{"gene":"FBXO38","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2004,"finding":"FBXO38 (MoKA) physically interacts with KLF7 transcription factor, confirmed by GST pull-down and co-immunoprecipitation, and functions as a KLF7 coactivator to stimulate transcription of target genes including p21(WAF1/Cip1). Distinct structural motifs of FBXO38 mediate KLF7 interaction and nucleocytoplasmic shuttling.","method":"Yeast two-hybrid screen, GST pull-down, co-immunoprecipitation, chromatin immunoprecipitation, transient transfection reporter assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (Y2H, GST pulldown, Co-IP, ChIP, reporter assay) in a single study establishing interaction and functional consequence","pmids":["14729953"],"is_preprint":false},{"year":2006,"finding":"FBXO38 (MoKA) shuttles between nucleus and cytoplasm via a single functional NLS recognized by karyopherin receptors and three distinct cytoplasmic retention/export sequences: one CRM1-dependent leucine-rich NES and two CRM1-independent export signals. The major transcriptional activation domain maps to a highly acidic sequence between the NLS and NES clusters.","method":"Forced expression of fusion proteins in mammalian cells, nuclear export inhibitor (leptomycin B) treatment, deletion/mutation analysis, GAL4 chimeric transcriptional assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (localization mapping, export-inhibitor treatment, GAL4 reporter) in a single focused study","pmids":["16990251"],"is_preprint":false},{"year":2013,"finding":"The FBXO38 p.Cys206Arg missense mutation impairs KLF7-mediated transactivation of a KLF7-responsive promoter and endogenous KLF7 target genes without altering subcellular localization of FBXO38, and this transcriptional dysregulation is associated with impaired neurite outgrowth in primary motor neurons.","method":"Transient transfection reporter assays in HEK293T cells, fibroblasts from patients with the mutation, primary motor neuron neurite outgrowth assay","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal functional readouts (reporter assay + neurite outgrowth), patient-derived cells, single lab","pmids":["24207122"],"is_preprint":false},{"year":2018,"finding":"FBXO38 is an E3 ubiquitin ligase that mediates Lys48-linked poly-ubiquitination of PD-1 and subsequent proteasome-dependent degradation after PD-1 internalization in activated T cells. Conditional T cell-specific Fbxo38 knockout led to elevated PD-1 on tumor-infiltrating T cells and faster tumor progression in mice, which was normalized by anti-PD-1 therapy.","method":"E3 ligase identification, ubiquitination assay (Lys48-linkage specificity), conditional knockout mice, tumor growth assays, anti-PD-1 rescue experiment","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro ubiquitination assay with linkage specificity, genetic KO with defined phenotype, pharmacological rescue, published in high-impact journal","pmids":["30487606"],"is_preprint":false},{"year":2019,"finding":"USP7 deubiquitylase stabilizes FBXO38 by protecting it from proteasomal degradation in a catalytic-activity-dependent manner. FBXO38 in turn stabilizes KIF20B (a Kinesin-6 required for cytokinesis) independently of an SCF complex. Depletion of either USP7 or FBXO38 reduces KIF20B levels and its midbody localization, causing cytokinetic defects; these defects are rescued by restoring FBXO38 or KIF20B.","method":"Affinity purification-mass spectrometry, BioID proximity labeling, co-immunoprecipitation, siRNA knockdown, proteasome inhibitor treatment, cytokinesis phenotype assay, rescue experiments","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal AP-MS and BioID, genetic knockdown with defined cytokinetic phenotype, epistatic rescue experiments across multiple targets","pmids":["30804394"],"is_preprint":false},{"year":2022,"finding":"FBXO38 functions as the substrate receptor of the SCF(FBXO38) E3 ubiquitin ligase complex and directly promotes ubiquitination and proteasome-dependent degradation of zinc finger proteins ZXDA and ZXDB. ZXDA/B associate with centromeric protein CENP-B, and their stabilization upon FBXO38 loss leads to upregulation of CENP-A and CENP-B positive centromeric chromatin, establishing a role for cullin-dependent degradation in centromere integrity control.","method":"Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor treatment, chromatin immunoprecipitation, mutant cell analysis","journal":"Frontiers in cell and developmental biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro/cellular ubiquitination assay, Co-IP substrate identification, ChIP, proteasome inhibitor rescue, single lab with multiple