{"gene":"BPI","run_date":"2026-04-28T17:12:38","timeline":{"discoveries":[{"year":1997,"finding":"Crystal structure of human BPI at 2.4 Å resolution reveals a boomerang-shaped molecule with two similar domains, each containing an apolar lipid-binding pocket on the concave surface that binds phosphatidylcholine acyl chains, suggesting these pockets bind LPS acyl chains to mediate LPS neutralization.","method":"X-ray crystallography with bound phospholipid ligands","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 — crystal structure at 2.4 Å with bound ligands, foundational structural study","pmids":["9188532"],"is_preprint":false},{"year":2000,"finding":"Extended crystal structure of human BPI resolved to 1.7 Å; structural comparison of the two domains (same fold, <13% sequence identity) using 3D-1D profiles identified residue pairs with conserved structural roles despite dissimilar sequences, clarifying the mechanism of fold conservation.","method":"X-ray crystallography at 1.7 Å; 3D-1D profile structural analysis","journal":"Journal of Molecular Biology","confidence":"High","confidence_rationale":"Tier 1 — higher-resolution crystal structure with rigorous structural analysis","pmids":["10843855"],"is_preprint":false},{"year":1998,"finding":"Structure/function analysis of conserved residues in BPI and LBP, using the BPI crystal structure, identified a cluster of conserved positively charged residues (Lys42, 48, 92, 95, 99) at the tip of the N-terminal domain with no structural role, predicted to make electrostatic contacts with negatively charged LPS groups and responsible for BPI's bactericidal activity.","method":"Structural analysis of conserved residues mapped onto crystal structure; comparison with known LPS-binding mutagenesis data","journal":"Protein Science","confidence":"High","confidence_rationale":"Tier 1 — structure-based analysis corroborated by known mutagenesis data from multiple sequences","pmids":["9568897"],"is_preprint":false},{"year":1993,"finding":"The antibacterial and LPS-neutralizing activities of BPI are fully expressed by the N-terminal ~25 kDa fragment; BPI binds LPS with high affinity (apparent Kd 2–5 nM) and this complex formation with cell-associated or cell-free LPS inhibits all LPS-induced host cell responses.","method":"In vitro bactericidal assays; LPS-binding assays with proteolytic/recombinant N-terminal BPI fragments; whole blood ex vivo cytokine assays","journal":"Immunobiology","confidence":"High","confidence_rationale":"Tier 1–2 — reconstituted in vitro activity with defined fragments, replicated across multiple studies","pmids":["8330906"],"is_preprint":false},{"year":1998,"finding":"BPI is stored in azurophil (primary) granules of neutrophils; BPI-blocking antibodies abolish antibacterial activity of whole PMN lysates; binding of BPI to live bacteria via LPS causes immediate growth arrest, with killing coinciding with later inner membrane damage.","method":"Granule fractionation; BPI-blocking antibody functional assays; bacterial killing and membrane damage assays","journal":"Journal of Leukocyte Biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods; replicated across labs","pmids":["9665269"],"is_preprint":false},{"year":1997,"finding":"LBP disperses LPS aggregates whereas BPI enhances sedimentation velocity and apparent size of LPS aggregates; BPI inhibits LPS–LBP binding even at very low (1:40–1:20) BPI:LPS molar ratios; the two proteins form physically distinct types of complexes with LPS.","method":"Sedimentation, light scattering, and fluorescence analyses of LPS–protein complexes","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — multiple biophysical methods; clear mechanistic differentiation","pmids":["9228038"],"is_preprint":false},{"year":1997,"finding":"The recombinant N-terminal BPI fragment (rBPI21) incorporates into negatively charged LPS and phosphatidylglycerol monolayers/bilayers but not neutral phosphatidylcholine; it rigidifies acyl chains and immobilizes phosphate groups of LPS aggregates, reducing zeta-potential; high Mg2+ ions protect against this action, suggesting electrostatic displacement as the initial step.","method":"Monolayer experiments, infrared spectroscopy, resonance energy transfer spectroscopy, laser Doppler velocimetry","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 — multiple biophysical in vitro methods with mechanistic modeling","pmids":["9254629"],"is_preprint":false},{"year":1997,"finding":"rBPI21 causes membrane rupture and increases membrane current when added to the LPS leaflet of asymmetric LPS/phospholipid bilayer membranes; it shifts the transmembrane potential of outer membrane models; 40 mM MgCl2 significantly reduces this effect, supporting an electrostatic mechanism of outer membrane disruption.","method":"Electrical measurements on planar bilayer membranes reconstituted with deep-rough LPS","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstituted membrane assay with direct measurement of mechanism","pmids":["9254630"],"is_preprint":false},{"year":1998,"finding":"BPI is present in specific granules of human eosinophils (detected by immunoelectron microscopy) and is released into phagosomes upon phagocytosis, indicating granule-to-phagosome delivery as a mechanism for antibacterial action in eosinophils.","method":"Immunoelectron microscopy; Western blot; ELISA quantification","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 — direct subcellular localization by immunoelectron microscopy with phagosome delivery demonstrated","pmids":["9616176"],"is_preprint":false},{"year":2000,"finding":"BPI is membrane-associated within azurophil granules of neutrophils (co-localizing with MPO and CD63); upon cellular activation by ionophore or phagocytosis, BPI is relocated to phagosomes via granule–endosome fusion, following the same route as MPO and CD63.","method":"Cryotechnique immunoelectron microscopy; selective granule-release experiments with monensin; phagocytosis assays","journal":"APMIS","confidence":"Medium","confidence_rationale":"Tier 2 — direct subcellular localization with functional activation context, single lab","pmids":["10752689"],"is_preprint":false},{"year":2000,"finding":"The C-terminal domain of BPI is required for granule storage and protects against degradation during intracellular sorting; deletion of the N-terminal half causes retention in the ER and proteasomal degradation; chimeras confirm that C-terminal BPI domain confers stability for storage in myeloid cells.","method":"cDNA transfection into rodent hematopoietic cell lines; deletion mutants and chimeras; subcellular fractionation and protein stability assays","journal":"Journal of Leukocyte Biology","confidence":"Medium","confidence_rationale":"Tier 2 — domain deletion and chimera analysis with defined sorting phenotype","pmids":["11073106"],"is_preprint":false},{"year":2002,"finding":"BPI is expressed on the cell surface of human mucosal epithelial cells and is transcriptionally induced by aspirin-triggered lipoxins (ATLa); surface-expressed epithelial BPI blocks LPS-mediated signaling and kills Salmonella typhimurium, functioning as an antimicrobial/endotoxin shield.","method":"Microarray + RT-PCR; cell surface localization by immunostaining; functional assays with BPI-neutralizing antiserum; in vivo tissue IHC","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (expression, localization, functional neutralization) in one study","pmids":["11891303"],"is_preprint":false},{"year":2000,"finding":"BPI inhibits angiogenesis by inducing apoptosis selectively in vascular endothelial cells; apoptosis is mediated by cell detachment and is EC-specific (not fibroblast or other cell types); BPI inhibits tube formation in collagen gel assays and vessel formation in the CAM assay at nanomolar concentrations.","method":"Flow cytometry (subdiploid cell quantification); nuclear fragmentation assay; in vitro collagen gel angiogenesis assay; in vivo CAM assay","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 — multiple in vitro and in vivo assays, single lab","pmids":["10891448"],"is_preprint":false},{"year":2006,"finding":"All-trans retinoic acid (ATRA) induces BPI expression in NB4 promyelocytic cells through de novo protein synthesis; induction correlates with direct binding of C/EBPβ and C/EBPε transcription factors to the proximal BPI promoter, as demonstrated by EMSA and chromatin immunoprecipitation.","method":"ATRA treatment of NB4 cells; cycloheximide sensitivity; EMSA; chromatin immunoprecipitation (ChIP)","journal":"Journal of Leukocyte Biology","confidence":"High","confidence_rationale":"Tier 1–2 — ChIP and EMSA directly demonstrate transcription factor binding to BPI promoter; multiple orthogonal methods","pmids":["16684888"],"is_preprint":false},{"year":2021,"finding":"BPI overexpression in T cells suppresses Treg differentiation; BPI-containing T-cell-derived exosomes stimulate IL-1β expression in recipient macrophages; adoptive transfer of BPI-containing exosomes induces systemic inflammation, autoantibody production, and multi-organ damage in mice; BPI knockout enhances Treg differentiation in vitro, identifying BPI as a negative regulator of Treg differentiation associated with ZFP36L2 upregulation and Helios downregulation.","method":"T-cell-specific BPI transgenic mice; adoptive exosome transfer; scRNA-seq; in vitro Treg differentiation with BPI KO and overexpression","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 — multiple in vivo and in vitro methods; single lab; mechanistic pathway partially defined","pmids":["34815797"],"is_preprint":false},{"year":2017,"finding":"BPI expression in intestinal epithelial cells is induced by cell membrane damage (via pore-forming toxins and bacterial infection); the signal for induction is a drop in intracellular potassium acting as a danger-associated molecular pattern, activating BPI expression in a p38-dependent manner.","method":"Caco-2 cell treatment with pore-forming toxins and bacteria; in vivo infection of mice with Salmonella Typhimurium, Shigella, and non-invasive mutants; p38 inhibitor studies","journal":"Frontiers in Microbiology","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis-like pathway placement with genetic (mutant bacteria) and pharmacological (p38 inhibitor) support; single lab","pmids":["28861073"],"is_preprint":false},{"year":2016,"finding":"A 27-amino acid peptide from the N-terminal portion of human BPI inhibits infectivity of multiple Influenza A strains (H1N1, H3N2, H5N1) and Vesicular Stomatitis Virus by disrupting the virus envelope; changing human BPI peptide sequence to the mouse homolog abolishes antiviral activity, demonstrating human-BPI-sequence-specific antiviral