{"gene":"SEMA7A","run_date":"2026-06-10T07:46:30","timeline":{"discoveries":[{"year":2002,"finding":"Sema7A, expressed as a GPI-anchored cell-surface protein on monocytes and likely released through proteolysis, acts as a potent autocrine activator of monocytes, stimulating chemotaxis at 0.1 pM and inducing inflammatory cytokine production (IL-1β, TNF-α, IL-6, IL-8) and superoxide release at 1–10 pM; it also induced monocyte differentiation toward a dendritic cell morphology. No stimulation of B or T cells was detected.","method":"Recombinant protein stimulation of primary human monocytes, cytokine ELISA, superoxide assay, chemotaxis assay, morphological analysis","journal":"Scandinavian journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean functional assays with recombinant protein on primary cells, multiple orthogonal readouts, single lab","pmids":["12193228"],"is_preprint":false},{"year":2018,"finding":"Sema7A is expressed in olfactory sensory neurons (OSNs) in an activity-dependent manner and signals through its receptor PlexinC1 (localized to mitral/tufted cell dendrites in the first postnatal week) to promote post-synaptic assembly and dendrite selection in mitral/tufted cells; Sema7A or PlxnC1 knockout mice showed defective synapse initiation and dendrite selection, which was rescued by reconstitution experiments demonstrating that Sema7A–PlxnC1 interaction is essential.","method":"Knockout mouse models (Sema7A-KO, PlxnC1-KO), reconstitution experiments, rescue experiments, immunohistochemistry, pharmacological blocking","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal KO phenotypes in two genes, reconstitution/rescue experiments, replicated in follow-up study (PMID:33780330)","pmids":["29743476","33780330"],"is_preprint":false},{"year":2021,"finding":"Sema7A orchestrates macrophage chemotaxis/chemokinesis, promotes M2 proresolving polarization, and regulates macrophage metabolic reprogramming via mTOR and AKT2 signaling pathways; peritoneal macrophages from Sema7A-/- mice showed reduced fatty acid oxidation and oxidative phosphorylation, increased glycolysis and pentose phosphate pathway activity, truncated TCA cycle, and decreased citrate/prostaglandin synthesis, impairing lipid-mediator class switching and generation of specialized pro-resolving lipid mediators.","method":"Sema7A-/- macrophage metabolomics, lipid mediator profiling, signaling pathway analysis, murine peritonitis and polymicrobial sepsis models, recombinant Sema7A administration","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with multiple orthogonal metabolomic/lipidomic methods plus in vivo rescue with recombinant protein, single lab but comprehensive","pmids":["33637648"],"is_preprint":false},{"year":2023,"finding":"SEMA7A regulates integrin signaling through cis-coupling with active integrin α5β1 on the plasma membrane, enabling rapid integrin adhesion strengthening to fibronectin and normal downstream mechanotransduction; loss of SEMA7A impairs fibroblast adhesion, cytoskeletal organization, migration, ECM assembly, and results in significantly delayed tissue repair in vivo.","method":"Co-immunoprecipitation (cis-coupling), integrin adhesion strengthening assays, fibroblast KD/KO phenotyping (migration, ECM assembly), in vivo wound healing model, transcriptomic/chromatin analyses","journal":"Matrix biology : journal of the International Society for Matrix Biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP for cis-coupling, multiple orthogonal functional assays, in vivo validation, single lab","pmids":["37422024"],"is_preprint":false},{"year":2023,"finding":"Sema7A inhibits adipogenesis of adipose-derived mesenchymal stem cells and lipogenesis of mature adipocytes through its receptor integrin β1 and downstream FAK signaling; Sema7A-/- mice showed enhanced adipogenesis and aggravated HFD-induced obesity and hepatic steatosis, while administration of recombinant Sema7A protected against diet-induced obesity.","method":"Sema7A-/- mouse model, recombinant Sema7A treatment, primary ADSC adipogenesis assays, integrin β1 pathway analysis, in vivo HFD model","journal":"Molecular metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO plus recombinant protein rescue, multiple orthogonal assays (cell-based and in vivo), single lab","pmids":["36842496"],"is_preprint":false},{"year":2024,"finding":"FUT8 catalyzes aberrant core fucosylation of SEMA7A at five N-linked glycosylation sites (Asn 105, 157, 258, 330, and 602) via direct protein–protein interaction; this glycosylated state is necessary for intracellular trafficking of SEMA7A from cytoplasm to cell membrane. EGF increases SEMA7A-FUT8 binding affinity, while TGF-β1 promotes abnormal glycosylation via EMT induction.","method":"Mass spectrometry glycosylation site mapping, Co-IP (FUT8-SEMA7A direct interaction), subcellular fractionation/trafficking assays, deglycosylation experiments, cytokine stimulation assays","journal":"International journal of oral science","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — site-specific glycosylation mapping by MS, reciprocal Co-IP, functional trafficking assay, multiple orthogonal methods in single lab","pmids":["38548747"],"is_preprint":false},{"year":2020,"finding":"PfRipr (Plasmodium falciparum Rh5 interacting protein) interacts with SEMA7A on the erythrocyte surface as part of the invasion machinery; antibodies against PfRipr truncate 5 (C720-D934, within C-terminal EGF-like domains) block both PfRipr/Rh5 and PfRipr/SEMA7A interactions, inhibiting merozoite invasion.","method":"Recombinant protein expression, ELISA binding assays, invasion inhibition assays, antibody blockade","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional invasion inhibition assays with recombinant proteins and blocking antibodies, single lab, two orthogonal readouts","pmids":["32313230"],"is_preprint":false},{"year":2007,"finding":"Missense mutations in the semaphorin domain of SEMA7A (affecting codons 207 and 460/461) underlie variant JMH blood group phenotypes, resulting in reduced surface expression or qualitative changes; topological modeling showed SEMA7A polymorphisms are located on the top and bottom of the semaphorin domain, suggesting functional relevance for ligand-binding surfaces.","method":"Sanger sequencing, flow cytometry, Western blot, recombinant Sema7A protein expression, 3D structural modeling, genotype-phenotype correlation in 44 individuals","journal":"Transfusion","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (serology, flow, WB, recombinant protein), structural modeling, single lab","pmids":["17207242"],"is_preprint":false},{"year":2025,"finding":"In gallbladder cancer, fibroblast-secreted SEMA7A binds integrin β1 (not PlexinC1) on cancer cells, inducing phosphorylation of the transcriptional coactivator p300 at S1834 via Akt activation (p-Akt at S473), thereby promoting EMT and cancer stem-like traits.","method":"Co-immunoprecipitation, Western blot, mutation assays, ELISA, Transwell/tumorsphere assays, subcutaneous tumor co-injection model","journal":"Biology direct","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for receptor binding, phosphorylation site specificity by mutation, in vivo model, single lab","pmids":["40830485"],"is_preprint":false},{"year":2025,"finding":"The SEMA7A N559Y mutation strengthens its interaction with integrin β1, triggering the PI3K/Akt pathway and increasing ROS production, which activates the NLRP3 inflammasome and promotes hepatic cell pyroptosis, worsening metabolic dysfunction-associated steatotic liver disease.","method":"Heterozygous Sema7aN557Y knockin mice on HFD, Western blotting, biochemical/histological assays, Co-IP (enhanced SEMA7A-integrin β1 interaction)","journal":"Metabolism: clinical and experimental","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo knockin model with mechanistic pathway validation, single lab","pmids":["41429256"],"is_preprint":false},{"year":2025,"finding":"In colorectal cancer, SEMA7A activates the RAP1/AKT signaling pathway through its high-affinity receptor PlexinC1 in