orthogonal methods","pmids":["35813202"],"is_preprint":false},{"year":2022,"finding":"In Sertoli cells, FBXO38 controls centromeric chromatin integrity through ZXDB degradation. Loss of FBXO38 in mice causes ZXDB stabilization, upregulated centromeric chromatin, defective Sertoli cell maturation (dysregulation of retinoic acid metabolism and intercellular communication genes), and impaired spermatogonial differentiation, leading to reduced sperm production and fertility.","method":"Fbxo38 conditional knockout mice, immunofluorescence, gene expression profiling, histological analysis of testes","journal":"Frontiers in cell and developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional KO mouse model with defined molecular and cellular phenotypes, multiple orthogonal readouts in single study","pmids":["35769260"],"is_preprint":false},{"year":2023,"finding":"FBXO38 promotes macrophage immunosuppressive (M2-like) polarization by upregulating M2-like gene expression via MAPK and IRF4 signaling pathways, without affecting M1-like polarization. Fbxo38 deletion in macrophages blocks tumor development and protects against DSS-induced colitis in mice.","method":"Macrophage-specific conditional knockout mice, tumor growth assay, DSS colitis model, gene expression analysis, pathway analysis (MAPK/IRF4)","journal":"Cellular & molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with two in vivo disease models, pathway identification; single lab","pmids":["37821621"],"is_preprint":false},{"year":2023,"finding":"FBXO38 interacts with and ubiquitylates FGL1, promoting its proteasome-dependent degradation. Depletion of FBXO38 markedly increases FGL1 abundance, suppresses CD8+ T cell infiltration, and enhances immune evasion. Additionally, FBXO38 deficiency increases IL-6 levels in vivo and in cancer specimens.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, in vitro and in vivo tumor models, correlation analysis in patient specimens","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assay establish substrate relationship; in vivo model confirms functional consequence; single lab","pmids":["37938970"],"is_preprint":false},{"year":2024,"finding":"FBXO38 deficiency reduces STING protein levels through lysosome-mediated (not proteasomal) degradation, thereby inhibiting cGAS-STING pathway activation, reducing downstream IFNA1 and CCL5 production, enhancing tumor proliferation, and reducing CD8+ T cell infiltration.","method":"siRNA knockdown, in vitro and in vivo tumor models, lysosome inhibitor vs. proteasome inhibitor treatment, pathway activation assays (IFNA1, CCL5 measurement)","journal":"Neoplasia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic dissection using specific inhibitors (lysosome vs. proteasome), in vitro and in vivo models; single lab","pmids":["38277817"],"is_preprint":false},{"year":2024,"finding":"FBXO38 is dispensable for PD-1 regulation in T cells. Experimental re-examination failed to support the notion that SCF(FBXO38) directly or indirectly controls the abundance and stability of PD-1 in T cells, contradicting the earlier report (PMID:30487606).","method":"Genetic T cell-specific knockout/re-examination, protein stability assays in T cells","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct genetic re-examination with negative finding; contradicts a prior high-profile study; single lab reporting negative result","pmids":["39266770"],"is_preprint":false},{"year":2024,"finding":"FBXO38 deficiency in NK cells enhances TGF-β signaling (elevating Smad2 and Smad3), which suppresses expression of transcription factor Eomes and reduces surface IL15Rβ and IL15Rγc expression on NK cells, leading to NK cell hyporesponsiveness to IL-15 and impaired proliferation/survival. FBXO38 overexpression in human NK cells enhances antitumor activity in vivo.","method":"NK-cell-specific conditional knockout mice, tumor growth and metastasis assays, flow cytometry, gene expression analysis, adoptive transfer of FBXO38-overexpressing human NK cells","journal":"Cancer immunology research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with mechanistic pathway dissection (TGF-β/Smad/Eomes/IL15R axis) and in vivo gain-of-function; single lab","pmids":["38990095"],"is_preprint":false},{"year":2025,"finding":"FBXO38 directly interacts with NADPH oxidase Nox1 and promotes its ubiquitin-proteasome-dependent degradation in endothelial cells. Under low oscillatory shear stress, FBXO38 protein levels are reduced (~60%), leading to Nox1 accumulation (~2-fold), increased ROS production, and endothelial apoptosis. FBXO38 overexpression attenuates Nox1 accumulation and reduces ROS under these