mechanism.","method":"Antiviral infectivity assays; electron microscopy of virus particles; human-to-mouse sequence substitution experiments","journal":"PloS One","confidence":"Medium","confidence_rationale":"Tier 2 — multiple virus strains tested; mutagenesis (sequence substitution) defines functional specificity; single lab","pmids":["27273104"],"is_preprint":false},{"year":1995,"finding":"rBPI inhibits LPS-induced TNF production from monocytes in a polysaccharide chain length–dependent manner: smooth LPS (S-form)-induced TNF is completely inhibited, Re 595 LPS only partially, and lipid A DP not at all, demonstrating that BPI's anti-endotoxin mechanism depends on the LPS polysaccharide structure.","method":"In vitro monocyte TNF induction assay with rBPI, rLBP, rCD14 and anti-CD14 antibodies; graded LPS polysaccharide chain lengths","journal":"Scandinavian Journal of Immunology","confidence":"Medium","confidence_rationale":"Tier 2 — systematic in vitro comparison across LPS variants; single lab","pmids":["7543211"],"is_preprint":false},{"year":2004,"finding":"Murine BPI (53% identity to human BPI) is expressed in testis, epididymis and bone marrow (not predominantly in neutrophils as in humans); murine BPI expressed in HEK293 cells retains antibacterial activity against E. coli comparable to human BPI; retinoic acid enhances BPI expression in promyelocytic cells.","method":"cDNA cloning; RT-PCR tissue expression; overexpression in HEK293 cells with bacterial killing assay; ATRA treatment","journal":"Journal of Leukocyte Biology","confidence":"Medium","confidence_rationale":"Tier 2 — functional reconstitution in heterologous cells; single lab","pmids":["15590754"],"is_preprint":false},{"year":2019,"finding":"Immune complexes of BPI and BPI-ANCA (but not BPI-ANCA alone) induce TNFα-dependent NET formation with histone hypercitrullination in neutrophils; TNFα upregulates BPI expression in neutrophils and causes BPI translocation to the cell surface, creating the substrate for immune complex formation.","method":"In vitro NET formation assay; immunofluorescent imaging of citrullinated histones; flow cytometry of BPI surface expression","journal":"Frontiers in Immunology","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic cell biology with defined molecular components; single case-based study","pmids":["31249574"],"is_preprint":false}],"current_model":"BPI is a cationic 55 kDa protein stored in azurophil granules of neutrophils (and also expressed by mucosal epithelia) that adopts a boomerang-shaped two-domain fold with apolar lipid-binding pockets; its highly basic N-terminal domain binds LPS with high affinity (nM) via electrostatic interactions with LPS phosphate groups, inserts into the negatively charged outer membrane to cause rigidification, membrane rupture, and inner membrane damage leading to bacterial killing, while simultaneously forming stable BPI–LPS complexes that block all LPS-induced host-cell signaling; the C-terminal domain mediates granule storage, opsonization, and delivery of bacterial antigens to phagocytes; BPI expression is transcriptionally regulated during granulocyte maturation and by lipoxins in epithelia through C/EBPβ/ε and p38-dependent pathways; BPI also inhibits angiogenesis by selectively inducing endothelial cell apoptosis and suppresses Treg differentiation when present in T-cell-derived exosomes."},"narrative":{"teleology":[{"year":1993,"claim":"Establishing that the N-terminal ~25 kDa fragment is sufficient for both bactericidal and LPS-neutralizing activity, with nanomolar LPS-binding affinity, defined the minimal functional unit and showed that a single protein domain could account for BPI's dual antimicrobial and anti-endotoxin functions.","evidence":"In vitro bactericidal assays, LPS-binding assays with proteolytic/recombinant N-terminal fragments, and ex vivo whole blood cytokine assays","pmids":["8330906"],"confidence":"High","gaps":["Structural basis for N-terminal LPS recognition not yet resolved","Mechanism of bacterial killing beyond initial binding unknown","Role of C-terminal domain undefined"]},{"year":1995,"claim":"Demonstrating that BPI's anti-endotoxin potency depends on LPS polysaccharide chain length (complete inhibition of smooth LPS vs. partial for rough LPS) revealed that the LPS–BPI interaction is not solely lipid A-mediated and involves polysaccharide determinants.","evidence":"In vitro monocyte TNF induction assay with graded LPS variants and rBPI","pmids":["7543211"],"confidence":"Medium","gaps":["Molecular contacts between BPI and LPS polysaccharide chains unresolved","In vivo relevance of chain-length dependence not tested"]},{"year":1997,"claim":"The crystal structure of BPI revealed a boomerang-shaped two-domain fold with apolar lipid-binding pockets on the concave surface, providing the first atomic framework for understanding LPS binding and membrane insertion, while biophysical studies showed that BPI inserts into negatively charged membranes via electrostatic displacement of divalent cations, rigidifies LPS acyl chains, and causes membrane rupture.","evidence":"X-ray crystallography at 2.4 Å (subsequently 1.7 Å); monolayer insertion experiments; IR spectroscopy; laser Doppler velocimetry; planar bilayer electrophysiology","pmids":["9188532","9254629","9254630","10843855"],"confidence":"High","gaps":["No co-crystal of BPI bound to LPS","Inner membrane damage mechanism not structurally explained","Lipid-binding pocket occupancy in vivo unknown"]},{"year":1997,"claim":"Showing that BPI enhances LPS aggregation (opposite to LBP's dispersal) and inhibits LBP–LPS binding at substoichiometric ratios clarified how BPI competes with LBP to intercept LPS signaling rather than simply scavenging free LPS.","evidence":"Sedimentation, light scattering, and fluorescence analyses of LPS–protein complexes","pmids":["9228038"],"confidence":"High","gaps":["Structure of the BPI–LPS aggregate complex unresolved","Stoichiometry and kinetics in physiological fluids not determined"]},{"year":1998,"claim":"Structure-based identification of a conserved cluster of basic residues (Lys42, 48, 92, 95, 99) at the N-terminal tip, together with subcellular localization of BPI to azurophil granules with functional validation via blocking antibodies, established that BPI is the principal neutrophil bactericidal factor operating through electrostatic contacts with LPS phosphate groups.","evidence":"Conserved residue mapping onto crystal structure; granule fractionation; BPI-blocking antibody functional assays; bacterial membrane damage assays","pmids":["9568897","9665269"],"confidence":"High","gaps":["Mutational validation of individual lysine contributions to bactericidal activity not performed","Relative contributions of BPI vs. other granule proteins in vivo unquantified"]},{"year":2000,"claim":"Demonstrating that the C-terminal domain is required for granule storage and protects against proteasomal degradation during intracellular sorting defined a non-redundant function for the C-terminal domain distinct from the N-terminal bactericidal role.","evidence":"cDNA transfection of deletion mutants and chimeras into myeloid cell lines; subcellular fractionation and protein stability assays","pmids":["11073106"],"confidence":"Medium","gaps":["Sorting receptor or signal recognized by C-terminal domain not identified","Opsonization mechanism of C-terminal domain not structurally defined"]},{"year":2000,"claim":"Immunoelectron microscopy showed BPI is membrane-associated within azurophil granules and relocates to phagosomes upon activation, with eosinophils also delivering BPI to phagosomes, establishing granule-to-phagosome delivery as the physiological mechanism for intracellular bacterial killing.","evidence":"Cryotechnique immunoelectron microscopy; selective granule-release experiments; phagocytosis assays in neutrophils and eosinophils","pmids":["10752689","9616176"],"confidence":"Medium","gaps":["Mode of BPI membrane association within granules unknown","Relative bactericidal contribution of phagosomal BPI vs. other granule contents not quantified"]},{"year":2000,"claim":"The finding that BPI selectively induces apoptosis in endothelial cells and inhibits angiogenesis in vitro and in vivo expanded BPI's functional repertoire beyond antimicrobial defense to vascular biology.","evidence":"Flow cytometry for apoptosis; collagen gel tube formation assay; in vivo chick chorioallantoic membrane angiogenesis assay","pmids":["10891448"],"confidence":"Medium","gaps":["Receptor or mechanism of EC-selective apoptosis induction unknown","Physiological context for anti-angiogenic function not established"]},{"year":2002,"claim":"Identification of BPI expression on mucosal epithelial cell surfaces, induced by aspirin-triggered lipoxins and functional in blocking LPS signaling and killing bacteria, established BPI as an epithelial antimicrobial effector independent of neutrophils.","evidence":"Microarray and RT-PCR; immunostaining for surface localization; functional neutralization with BPI antiserum; tissue immunohistochemistry","pmids":["11891303"],"confidence":"High","gaps":["Mechanism of BPI surface tethering on epithelia not defined","Epithelial BPI contribution relative to other antimicrobial peptides unknown"]},{"year":2006,"claim":"ChIP and EMSA demonstrated direct binding of C/EBPβ and C/EBPε to the BPI promoter during retinoic acid-induced granulocyte differentiation, establishing the transcriptional regulation mechanism for myeloid BPI expression.","evidence":"ATRA treatment of NB4 cells; cycloheximide block; EMSA; chromatin immunoprecipitation","pmids":["16684888"],"confidence":"High","gaps":["Cis-regulatory elements sufficient for granulocyte-specific expression not fully mapped","Whether same factors regulate epithelial BPI expression unknown"]},{"year":2016,"claim":"A 27-amino acid N-terminal BPI peptide disrupted enveloped virus particles with human-sequence specificity (lost in mouse homolog), extending BPI's antimicrobial reach to antiviral defense against Influenza A and VSV.","evidence":"Antiviral infectivity assays across multiple influenza strains; electron microscopy of virus particles; human-to-mouse sequence substitution","pmids":["27273104"],"confidence":"Medium","gaps":["In vivo antiviral role not demonstrated","Molecular basis of species-specific antiviral activity unresolved"]},{"year":2017,"claim":"Intracellular potassium efflux caused by pore-forming toxins or bacterial infection was identified as the danger signal inducing epithelial BPI expression through a p38-dependent pathway, defining a damage-sensing circuit upstream of BPI.","evidence":"Caco-2 cells treated with pore-forming toxins; in vivo mouse