plasma kallikrein to release bradykinin and yield a two-chain disulfide-linked molecule composed of a heavy chain (~65 kDa) and a histidine-rich light chain (~44 kDa). The isolated light chain retains full procoagulant activity and has high affinity for negatively charged surfaces. Cleavage of HMW kininogen also occurs in plasma during contact activation and requires prekallikrein and factor XII.\",\n      \"method\": \"Protein purification, SDS-PAGE, sedimentation equilibrium, in vitro kallikrein cleavage assay, 125I-radiolabeling and plasma contact activation with kaolin, procoagulant activity assay of isolated light chain\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution with purified proteins, multiple orthogonal biochemical methods, direct functional readout\",\n      \"pmids\": [\"500690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1984,\n      \"finding\": \"Alpha-2-thiol proteinase inhibitor (a cysteine proteinase inhibitor isolated from human plasma) is identical to low molecular weight (LMW) kininogen, establishing that KNG1 encodes a dual-function protein: a kinin precursor and a cysteine proteinase inhibitor. The cDNA contained 1,281 bp encoding the pre-protein including the bradykinin nonapeptide sequence, and showed 74% amino acid homology to bovine LMW kininogen.\",\n      \"method\": \"lambda gt11 cDNA library screening with antibody to alpha-2-thiol proteinase inhibitor, cDNA sequencing, partial N-terminal amino acid sequencing of light chain, immunological cross-reactivity\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cDNA cloning and sequencing with protein sequence confirmation, establishing molecular identity\",\n      \"pmids\": [\"6441591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1985,\n      \"finding\": \"Human HMW and LMW prekininogens are produced from a single gene (KNG1) by alternative RNA processing. The two mRNAs share identical sequence through the heavy chain and bradykinin-coding regions but completely diverge thereafter, yielding light chains of 255 (HMW) and 38 (LMW) amino acids respectively. The heavy chain contains 17 cysteines conserved with bovine kininogen, supporting eight disulfide-bonded loop structures.\",\n      \"method\": \"cDNA cloning and sequence analysis, S1 nuclease mapping, Northern blot hybridization, comparison with bovine sequence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — complete cDNA sequence determination confirmed by S1 mapping and Northern blot, establishing alternative splicing mechanism\",\n      \"pmids\": [\"2989293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1985,\n      \"finding\": \"The KNG1 gene spans ~27 kb and contains 11 exons. The nine 5'-terminal exons encode the signal peptide and heavy chain common to both HMW and LMW kininogens. Exon 10 encodes bradykinin plus the HMW-specific sequence continuation; exon 11 encodes the LMW-unique sequence. This structure demonstrates that the gene underwent two successive domain duplications (exons 3–5 and 6–8 are most closely related), generating the triply repeated cystatin-like domain structure of the heavy chain.\",\n      \"method\": \"Genomic DNA cloning, restriction enzyme mapping, nucleotide sequence determination of all 11 exons and exon-intron boundaries\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — complete gene structure determination with sequence evidence, evolutionary model supported by sequence comparison\",\n      \"pmids\": [\"2989294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1986,\n      \"finding\": \"LMW kininogen (a KNG1 product) functions as a cysteine proteinase inhibitor in biological fluids. Purified LMW kininogen inhibits papain and human cathepsin B; combined enzyme kinetic and concentration measurements showed that kininogen has the capacity to play physiologically important roles as a cysteine proteinase inhibitor in blood plasma, synovial fluid, and amniotic fluid, where it is the most abundant cysteine proteinase inhibitor.\",\n      \"method\": \"Affinity chromatography on immobilized carboxymethylpapain, ion exchange chromatography, immunosorption; inhibition and rate constant measurements with papain and cathepsin B; immunochemical concentration determinations in biological fluids\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro enzyme kinetic assays with purified protein, quantitative inhibition constants determined\",\n      \"pmids\": [\"3488317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1988,\n      \"finding\": \"Human umbilical vein endothelial cells (HUVEC) both synthesize HMW kininogen (a 120 kDa protein detected by 35S-methionine labeling and anti-kininogen immunoisolation, with a 3,500-nt mRNA on Northern blot) and express specific zinc-dependent cell-surface binding sites for HMWK (~9.3×10^5 sites/cell, Kd ~52 nM). Binding is reversible, saturable at 4°C, and not competed by kallikrein, factor XII, fibrinogen, fibronectin, or thrombin, establishing HUVEC as a site for contact activation and cysteine protease regulation.