conditions.","method":"Co-immunoprecipitation, overexpression and knockdown in HUVECs, in vitro shear stress model, in vivo partial carotid ligation mouse model, western blotting, immunofluorescence","journal":"Cardiovascular therapeutics","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP plus in vitro and in vivo gain/loss-of-function with quantified molecular readouts; single lab","pmids":["40313652"],"is_preprint":false}],"current_model":"FBXO38 is an F-box-containing E3 ubiquitin ligase that acts as the substrate receptor for SCF(FBXO38) complexes to mediate Lys48-linked ubiquitination and proteasomal degradation of multiple substrates including ZXDA/B (controlling centromere integrity), FGL1, and Nox1; it also stabilizes KIF20B (required for cytokinesis) independently of SCF, is itself stabilized by the deubiquitylase USP7, functions as a transcriptional coactivator of KLF7 with nucleocytoplasmic shuttling regulated by distinct NLS and NES elements, and plays cell-type-specific roles in T cells, NK cells, macrophages, and Sertoli cells to regulate immune checkpoints and reproductive function—though whether FBXO38 directly degrades PD-1 in T cells remains contested."},"narrative":{"mechanistic_narrative":"FBXO38 is an F-box protein that serves as the substrate receptor of SCF(FBXO38) E3 ubiquitin ligase complexes, directing Lys48-linked poly-ubiquitination and proteasomal degradation of multiple substrates and thereby governing centromere integrity, immune cell function, and vascular homeostasis [PMID:35813202, PMID:37938970]. As a degradation receptor it directly ubiquitylates the zinc-finger proteins ZXDA and ZXDB, restraining CENP-A/CENP-B-positive centromeric chromatin, a function that is required for Sertoli cell maturation and spermatogonial differentiation in vivo [PMID:35813202, PMID:35769260]. The same degradative activity targets the LAG-3 ligand FGL1 and the NADPH oxidase Nox1, linking FBXO38 to CD8+ T cell-mediated immune surveillance and to endothelial redox balance under shear stress [PMID:37938970, PMID:40313652]. Beyond canonical SCF activity, FBXO38 is itself stabilized by the deubiquitylase USP7 and acts non-degradatively to stabilize the cytokinesis kinesin KIF20B at the midbody, such that loss of either USP7 or FBXO38 causes cytokinetic defects [PMID:30804394]. Independently of ubiquitin ligase function, FBXO38 (MoKA) is a nucleocytoplasmic shuttling transcriptional coactivator of KLF7 that stimulates target genes including p21(WAF1/Cip1), an activity disrupted by the p.Cys206Arg mutation associated with impaired motor neuron neurite outgrowth [PMID:14729953, PMID:24207122]. At the organismal level FBXO38 exerts cell-type-specific control over immune responses, promoting M2-like macrophage polarization via MAPK/IRF4 signaling and supporting IL-15 responsiveness of NK cells by restraining TGF-β/Smad signaling [PMID:37821621, PMID:38990095]. Its reported role in degrading PD-1 in T cells [PMID:30487606] has been contradicted by genetic re-examination finding FBXO38 dispensable for PD-1 regulation [PMID:39266770].","teleology":[{"year":2004,"claim":"Established the first molecular function of FBXO38 (MoKA) as a transcriptional coactivator, defining a partner and a downstream target before its ubiquitin ligase role was known.","evidence":"Y2H, GST pull-down, Co-IP, ChIP and reporter assays linking FBXO38 to KLF7 and p21 transcription","pmids":["14729953"],"confidence":"High","gaps":["Did not address how coactivation relates to any ubiquitin ligase activity","Domain basis of KLF7 interaction not resolved structurally"]},{"year":2006,"claim":"Resolved how FBXO38 traffics between compartments, mapping discrete NLS, CRM1-dependent and CRM1-independent export signals and the acidic activation domain controlling its transcriptional function.","evidence":"Fusion protein localization, leptomycin B treatment, deletion/mutation analysis and GAL4 chimeric reporter assays in mammalian cells","pmids":["16990251"],"confidence":"High","gaps":["Did not connect shuttling regulation to substrate degradation","Physiological signals regulating shuttling not identified"]},{"year":2013,"claim":"Connected a disease-associated missense variant to loss of KLF7 coactivation, providing the first genotype-phenotype link for the transcriptional function.","evidence":"Reporter assays and patient-derived fibroblasts plus primary motor neuron neurite outgrowth assay for the p.Cys206Arg mutation","pmids":["24207122"],"confidence":"Medium","gaps":["Mechanism by which the mutation impairs coactivation not defined","Single lab; effect on ligase function not tested"]},{"year":2018,"claim":"Reframed FBXO38 as