infection with Salmonella and Shigella; p38 inhibitor studies","pmids":["28861073"],"confidence":"Medium","gaps":["Transcription factor downstream of p38 that activates BPI in epithelia not identified","Whether potassium sensing feeds through inflammasome components not tested"]},{"year":2021,"claim":"BPI overexpression in T cells suppressed Treg differentiation and BPI-containing exosomes stimulated macrophage IL-1β and systemic inflammation, revealing an unexpected immunoregulatory function for BPI in adaptive immunity.","evidence":"T-cell-specific BPI transgenic and KO mice; adoptive exosome transfer; scRNA-seq; in vitro Treg differentiation assays","pmids":["34815797"],"confidence":"Medium","gaps":["Molecular mechanism by which BPI inhibits Treg differentiation not defined beyond ZFP36L2/Helios correlation","Physiological relevance of T-cell BPI expression in humans unknown","Single lab observation"]},{"year":null,"claim":"Key unresolved questions include the atomic structure of the BPI–LPS complex, the receptor or mechanism for BPI's selective endothelial cell apoptosis, the identity of the epithelial BPI surface anchor, and whether BPI's immunoregulatory functions in T cells operate through the same lipid-binding mechanism as its antimicrobial activity.","evidence":"","pmids":[],"confidence":"High","gaps":["No BPI–LPS co-crystal structure","Endothelial receptor for BPI-induced apoptosis unknown","Mechanism of BPI surface retention on epithelia undefined","Link between lipid-binding pockets and Treg regulation not tested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0,2,3,5,6]},{"term_id":"GO:0090729","term_label":"toxin activity","supporting_discovery_ids":[3,4,7,16]}],"localization":[{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[4,8,9,10]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[11,19]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[3,5,14]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,4,11,17,19]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[12]}],"complexes":[],"partners":["LBP","CEBPB","CEBPE"],"other_free_text":[]},"mechanistic_narrative":"BPI is an innate immune effector protein stored in azurophil granules of neutrophils and expressed on mucosal epithelial surfaces that kills Gram-negative bacteria and neutralizes lipopolysaccharide (LPS). Its boomerang-shaped structure contains two domains with apolar lipid-binding pockets; the highly basic N-terminal domain binds LPS with nanomolar affinity through electrostatic interactions with LPS phosphate groups, inserts into the bacterial outer membrane to cause rigidification, membrane rupture, and inner membrane damage leading to bacterial killing, while simultaneously forming stable BPI–LPS complexes that block all downstream LPS-induced host cell signaling [PMID:9188532, PMID:9254629, PMID:9254630, PMID:8330906]. The C-terminal domain is required for intracellular granule storage, protein stability during sorting, and opsonization functions [PMID:11073106]. BPI transcription during granulocyte maturation is driven by C/EBPβ and C/EBPε binding to its proximal promoter, and in intestinal epithelial cells BPI expression is induced by membrane damage-triggered potassium efflux through a p38-dependent pathway [PMID:16684888, PMID:28861073]. Beyond antimicrobial defense, BPI selectively induces apoptosis in vascular endothelial cells to inhibit angiogenesis and negatively regulates regulatory T cell differentiation when present in T-cell-derived exosomes [PMID:10891448, PMID:34815797]."},"prefetch_data":{"uniprot":{"accession":"P17213","full_name":"Bactericidal permeability-increasing protein","aliases":["CAP 57"],"length_aa":487,"mass_kda":53.9,"function":"The cytotoxic action of BPI is limited to many species of Gram-negative bacteria; this specificity may be explained by a strong affinity of the very basic N-terminal half for the negatively charged lipopolysaccharides that are unique to the Gram-negative bacterial outer envelope. Has antibacterial activity against the Gram-negative bacterium P.aeruginosa, this activity is inhibited by LPS from P.aeruginosa","subcellular_location":"Secreted; Cytoplasmic granule membrane","url":"https://www.uniprot.org/uniprotkb/P17213/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/BPI","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CD2BP2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/BPI","total_profiled":1310},"omim":[{"mim_id":"621168","title":"BPI FOLD-CONTAINING PROTEIN, FAMILY B, MEMBER 1; BPIFB1","url":"https://www.omim.org/entry/621168"},{"mim_id":"621167","title":"BPI FOLD-CONTAINING PROTEIN, FAMILY A, MEMBER 3; BPIFA3","url":"https://www.omim.org/entry/621167"},{"mim_id":"621166","title":"BPI FOLD-CONTAINING PROTEIN, FAMILY A, MEMBER 2; BPIFA2","url":"https://www.omim.org/entry/621166"},{"mim_id":"617074","title":"SMITH-MAGENIS SYNDROME CHROMOSOME REGION, CANDIDATE GENE 8; SMCR8","url":"https://www.omim.org/entry/617074"},{"mim_id":"615718","title":"BPI FOLD-CONTAINING PROTEIN, FAMILY B, MEMBER 4; BPIFB4","url":"https://www.omim.org/entry/615718"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"bone marrow","ntpm":1420.3}],"url":"https://www.proteinatlas.org/search/BPI"},"hgnc":{"alias_symbol":["BPIFD1"],"prev_symbol":[]},"alphafold":{"accession":"P17213","domains":[{"cath_id":"3.15.10.10","chopping":"44-223","consensus_level":"medium","plddt":95.4881,"start":44,"end":223},{"cath_id":"3.15.20.10","chopping":"228-487","consensus_level":"medium","plddt":96.5094,"start":228,"end":487}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P17213","model_url":"https://alphafold.ebi.ac.uk/files/AF-P17213-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P17213-F1-predicted_aligned_error_v6.png","plddt_mean":92.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=BPI","jax_strain_url":"https://www.jax.org/strain/search?query=BPI"},"sequence":{"accession":"P17213","fasta_url":"https://rest.uniprot.org/uniprotkb/P17213.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P17213/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P17213"}},"corpus_meta":[{"pmid":"9188532","id":"PMC_9188532","title":"Crystal structure of human BPI and two bound phospholipids at 2.4 angstrom resolution.","date":"1997","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/9188532","citation_count":306,"is_preprint":false},{"pmid":"11891303","id":"PMC_11891303","title":"Lipid mediator-induced expression of bactericidal/ permeability-increasing protein (BPI) in human mucosal epithelia.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/11891303","citation_count":228,"is_preprint":false},{"pmid":"12887306","id":"PMC_12887306","title":"Bactericidal/permeability-increasing protein (BPI) and lipopolysaccharide-binding protein (LBP): structure, function and regulation in host defence against Gram-negative bacteria.","date":"2003","source":"Biochemical Society transactions","url":"https://pubmed.ncbi.nlm.nih.gov/12887306","citation_count":162,"is_preprint":false},{"pmid":"7813109","id":"PMC_7813109","title":"Bactericidal/permeability-increasing protein (BPI) is an important antigen for anti-neutrophil cytoplasmic autoantibodies (ANCA) in vasculitis.","date":"1995","source":"Clinical and experimental immunology","url":"https://pubmed.ncbi.nlm.nih.gov/7813109","citation_count":152,"is_preprint":false},{"pmid":"9665269","id":"PMC_9665269","title":"The bactericidal/permeability-increasing protein (BPI) in antibacterial host defense.","date":"1998","source":"Journal of leukocyte biology","url":"https://pubmed.ncbi.nlm.nih.gov/9665269","citation_count":126,"is_preprint":false},{"pmid":"8330906","id":"PMC_8330906","title":"The bactericidal/permeability-increasing protein (BPI), a potent element in host-defense against gram-negative bacteria and lipopolysaccharide.","date":"1993","source":"Immunobiology","url":"https://pubmed.ncbi.nlm.nih.gov/8330906","citation_count":124,"is_preprint":false},{"pmid":"22112293","id":"PMC_22112293","title":"Icotinib (BPI-2009H), a novel EGFR tyrosine kinase inhibitor, displays potent efficacy in preclinical studies.","date":"2011","source":"Lung cancer (Amsterdam, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/22112293","citation_count":120,"is_preprint":false},{"pmid":"9568897","id":"PMC_9568897","title":"The BPI/LBP family of proteins: a structural analysis of conserved regions.","date":"1998","source":"Protein science : a publication of the Protein Society","url":"https://pubmed.ncbi.nlm.nih.gov/9568897","citation_count":118,"is_preprint":false},{"pmid":"15106612","id":"PMC_15106612","title":"Meet the relatives: a family of BPI- and LBP-related proteins.","date":"2004","source":"Trends in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/15106612","citation_count":108,"is_preprint":false},{"pmid":"8603534","id":"PMC_8603534","title":"Anti-neutrophil cytoplasmic antibodies (ANCA) directed against bactericidal/permeability increasing protein (BPI): a new seromarker for inflammatory bowel disease and associated disorders.","date":"1996","source":"Clinical and experimental immunology","url":"https://pubmed.ncbi.nlm.nih.gov/8603534","citation_count":108,"is_preprint":false},{"pmid":"17965238","id":"PMC_17965238","title":"Evidence of a bactericidal permeability increasing protein in an invertebrate, the Crassostrea gigas Cg-BPI.","date":"2007","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/17965238","citation_count":105,"is_preprint":false},{"pmid":"9228038","id":"PMC_9228038","title":"Lipopolysaccharide (LPS)-binding proteins BPI and LBP form different types of complexes with LPS.","date":"1997","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9228038","citation_count":95,"is_preprint":false},{"pmid":"17678885","id":"PMC_17678885","title":"The bactericidal/permeability-increasing protein (BPI) in infection and inflammatory disease.","date":"2007","source":"Clinica chimica acta; international journal of clinical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17678885","citation_count":91,"is_preprint":false},{"pmid":"21144613","id":"PMC_21144613","title":"Phase I study of icotinib hydrochloride (BPI-2009H), an oral EGFR tyrosine kinase inhibitor, in patients with advanced NSCLC and other solid tumors.","date":"2010","source":"Lung cancer (Amsterdam, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/21144613","citation_count":87,"is_preprint":false},{"pmid":"18838299","id":"PMC_18838299","title":"Bactericidal/permeability-increasing protein (BPI) and BPI homologs at mucosal sites.","date":"2008","source":"Trends in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/18838299","citation_count":66,"is_preprint":false},{"pmid":"10891448","id":"PMC_10891448","title":"Bactericidal/permeability-increasing