\",\n      \"method\": \"35S-methionine metabolic labeling and immunoprecipitation, Northern blot, 125I-HMWK binding assays, saturation/competition binding analysis, SDS-PAGE\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct binding assay with purified radiolabeled protein, biosynthesis confirmed by metabolic labeling; multiple methods\",\n      \"pmids\": [\"2460446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The zinc-dependent endothelial cell receptor for HMW kininogen (and factor XII) on HUVECs was identified as gC1q-R, a 33-kDa membrane glycoprotein. Using HK-affinity chromatography of solubilized HUVEC membranes in the presence of ZnCl2, a single major 33-kDa protein was eluted and identified by partial N-terminal sequencing and anti-gC1q-R monoclonal antibodies. Recombinant gC1q-R binds biotinylated HK and factor XII in a zinc-dependent manner. Anti-gC1q-R antibodies block 125I-HK binding to HUVEC. The HK-binding site on gC1q-R is distinct from the C1q-binding site.\",\n      \"method\": \"HK-affinity chromatography of HUVEC membranes ± ZnCl2, SDS-PAGE and silver staining, N-terminal partial sequencing, Western blot with anti-gC1q-R monoclonal antibodies, ligand blot and dot blot with biotinylated HK and factor XII, 125I-HK competition binding assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — receptor identification by affinity purification with sequence confirmation, functional validation by competition binding and antibody blocking, multiple orthogonal methods\",\n      \"pmids\": [\"8710908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Cleaved HMW kininogen (HKa, the two-chain form generated after kallikrein-mediated bradykinin release) inhibits angiogenesis, while intact HMW kininogen (HK) promotes angiogenesis through its released bradykinin moiety. These represent opposing functions of the KNG1 protein before and after kallikrein cleavage: HK serves as a proangiogenic bradykinin precursor, while HKa is an antiangiogenic molecule acting on endothelial cells.\",\n      \"method\": \"Review synthesizing experimental data including endothelial cell binding studies, in vitro angiogenesis assays, and molecular mechanism studies of HKa antiangiogenic activity\",\n      \"journal\": \"Journal of thrombosis and haemostasis : JTH\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — review of prior experimental findings; mechanistic basis established in underlying primary studies cited\",\n      \"pmids\": [\"15733059\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KNG1 encodes a single-gene precursor processed by alternative splicing into high molecular weight (HMW) and low molecular weight (LMW) kininogens; both isoforms share a heavy chain with three cystatin-like domains that inhibit cysteine proteases (papain, cathepsin B), contain the bradykinin nonapeptide, and differ in their light chains. Plasma kallikrein cleaves HMW kininogen (HK) at two sites to release bradykinin, generating the two-chain disulfide-linked HKa whose histidine-rich light chain binds negatively charged surfaces and retains full procoagulant cofactor activity; HK binds to endothelial cells via the zinc-dependent receptor gC1q-R (~9.3×10^5 sites/cell, Kd ~52 nM), positioning it as an obligate cofactor for contact activation of factor XII and prekallikrein, while the intact HK promotes angiogenesis (via bradykinin) and the cleaved form HKa is antiangiogenic.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"KNG1 (high-molecular-weight kininogen) is a multifunctional plasma protein that binds endothelial cells and is cleaved by plasma kallikrein to release bradykinin; the intact protein and its cleaved form (HKa) exert opposing effects on angiogenesis, with HKa inhibiting and bradykinin promoting new vessel formation [PMID:15733059]. In alveolar epithelial cells, KNG1 modulates inflammatory and oxidative stress responses through the NF-κB and Nrf2/HO-1 signaling pathways, and its overexpression amplifies LPS-induced inflammation [PMID:33000200].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Establishing that KNG1 cleavage by plasma kallikrein on endothelial cells generates two products with opposing angiogenic activities resolved how a single precursor could both promote and inhibit vascular growth.\",\n      \"evidence\": \"Biochemical cleavage assays, endothelial cell binding studies, and angiogenesis assays synthesized in a review of experimental work\",\n      \"pmids\": [\"15733059\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Precise endothelial receptor mediating HKa anti-angiogenic signaling not fully defined\",\n        \"Quantitative contribution of KNG1-derived bradykinin vs. other bradykinin sources in vivo unclear\",\n        \"Structural basis of how cleavage switches KNG1 from pro- to anti-angiogenic conformation not resolved\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrating that KNG1 overexpression in lung epithelial cells amplifies LPS-induced inflammation via NF-κB and Nrf2/HO-1 pathways extended KNG1 function beyond vascular biology to innate immune inflammatory signaling.\",\n      \"evidence\": \"KNG1 overexpression in AEC II cells with western blot, ELISA, and rat sepsis model\",\n      \"pmids\": [\"33000200\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct molecular target of KNG1 within NF-κB and Nrf2/HO-1 cascades not identified\",\n        \"Whether intracellular KNG1 or secreted/extracellular KNG1 mediates the effect is unresolved\",\n        \"No loss-of-function or rescue experiment with catalytically defined KNG1 domains\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct molecular interactions through which KNG1 engages intracellular inflammatory signaling cascades, and whether its pro-inflammatory role in epithelia depends on kallikrein-mediated cleavage, remain uncharacterized.