an E3 ubiquitin ligase by reporting Lys48-linked ubiquitination and degradation of PD-1, with a tumor immunity phenotype in conditional knockout mice.","evidence":"In vitro ubiquitination with linkage specificity, T cell-specific conditional knockout, tumor growth and anti-PD-1 rescue","pmids":["30487606"],"confidence":"High","gaps":["Substrate relationship later contradicted by genetic re-examination","SCF complex requirement for PD-1 not dissected here"]},{"year":2019,"claim":"Defined the upstream stabilizer of FBXO38 and a non-degradative output, showing USP7 protects FBXO38 which in turn stabilizes KIF20B for cytokinesis independently of SCF.","evidence":"AP-MS, BioID, Co-IP, siRNA knockdown, proteasome inhibition and cytokinesis rescue experiments","pmids":["30804394"],"confidence":"High","gaps":["Molecular basis of SCF-independent KIF20B stabilization unknown","How USP7 selectively targets FBXO38 not defined"]},{"year":2022,"claim":"Identified bona fide SCF(FBXO38) substrates ZXDA/B and linked their degradation to centromeric chromatin control, both in cells and in a Sertoli cell/fertility context.","evidence":"Co-IP, ubiquitination assays, proteasome inhibition, ChIP, and Fbxo38 conditional knockout mice with testis phenotyping","pmids":["35813202","35769260"],"confidence":"High","gaps":["Direct enzymatic reconstitution of SCF(FBXO38) on ZXDA/B not shown","Link between centromeric chromatin changes and the spermatogenic phenotype is correlative"]},{"year":2023,"claim":"Extended FBXO38 substrate range to FGL1 and assigned a macrophage-intrinsic role in M2 polarization, broadening its immunoregulatory functions.","evidence":"Co-IP/ubiquitination with siRNA and tumor models for FGL1; macrophage-specific knockout with tumor and DSS colitis models and MAPK/IRF4 pathway analysis","pmids":["37938970","37821621"],"confidence":"Medium","gaps":["Whether macrophage M2 effect is ubiquitination-dependent not established","Direct substrate in the MAPK/IRF4 axis not identified","Single lab for each finding"]},{"year":2024,"claim":"Challenged the original PD-1 model and added new degradation-independent and lysosomal mechanisms, indicating FBXO38 outputs are context- and substrate-specific.","evidence":"Genetic re-examination in T cells (PD-1); lysosome vs proteasome inhibitor dissection of STING; NK-cell conditional knockout dissecting the TGF-β/Smad/Eomes/IL15R axis","pmids":["39266770","38277817","38990095"],"confidence":"Medium","gaps":["Source of discrepancy in PD-1 regulation unresolved","Mechanism by which FBXO38 affects STING lysosomal turnover unclear","Direct substrate in the NK TGF-β axis not defined"]},{"year":2025,"claim":"Showed FBXO38 degrades Nox1 to limit endothelial ROS, linking shear-stress-regulated FBXO38 abundance to vascular oxidative stress and apoptosis.","evidence":"Co-IP, gain/loss-of-function in HUVECs, in vitro shear stress model and in vivo partial carotid ligation","pmids":["40313652"],"confidence":"Medium","gaps":["Ubiquitin linkage specificity on Nox1 not characterized","Mechanism reducing FBXO38 under oscillatory shear not defined"]},{"year":null,"claim":"It remains unresolved which FBXO38 functions require SCF-dependent ubiquitination versus degradation-independent or transcriptional activities, and how substrate selection is partitioned across cell types.","evidence":"No single study integrates the ligase, stabilizer, lysosomal, and coactivator activities under a unified mechanistic framework","pmids":[],"confidence":"Low","gaps":["No structural model of substrate recognition by SCF(FBXO38)","Unknown determinants of substrate-specific proteasomal vs lysosomal routing","Reconciliation of the contested PD-1 phenotype outstanding"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[3,5,8,12]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[3,5]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,2]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[5,6]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[3,5,8]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[7,8,11]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[4]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0]}],"complexes":["SCF(FBXO38)"],"partners":["KLF7","USP7","KIF20B","ZXDA","ZXDB","FGL1","NOX1","PDCD1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6PIJ6","full_name":"F-box only protein 38","aliases":[],"length_aa":1188,"mass_kda":133.9,"function":"Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of PDCD1/PD-1, thereby regulating T-cells-mediated immunity (PubMed:30487606). Required for anti-tumor activity of T-cells by promoting the degradation of PDCD1/PD-1; the PDCD1-mediated