tumor-associated macrophages, promoting M2 polarization; rescue experiments with recombinant SEMA7A confirmed that blocking PlexinC1 suppresses M2-like TAM conversion.","method":"SEMA7A knockdown in CRC cell lines, transcriptomic analysis, recombinant SEMA7A rescue experiments, PlexinC1 blockade, in vivo AOM/DSS colitis-associated CRC model","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway identification by transcriptomics plus functional rescue experiments, in vivo model, single lab","pmids":["41407164"],"is_preprint":false},{"year":2025,"finding":"In endometrial cancer, SEMA7A binds the PI3K regulatory subunit p85, activating the PI3K-AKT signaling pathway; NCAPG promotes SEMA7A transcription by facilitating LEF1 binding to chromatin, establishing an NCAPG/LEF1/SEMA7A/PI3K-AKT axis that drives cancer cell proliferation, migration and invasion.","method":"ATAC-seq, ChIP-qPCR, Co-immunoprecipitation (SEMA7A-p85 interaction), functional cell assays","journal":"Journal of Cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for SEMA7A-p85 interaction, ChIP for transcriptional regulation, multiple orthogonal methods, single lab","pmids":["39744480"],"is_preprint":false},{"year":2024,"finding":"In pancreatic cancer, SEMA7A expressed on tumor cell membranes (facilitated by ATP1A1) acts in juxtacrine fashion by binding fibroblasts and inducing IGFBP-3 secretion, which in turn increases IL-17RB expression via SNAI2 to promote tumor invasion.","method":"Co-culture experiments (tumor cell-fibroblast), knockdown/overexpression assays, IGFBP-3 secretion measurement, IL-17RB/SNAI2 signaling analysis","journal":"Cancer gene therapy","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional co-culture mechanistic dissection with multiple pathway readouts, single lab","pmids":["39448803"],"is_preprint":false},{"year":2026,"finding":"RBC-derived Sema7A interacts with platelet integrin αIIb (identified by mass spectrometry and Co-IP), promoting recruitment of Talin1 and Lims1 and facilitating integrin-dependent signaling to enhance platelet activation and adhesion, thereby accelerating arterial thrombosis under disturbed flow; erythrocyte-specific Sema7A deletion reduced thrombus size and delayed vessel occlusion.","method":"Mass spectrometry, co-immunoprecipitation, global and erythrocyte-specific Sema7A KO mice, arterial thrombosis model (partial carotid ligation + FeCl3), flow chamber analysis, recombinant human Sema7A platelet activation assays, antibody blockade","journal":"Journal of thrombosis and haemostasis : JTH","confidence":"High","confidence_rationale":"Tier 2 / Strong — MS identification of binding partner confirmed by Co-IP, genetic KO (global and cell-type specific), recombinant protein and antibody blockade as orthogonal approaches, in vivo model","pmids":["42173291"],"is_preprint":false},{"year":2022,"finding":"Sema7A mediates osteogenic responses to hierarchical Ti6Al4V implant surface topography through the ITGB1/FAK/ERK signaling pathway, as revealed by RNA-seq with downstream pathway validation.","method":"RNA-seq of cells on implant surfaces, pathway validation (ITGB1/FAK/ERK), in vitro and in vivo osseointegration assays","journal":"ACS applied materials & interfaces","confidence":"Low","confidence_rationale":"Tier 3 / Weak — RNA-seq-based discovery with limited mechanistic follow-up of SEMA7A specifically, single lab","pmids":["35776897"],"is_preprint":false},{"year":2019,"finding":"Knockdown of SEMA7A in MPP+-stimulated BV2 microglia reduced apoptosis and inflammation via PPAR-γ activation and MAPK signaling pathway inactivation; PPAR-γ inhibitor and MAPK activator blocked the protective effects of SEMA7A knockdown, placing SEMA7A upstream of these two pathways.","method":"SEMA7A knockdown (siRNA) in BV2 cells, PPAR-γ inhibitor and MAPK activator pharmacological epistasis, ELISA for cytokines, Western blot for iNOS/COX-2, viability and apoptosis assays","journal":"Immunity, inflammation and disease","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pharmacological epistasis in cell culture, single lab, single cell model","pmids":["36705403"],"is_preprint":false},{"year":2025,"finding":"In breast cancer, loss of Sema7A reduced KDM4A expression, induced DNA replication stress, and activated the cGAS-STING signaling pathway, increasing IFN-β and CXCL10 secretion and enhancing CD8+ T cell chemotaxis; KDM4A overexpression reversed these antitumor effects, establishing a Sema7A-KDM4A axis regulating the immunosuppressive microenvironment.","method":"SEMA7A loss-of-function in breast cancer cell lines, KDM4A overexpression rescue, cGAS-STING pathway measurement (IFN-β, CXCL10), CD8+ T cell chemotaxis assays, in vivo tumor growth/metastasis","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (KO + rescue), multiple pathway readouts, in vivo validation, single lab","pmids":["41366110"],"is_preprint":false},{"year":2025,"finding":"SEMA7A binds integrins β1 and β4 via its RGD domain and activates AKT-mediated pro-survival signaling, contributing to endocrine therapy resistance in ER+ breast cancer; direct inhibition with an anti-SEMA7A monoclonal antibody (SmAbH1) significantly reduced tumor growth and, combined with fulvestrant, showed enhanced efficacy.","method":"Binding assays (integrin β1/β4), AKT pathway analysis, syngeneic ER+ mouse tumor models, PI3K inhibitor treatment, anti-SEMA7A antibody (SmAbH1) treatment in vivo","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, receptor binding and signaling data described but full mechanistic rigor unclear from abstract, single lab","pmids":["bio_10.1101_2025.05.21.655360"],"is_preprint":true},{"year":2021,"finding":"The olfactory critical period is determined by Sema7A/PlxnC1 signaling: activity-induced Sema7A in OSNs signals through PlxnC1 on mitral/tufted cell dendrites (restricted to the first postnatal week) to promote glomerular enlargement and increase sensitivity to experienced odors; this signaling operates independently from oxytocin-mediated positive imprinting of odor memory.","method":"Sema7A-KO and PlxnC1-KO mice, oxytocin-KO mice, knockout and rescue experiments, behavioral odor preference assays, glomerular morphology analysis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — replication of KO phenotypes (independent from prior study PMID:29743476), genetic epistasis with oxytocin-KO, multiple orthogonal behavioral and morphological readouts","pmids":["33780330"],"is_preprint":false}],"current_model":"SEMA7A is a GPI-anchored semaphorin glycoprotein that signals through two principal receptors—PlexinC1 and integrin β1 (and related integrins)—to regulate diverse processes: in the nervous system, activity-induced SEMA7A in olfactory sensory neurons signals via PlexinC1 on mitral/tufted cells to drive activity-dependent synapse formation and olfactory critical period plasticity; in the immune system, SEMA7A potently activates monocytes/macrophages, promotes proresolving M2 polarization via mTOR/AKT2-dependent metabolic reprogramming (enhancing fatty acid oxidation and prostaglandin/SPM synthesis), and regulates macrophage polarization via the RAP1/AKT pathway downstream of PlexinC1; in stromal and metabolic contexts, SEMA7A cis-couples with integrin α5β1 to prime mechanotransduction and fibroblast function, inhibits adipogenesis via integrin β1/FAK signaling, and on erythrocytes interacts with platelet integrin αIIb (recruiting Talin1/Lims1) to promote arterial thrombosis; additionally, FUT8 catalyzes SEMA7A N-glycosylation at five sites required for its trafficking to the cell membrane, and specific mutations (e.g., N559Y) enhance integrin β1 binding to activate PI3K/Akt/ROS/NLRP3 pyroptosis signaling."