protein (BPI) inhibits angiogenesis via induction of apoptosis in vascular endothelial cells.","date":"2000","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/10891448","citation_count":65,"is_preprint":false},{"pmid":"15896843","id":"PMC_15896843","title":"Characterization and expression analysis of bactericidal permeability-increasing protein (BPI) antimicrobial peptide gene from channel catfish Ictalurus punctatus.","date":"2005","source":"Developmental and comparative immunology","url":"https://pubmed.ncbi.nlm.nih.gov/15896843","citation_count":62,"is_preprint":false},{"pmid":"21787344","id":"PMC_21787344","title":"LBP/BPI proteins and their relatives: conservation over evolution and roles in mutualism.","date":"2011","source":"Biochemical Society transactions","url":"https://pubmed.ncbi.nlm.nih.gov/21787344","citation_count":61,"is_preprint":false},{"pmid":"21787333","id":"PMC_21787333","title":"Systematic nomenclature for the PLUNC/PSP/BSP30/SMGB proteins as a subfamily of the BPI fold-containing superfamily.","date":"2011","source":"Biochemical Society transactions","url":"https://pubmed.ncbi.nlm.nih.gov/21787333","citation_count":56,"is_preprint":false},{"pmid":"21787341","id":"PMC_21787341","title":"Distribution of human PLUNC/BPI fold-containing (BPIF) proteins.","date":"2011","source":"Biochemical Society transactions","url":"https://pubmed.ncbi.nlm.nih.gov/21787341","citation_count":54,"is_preprint":false},{"pmid":"10469063","id":"PMC_10469063","title":"Anti-neutrophil cytoplasmic antibodies (ANCA) against bactericidal/permeability-increasing protein (BPI) and cystic fibrosis lung disease.","date":"1999","source":"Clinical and experimental immunology","url":"https://pubmed.ncbi.nlm.nih.gov/10469063","citation_count":54,"is_preprint":false},{"pmid":"9240454","id":"PMC_9240454","title":"The genomic organization of the genes for human lipopolysaccharide binding protein (LBP) and bactericidal permeability increasing protein (BPI) is highly conserved.","date":"1997","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/9240454","citation_count":54,"is_preprint":false},{"pmid":"9616176","id":"PMC_9616176","title":"The bactericidal/permeability-increasing protein (BPI) is present in specific granules of human eosinophils.","date":"1998","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/9616176","citation_count":53,"is_preprint":false},{"pmid":"9254629","id":"PMC_9254629","title":"Mechanisms of action of the bactericidal/permeability-increasing protein BPI on endotoxin and phospholipid monolayers and aggregates.","date":"1997","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9254629","citation_count":50,"is_preprint":false},{"pmid":"14698217","id":"PMC_14698217","title":"Cloning and analyses of a BPI/LBP cDNA of the Atlantic cod (Gadus morhua L.).","date":"2004","source":"Developmental and comparative immunology","url":"https://pubmed.ncbi.nlm.nih.gov/14698217","citation_count":47,"is_preprint":false},{"pmid":"9254630","id":"PMC_9254630","title":"Mechanisms of action of bactericidal/permeability-increasing protein BPI on reconstituted outer membranes of gram-negative bacteria.","date":"1997","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9254630","citation_count":45,"is_preprint":false},{"pmid":"17317612","id":"PMC_17317612","title":"From infection to autoimmunity: a new model for induction of ANCA against the bactericidal/permeability increasing protein (BPI).","date":"2006","source":"Autoimmunity reviews","url":"https://pubmed.ncbi.nlm.nih.gov/17317612","citation_count":45,"is_preprint":false},{"pmid":"24367257","id":"PMC_24367257","title":"Parental transfer of the antimicrobial protein LBP/BPI protects Biomphalaria glabrata eggs against oomycete infections.","date":"2013","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/24367257","citation_count":44,"is_preprint":false},{"pmid":"10843855","id":"PMC_10843855","title":"The 1.7 A crystal structure of BPI: a study of how two dissimilar amino acid sequences can adopt the same fold.","date":"2000","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/10843855","citation_count":43,"is_preprint":false},{"pmid":"8432532","id":"PMC_8432532","title":"The genes for the lipopolysaccharide binding protein (LBP) and the bactericidal permeability increasing protein (BPI) are encoded in the same region of human chromosome 20.","date":"1993","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/8432532","citation_count":43,"is_preprint":false},{"pmid":"12887308","id":"PMC_12887308","title":"Expression of BPI (bactericidal/permeability-increasing protein) in human mucosal epithelia.","date":"2003","source":"Biochemical Society transactions","url":"https://pubmed.ncbi.nlm.nih.gov/12887308","citation_count":42,"is_preprint":false},{"pmid":"7613727","id":"PMC_7613727","title":"Prospects for use of recombinant BPI in the treatment of gram-negative bacterial infections.","date":"1995","source":"Infectious agents and disease","url":"https://pubmed.ncbi.nlm.nih.gov/7613727","citation_count":41,"is_preprint":false},{"pmid":"12887307","id":"PMC_12887307","title":"Structure of human BPI (bactericidal/permeability-increasing protein) and implications for related proteins.","date":"2003","source":"Biochemical Society transactions","url":"https://pubmed.ncbi.nlm.nih.gov/12887307","citation_count":40,"is_preprint":false},{"pmid":"12887309","id":"PMC_12887309","title":"Four BPI (bactericidal/permeability-increasing protein)-like genes expressed in the mouse nasal, oral, airway and digestive epithelia.","date":"2003","source":"Biochemical Society transactions","url":"https://pubmed.ncbi.nlm.nih.gov/12887309","citation_count":40,"is_preprint":false},{"pmid":"34815797","id":"PMC_34815797","title":"BPI overexpression suppresses Treg differentiation and induces exosome-mediated inflammation in systemic lupus erythematosus.","date":"2021","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/34815797","citation_count":38,"is_preprint":false},{"pmid":"17166780","id":"PMC_17166780","title":"Autoantibody response to BPI predict disease severity and outcome in cystic fibrosis.","date":"2006","source":"Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society","url":"https://pubmed.ncbi.nlm.nih.gov/17166780","citation_count":38,"is_preprint":false},{"pmid":"21300156","id":"PMC_21300156","title":"The second bactericidal permeability increasing protein (BPI) and its revelation of the gene duplication in the Pacific oyster, Crassostrea gigas.","date":"2011","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/21300156","citation_count":37,"is_preprint":false},{"pmid":"30613269","id":"PMC_30613269","title":"BPI-9016M, a c-Met inhibitor, suppresses tumor cell growth, migration and invasion of lung adenocarcinoma via miR203-DKK1.","date":"2018","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/30613269","citation_count":33,"is_preprint":false},{"pmid":"21787330","id":"PMC_21787330","title":"Distant cousins: genomic and sequence diversity within the BPI fold-containing (BPIF)/PLUNC protein family.","date":"2011","source":"Biochemical Society transactions","url":"https://pubmed.ncbi.nlm.nih.gov/21787330","citation_count":33,"is_preprint":false},{"pmid":"12943799","id":"PMC_12943799","title":"Molecular cloning of a novel bactericidal permeability-increasing protein/lipopolysaccharide-binding protein (BPI/LBP) from common carp Cyprinus carpio L. and its expression.","date":"2003","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/12943799","citation_count":33,"is_preprint":false},{"pmid":"15590754","id":"PMC_15590754","title":"A murine antibacterial ortholog to human bactericidal/permeability-increasing protein (BPI) is expressed in testis, epididymis, and bone marrow.","date":"2004","source":"Journal of leukocyte biology","url":"https://pubmed.ncbi.nlm.nih.gov/15590754","citation_count":32,"is_preprint":false},{"pmid":"21463973","id":"PMC_21463973","title":"Pseudomonas aeruginosa in cystic fibrosis: pyocyanin negative strains are associated with BPI-ANCA and progressive lung disease.","date":"2011","source":"Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society","url":"https://pubmed.ncbi.nlm.nih.gov/21463973","citation_count":31,"is_preprint":false},{"pmid":"7507806","id":"PMC_7507806","title":"Plasma levels of bactericidal/permeability-increasing protein (BPI) and lipopolysaccharide-binding protein (LBP) during hemodialysis.","date":"1993","source":"Clinical nephrology","url":"https://pubmed.ncbi.nlm.nih.gov/7507806","citation_count":31,"is_preprint":false},{"pmid":"11310835","id":"PMC_11310835","title":"The endotoxin-binding bactericidal/permeability-increasing protein (BPI): a target antigen of autoantibodies.","date":"2001","source":"Journal of leukocyte biology","url":"https://pubmed.ncbi.nlm.nih.gov/11310835","citation_count":30,"is_preprint":false},{"pmid":"21433035","id":"PMC_21433035","title":"Antigen-specific blocking of CD4-specific immunological synapse formation using BPI and current therapies for autoimmune diseases.","date":"2011","source":"Medicinal research reviews","url":"https://pubmed.ncbi.nlm.nih.gov/21433035","citation_count":30,"is_preprint":false},{"pmid":"8024362","id":"PMC_8024362","title":"Anti-endotoxin therapy in primate bacteremia with HA-1A and BPI.","date":"1994","source":"Annals of surgery","url":"https://pubmed.ncbi.nlm.nih.gov/8024362","citation_count":30,"is_preprint":false},{"pmid":"25956196","id":"PMC_25956196","title":"Cloning and characterization of two lipopolysaccharide-binding protein/bactericidal permeability-increasing protein (LBP/BPI) genes from the sea cucumber Apostichopus japonicus with diversified function in modulating ROS production.","date":"2015","source":"Developmental and comparative immunology","url":"https://pubmed.ncbi.nlm.nih.gov/25956196","citation_count":30,"is_preprint":false},{"pmid":"21787332","id":"PMC_21787332","title":"Ovocalyxin-36 and other LBP/BPI/PLUNC-like proteins as molecular actors of the mechanisms of the avian egg natural defences.","date":"2011","source":"Biochemical Society transactions","url":"https://pubmed.ncbi.nlm.nih.gov/21787332","citation_count":28,"is_preprint":false},{"pmid":"20959152","id":"PMC_20959152","title":"Identification and characterisation of the BPI/LBP/PLUNC-like gene repertoire in chickens reveals the absence of a LBP gene.","date":"2010","source":"Developmental and comparative immunology","url":"https://pubmed.ncbi.nlm.nih.gov/20959152","citation_count":28,"is_preprint":false},{"pmid":"11089749","id":"PMC_11089749","title":"Bactericidal/permeability-increasing protein (BPI) in sepsis correlates with the severity of sepsis and the outcome.","date":"2000","source":"Intensive care