inhibitory pathway being exploited by tumors to attenuate anti-tumor immunity and facilitate tumor survival (PubMed:30487606). May indirectly stimulate the activity of transcription factor KLF7, a regulator of neuronal differentiation, without promoting KLF7 ubiquitination (By similarity)","subcellular_location":"Cytoplasm, cytosol; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q6PIJ6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FBXO38","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":[],"url":"https://opencell.sf.czbiohub.org/search/FBXO38","total_profiled":1310},"omim":[{"mim_id":"615575","title":"NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 6; HMND6","url":"https://www.omim.org/entry/615575"},{"mim_id":"608533","title":"F-BOX ONLY PROTEIN 38; FBXO38","url":"https://www.omim.org/entry/608533"},{"mim_id":"604327","title":"BETA-1,4-GALACTOSYLTRANSFERASE 7; B4GALT7","url":"https://www.omim.org/entry/604327"},{"mim_id":"600244","title":"PROGRAMMED CELL DEATH 1; PDCD1","url":"https://www.omim.org/entry/600244"},{"mim_id":"182960","title":"NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 1; HMND1","url":"https://www.omim.org/entry/182960"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Approved"},{"location":"Primary cilium","reliability":"Additional"},{"location":"Basal body","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/FBXO38"},"hgnc":{"alias_symbol":["MOKA","SP329","FLJ13962","Fbx38"],"prev_symbol":[]},"alphafold":{"accession":"Q6PIJ6","domains":[{"cath_id":"-","chopping":"984-993_1002-1125_1140-1175","consensus_level":"high","plddt":82.3352,"start":984,"end":1175}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6PIJ6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6PIJ6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6PIJ6-F1-predicted_aligned_error_v6.png","plddt_mean":67.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FBXO38","jax_strain_url":"https://www.jax.org/strain/search?query=FBXO38"},"sequence":{"accession":"Q6PIJ6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6PIJ6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6PIJ6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6PIJ6"}},"corpus_meta":[{"pmid":"30487606","id":"PMC_30487606","title":"FBXO38 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abnormalities by chromosome conformation based karyotyping (C-MoKa) in patients with conception failure and pregnancy loss.","date":"2024","source":"Clinica chimica acta; international journal of clinical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/39674306","citation_count":5,"is_preprint":false},{"pmid":"40313652","id":"PMC_40313652","title":"FBXO38 Regulates Nox1 Stability to Reduce Vascular Endothelial Damage Induced by Low Oscillatory Shear Stress.","date":"2025","source":"Cardiovascular therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/40313652","citation_count":0,"is_preprint":false},{"pmid":"41546764","id":"PMC_41546764","title":"Chebulagic acid targets FBXO38 to enhance natural killer cell-mediated anti-tumor immunity in lung adenocarcinoma.","date":"2026","source":"Human cell","url":"https://pubmed.ncbi.nlm.nih.gov/41546764","citation_count":0,"is_preprint":false},{"pmid":"41417631","id":"PMC_41417631","title":"MOKA: a pipeline for multiomics bridged SNP-set kernel 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biology","url":"https://pubmed.ncbi.nlm.nih.gov/36211459","citation_count":0,"is_preprint":false},{"pmid":"41621847","id":"PMC_41621847","title":"[Precise identification of a cryptic balanced translocation in a couple with recurrent spontaneous abortions using C-MoKa technique].","date":"2026","source":"Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/41621847","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.07.08.24310079","title":"Overlap between COPD genetic association results and transcriptional quantitative trait loci","date":"2024-07-08","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.08.24310079","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.07.06.25330974","title":"MOKA: A pipeline for multi-omics bridged SNP-set kernel association test","date":"2025-07-07","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.06.25330974","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13704,"output_tokens":3553,"usd":0.047204,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11183,"output_tokens":3673,"usd":0.07387,"stage2_stop_reason":"end_turn"},"total_usd":0.121074,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"FBXO38 (MoKA) physically interacts with KLF7 transcription factor, confirmed by GST pull-down and co-immunoprecipitation, and functions as a KLF7 coactivator to stimulate transcription of target genes including p21(WAF1/Cip1). Distinct structural motifs of FBXO38 mediate KLF7 interaction and nucleocytoplasmic shuttling.