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No loss-of-function genetic model for KNG1 inflammatory function\",\n        \"Relationship between vascular (anti-angiogenic HKa) and epithelial (pro-inflammatory) activities not integrated\",\n        \"No structural or biophysical characterization linking KNG1 domains to specific signaling outcomes\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"KLKB1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\nWait — I need to correct the pathway field. Let me fix that; pathways should use Reactome IDs.\n\n```json\n{\n  \"mechanistic_narrative\": \"KNG1 (high-molecular-weight kininogen) is a multifunctional plasma protein that binds endothelial cells and is cleaved by plasma kallikrein to release bradykinin; the intact protein and its cleaved form (HKa) exert opposing effects on angiogenesis, with HKa inhibiting and bradykinin promoting new vessel formation [PMID:15733059]. In alveolar epithelial cells, KNG1 modulates inflammatory and oxidative stress responses through the NF-κB and Nrf2/HO-1 signaling pathways, and its overexpression amplifies LPS-induced inflammation [PMID:33000200].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Establishing that KNG1 cleavage by plasma kallikrein on endothelial cells generates two products with opposing angiogenic activities resolved how a single precursor could both promote and inhibit vascular growth.\",\n      \"evidence\": \"Biochemical cleavage assays, endothelial cell binding studies, and angiogenesis assays synthesized in a review of experimental work\",\n      \"pmids\": [\"15733059\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Precise endothelial receptor mediating HKa anti-angiogenic signaling not fully defined\",\n        \"Quantitative contribution of KNG1-derived bradykinin vs. other bradykinin sources in vivo unclear\",\n        \"Structural basis of how cleavage switches KNG1 from pro- to anti-angiogenic conformation not resolved\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrating that KNG1 overexpression in lung epithelial cells amplifies LPS-induced inflammation via NF-κB and Nrf2/HO-1 pathways extended KNG1 function beyond vascular biology to innate immune inflammatory signaling.\",\n      \"evidence\": \"KNG1 overexpression in AEC II cells with western blot, ELISA, and rat sepsis model\",\n      \"pmids\": [\"33000200\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct molecular target of KNG1 within NF-κB and Nrf2/HO-1 cascades not identified\",\n        \"Whether intracellular KNG1 or secreted/extracellular KNG1 mediates the effect is unresolved\",\n        \"No loss-of-function or rescue experiment with catalytically defined KNG1 domains\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct molecular interactions through which KNG1 engages intracellular inflammatory signaling cascades, and whether its pro-inflammatory role in epithelia depends on kallikrein-mediated cleavage, remain uncharacterized.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No loss-of-function genetic model for KNG1 inflammatory function\",\n        \"Relationship between vascular (anti-angiogenic HKa) and epithelial (pro-inflammatory) activities not integrated\",\n        \"No structural or biophysical characterization linking KNG1 domains to specific signaling outcomes\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"KLKB1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"KNG1 encodes a single-gene precursor that is alternatively spliced to produce high molecular weight (HMW) and low molecular weight (LMW) kininogens, both sharing a heavy chain with three cystatin-like domains that inhibit cysteine proteases such as papain and cathepsin B [PMID:3488317, PMID:6441591]. HMW kininogen serves as an obligate cofactor for contact activation of factor XII and prekallikrein on negatively charged surfaces; its histidine-rich light chain, generated by plasma kallikrein cleavage that simultaneously releases bradykinin, retains full procoagulant activity and binds the endothelial receptor gC1q-R in a zinc-dependent manner [PMID:1202089, PMID:500690, PMID:8710908]. KNG1 deficiency (Williams trait) abolishes surface-activated coagulation, fibrinolysis, and kinin generation [PMID:1202089]. Intact HMW kininogen is proangiogenic through bradykinin release, whereas the cleaved two-chain form (HKa) is antiangiogenic, establishing opposing vascular functions governed by kallikrein processing [PMID:15733059].\",\n  \"teleology\": [\n    {\n      \"year\": 1975,\n      \"claim\": \"Identification of HMW kininogen as the missing plasma factor (Williams factor) resolved how surface-dependent contact activation of coagulation, fibrinolysis, and kinin generation are coupled through a single cofactor.\",\n      \"evidence\": \"Reconstitution of contact activation in kininogen-deficient patient plasma with purified HMWK across coagulation, fibrinolytic, and kinin-generating assays\",\n      \"pmids\": [\"1202089\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular structure of the cofactor not yet known\", \"Mechanism by which kininogen promotes factor XII activation on surfaces undefined\"]\n    },\n    {\n      \"year\": 1979,\n      \"claim\": \"Elucidation of the kallikrein cleavage products of HMW kininogen — a heavy chain, bradykinin, and a histidine-rich light chain retaining procoagulant activity — established the molecular architecture underlying the bifunctional (kinin precursor + coagulation cofactor) nature of KNG1.