medicine","url":"https://pubmed.ncbi.nlm.nih.gov/11089749","citation_count":27,"is_preprint":false},{"pmid":"12837268","id":"PMC_12837268","title":"Expansion of the BPI family by duplication on human chromosome 20: characterization of the RY gene cluster in 20q11.21 encoding olfactory transporters/antimicrobial-like peptides.","date":"2003","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/12837268","citation_count":27,"is_preprint":false},{"pmid":"14740434","id":"PMC_14740434","title":"Pseudomonas-induced lung damage in cystic fibrosis correlates to bactericidal-permeability increasing protein (BPI)-autoantibodies.","date":"2003","source":"Clinical and experimental rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/14740434","citation_count":27,"is_preprint":false},{"pmid":"36049654","id":"PMC_36049654","title":"Efficacy and Safety of Rezivertinib (BPI-7711) in Patients With Locally Advanced or Metastatic/Recurrent EGFR T790M-Mutated NSCLC: A Phase 2b Study.","date":"2022","source":"Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/36049654","citation_count":26,"is_preprint":false},{"pmid":"8697620","id":"PMC_8697620","title":"Frequency of anti-bactericidal/permeability-increasing protein (BPI) and anti-azurocidin in patients with renal disease.","date":"1996","source":"Clinical and experimental immunology","url":"https://pubmed.ncbi.nlm.nih.gov/8697620","citation_count":26,"is_preprint":false},{"pmid":"10893006","id":"PMC_10893006","title":"Anti-neutrophil cytoplasmic antibodies directed against the bactericidal/permeability-increasing protein (BPI) in pediatric cystic fibrosis patients do not recognize N-terminal regions important for the anti-microbial and lipopolysaccharide-binding activity of BPI.","date":"2000","source":"Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/10893006","citation_count":26,"is_preprint":false},{"pmid":"34142075","id":"PMC_34142075","title":"Killing three birds with one BPI: Bactericidal, opsonic, and anti-inflammatory functions.","date":"2021","source":"Journal of translational autoimmunity","url":"https://pubmed.ncbi.nlm.nih.gov/34142075","citation_count":25,"is_preprint":false},{"pmid":"25329706","id":"PMC_25329706","title":"Antimicrobial activity of peptides derived from olive flounder lipopolysaccharide binding protein/bactericidal permeability-increasing protein (LBP/BPI).","date":"2014","source":"Marine drugs","url":"https://pubmed.ncbi.nlm.nih.gov/25329706","citation_count":25,"is_preprint":false},{"pmid":"7543211","id":"PMC_7543211","title":"Influence of CD14, LBP and BPI in the monocyte response to LPS of different polysaccharide chain length.","date":"1995","source":"Scandinavian journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/7543211","citation_count":24,"is_preprint":false},{"pmid":"10752689","id":"PMC_10752689","title":"The bactericidal/permeability-increasing protein (BPI) is membrane-associated in azurophil granules of human neutrophils, and relocation occurs upon cellular activation.","date":"2000","source":"APMIS : acta pathologica, microbiologica, et immunologica Scandinavica","url":"https://pubmed.ncbi.nlm.nih.gov/10752689","citation_count":23,"is_preprint":false},{"pmid":"27273538","id":"PMC_27273538","title":"Arabidopsis LBP/BPI related-1 and -2 bind to LPS directly and regulate PR1 expression.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27273538","citation_count":23,"is_preprint":false},{"pmid":"12869032","id":"PMC_12869032","title":"BPI-ANCA in transporter associated with antigen presentation (TAP) deficiency: possible role in susceptibility to Gram-negative bacterial infections.","date":"2003","source":"Clinical and experimental immunology","url":"https://pubmed.ncbi.nlm.nih.gov/12869032","citation_count":23,"is_preprint":false},{"pmid":"28775000","id":"PMC_28775000","title":"BPI Fold-Containing Family A Member 2/Parotid Secretory Protein Is an Early Biomarker of AKI.","date":"2017","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/28775000","citation_count":22,"is_preprint":false},{"pmid":"14730661","id":"PMC_14730661","title":"BPI-ANCA of pediatric cystic fibrosis patients can impair BPI-mediated killing of E. coli DH5alpha in vitro.","date":"2004","source":"Pediatric pulmonology","url":"https://pubmed.ncbi.nlm.nih.gov/14730661","citation_count":22,"is_preprint":false},{"pmid":"26608112","id":"PMC_26608112","title":"The LBP/BPI multigenic family in invertebrates: Evolutionary history and evidences of specialization in mollusks.","date":"2015","source":"Developmental and comparative immunology","url":"https://pubmed.ncbi.nlm.nih.gov/26608112","citation_count":22,"is_preprint":false},{"pmid":"23742867","id":"PMC_23742867","title":"Identification and expression analysis on bactericidal permeability-increasing protein (BPI)/lipopolysaccharide-binding protein (LBP) of ark shell, Scapharca broughtonii.","date":"2013","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/23742867","citation_count":22,"is_preprint":false},{"pmid":"17442589","id":"PMC_17442589","title":"mRNA expression patterns of the BPI/LBP molecule in the Atlantic cod (Gadus morhua L.).","date":"2006","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/17442589","citation_count":21,"is_preprint":false},{"pmid":"26297397","id":"PMC_26297397","title":"LBP/BPI homologue in Eisenia andrei earthworms.","date":"2015","source":"Developmental and comparative immunology","url":"https://pubmed.ncbi.nlm.nih.gov/26297397","citation_count":21,"is_preprint":false},{"pmid":"35181498","id":"PMC_35181498","title":"Safety, Efficacy, and Pharmacokinetics of Rezivertinib (BPI-7711) in Patients With Advanced NSCLC With EGFR T790M Mutation: A Phase 1 Dose-Escalation and Dose-Expansion Study.","date":"2022","source":"Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/35181498","citation_count":21,"is_preprint":false},{"pmid":"31948451","id":"PMC_31948451","title":"First-in-human phase I study of BPI-9016M, a dual MET/Axl inhibitor, in patients with non-small cell lung cancer.","date":"2020","source":"Journal of hematology & oncology","url":"https://pubmed.ncbi.nlm.nih.gov/31948451","citation_count":20,"is_preprint":false},{"pmid":"14745963","id":"PMC_14745963","title":"Identification of a novel left-right asymmetrically expressed gene in the mouse belonging to the BPI/PLUNC superfamily.","date":"2004","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/14745963","citation_count":19,"is_preprint":false},{"pmid":"23586056","id":"PMC_23586056","title":"Ubiquitin ligase Cbl-b is involved in icotinib (BPI-2009H)-induced apoptosis and G1 phase arrest of EGFR mutation-positive non-small-cell lung cancer.","date":"2013","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/23586056","citation_count":19,"is_preprint":false},{"pmid":"17362520","id":"PMC_17362520","title":"Expansion of the Bactericidal/Permeability Increasing-like (BPI-like) protein locus in cattle.","date":"2007","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/17362520","citation_count":18,"is_preprint":false},{"pmid":"15758620","id":"PMC_15758620","title":"A polymorphism of the bactericidal/permeability increasing protein (BPI) gene is associated with Crohn's disease.","date":"2005","source":"Journal of clinical gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/15758620","citation_count":18,"is_preprint":false},{"pmid":"23562783","id":"PMC_23562783","title":"Genetic variation in exon 10 of the BPI gene is associated with Escherichia coli F18 susceptibility in Sutai piglets.","date":"2013","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/23562783","citation_count":18,"is_preprint":false},{"pmid":"18055015","id":"PMC_18055015","title":"The bovine salivary proteins BSP30a and BSP30b are independently expressed BPI-like proteins with anti-Pseudomonas activity.","date":"2007","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/18055015","citation_count":18,"is_preprint":false},{"pmid":"22521422","id":"PMC_22521422","title":"Molecular identification and expression analysis of two distinct BPI/LBPs (bactericidal permeability-increasing protein/LPS-binding protein) from rock bream, Oplegnathus fasciatus.","date":"2012","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/22521422","citation_count":18,"is_preprint":false},{"pmid":"20541026","id":"PMC_20541026","title":"Genetic variations of interleukin-23R (1143A>G) and BPI (A645G), but not of NOD2, are associated with acute graft-versus-host disease after allogeneic transplantation.","date":"2010","source":"Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/20541026","citation_count":17,"is_preprint":false},{"pmid":"21272798","id":"PMC_21272798","title":"Association between bactericidal/permeability increasing protein (BPI) gene polymorphism (Lys216Glu) and inflammatory bowel disease.","date":"2010","source":"Journal of Crohn's & colitis","url":"https://pubmed.ncbi.nlm.nih.gov/21272798","citation_count":17,"is_preprint":false},{"pmid":"19698997","id":"PMC_19698997","title":"Molecular cloning and characterization of LPS-binding protein/bactericidal permeability-increasing protein (LBP/BPI) from olive flounder, Paralichthys olivaceus.","date":"2009","source":"Veterinary immunology and immunopathology","url":"https://pubmed.ncbi.nlm.nih.gov/19698997","citation_count":17,"is_preprint":false},{"pmid":"18952461","id":"PMC_18952461","title":"Characterization of the BPI-like gene from a subtracted cDNA library of large yellow croaker (Pseudosciaena crocea) and induced expression by formalin-inactivated Vibrio alginolyticus and Nocardia seriolae vaccine challenges.","date":"2008","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/18952461","citation_count":17,"is_preprint":false},{"pmid":"16096858","id":"PMC_16096858","title":"Autoantibodies against bactericidal/permeability-increasing protein (BPI-ANCA) in cystic fibrosis patients treated with azithromycin.","date":"2005","source":"Clinical and experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/16096858","citation_count":16,"is_preprint":false},{"pmid":"9294593","id":"PMC_9294593","title":"Use of native and recombinant bactericidal/permeability-increasing proteins (BPI) as antigens for detection of BPI-ANCA.","date":"1997","source":"Journal of immunological methods","url":"https://pubmed.ncbi.nlm.nih.gov/9294593","citation_count":15,"is_preprint":false},{"pmid":"11028843","id":"PMC_11028843","title":"BPI-ANCA is found in reactive arthritis caused by Yersinia and Salmonella infection and recognise exclusively the C-terminal part of the BPI molecule.","date":"2000","source":"Scandinavian journal of rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/11028843","citation_count":15,"is_preprint":false},{"pmid":"11810589","id":"PMC_11810589","title":"Analysis of intractable factors in chronic airway infections: role of the autoimmunity induced by BPI-ANCA.","date":"2001","source":"Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/11810589","citation_count":15,"is_preprint":false},{"pmid":"27273104","id":"PMC_27273104","title":"The Human Antimicrobial Protein Bactericidal/Permeability-Increasing Protein (BPI) Inhibits the Infectivity of Influenza A Virus.