\",\n      \"method\": \"Yeast two-hybrid screen, GST pull-down, co-immunoprecipitation, chromatin immunoprecipitation, transient transfection reporter assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (Y2H, GST pulldown, Co-IP, ChIP, reporter assay) in a single study establishing interaction and functional consequence\",\n      \"pmids\": [\"14729953\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"FBXO38 (MoKA) shuttles between nucleus and cytoplasm via a single functional NLS recognized by karyopherin receptors and three distinct cytoplasmic retention/export sequences: one CRM1-dependent leucine-rich NES and two CRM1-independent export signals. The major transcriptional activation domain maps to a highly acidic sequence between the NLS and NES clusters.\",\n      \"method\": \"Forced expression of fusion proteins in mammalian cells, nuclear export inhibitor (leptomycin B) treatment, deletion/mutation analysis, GAL4 chimeric transcriptional assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (localization mapping, export-inhibitor treatment, GAL4 reporter) in a single focused study\",\n      \"pmids\": [\"16990251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The FBXO38 p.Cys206Arg missense mutation impairs KLF7-mediated transactivation of a KLF7-responsive promoter and endogenous KLF7 target genes without altering subcellular localization of FBXO38, and this transcriptional dysregulation is associated with impaired neurite outgrowth in primary motor neurons.\",\n      \"method\": \"Transient transfection reporter assays in HEK293T cells, fibroblasts from patients with the mutation, primary motor neuron neurite outgrowth assay\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal functional readouts (reporter assay + neurite outgrowth), patient-derived cells, single lab\",\n      \"pmids\": [\"24207122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FBXO38 is an E3 ubiquitin ligase that mediates Lys48-linked poly-ubiquitination of PD-1 and subsequent proteasome-dependent degradation after PD-1 internalization in activated T cells. Conditional T cell-specific Fbxo38 knockout led to elevated PD-1 on tumor-infiltrating T cells and faster tumor progression in mice, which was normalized by anti-PD-1 therapy.\",\n      \"method\": \"E3 ligase identification, ubiquitination assay (Lys48-linkage specificity), conditional knockout mice, tumor growth assays, anti-PD-1 rescue experiment\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro ubiquitination assay with linkage specificity, genetic KO with defined phenotype, pharmacological rescue, published in high-impact journal\",\n      \"pmids\": [\"30487606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"USP7 deubiquitylase stabilizes FBXO38 by protecting it from proteasomal degradation in a catalytic-activity-dependent manner. FBXO38 in turn stabilizes KIF20B (a Kinesin-6 required for cytokinesis) independently of an SCF complex. Depletion of either USP7 or FBXO38 reduces KIF20B levels and its midbody localization, causing cytokinetic defects; these defects are rescued by restoring FBXO38 or KIF20B.\",\n      \"method\": \"Affinity purification-mass spectrometry, BioID proximity labeling, co-immunoprecipitation, siRNA knockdown, proteasome inhibitor treatment, cytokinesis phenotype assay, rescue experiments\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal AP-MS and BioID, genetic knockdown with defined cytokinetic phenotype, epistatic rescue experiments across multiple targets\",\n      \"pmids\": [\"30804394\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FBXO38 functions as the substrate receptor of the SCF(FBXO38) E3 ubiquitin ligase complex and directly promotes ubiquitination and proteasome-dependent degradation of zinc finger proteins ZXDA and ZXDB. ZXDA/B associate with centromeric protein CENP-B, and their stabilization upon FBXO38 loss leads to upregulation of CENP-A and CENP-B positive centromeric chromatin, establishing a role for cullin-dependent degradation in centromere integrity control.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor treatment, chromatin immunoprecipitation, mutant cell analysis\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro/cellular ubiquitination assay, Co-IP substrate identification, ChIP, proteasome inhibitor rescue, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"35813202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In Sertoli cells, FBXO38 controls centromeric chromatin integrity through ZXDB degradation. Loss of FBXO38 in mice causes ZXDB stabilization, upregulated centromeric chromatin, defective Sertoli cell maturation (dysregulation of retinoic acid metabolism and intercellular communication genes), and impaired spermatogonial differentiation, leading to reduced sperm production and fertility.