\",\n      \"evidence\": \"In vitro kallikrein cleavage, SDS-PAGE, radiolabeled plasma contact activation, isolated light chain procoagulant assay\",\n      \"pmids\": [\"500690\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Complete amino acid sequence not determined\", \"Basis for light chain surface binding not characterized\"]\n    },\n    {\n      \"year\": 1984,\n      \"claim\": \"Demonstrating that LMW kininogen is identical to alpha-2-thiol proteinase inhibitor unified two research fields and revealed that KNG1 encodes a dual-function protein — both a kinin precursor and a cysteine proteinase inhibitor.\",\n      \"evidence\": \"cDNA cloning with antibody screening, sequencing confirming bradykinin-containing reading frame, immunological cross-reactivity with LMW kininogen\",\n      \"pmids\": [\"6441591\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length HMW kininogen cDNA not yet cloned\", \"Inhibitory domains not mapped\"]\n    },\n    {\n      \"year\": 1985,\n      \"claim\": \"Complete gene structure determination showed that KNG1 spans 11 exons (~27 kb) and that HMW and LMW kininogens arise by alternative RNA splicing at the bradykinin-encoding exon boundary, with the heavy chain containing triply repeated cystatin-like domains generated by successive gene duplications.\",\n      \"evidence\": \"cDNA cloning and sequencing of both isoforms, S1 nuclease mapping, genomic sequencing of all 11 exons and splice junctions\",\n      \"pmids\": [\"2989293\", \"2989294\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Regulatory elements controlling alternative splicing not identified\", \"Functional contribution of individual cystatin-like domains not dissected\"]\n    },\n    {\n      \"year\": 1986,\n      \"claim\": \"Quantitative enzyme kinetic studies established LMW kininogen as the most abundant cysteine proteinase inhibitor in plasma, synovial fluid, and amniotic fluid, defining its physiological protease-regulatory role.\",\n      \"evidence\": \"Purification by carboxymethylpapain affinity chromatography, inhibition kinetics against papain and cathepsin B, immunochemical concentration measurements in biological fluids\",\n      \"pmids\": [\"3488317\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo significance of kininogen-mediated cysteine protease inhibition not tested\", \"Relative contributions of HMW vs. LMW kininogen to protease inhibition in tissues unknown\"]\n    },\n    {\n      \"year\": 1988,\n      \"claim\": \"Discovery that endothelial cells both synthesize HMW kininogen and express specific zinc-dependent surface binding sites placed KNG1 at the interface of contact activation and vascular biology.\",\n      \"evidence\": \"35S-methionine metabolic labeling and immunoprecipitation in HUVEC, 125I-HMWK saturation binding yielding Kd ~52 nM and ~9.3×10^5 sites/cell\",\n      \"pmids\": [\"2460446\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular identity of the endothelial receptor unknown\", \"Physiological consequence of endothelial kininogen synthesis not established\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Identification of gC1q-R as the zinc-dependent endothelial receptor for HMW kininogen and factor XII resolved the molecular basis for assembly of the contact activation complex on endothelial surfaces.\",\n      \"evidence\": \"HK-affinity chromatography of HUVEC membranes with zinc, N-terminal sequencing, anti-gC1q-R antibody blocking of 125I-HK binding, recombinant gC1q-R ligand binding\",\n      \"pmids\": [\"8710908\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of HK–gC1q-R interaction not resolved\", \"Role of cytokeratin 1 and uPAR as co-receptors described elsewhere not yet integrated\", \"In vivo validation of gC1q-R as contact activation platform lacking\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Recognition that intact HMW kininogen (proangiogenic via bradykinin) and cleaved HKa (antiangiogenic) exert opposing vascular functions revealed that kallikrein processing acts as a molecular switch on KNG1-dependent angiogenic regulation.\",\n      \"evidence\": \"Review synthesizing endothelial cell binding, in vitro angiogenesis, and molecular mechanism studies\",\n      \"pmids\": [\"15733059\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Antiangiogenic receptor and signaling pathway for HKa on endothelial cells incompletely defined\", \"In vivo relevance of HKa antiangiogenesis in tumor models not independently confirmed in this source\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis for kallikrein cleavage-dependent conformational changes in HKa that convert it from proangiogenic cofactor to antiangiogenic effector, and the in vivo physiological significance of endothelial kininogen synthesis, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal structure of full-length HMW kininogen or HKa available\", \"Endothelial autocrine/paracrine role of locally synthesized kininogen untested in vivo\", \"Relative contributions of gC1q-R versus other candidate receptors (cytokeratin 1, uPAR) to HK-mediated contact activation in vivo undetermined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 5, 8]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [1, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1, 5, 6]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [6, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [0, 1, 7]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5, 8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"F12\",\n      \"KLKB1\",\n      \"C1QBP\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}