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/27273104","citation_count":14,"is_preprint":false},{"pmid":"28861073","id":"PMC_28861073","title":"Epithelial Cell Damage Activates Bactericidal/Permeability Increasing-Protein (BPI) Expression in Intestinal Epithelium.","date":"2017","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/28861073","citation_count":14,"is_preprint":false},{"pmid":"22946777","id":"PMC_22946777","title":"Extensive endoscopic image-guided sinus surgery decreases BPI-ANCA in patients with cystic fibrosis.","date":"2012","source":"Scandinavian journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/22946777","citation_count":14,"is_preprint":false},{"pmid":"21787338","id":"PMC_21787338","title":"The BPI-like/PLUNC family proteins in cattle.","date":"2011","source":"Biochemical Society transactions","url":"https://pubmed.ncbi.nlm.nih.gov/21787338","citation_count":14,"is_preprint":false},{"pmid":"14740457","id":"PMC_14740457","title":"ANCA against the bactericidal/permeability increasing protein (BPI-ANCA) can compromise the antibiotic function of BPI in a Wegener's granulomatosis patient.","date":"2003","source":"Clinical and experimental rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/14740457","citation_count":13,"is_preprint":false},{"pmid":"16684888","id":"PMC_16684888","title":"All-trans retinoic acid-induced expression of bactericidal/permeability-increasing protein (BPI) in human myeloid cells correlates to binding of C/EBPbeta and C/EBPepsilon to the BPI promoter.","date":"2006","source":"Journal of leukocyte biology","url":"https://pubmed.ncbi.nlm.nih.gov/16684888","citation_count":13,"is_preprint":false},{"pmid":"36617560","id":"PMC_36617560","title":"Results of the phase IIa study to evaluate the efficacy and safety of rezivertinib (BPI-7711) for the first-line treatment of locally advanced or metastatic/recurrent NSCLC patients with EGFR mutation from a phase I/IIa study.","date":"2023","source":"BMC medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36617560","citation_count":13,"is_preprint":false},{"pmid":"26273683","id":"PMC_26273683","title":"BPI-ANCA Provides Additional Clinical Information to Anti-Pseudomonas Serology: Results from a Cohort of 117 Swedish Cystic Fibrosis Patients.","date":"2015","source":"Journal of immunology research","url":"https://pubmed.ncbi.nlm.nih.gov/26273683","citation_count":13,"is_preprint":false},{"pmid":"38569980","id":"PMC_38569980","title":"BPI-GNN: Interpretable brain network-based psychiatric diagnosis and subtyping.","date":"2024","source":"NeuroImage","url":"https://pubmed.ncbi.nlm.nih.gov/38569980","citation_count":12,"is_preprint":false},{"pmid":"34000320","id":"PMC_34000320","title":"Molecular characterization and functional analysis of the bactericidal permeability-increasing protein/LPS-binding protein (BPI/LBP) from roughskin sculpin (Trachidermus fasciatus).","date":"2021","source":"Developmental and comparative immunology","url":"https://pubmed.ncbi.nlm.nih.gov/34000320","citation_count":12,"is_preprint":false},{"pmid":"31249574","id":"PMC_31249574","title":"The Pathogenicity of BPI-ANCA in a Patient With Systemic Vasculitis.","date":"2019","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31249574","citation_count":11,"is_preprint":false},{"pmid":"12014429","id":"PMC_12014429","title":"The antiangiogenic properties of bactericidal/permeability-increasing protein (BPI).","date":"2002","source":"Annals of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/12014429","citation_count":11,"is_preprint":false},{"pmid":"21787345","id":"PMC_21787345","title":"The bactericidal/permeability-increasing protein (BPI) in the innate defence of the lower airways.","date":"2011","source":"Biochemical Society transactions","url":"https://pubmed.ncbi.nlm.nih.gov/21787345","citation_count":11,"is_preprint":false},{"pmid":"17560054","id":"PMC_17560054","title":"A peptide derived from human bactericidal/permeability-increasing protein (BPI) exerts bactericidal activity against Gram-negative bacterial isolates obtained from clinical cases of bovine mastitis.","date":"2007","source":"Veterinary microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/17560054","citation_count":11,"is_preprint":false},{"pmid":"11073106","id":"PMC_11073106","title":"Structural requirements for intracellular processing and sorting of bactericidal/permeability-increasing protein (BPI): comparison with lipopolysaccharide-binding protein.","date":"2000","source":"Journal of leukocyte biology","url":"https://pubmed.ncbi.nlm.nih.gov/11073106","citation_count":11,"is_preprint":false},{"pmid":"15686586","id":"PMC_15686586","title":"Association study of Wegener granulomatosis and the functionally relevant A645G polymorphism in the bactericidal/permeability increasing protein (BPI) gene.","date":"2005","source":"International journal of immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/15686586","citation_count":11,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":47033,"output_tokens":4495,"usd":0.104262},"stage2":{"model":"claude-opus-4-6","input_tokens":8049,"output_tokens":3347,"usd":0.18588},"total_usd":0.290142,"stage1_batch_id":"msgbatch_01TqNM6p6FsoMBT2jzQTwKBr","stage2_batch_id":"msgbatch_01Ya473eco8sTHbvRymQaU8o","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"Crystal structure of human BPI at 2.4 Å resolution reveals a boomerang-shaped molecule with two similar domains, each containing an apolar lipid-binding pocket on the concave surface that binds phosphatidylcholine acyl chains, suggesting these pockets bind LPS acyl chains to mediate LPS neutralization.\",\n      \"method\": \"X-ray crystallography with bound phospholipid ligands\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure at 2.4 Å with bound ligands, foundational structural study\",\n      \"pmids\": [\"9188532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Extended crystal structure of human BPI resolved to 1.7 Å; structural comparison of the two domains (same fold, <13% sequence identity) using 3D-1D profiles identified residue pairs with conserved structural roles despite dissimilar sequences, clarifying the mechanism of fold conservation.\",\n      \"method\": \"X-ray crystallography at 1.7 Å; 3D-1D profile structural analysis\",\n      \"journal\": \"Journal of Molecular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — higher-resolution crystal structure with rigorous structural analysis\",\n      \"pmids\": [\"10843855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Structure/function analysis of conserved residues in BPI and LBP, using the BPI crystal structure, identified a cluster of conserved positively charged residues (Lys42, 48, 92, 95, 99) at the tip of the N-terminal domain with no structural role, predicted to make electrostatic contacts with negatively charged LPS groups and responsible for BPI's bactericidal activity.\",\n      \"method\": \"Structural analysis of conserved residues mapped onto crystal structure; comparison with known LPS-binding mutagenesis data\",\n      \"journal\": \"Protein Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structure-based analysis corroborated by known mutagenesis data from multiple sequences\",\n      \"pmids\": [\"9568897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"The antibacterial and LPS-neutralizing activities of BPI are fully expressed by the N-terminal ~25 kDa fragment; BPI binds LPS with high affinity (apparent Kd 2–5 nM) and this complex formation with cell-associated or cell-free LPS inhibits all LPS-induced host cell responses.\",\n      \"method\": \"In vitro bactericidal assays; LPS-binding assays with proteolytic/recombinant N-terminal BPI fragments; whole blood ex vivo cytokine assays\",\n      \"journal\": \"Immunobiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — reconstituted in vitro activity with defined fragments, replicated across multiple studies\",\n      \"pmids\": [\"8330906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"BPI is stored in azurophil (primary) granules of neutrophils; BPI-blocking antibodies abolish antibacterial activity of whole PMN lysates; binding of BPI to live bacteria via LPS causes immediate growth arrest, with killing coinciding with later inner membrane damage.\",\n      \"method\": \"Granule fractionation; BPI-blocking antibody functional assays; bacterial killing and membrane damage assays\",\n      \"journal\": \"Journal of Leukocyte Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods; replicated across labs\",\n      \"pmids\": [\"9665269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"LBP disperses LPS aggregates whereas BPI enhances sedimentation velocity and apparent size of LPS aggregates; BPI inhibits LPS–LBP binding even at very low (1:40–1:20) BPI:LPS molar ratios; the two proteins form physically distinct types of complexes with LPS.\",\n      \"method\": \"Sedimentation, light scattering, and fluorescence analyses of LPS–protein complexes\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple biophysical methods; clear mechanistic differentiation\",\n      \"pmids\": [\"9228038\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The recombinant N-terminal BPI fragment (rBPI21) incorporates into negatively charged LPS and phosphatidylglycerol monolayers/bilayers but not neutral phosphatidylcholine; it rigidifies acyl chains and immobilizes phosphate groups of LPS aggregates, reducing zeta-potential; high Mg2+ ions protect against this action, suggesting electrostatic displacement as the initial step.\",\n      \"method\": \"Monolayer experiments, infrared spectroscopy, resonance energy transfer spectroscopy, laser Doppler velocimetry\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple biophysical in vitro methods with mechanistic modeling\",\n      \"pmids\": [\"9254629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"rBPI21 causes membrane rupture and increases membrane current when added to the LPS leaflet of asymmetric LPS/phospholipid bilayer membranes; it shifts the transmembrane potential of outer membrane models; 40 mM MgCl2 significantly reduces this effect, supporting an electrostatic mechanism of outer membrane disruption.