},"narrative":{"mechanistic_narrative":"SEMA7A is a GPI-anchored semaphorin glycoprotein that acts as a signaling ligand across the nervous, immune, stromal, and vascular systems by engaging two principal receptor classes—PlexinC1 and integrins [PMID:29743476, PMID:33780330, PMID:37422024]. In the olfactory system, activity-induced SEMA7A in olfactory sensory neurons signals through PlexinC1 on mitral/tufted cell dendrites to drive post-synaptic assembly, dendrite selection, and glomerular enlargement, thereby defining the olfactory critical period during the first postnatal week [PMID:29743476, PMID:33780330]. In the immune compartment, SEMA7A is a potent autocrine activator of monocytes—inducing chemotaxis, inflammatory cytokine output, and superoxide release [PMID:12193228]—and it programs macrophage behavior by promoting pro-resolving M2 polarization and metabolic reprogramming toward fatty acid oxidation and specialized pro-resolving lipid mediator synthesis via mTOR and AKT2 signaling [PMID:33637648]. In stromal and metabolic contexts, SEMA7A cis-couples with active integrin α5β1 to strengthen adhesion to fibronectin and enable mechanotransduction, supporting fibroblast migration, ECM assembly, and tissue repair [PMID:37422024], and it restrains adipogenesis through integrin β1/FAK signaling, protecting against diet-induced obesity and hepatic steatosis [PMID:36842496]. On erythrocytes, SEMA7A binds platelet integrin αIIb to recruit Talin1 and Lims1, promoting platelet activation and arterial thrombosis [PMID:42173291]. SEMA7A trafficking to the cell membrane depends on FUT8-catalyzed core fucosylation at five N-linked glycosylation sites [PMID:38548747]. Across multiple cancers, SEMA7A–integrin β1 and SEMA7A–PlexinC1 signaling activate PI3K/AKT-dependent programs that promote EMT, stem-like traits, and M2-skewed tumor-associated macrophages [PMID:40830485, PMID:41407164]. Missense mutations in the semaphorin domain underlie variant JMH blood group phenotypes by altering surface expression [PMID:17207242].","teleology":[{"year":2002,"claim":"Established SEMA7A as a functionally active immune ligand rather than a purely neural cue, showing it directly activates innate immune cells.","evidence":"Recombinant protein stimulation of primary human monocytes with cytokine, superoxide, chemotaxis, and morphology readouts","pmids":["12193228"],"confidence":"Medium","gaps":["Receptor mediating monocyte activation not identified","Single lab, no in vivo confirmation","Mechanism of proteolytic release not defined"]},{"year":2007,"claim":"Linked SEMA7A semaphorin-domain polymorphisms to the JMH blood group, mapping functionally relevant surface residues.","evidence":"Sanger sequencing, flow cytometry, Western blot, recombinant protein, and structural modeling across 44 individuals","pmids":["17207242"],"confidence":"Medium","gaps":["Functional consequence for ligand-receptor binding not directly tested","Effects on downstream signaling unknown"]},{"year":2018,"claim":"Defined the SEMA7A–PlexinC1 axis as an essential driver of activity-dependent synapse formation, establishing a directional ligand-receptor signaling relationship in the brain.","evidence":"Reciprocal Sema7A-KO and PlxnC1-KO mice with reconstitution and rescue, immunohistochemistry, pharmacological blockade","pmids":["29743476","33780330"],"confidence":"High","gaps":["Intracellular signaling downstream of PlexinC1 in neurons not fully resolved","Activity-dependent transcriptional control of Sema7A not detailed"]},{"year":2021,"claim":"Showed the SEMA7A/PlexinC1 axis times the olfactory critical period, distinguishing it from parallel oxytocin-driven imprinting.","evidence":"Sema7A-KO, PlxnC1-KO, and oxytocin-KO mice with rescue, behavioral odor assays, and glomerular morphology","pmids":["33780330"],"confidence":"High","gaps":["Molecular basis restricting the time window to the first postnatal week unknown"]},{"year":2021,"claim":"Revealed that SEMA7A controls macrophage fate by metabolic reprogramming, connecting it to inflammation resolution through lipid-mediator class switching.","evidence":"Sema7A-/- macrophage metabolomics and lipidomics, mTOR/AKT2 pathway analysis, murine peritonitis and sepsis models with recombinant protein rescue","pmids":["33637648"],"confidence":"High","gaps":["Receptor coupling mTOR/AKT2 in macrophages not pinpointed","Single lab"]},{"year":2023,"claim":"Identified cis-coupling of SEMA7A with active integrin α5β1 as the mechanism by which it primes adhesion strengthening and mechanotransduction in stroma.","evidence":"Reciprocal Co-IP, integrin adhesion strengthening assays, fibroblast KD/KO phenotyping, and in vivo wound healing","pmids":["37422024"],"confidence":"High","gaps":["Structural basis of cis vs trans integrin engagement unresolved","Relationship to PlexinC1 signaling in same cells unclear"]},{"year":2023,"claim":"Placed SEMA7A as a brake on adipogenesis via integrin β1/FAK, extending its integrin signaling role to whole-body metabolism.","evidence":"Sema7A-/- mice, recombinant protein rescue, primary ADSC adipogenesis assays, and HFD obesity model","pmids":["36842496"],"confidence":"High","gaps":["Direct integrin β1 binding in adipocytes not biochemically mapped","Tissue source of relevant SEMA7A in vivo unclear"]},{"year":2024,"claim":"Demonstrated that FUT8-mediated core fucosylation at five N-glycosylation sites is required for SEMA7A membrane trafficking, defining a post-translational gate on its surface availability.","evidence":"MS glycosite mapping, reciprocal Co-IP, subcellular fractionation/trafficking and deglycosylation assays, cytokine stimulation","pmids":["38548747"],"confidence":"High","gaps":["Whether fucosylation modulates receptor binding affinity not tested","Generality across cell types beyond the studied context unknown"]},{"year":2024,"claim":"Showed SEMA7A juxtacrine signaling between tumor cells and fibroblasts drives invasion through an IGFBP-3/IL-17RB/SNAI2 cascade.","evidence":"Tumor cell–fibroblast co-culture, knockdown/overexpression, secretion measurement, and pathway analysis","pmids":["39448803"],"confidence":"Medium","gaps":["Receptor on fibroblasts mediating SEMA7A binding not identified","In vivo validation limited"]},{"year":2025,"claim":"Mapped multiple cancer-context signaling outputs of SEMA7A through integrin β1 and PlexinC1, converging on PI3K/AKT to drive EMT, stemness, and M2 TAM polarization.","evidence":"Co-IP receptor identification, phospho-site mutation assays, transcriptomics, PlexinC1 blockade, and in vivo tumor models in gallbladder, colorectal, and endometrial cancers","pmids":["40830485","41407164","39744480"],"confidence":"Medium","gaps":["Determinants of receptor choice (integrin β1 vs PlexinC1) across tissues unknown","Each axis from a single lab/context"]},{"year":2025,"claim":"Linked a SEMA7A-KDM4A axis to immune evasion, showing SEMA7A loss triggers replication stress and cGAS-STING activation to recruit CD8+ T cells.","evidence":"SEMA7A loss-of-function with KDM4A overexpression rescue, cGAS-STING readouts, T cell chemotaxis assays, and in vivo breast tumor models","pmids":["41366110"],"confidence":"Medium","gaps":["Mechanism linking SEMA7A to KDM4A expression unresolved","Whether this depends on surface signaling or intracellular function unclear"]},{"year":2025,"claim":"Showed a SEMA7A N559Y gain-of-function mutation enhances integrin β1 binding to drive PI3K/Akt/ROS/NLRP3 pyroptosis in metabolic liver disease.","evidence":"Sema7aN557Y knockin mice on HFD, Co-IP, and biochemical/histological pathway validation","pmids":["41429256"],"confidence":"Medium","gaps":["Structural basis for enhanced integrin binding not determined","Single lab"]},{"year":2026,"claim":"Established an erythrocyte-platelet SEMA7A signaling role, where RBC SEMA7A engages integrin αIIb to recruit Talin1/Lims1 and accelerate arterial thrombosis.","evidence":"MS and Co-IP partner identification, global and erythrocyte-specific KO mice, arterial thrombosis and flow chamber models, recombinant protein and antibody blockade","pmids":["42173291"],"confidence":"High","gaps":["Whether RBC SEMA7A is membrane-bound or shed during the interaction not fully defined","Relevance to human thrombotic disease not established"]},{"year":null,"claim":"How SEMA7A selects between PlexinC1 and distinct integrins in a given cell type, and how glycosylation and the GPI anchor tune this receptor choice, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model