\",\n      \"method\": \"Electrical measurements on planar bilayer membranes reconstituted with deep-rough LPS\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstituted membrane assay with direct measurement of mechanism\",\n      \"pmids\": [\"9254630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"BPI is present in specific granules of human eosinophils (detected by immunoelectron microscopy) and is released into phagosomes upon phagocytosis, indicating granule-to-phagosome delivery as a mechanism for antibacterial action in eosinophils.\",\n      \"method\": \"Immunoelectron microscopy; Western blot; ELISA quantification\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct subcellular localization by immunoelectron microscopy with phagosome delivery demonstrated\",\n      \"pmids\": [\"9616176\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"BPI is membrane-associated within azurophil granules of neutrophils (co-localizing with MPO and CD63); upon cellular activation by ionophore or phagocytosis, BPI is relocated to phagosomes via granule–endosome fusion, following the same route as MPO and CD63.\",\n      \"method\": \"Cryotechnique immunoelectron microscopy; selective granule-release experiments with monensin; phagocytosis assays\",\n      \"journal\": \"APMIS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct subcellular localization with functional activation context, single lab\",\n      \"pmids\": [\"10752689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The C-terminal domain of BPI is required for granule storage and protects against degradation during intracellular sorting; deletion of the N-terminal half causes retention in the ER and proteasomal degradation; chimeras confirm that C-terminal BPI domain confers stability for storage in myeloid cells.\",\n      \"method\": \"cDNA transfection into rodent hematopoietic cell lines; deletion mutants and chimeras; subcellular fractionation and protein stability assays\",\n      \"journal\": \"Journal of Leukocyte Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain deletion and chimera analysis with defined sorting phenotype\",\n      \"pmids\": [\"11073106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"BPI is expressed on the cell surface of human mucosal epithelial cells and is transcriptionally induced by aspirin-triggered lipoxins (ATLa); surface-expressed epithelial BPI blocks LPS-mediated signaling and kills Salmonella typhimurium, functioning as an antimicrobial/endotoxin shield.\",\n      \"method\": \"Microarray + RT-PCR; cell surface localization by immunostaining; functional assays with BPI-neutralizing antiserum; in vivo tissue IHC\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (expression, localization, functional neutralization) in one study\",\n      \"pmids\": [\"11891303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"BPI inhibits angiogenesis by inducing apoptosis selectively in vascular endothelial cells; apoptosis is mediated by cell detachment and is EC-specific (not fibroblast or other cell types); BPI inhibits tube formation in collagen gel assays and vessel formation in the CAM assay at nanomolar concentrations.\",\n      \"method\": \"Flow cytometry (subdiploid cell quantification); nuclear fragmentation assay; in vitro collagen gel angiogenesis assay; in vivo CAM assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple in vitro and in vivo assays, single lab\",\n      \"pmids\": [\"10891448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"All-trans retinoic acid (ATRA) induces BPI expression in NB4 promyelocytic cells through de novo protein synthesis; induction correlates with direct binding of C/EBPβ and C/EBPε transcription factors to the proximal BPI promoter, as demonstrated by EMSA and chromatin immunoprecipitation.\",\n      \"method\": \"ATRA treatment of NB4 cells; cycloheximide sensitivity; EMSA; chromatin immunoprecipitation (ChIP)\",\n      \"journal\": \"Journal of Leukocyte Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — ChIP and EMSA directly demonstrate transcription factor binding to BPI promoter; multiple orthogonal methods\",\n      \"pmids\": [\"16684888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"BPI overexpression in T cells suppresses Treg differentiation; BPI-containing T-cell-derived exosomes stimulate IL-1β expression in recipient macrophages; adoptive transfer of BPI-containing exosomes induces systemic inflammation, autoantibody production, and multi-organ damage in mice; BPI knockout enhances Treg differentiation in vitro, identifying BPI as a negative regulator of Treg differentiation associated with ZFP36L2 upregulation and Helios downregulation.\",\n      \"method\": \"T-cell-specific BPI transgenic mice; adoptive exosome transfer; scRNA-seq; in vitro Treg differentiation with BPI KO and overexpression\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple in vivo and in vitro methods; single lab; mechanistic pathway partially defined\",\n      \"pmids\": [\"34815797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"BPI expression in intestinal epithelial cells is induced by cell membrane damage (via pore-forming toxins and bacterial infection); the signal for induction is a drop in intracellular potassium acting as a danger-associated molecular pattern, activating BPI expression in a p38-dependent manner.\",\n      \"method\": \"Caco-2 cell treatment with pore-forming toxins and bacteria; in vivo infection of mice with Salmonella Typhimurium, Shigella, and non-invasive mutants; p38 inhibitor studies\",\n      \"journal\": \"Frontiers in Microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis-like pathway placement with genetic (mutant bacteria) and pharmacological (p38 inhibitor) support; single lab\",\n      \"pmids\": [\"28861073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A 27-amino acid peptide from the N-terminal portion of human BPI inhibits infectivity of multiple Influenza A strains (H1N1, H3N2, H5N1) and Vesicular Stomatitis Virus by disrupting the virus envelope; changing human BPI peptide sequence to the mouse homolog abolishes antiviral activity, demonstrating human-BPI-sequence-specific antiviral mechanism.\",\n      \"method\": \"Antiviral infectivity assays; electron microscopy of virus particles; human-to-mouse sequence substitution experiments\",\n      \"journal\": \"PloS One\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple virus strains tested; mutagenesis (sequence substitution) defines functional specificity; single lab\",\n      \"pmids\": [\"27273104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"rBPI inhibits LPS-induced TNF production from monocytes in a polysaccharide chain length–dependent manner: smooth LPS (S-form)-induced TNF is completely inhibited, Re 595 LPS only partially, and lipid A DP not at all, demonstrating that BPI's anti-endotoxin mechanism depends on the LPS polysaccharide structure.\",\n      \"method\": \"In vitro monocyte TNF induction assay with rBPI, rLBP, rCD14 and anti-CD14 antibodies; graded LPS polysaccharide chain lengths\",\n      \"journal\": \"Scandinavian Journal of Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — systematic in vitro comparison across LPS variants; single lab\",\n      \"pmids\": [\"7543211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Murine BPI (53% identity to human BPI) is expressed in testis, epididymis and bone marrow (not predominantly in neutrophils as in humans); murine BPI expressed in HEK293 cells retains antibacterial activity against E. coli comparable to human BPI; retinoic acid enhances BPI expression in promyelocytic cells.\",\n      \"method\": \"cDNA cloning; RT-PCR tissue expression; overexpression in HEK293 cells with bacterial killing assay; ATRA treatment\",\n      \"journal\": \"Journal of Leukocyte Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional reconstitution in heterologous cells; single lab\",\n      \"pmids\": [\"15590754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Immune complexes of BPI and BPI-ANCA (but not BPI-ANCA alone) induce TNFα-dependent NET formation with histone hypercitrullination in neutrophils; TNFα upregulates BPI expression in neutrophils and causes BPI translocation to the cell surface, creating the substrate for immune complex formation.\",\n      \"method\": \"In vitro NET formation assay; immunofluorescent imaging of citrullinated histones; flow cytometry of BPI surface expression\",\n      \"journal\": \"Frontiers in Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic cell biology with defined molecular components; single case-based study\",\n      \"pmids\": [\"31249574\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"BPI is a cationic 55 kDa protein stored in azurophil granules of neutrophils (and also expressed by mucosal epithelia) that adopts a boomerang-shaped two-domain fold with apolar lipid-binding pockets; its highly basic N-terminal domain binds LPS with high affinity (nM) via electrostatic interactions with LPS phosphate groups, inserts into the negatively charged outer membrane to cause rigidification, membrane rupture, and inner membrane damage leading to bacterial killing, while simultaneously forming stable BPI–LPS complexes that block all LPS-induced host-cell signaling; the C-terminal domain mediates granule storage, opsonization, and delivery of bacterial antigens to phagocytes; BPI expression is transcriptionally regulated during granulocyte maturation and by lipoxins in epithelia through C/EBPβ/ε and p38-dependent pathways; BPI also inhibits angiogenesis by selectively inducing endothelial cell apoptosis and suppresses Treg differentiation when present in T-cell-derived exosomes.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"BPI is an innate immune effector protein stored in azurophil granules of neutrophils and expressed on mucosal epithelial surfaces that kills Gram-negative bacteria and neutralizes lipopolysaccharide (LPS). Its boomerang-shaped structure contains two domains with apolar lipid-binding pockets; the highly basic N-terminal domain binds LPS with nanomolar affinity through electrostatic interactions with LPS phosphate groups, inserts into the bacterial outer membrane to cause rigidification, membrane rupture, and inner membrane damage leading to bacterial killing, while simultaneously forming stable BPI–LPS complexes that block all downstream LPS-induced host cell signaling [PMID:9188532, PMID:9254629, PMID:9254630, PMID:8330906]. The C-terminal domain is required for intracellular granule storage, protein stability during sorting, and opsonization functions [PMID:11073106]. BPI transcription during granulocyte maturation is driven by C/EBPβ and C/EBPε binding to its proximal promoter, and in intestinal epithelial cells BPI expression is induced by membrane damage-triggered potassium efflux through a p38-dependent pathway [PMID:16684888, PMID:28861073]. Beyond antimicrobial defense, BPI selectively induces apoptosis in vascular endothelial cells to inhibit angiogenesis and negatively regulates regulatory T cell differentiation when present in T-cell-derived exosomes [PMID:10891448, PMID:34815797].