defining concurrent PlexinC1 vs integrin engagement","Determinants of cis vs trans signaling across tissues unknown","Link between FUT8 fucosylation and receptor affinity untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[1,0,18]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,4,13]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[3,13]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,3,5]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,3,4]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,2,10]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[1,18]},{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[13]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[3]}],"complexes":[],"partners":["PLXNC1","ITGB1","ITGA5","ITGB4","ITGA2B","FUT8","TLN1","LIMS1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O75326","full_name":"Semaphorin-7A","aliases":["CDw108","JMH blood group antigen","John-Milton-Hargen human blood group Ag","Semaphorin-K1","Sema K1","Semaphorin-L","Sema L"],"length_aa":666,"mass_kda":74.8,"function":"Plays an important role in integrin-mediated signaling and functions both in regulating cell migration and immune responses. Promotes formation of focal adhesion complexes, activation of the protein kinase PTK2/FAK1 and subsequent phosphorylation of MAPK1 and MAPK3. Promotes production of pro-inflammatory cytokines by monocytes and macrophages. Plays an important role in modulating inflammation and T-cell-mediated immune responses. Promotes axon growth in the embryonic olfactory bulb. Promotes attachment, spreading and dendrite outgrowth in melanocytes","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/O75326/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SEMA7A","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SEMA7A","total_profiled":1310},"omim":[{"mim_id":"619874","title":"CHOLESTASIS, PROGRESSIVE FAMILIAL INTRAHEPATIC, 11; PFIC11","url":"https://www.omim.org/entry/619874"},{"mim_id":"614745","title":"BLOOD GROUP, JOHN MILTON HAGEN SYSTEM; JMH","url":"https://www.omim.org/entry/614745"},{"mim_id":"607961","title":"SEMAPHORIN 7A; SEMA7A","url":"https://www.omim.org/entry/607961"},{"mim_id":"603961","title":"SEMAPHORIN 3A; SEMA3A","url":"https://www.omim.org/entry/603961"},{"mim_id":"211600","title":"CHOLESTASIS, PROGRESSIVE FAMILIAL INTRAHEPATIC, 1; PFIC1","url":"https://www.omim.org/entry/211600"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Vesicles","reliability":"Uncertain"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":61.8},{"tissue":"lymphoid tissue","ntpm":55.3},{"tissue":"retina","ntpm":32.1}],"url":"https://www.proteinatlas.org/search/SEMA7A"},"hgnc":{"alias_symbol":["H-Sema-L","CD108"],"prev_symbol":["SEMAL"]},"alphafold":{"accession":"O75326","domains":[{"cath_id":"2.130.10.10","chopping":"178-305_312-400","consensus_level":"medium","plddt":96.9703,"start":178,"end":400},{"cath_id":"2.60.40.10","chopping":"552-632","consensus_level":"high","plddt":96.0195,"start":552,"end":632}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O75326","model_url":"https://alphafold.ebi.ac.uk/files/AF-O75326-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O75326-F1-predicted_aligned_error_v6.png","plddt_mean":89.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SEMA7A","jax_strain_url":"https://www.jax.org/strain/search?query=SEMA7A"},"sequence":{"accession":"O75326","fasta_url":"https://rest.uniprot.org/uniprotkb/O75326.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O75326/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O75326"}},"corpus_meta":[{"pmid":"12193228","id":"PMC_12193228","title":"Sema7A is a potent monocyte stimulator.","date":"2002","source":"Scandinavian journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/12193228","citation_count":133,"is_preprint":false},{"pmid":"24522099","id":"PMC_24522099","title":"Mutation screening of SEMA3A and SEMA7A in patients with congenital hypogonadotropic hypogonadism.","date":"2014","source":"Pediatric research","url":"https://pubmed.ncbi.nlm.nih.gov/24522099","citation_count":57,"is_preprint":false},{"pmid":"33637648","id":"PMC_33637648","title":"Sema7A is crucial for resolution of severe inflammation.","date":"2021","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/33637648","citation_count":51,"is_preprint":false},{"pmid":"16372136","id":"PMC_16372136","title":"Association study of semaphorin 7a (sema7a) polymorphisms with bone mineral density and fracture risk in postmenopausal Korean women.","date":"2005","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16372136","citation_count":47,"is_preprint":false},{"pmid":"29743476","id":"PMC_29743476","title":"Sema7A/PlxnCl signaling triggers activity-dependent olfactory synapse formation.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/29743476","citation_count":44,"is_preprint":false},{"pmid":"31732974","id":"PMC_31732974","title":"LncRNA LOXL1-AS1/miR-28-5p/SEMA7A axis facilitates pancreatic cancer progression.","date":"2019","source":"Cell biochemistry and function","url":"https://pubmed.ncbi.nlm.nih.gov/31732974","citation_count":42,"is_preprint":false},{"pmid":"26686462","id":"PMC_26686462","title":"Differential expression of sema3A and sema7A in a murine model of multiple sclerosis: Implications for a therapeutic design.","date":"2015","source":"Clinical immunology (Orlando, Fla.)","url":"https://pubmed.ncbi.nlm.nih.gov/26686462","citation_count":31,"is_preprint":false},{"pmid":"17207242","id":"PMC_17207242","title":"The molecular diversity of Sema7A, the semaphorin that carries the JMH blood group antigens.","date":"2007","source":"Transfusion","url":"https://pubmed.ncbi.nlm.nih.gov/17207242","citation_count":27,"is_preprint":false},{"pmid":"33780330","id":"PMC_33780330","title":"The olfactory critical period is determined by activity-dependent Sema7A/PlxnC1 signaling within glomeruli.","date":"2021","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/33780330","citation_count":26,"is_preprint":false},{"pmid":"16804892","id":"PMC_16804892","title":"Sema3D and Sema7A have distinct expression patterns in chick embryonic development.","date":"2006","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/16804892","citation_count":23,"is_preprint":false},{"pmid":"32313230","id":"PMC_32313230","title":"Antibodies against a short region of PfRipr inhibit Plasmodium falciparum merozoite invasion and PfRipr interaction with Rh5 and SEMA7A.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/32313230","citation_count":23,"is_preprint":false},{"pmid":"33022522","id":"PMC_33022522","title":"SEMal: Accurate protein malonylation site predictor using structural and evolutionary information.","date":"2020","source":"Computers in biology and medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33022522","citation_count":21,"is_preprint":false},{"pmid":"38548747","id":"PMC_38548747","title":"FUT8-mediated aberrant N-glycosylation of SEMA7A promotes head and neck squamous cell carcinoma progression.","date":"2024","source":"International journal of oral science","url":"https://pubmed.ncbi.nlm.nih.gov/38548747","citation_count":20,"is_preprint":false},{"pmid":"35776897","id":"PMC_35776897","title":"Construction of a Hierarchical Micro-/Submicro-/Nanostructured 3D-Printed Ti6Al4V Surface Feature to Promote Osteogenesis: Involvement of Sema7A through the ITGB1/FAK/ERK Signaling Pathway.","date":"2022","source":"ACS applied materials & interfaces","url":"https://pubmed.ncbi.nlm.nih.gov/35776897","citation_count":20,"is_preprint":false},{"pmid":"37422024","id":"PMC_37422024","title":"SEMA7a primes integrin α5β1 engagement instructing fibroblast mechanotransduction, phenotype and transcriptional programming.","date":"2023","source":"Matrix biology : journal of the International Society for Matrix Biology","url":"https://pubmed.ncbi.nlm.nih.gov/37422024","citation_count":17,"is_preprint":false},{"pmid":"36842496","id":"PMC_36842496","title":"Sema7A protects against high-fat diet-induced obesity and hepatic steatosis by regulating adipo/lipogenesis.","date":"2023","source":"Molecular metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/36842496","citation_count":13,"is_preprint":false},{"pmid":"31179640","id":"PMC_31179640","title":"Sema7A, a brain immune regulator, regulates seizure activity in PTZ-kindled epileptic rats.","date":"2019","source":"CNS neuroscience & therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/31179640","citation_count":13,"is_preprint":false},{"pmid":"18422858","id":"PMC_18422858","title":"Rapid detection of JMH antibodies with recombinant Sema7A (CD108) protein and the particle gel immunoassay.","date":"2008","source":"Transfusion","url":"https://pubmed.ncbi.nlm.nih.gov/18422858","citation_count":10,"is_preprint":false},{"pmid":"36705403","id":"PMC_36705403","title":"Knockdown of SEMA7A alleviates MPP+ -induced apoptosis and inflammation in BV2 microglia via PPAR-γ activation and MAPK inactivation.","date":"2023","source":"Immunity, inflammation and disease","url":"https://pubmed.ncbi.nlm.nih.gov/36705403","citation_count":9,"is_preprint":false},{"pmid":"38163490","id":"PMC_38163490","title":"Extracellular vesicles of Bacteroides fragilis regulated macrophage polarization through promoted Sema7a expression.","date":"2023","source":"Microbial pathogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/38163490","citation_count":8,"is_preprint":false},{"pmid":"31650878","id":"PMC_31650878","title":"A novel heterozygous intron mutation in SEMA7A causing kallmann syndrome in a female.","date":"2019","source":"Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/31650878","citation_count":6,"is_preprint":false},{"pmid":"20854351","id":"PMC_20854351","title":"A new SEMA7A variant found in Native Americans with alloantibody.","date":"2010","source":"Vox sanguinis","url":"https://pubmed.ncbi.nlm.nih.gov/20854351","citation_count":5,"is_preprint":false},{"pmid":"41019072","id":"PMC_41019072","title":"Tumor-derived SEMA7A regulates fatty acid oxidation in the tumor-associated macrophages to promote the progression of non-small cell lung cancer.","date":"2025","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/41019072","citation_count":4,"is_preprint":false},{"pmid":"39448803","id":"PMC_39448803","title":"SEMA7A-mediated juxtacrine stimulation of IGFBP-3 upregulates IL-17RB at pancreatic cancer invasive front.","date":"2024","source":"Cancer gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/39448803","citation_count":4,"is_preprint":false},{"pmid":"39744480","id":"PMC_39744480","title":"NCAPG promotes the malignant progression of endometrioid cancer through LEF1/SEMA7A/PI3K-AKT.","date":"2025","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/39744480","citation_count":3,"is_preprint":false},{"pmid":"40480556","id":"PMC_40480556","title":"SEMA7A: A glycoprotein with therapeutic potential in inflammatory diseases and tumor development.","date":"2025","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/40480556","citation_count":2,"is_preprint":false},{"pmid":"39329961","id":"PMC_39329961","title":"Associations of SEMA7A, SEMA4D, ADAMTS10, and ADAM8 with KRAS, NRAS, BRAF, PIK3CA, and AKT Gene Mutations, Microsatellite Instability Status, and Cytokine Expression in Colorectal Cancer Tissue.","date":"2024","source":"Current issues in molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/39329961","citation_count":2,"is_preprint":false},{"pmid":"41366110","id":"PMC_41366110","title":"Sema7a drives an immunosuppressive microenvironment of breast cancer via Kdm4a-mediated DNA replication regulation.","date":"2025","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/41366110","citation_count":1,"is_preprint":false},{"pmid":"40830485","id":"PMC_40830485","title":"Matrix stiffness induced gallbladder fibroblasts activation and paracrine SEMA7A promotes gallbladder cancer cell epithelial-mesenchymal transition and cancer stem cell-like properties by modulating AKT/p300 signalling.","date":"2025","source":"Biology direct","url":"https://pubmed.ncbi.nlm.nih.gov/40830485","citation_count":1,"is_preprint":false},{"pmid":"41429256","id":"PMC_41429256","title":"The SEMA7AN559Y mutation facilitates the development of metabolic dysfunction-associated steatotic liver disease by inducing ROS/NLRP3-mediated hepatic cell pyroptosis.","date":"2025","source":"Metabolism: clinical and experimental","url":"https://pubmed.ncbi.nlm.nih.gov/41429256","citation_count":1,"is_preprint":false},{"pmid":"41407164","id":"PMC_41407164","title":"SEMA7A orchestrates the colorectal cancer tumor microenvironment via PlexinC1: coordinating angiogenesis and macrophage M2 polarization.","date":"2025","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/41407164","citation_count":1,"is_preprint":false},{"pmid":"42239249","id":"PMC_42239249","title":"SOX9 and SEMA7A regulate cell plasticity in the postpartum mammary gland with implications for breast cancer.","date":"2026","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/42239249","citation_count":0,"is_preprint":false},{"pmid":"42173291","id":"PMC_42173291","title":"Red blood cell-derived Sema7A accelerates carotid arterial thrombosis under disturbed flow via interacting with platelet αIIbβ3.","date":"2026","source":"Journal of thrombosis and haemostasis : JTH","url":"https://pubmed.ncbi.nlm.nih.gov/42173291","citation_count":0,"is_preprint":false},{"pmid":"41351979","id":"PMC_41351979","title":"Glycitein in Zhi-Zi-Chi decoction alleviates anxiety via inosine enrichment mediated by Akkermansia muciniphila to regulate MT3-Sema7a interaction.","date":"2025","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/41351979","citation_count":0,"is_preprint":false},{"pmid":"41713818","id":"PMC_41713818","title":"Tanreqing injection regulates Sema7a/Plxnc1 signaling pathway mediated neutrophil extracellular trap formation to alleviate lipopolysaccharide-induced acute lung injury.","date":"2026","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/41713818","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.05.21.655360","title":"Targeting Semaphorin 7a signaling in preclinical models of estrogen receptor-positive breast 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monocyte differentiation toward a dendritic cell morphology. No stimulation of B or T cells was detected.\",\n      \"method\": \"Recombinant protein stimulation of primary human monocytes, cytokine ELISA, superoxide assay, chemotaxis assay, morphological analysis\",\n      \"journal\": \"Scandinavian journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean functional assays with recombinant protein on primary cells, multiple orthogonal readouts, single lab\",\n      \"pmids\": [\"12193228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Sema7A is expressed in olfactory sensory neurons (OSNs) in an activity-dependent manner and signals through its receptor PlexinC1 (localized to mitral/tufted cell dendrites in the first postnatal week) to promote post-synaptic assembly and dendrite selection in mitral/tufted cells; Sema7A or PlxnC1 knockout mice showed defective synapse initiation and dendrite selection, which was rescued by reconstitution experiments demonstrating that Sema7A–PlxnC1 interaction is essential.\",\n      \"method\": \"Knockout mouse models (Sema7A-KO, PlxnC1-KO), reconstitution experiments, rescue experiments, immunohistochemistry, pharmacological blocking\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal KO phenotypes in two genes, reconstitution/rescue experiments, replicated in follow-up study (PMID:33780330)\",\n      \"pmids\": [\"29743476\", \"33780330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Sema7A orchestrates macrophage chemotaxis/chemokinesis, promotes M2 proresolving polarization, and regulates macrophage metabolic reprogramming via mTOR and AKT2 signaling pathways; peritoneal macrophages from Sema7A-/- mice showed reduced fatty acid oxidation and oxidative phosphorylation, increased glycolysis and pentose phosphate pathway activity, truncated TCA cycle, and decreased citrate/prostaglandin synthesis, impairing lipid-mediator class switching and generation of specialized pro-resolving lipid mediators.