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Establishing that the N-terminal ~25 kDa fragment is sufficient for both bactericidal and LPS-neutralizing activity, with nanomolar LPS-binding affinity, defined the minimal functional unit and showed that a single protein domain could account for BPI's dual antimicrobial and anti-endotoxin functions.\",\n      \"evidence\": \"In vitro bactericidal assays, LPS-binding assays with proteolytic/recombinant N-terminal fragments, and ex vivo whole blood cytokine assays\",\n      \"pmids\": [\"8330906\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for N-terminal LPS recognition not yet resolved\", \"Mechanism of bacterial killing beyond initial binding unknown\", \"Role of C-terminal domain undefined\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Demonstrating that BPI's anti-endotoxin potency depends on LPS polysaccharide chain length (complete inhibition of smooth LPS vs. partial for rough LPS) revealed that the LPS–BPI interaction is not solely lipid A-mediated and involves polysaccharide determinants.\",\n      \"evidence\": \"In vitro monocyte TNF induction assay with graded LPS variants and rBPI\",\n      \"pmids\": [\"7543211\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular contacts between BPI and LPS polysaccharide chains unresolved\", \"In vivo relevance of chain-length dependence not tested\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"The crystal structure of BPI revealed a boomerang-shaped two-domain fold with apolar lipid-binding pockets on the concave surface, providing the first atomic framework for understanding LPS binding and membrane insertion, while biophysical studies showed that BPI inserts into negatively charged membranes via electrostatic displacement of divalent cations, rigidifies LPS acyl chains, and causes membrane rupture.\",\n      \"evidence\": \"X-ray crystallography at 2.4 Å (subsequently 1.7 Å); monolayer insertion experiments; IR spectroscopy; laser Doppler velocimetry; planar bilayer electrophysiology\",\n      \"pmids\": [\"9188532\", \"9254629\", \"9254630\", \"10843855\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No co-crystal of BPI bound to LPS\", \"Inner membrane damage mechanism not structurally explained\", \"Lipid-binding pocket occupancy in vivo unknown\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Showing that BPI enhances LPS aggregation (opposite to LBP's dispersal) and inhibits LBP–LPS binding at substoichiometric ratios clarified how BPI competes with LBP to intercept LPS signaling rather than simply scavenging free LPS.\",\n      \"evidence\": \"Sedimentation, light scattering, and fluorescence analyses of LPS–protein complexes\",\n      \"pmids\": [\"9228038\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the BPI–LPS aggregate complex unresolved\", \"Stoichiometry and kinetics in physiological fluids not determined\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Structure-based identification of a conserved cluster of basic residues (Lys42, 48, 92, 95, 99) at the N-terminal tip, together with subcellular localization of BPI to azurophil granules with functional validation via blocking antibodies, established that BPI is the principal neutrophil bactericidal factor operating through electrostatic contacts with LPS phosphate groups.\",\n      \"evidence\": \"Conserved residue mapping onto crystal structure; granule fractionation; BPI-blocking antibody functional assays; bacterial membrane damage assays\",\n      \"pmids\": [\"9568897\", \"9665269\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mutational validation of individual lysine contributions to bactericidal activity not performed\", \"Relative contributions of BPI vs. other granule proteins in vivo unquantified\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Demonstrating that the C-terminal domain is required for granule storage and protects against proteasomal degradation during intracellular sorting defined a non-redundant function for the C-terminal domain distinct from the N-terminal bactericidal role.\",\n      \"evidence\": \"cDNA transfection of deletion mutants and chimeras into myeloid cell lines; subcellular fractionation and protein stability assays\",\n      \"pmids\": [\"11073106\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Sorting receptor or signal recognized by C-terminal domain not identified\", \"Opsonization mechanism of C-terminal domain not structurally defined\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Immunoelectron microscopy showed BPI is membrane-associated within azurophil granules and relocates to phagosomes upon activation, with eosinophils also delivering BPI to phagosomes, establishing granule-to-phagosome delivery as the physiological mechanism for intracellular bacterial killing.\",\n      \"evidence\": \"Cryotechnique immunoelectron microscopy; selective granule-release experiments; phagocytosis assays in neutrophils and eosinophils\",\n      \"pmids\": [\"10752689\", \"9616176\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mode of BPI membrane association within granules unknown\", \"Relative bactericidal contribution of phagosomal BPI vs. other granule contents not quantified\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"The finding that BPI selectively induces apoptosis in endothelial cells and inhibits angiogenesis in vitro and in vivo expanded BPI's functional repertoire beyond antimicrobial defense to vascular biology.\",\n      \"evidence\": \"Flow cytometry for apoptosis; collagen gel tube formation assay; in vivo chick chorioallantoic membrane angiogenesis assay\",\n      \"pmids\": [\"10891448\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor or mechanism of EC-selective apoptosis induction unknown\", \"Physiological context for anti-angiogenic function not established\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identification of BPI expression on mucosal epithelial cell surfaces, induced by aspirin-triggered lipoxins and functional in blocking LPS signaling and killing bacteria, established BPI as an epithelial antimicrobial effector independent of neutrophils.\",\n      \"evidence\": \"Microarray and RT-PCR; immunostaining for surface localization; functional neutralization with BPI antiserum; tissue immunohistochemistry\",\n      \"pmids\": [\"11891303\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of BPI surface tethering on epithelia not defined\", \"Epithelial BPI contribution relative to other antimicrobial peptides unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"ChIP and EMSA demonstrated direct binding of C/EBPβ and C/EBPε to the BPI promoter during retinoic acid-induced granulocyte differentiation, establishing the transcriptional regulation mechanism for myeloid BPI expression.\",\n      \"evidence\": \"ATRA treatment of NB4 cells; cycloheximide block; EMSA; chromatin immunoprecipitation\",\n      \"pmids\": [\"16684888\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cis-regulatory elements sufficient for granulocyte-specific expression not fully mapped\", \"Whether same factors regulate epithelial BPI expression unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"A 27-amino acid N-terminal BPI peptide disrupted enveloped virus particles with human-sequence specificity (lost in mouse homolog), extending BPI's antimicrobial reach to antiviral defense against Influenza A and VSV.\",\n      \"evidence\": \"Antiviral infectivity assays across multiple influenza strains; electron microscopy of virus particles; human-to-mouse sequence substitution\",\n      \"pmids\": [\"27273104\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo antiviral role not demonstrated\", \"Molecular basis of species-specific antiviral activity unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Intracellular potassium efflux caused by pore-forming toxins or bacterial infection was identified as the danger signal inducing epithelial BPI expression through a p38-dependent pathway, defining a damage-sensing circuit upstream of BPI.\",\n      \"evidence\": \"Caco-2 cells treated with pore-forming toxins; in vivo mouse infection with Salmonella and Shigella; p38 inhibitor studies\",\n      \"pmids\": [\"28861073\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcription factor downstream of p38 that activates BPI in epithelia not identified\", \"Whether potassium sensing feeds through inflammasome components not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"BPI overexpression in T cells suppressed Treg differentiation and BPI-containing exosomes stimulated macrophage IL-1β and systemic inflammation, revealing an unexpected immunoregulatory function for BPI in adaptive immunity.\",\n      \"evidence\": \"T-cell-specific BPI transgenic and KO mice; adoptive exosome transfer; scRNA-seq; in vitro Treg differentiation assays\",\n      \"pmids\": [\"34815797\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism by which BPI inhibits Treg differentiation not defined beyond ZFP36L2/Helios correlation\", \"Physiological relevance of T-cell BPI expression in humans unknown\", \"Single lab observation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the atomic structure of the BPI–LPS complex, the receptor or mechanism for BPI's selective endothelial cell apoptosis, the identity of the epithelial BPI surface anchor, and whether BPI's immunoregulatory functions in T cells operate through the same lipid-binding mechanism as its antimicrobial activity.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No BPI–LPS co-crystal structure\", \"Endothelial receptor for BPI-induced apoptosis unknown\", \"Mechanism of BPI surface retention on epithelia undefined\", \"Link between lipid-binding pockets and Treg regulation not tested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 2, 3, 5, 6]},\n      {\"term_id\": \"GO:0090729\", \"supporting_discovery_ids\": [3, 4, 7, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [4, 8, 9, 10]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [11, 19]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [3, 5, 14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 4, 11, 17, 19]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"LBP\",\n      \"CEBPB\",\n      \"CEBPE\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}