\",\n      \"method\": \"Sema7A-/- macrophage metabolomics, lipid mediator profiling, signaling pathway analysis, murine peritonitis and polymicrobial sepsis models, recombinant Sema7A administration\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with multiple orthogonal metabolomic/lipidomic methods plus in vivo rescue with recombinant protein, single lab but comprehensive\",\n      \"pmids\": [\"33637648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SEMA7A regulates integrin signaling through cis-coupling with active integrin α5β1 on the plasma membrane, enabling rapid integrin adhesion strengthening to fibronectin and normal downstream mechanotransduction; loss of SEMA7A impairs fibroblast adhesion, cytoskeletal organization, migration, ECM assembly, and results in significantly delayed tissue repair in vivo.\",\n      \"method\": \"Co-immunoprecipitation (cis-coupling), integrin adhesion strengthening assays, fibroblast KD/KO phenotyping (migration, ECM assembly), in vivo wound healing model, transcriptomic/chromatin analyses\",\n      \"journal\": \"Matrix biology : journal of the International Society for Matrix Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP for cis-coupling, multiple orthogonal functional assays, in vivo validation, single lab\",\n      \"pmids\": [\"37422024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Sema7A inhibits adipogenesis of adipose-derived mesenchymal stem cells and lipogenesis of mature adipocytes through its receptor integrin β1 and downstream FAK signaling; Sema7A-/- mice showed enhanced adipogenesis and aggravated HFD-induced obesity and hepatic steatosis, while administration of recombinant Sema7A protected against diet-induced obesity.\",\n      \"method\": \"Sema7A-/- mouse model, recombinant Sema7A treatment, primary ADSC adipogenesis assays, integrin β1 pathway analysis, in vivo HFD model\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO plus recombinant protein rescue, multiple orthogonal assays (cell-based and in vivo), single lab\",\n      \"pmids\": [\"36842496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FUT8 catalyzes aberrant core fucosylation of SEMA7A at five N-linked glycosylation sites (Asn 105, 157, 258, 330, and 602) via direct protein–protein interaction; this glycosylated state is necessary for intracellular trafficking of SEMA7A from cytoplasm to cell membrane. EGF increases SEMA7A-FUT8 binding affinity, while TGF-β1 promotes abnormal glycosylation via EMT induction.\",\n      \"method\": \"Mass spectrometry glycosylation site mapping, Co-IP (FUT8-SEMA7A direct interaction), subcellular fractionation/trafficking assays, deglycosylation experiments, cytokine stimulation assays\",\n      \"journal\": \"International journal of oral science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — site-specific glycosylation mapping by MS, reciprocal Co-IP, functional trafficking assay, multiple orthogonal methods in single lab\",\n      \"pmids\": [\"38548747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PfRipr (Plasmodium falciparum Rh5 interacting protein) interacts with SEMA7A on the erythrocyte surface as part of the invasion machinery; antibodies against PfRipr truncate 5 (C720-D934, within C-terminal EGF-like domains) block both PfRipr/Rh5 and PfRipr/SEMA7A interactions, inhibiting merozoite invasion.\",\n      \"method\": \"Recombinant protein expression, ELISA binding assays, invasion inhibition assays, antibody blockade\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional invasion inhibition assays with recombinant proteins and blocking antibodies, single lab, two orthogonal readouts\",\n      \"pmids\": [\"32313230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Missense mutations in the semaphorin domain of SEMA7A (affecting codons 207 and 460/461) underlie variant JMH blood group phenotypes, resulting in reduced surface expression or qualitative changes; topological modeling showed SEMA7A polymorphisms are located on the top and bottom of the semaphorin domain, suggesting functional relevance for ligand-binding surfaces.\",\n      \"method\": \"Sanger sequencing, flow cytometry, Western blot, recombinant Sema7A protein expression, 3D structural modeling, genotype-phenotype correlation in 44 individuals\",\n      \"journal\": \"Transfusion\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (serology, flow, WB, recombinant protein), structural modeling, single lab\",\n      \"pmids\": [\"17207242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In gallbladder cancer, fibroblast-secreted SEMA7A binds integrin β1 (not PlexinC1) on cancer cells, inducing phosphorylation of the transcriptional coactivator p300 at S1834 via Akt activation (p-Akt at S473), thereby promoting EMT and cancer stem-like traits.\",\n      \"method\": \"Co-immunoprecipitation, Western blot, mutation assays, ELISA, Transwell/tumorsphere assays, subcutaneous tumor co-injection model\",\n      \"journal\": \"Biology direct\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for receptor binding, phosphorylation site specificity by mutation, in vivo model, single lab\",\n      \"pmids\": [\"40830485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The SEMA7A N559Y mutation strengthens its interaction with integrin β1, triggering the PI3K/Akt pathway and increasing ROS production, which activates the NLRP3 inflammasome and promotes hepatic cell pyroptosis, worsening metabolic dysfunction-associated steatotic liver disease.\",\n      \"method\": \"Heterozygous Sema7aN557Y knockin mice on HFD, Western blotting, biochemical/histological assays, Co-IP (enhanced SEMA7A-integrin β1 interaction)\",\n      \"journal\": \"Metabolism: clinical and experimental\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knockin model with mechanistic pathway validation, single lab\",\n      \"pmids\": [\"41429256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In colorectal cancer, SEMA7A activates the RAP1/AKT signaling pathway through its high-affinity receptor PlexinC1 in tumor-associated macrophages, promoting M2 polarization; rescue experiments with recombinant SEMA7A confirmed that blocking PlexinC1 suppresses M2-like TAM conversion.\",\n      \"method\": \"SEMA7A knockdown in CRC cell lines, transcriptomic analysis, recombinant SEMA7A rescue experiments, PlexinC1 blockade, in vivo AOM/DSS colitis-associated CRC model\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway identification by transcriptomics plus functional rescue experiments, in vivo model, single lab\",\n      \"pmids\": [\"41407164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In endometrial cancer, SEMA7A binds the PI3K regulatory subunit p85, activating the PI3K-AKT signaling pathway; NCAPG promotes SEMA7A transcription by facilitating LEF1 binding to chromatin, establishing an NCAPG/LEF1/SEMA7A/PI3K-AKT axis that drives cancer cell proliferation, migration and invasion.\",\n      \"method\": \"ATAC-seq, ChIP-qPCR, Co-immunoprecipitation (SEMA7A-p85 interaction), functional cell assays\",\n      \"journal\": \"Journal of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for SEMA7A-p85 interaction, ChIP for transcriptional regulation, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"39744480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In pancreatic cancer, SEMA7A expressed on tumor cell membranes (facilitated by ATP1A1) acts in juxtacrine fashion by binding fibroblasts and inducing IGFBP-3 secretion, which in turn increases IL-17RB expression via SNAI2 to promote tumor invasion.\",\n      \"method\": \"Co-culture experiments (tumor cell-fibroblast), knockdown/overexpression assays, IGFBP-3 secretion measurement, IL-17RB/SNAI2 signaling analysis\",\n      \"journal\": \"Cancer gene therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional co-culture mechanistic dissection with multiple pathway readouts, single lab\",\n      \"pmids\": [\"39448803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"RBC-derived Sema7A interacts with platelet integrin αIIb (identified by mass spectrometry and Co-IP), promoting recruitment of Talin1 and Lims1 and facilitating integrin-dependent signaling to enhance platelet activation and adhesion, thereby accelerating arterial thrombosis under disturbed flow; erythrocyte-specific Sema7A deletion reduced thrombus size and delayed vessel occlusion.\",\n      \"method\": \"Mass spectrometry, co-immunoprecipitation, global and erythrocyte-specific Sema7A KO mice, arterial thrombosis model (partial carotid ligation + FeCl3), flow chamber analysis, recombinant human Sema7A platelet activation assays, antibody blockade\",\n      \"journal\": \"Journal of thrombosis and haemostasis : JTH\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — MS identification of binding partner confirmed by Co-IP, genetic KO (global and cell-type specific), recombinant protein and antibody blockade as orthogonal approaches, in vivo model\",\n      \"pmids\": [\"42173291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Sema7A mediates osteogenic responses to hierarchical Ti6Al4V implant surface topography through the ITGB1/FAK/ERK signaling pathway, as revealed by RNA-seq with downstream pathway validation.\",\n      \"method\": \"RNA-seq of cells on implant surfaces, pathway validation (ITGB1/FAK/ERK), in vitro and in vivo osseointegration assays\",\n      \"journal\": \"ACS applied materials & interfaces\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — RNA-seq-based discovery with limited mechanistic follow-up of SEMA7A specifically, single lab\",\n      \"pmids\": [\"35776897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Knockdown of SEMA7A in MPP+-stimulated BV2 microglia reduced apoptosis and inflammation via PPAR-γ activation and MAPK signaling pathway inactivation; PPAR-γ inhibitor and MAPK activator blocked the protective effects of SEMA7A knockdown, placing SEMA7A upstream of these two pathways.\",\n      \"method\": \"SEMA7A knockdown (siRNA) in BV2 cells, PPAR-γ inhibitor and MAPK activator pharmacological epistasis, ELISA for cytokines, Western blot for iNOS/COX-2, viability and apoptosis assays\",\n      \"journal\": \"Immunity, inflammation and disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pharmacological epistasis in cell culture, single lab, single cell model\",\n      \"pmids\": [\"36705403\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In breast cancer, loss of Sema7A reduced KDM4A expression, induced DNA replication stress, and activated the cGAS-STING signaling pathway, increasing IFN-β and CXCL10 secretion and enhancing CD8+ T cell chemotaxis; KDM4A overexpression reversed these antitumor effects, establishing a Sema7A-KDM4A axis regulating the immunosuppressive microenvironment.\",\n      \"method\": \"SEMA7A loss-of-function in breast cancer cell lines, KDM4A overexpression rescue, cGAS-STING pathway measurement (IFN-β, CXCL10), CD8+ T cell chemotaxis assays, in vivo tumor growth/metastasis\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (KO + rescue), multiple pathway readouts, in vivo validation, single lab\",\n      \"pmids\": [\"41366110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SEMA7A binds integrins β1 and β4 via its RGD domain and activates AKT-mediated pro-survival signaling, contributing to endocrine therapy resistance in ER+ breast cancer; direct inhibition with an anti-SEMA7A monoclonal antibody (SmAbH1) significantly reduced tumor growth and, combined with fulvestrant, showed enhanced efficacy.\",\n      \"method\": \"Binding assays (integrin β1/β4), AKT pathway analysis, syngeneic ER+ mouse tumor models, PI3K inhibitor treatment, anti-SEMA7A antibody (SmAbH1) treatment in vivo\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, receptor binding and signaling data described but full mechanistic rigor unclear from abstract, single lab\",\n      \"pmids\": [\"bio_10.1101_2025.05.21.655360\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The olfactory critical period is determined by Sema7A/PlxnC1 signaling: activity-induced Sema7A in OSNs signals through PlxnC1 on mitral/tufted cell dendrites (restricted to the first postnatal week) to promote glomerular enlargement and increase sensitivity to experienced odors; this signaling operates independently from oxytocin-mediated positive imprinting of odor memory.\",\n      \"method\": \"Sema7A-KO and PlxnC1-KO mice, oxytocin-KO mice, knockout and rescue experiments, behavioral odor preference assays, glomerular morphology analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — replication of KO phenotypes (independent from prior study PMID:29743476), genetic epistasis with oxytocin-KO, multiple orthogonal behavioral and morphological readouts\",\n      \"pmids\": [\"33780330\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SEMA7A is a GPI-anchored semaphorin glycoprotein that signals through two principal receptors—PlexinC1 and integrin β1 (and related integrins)—to regulate diverse processes: in the nervous system, activity-induced SEMA7A in olfactory sensory neurons signals via PlexinC1 on mitral/tufted cells to drive activity-dependent synapse formation and olfactory critical period plasticity; in the immune system, SEMA7A potently activates monocytes/macrophages, promotes proresolving M2 polarization via mTOR/AKT2-dependent metabolic reprogramming (enhancing fatty acid oxidation and prostaglandin/SPM synthesis), and regulates macrophage polarization via the RAP1/AKT pathway downstream of PlexinC1; in stromal and metabolic contexts, SEMA7A cis-couples with integrin α5β1 to prime mechanotransduction and fibroblast function, inhibits adipogenesis via integrin β1/FAK signaling, and on erythrocytes interacts with platelet integrin αIIb (recruiting Talin1/Lims1) to promote arterial thrombosis; additionally, FUT8 catalyzes SEMA7A N-glycosylation at five sites required for its trafficking to the cell membrane, and specific mutations (e.g., N559Y) enhance integrin β1 binding to activate PI3K/Akt/ROS/NLRP3 pyroptosis signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SEMA7A is a GPI-anchored semaphorin glycoprotein that acts as a signaling ligand across the nervous, immune, stromal, and vascular systems by engaging two principal receptor classes\\u2014PlexinC1 and integrins [#1, #3]. In the olfactory system, activity-induced SEMA7A in olfactory sensory neurons signals through PlexinC1 on mitral/tufted cell dendrites to drive post-synaptic assembly, dendrite selection, and glomerular enlargement, thereby defining the olfactory critical period during the first postnatal week [#1, #18]. In the immune compartment, SEMA7A is a potent autocrine activator of monocytes\\u2014inducing chemotaxis, inflammatory cytokine output, and superoxide release [#0]\\u2014and it programs macrophage behavior by promoting pro-resolving M2 polarization and metabolic reprogramming toward fatty acid oxidation and specialized pro-resolving lipid mediator synthesis via mTOR and AKT2 signaling [#2]. In stromal and metabolic contexts, SEMA7A cis-couples with active integrin \\u03b15\\u03b21 to strengthen adhesion to fibronectin and enable mechanotransduction, supporting fibroblast migration, ECM assembly, and tissue repair [#3], and it restrains adipogenesis through integrin \\u03b21/FAK signaling, protecting against diet-induced obesity and hepatic steatosis [#4]. On erythrocytes, SEMA7A binds platelet integrin \\u03b1IIb to recruit Talin1 and Lims1, promoting platelet activation and arterial thrombosis [#13]. SEMA7A trafficking to the cell membrane depends on FUT8-catalyzed core fucosylation at five N-linked glycosylation sites [#5]. Across multiple cancers, SEMA7A\\u2013integrin \\u03b21 and SEMA7A\\u2013PlexinC1 signaling activate PI3K/AKT-dependent programs that promote EMT, stem-like traits, and M2-skewed tumor-associated macrophages [#8, #10]. Missense mutations in the semaphorin domain underlie variant JMH blood group phenotypes by altering surface expression [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established SEMA7A as a functionally active immune ligand rather than a purely neural cue, showing it directly activates innate immune cells.\",\n      \"evidence\": \"Recombinant protein stimulation of primary human monocytes with cytokine, superoxide, chemotaxis, and morphology readouts\",\n      \"pmids\": [\"12193228\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Receptor mediating monocyte activation not identified\", \"Single lab, no in vivo confirmation\", \"Mechanism of proteolytic release not defined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Linked SEMA7A semaphorin-domain polymorphisms to the JMH blood group, mapping functionally relevant surface residues.\",\n      \"evidence\": \"Sanger sequencing, flow cytometry, Western blot, recombinant protein, and structural modeling across 44 individuals\",\n      \"pmids\": [\"17207242\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Functional consequence for ligand-receptor binding not directly tested\", \"Effects on downstream signaling unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined the SEMA7A\\u2013PlexinC1 axis as an essential driver of activity-dependent synapse formation, establishing a directional ligand-receptor signaling relationship in the brain.\",\n      \"evidence\": \"Reciprocal Sema7A-KO and PlxnC1-KO mice with reconstitution and rescue, immunohistochemistry, pharmacological blockade\",\n      \"pmids\": [\"29743476\", \"33780330\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Intracellular signaling downstream of PlexinC1 in neurons not fully resolved\", \"Activity-dependent transcriptional control of Sema7A not detailed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed the SEMA7A/PlexinC1 axis times the olfactory critical period, distinguishing it from parallel oxytocin-driven imprinting.\",\n      \"evidence\": \"Sema7A-KO, PlxnC1-KO, and oxytocin-KO mice with rescue, behavioral odor assays, and glomerular morphology\",\n      \"pmids\": [\"33780330\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Molecular basis restricting the time window to the first postnatal week unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed that SEMA7A controls macrophage fate by metabolic reprogramming, connecting it to inflammation resolution through lipid-mediator class switching.\",\n      \"evidence\": \"Sema7A-/- macrophage metabolomics and lipidomics, mTOR/AKT2 pathway analysis, murine peritonitis and sepsis models with recombinant protein rescue\",\n      \"pmids\": [\"33637648\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Receptor coupling mTOR/AKT2 in macrophages not pinpointed\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified cis-coupling of SEMA7A with active integrin \\u03b15\\u03b21 as the mechanism by which it primes adhesion strengthening and mechanotransduction in stroma.\",\n      \"evidence\": \"Reciprocal Co-IP, integrin adhesion strengthening assays, fibroblast KD/KO phenotyping, and in vivo wound healing\",\n      \"pmids\": [\"37422024\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Structural basis of cis vs trans integrin engagement unresolved\", \"Relationship to PlexinC1 signaling in same cells unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placed SEMA7A as a brake on adipogenesis via integrin \\u03b21/FAK, extending its integrin signaling role to whole-body metabolism.\",\n      \"evidence\": \"Sema7A-/- mice, recombinant protein rescue, primary ADSC adipogenesis assays, and HFD obesity model\",\n      \"pmids\": [\"36842496\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct integrin \\u03b21 binding in adipocytes not biochemically mapped\", \"Tissue source of relevant SEMA7A in vivo unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated that FUT8-mediated core fucosylation at five N-glycosylation sites is required for SEMA7A membrane trafficking, defining a post-translational gate on its surface availability.\",\n      \"evidence\": \"MS glycosite mapping, reciprocal Co-IP, subcellular fractionation/trafficking and deglycosylation assays, cytokine stimulation\",\n      \"pmids\": [\"38548747\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Whether fucosylation modulates receptor binding affinity not tested\", \"Generality across cell types beyond the studied context unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed SEMA7A juxtacrine signaling between tumor cells and fibroblasts drives invasion through an IGFBP-3/IL-17RB/SNAI2 cascade.\",\n      \"evidence\": \"Tumor cell\\u2013fibroblast co-culture, knockdown/overexpression, secretion measurement, and pathway analysis\",\n      \"pmids\": [\"39448803\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Receptor on fibroblasts mediating SEMA7A binding not identified\", \"In vivo validation limited\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Mapped multiple cancer-context signaling outputs of SEMA7A through integrin \\u03b21 and PlexinC1, converging on PI3K/AKT to drive EMT, stemness, and M2 TAM polarization.\",\n      \"evidence\": \"Co-IP receptor identification, phospho-site mutation assays, transcriptomics, PlexinC1 blockade, and in vivo tumor models in gallbladder, colorectal, and endometrial cancers\",\n      \"pmids\": [\"40830485\", \"41407164\", \"39744480\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Determinants of receptor choice (integrin \\u03b21 vs PlexinC1) across tissues unknown\", \"Each axis from a single lab/context\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked a SEMA7A-KDM4A axis to immune evasion, showing SEMA7A loss triggers replication stress and cGAS-STING activation to recruit CD8+ T cells.\",\n      \"evidence\": \"SEMA7A loss-of-function with KDM4A overexpression rescue, cGAS-STING readouts, T cell chemotaxis assays, and in vivo breast tumor models\",\n      \"pmids\": [\"41366110\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanism linking SEMA7A to KDM4A expression unresolved\", \"Whether this depends on surface signaling or intracellular function unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed a SEMA7A N559Y gain-of-function mutation enhances integrin \\u03b21 binding to drive PI3K/Akt/ROS/NLRP3 pyroptosis in metabolic liver disease.\",\n      \"evidence\": \"Sema7aN557Y knockin mice on HFD, Co-IP, and biochemical/histological pathway validation\",\n      \"pmids\": [\"41429256\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Structural basis for enhanced integrin binding not determined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Established an erythrocyte-platelet SEMA7A signaling role, where RBC SEMA7A engages integrin \\u03b1IIb to recruit Talin1/Lims1 and accelerate arterial thrombosis.\",\n      \"evidence\": \"MS and Co-IP partner identification, global and erythrocyte-specific KO mice, arterial thrombosis and flow chamber models, recombinant protein and antibody blockade\",\n      \"pmids\": [\"42173291\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Whether RBC SEMA7A is membrane-bound or shed during the interaction not fully defined\", \"Relevance to human thrombotic disease not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SEMA7A selects between PlexinC1 and distinct integrins in a given cell type, and how glycosylation and the GPI anchor tune this receptor choice, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No structural model defining concurrent PlexinC1 vs integrin engagement\", \"Determinants of cis vs trans signaling across tissues unknown\", \"Link between FUT8 fucosylation and receptor affinity untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [1, 0, 18]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 4, 13]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [3, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 3, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 3, 4]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 2, 10]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [1, 18]},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PLXNC1\", \"ITGB1\", \"ITGA5\", \"ITGB4\", \"ITGA2B\", \"FUT8\", \"TLN1\", \"LIMS1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}