\",\n      \"method\": \"Fbxo38 conditional knockout mice, immunofluorescence, gene expression profiling, histological analysis of testes\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO mouse model with defined molecular and cellular phenotypes, multiple orthogonal readouts in single study\",\n      \"pmids\": [\"35769260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FBXO38 promotes macrophage immunosuppressive (M2-like) polarization by upregulating M2-like gene expression via MAPK and IRF4 signaling pathways, without affecting M1-like polarization. Fbxo38 deletion in macrophages blocks tumor development and protects against DSS-induced colitis in mice.\",\n      \"method\": \"Macrophage-specific conditional knockout mice, tumor growth assay, DSS colitis model, gene expression analysis, pathway analysis (MAPK/IRF4)\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with two in vivo disease models, pathway identification; single lab\",\n      \"pmids\": [\"37821621\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FBXO38 interacts with and ubiquitylates FGL1, promoting its proteasome-dependent degradation. Depletion of FBXO38 markedly increases FGL1 abundance, suppresses CD8+ T cell infiltration, and enhances immune evasion. Additionally, FBXO38 deficiency increases IL-6 levels in vivo and in cancer specimens.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, in vitro and in vivo tumor models, correlation analysis in patient specimens\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assay establish substrate relationship; in vivo model confirms functional consequence; single lab\",\n      \"pmids\": [\"37938970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FBXO38 deficiency reduces STING protein levels through lysosome-mediated (not proteasomal) degradation, thereby inhibiting cGAS-STING pathway activation, reducing downstream IFNA1 and CCL5 production, enhancing tumor proliferation, and reducing CD8+ T cell infiltration.\",\n      \"method\": \"siRNA knockdown, in vitro and in vivo tumor models, lysosome inhibitor vs. proteasome inhibitor treatment, pathway activation assays (IFNA1, CCL5 measurement)\",\n      \"journal\": \"Neoplasia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic dissection using specific inhibitors (lysosome vs. proteasome), in vitro and in vivo models; single lab\",\n      \"pmids\": [\"38277817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FBXO38 is dispensable for PD-1 regulation in T cells. Experimental re-examination failed to support the notion that SCF(FBXO38) directly or indirectly controls the abundance and stability of PD-1 in T cells, contradicting the earlier report (PMID:30487606).\",\n      \"method\": \"Genetic T cell-specific knockout/re-examination, protein stability assays in T cells\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct genetic re-examination with negative finding; contradicts a prior high-profile study; single lab reporting negative result\",\n      \"pmids\": [\"39266770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FBXO38 deficiency in NK cells enhances TGF-β signaling (elevating Smad2 and Smad3), which suppresses expression of transcription factor Eomes and reduces surface IL15Rβ and IL15Rγc expression on NK cells, leading to NK cell hyporesponsiveness to IL-15 and impaired proliferation/survival. FBXO38 overexpression in human NK cells enhances antitumor activity in vivo.\",\n      \"method\": \"NK-cell-specific conditional knockout mice, tumor growth and metastasis assays, flow cytometry, gene expression analysis, adoptive transfer of FBXO38-overexpressing human NK cells\",\n      \"journal\": \"Cancer immunology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with mechanistic pathway dissection (TGF-β/Smad/Eomes/IL15R axis) and in vivo gain-of-function; single lab\",\n      \"pmids\": [\"38990095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FBXO38 directly interacts with NADPH oxidase Nox1 and promotes its ubiquitin-proteasome-dependent degradation in endothelial cells. Under low oscillatory shear stress, FBXO38 protein levels are reduced (~60%), leading to Nox1 accumulation (~2-fold), increased ROS production, and endothelial apoptosis. FBXO38 overexpression attenuates Nox1 accumulation and reduces ROS under these conditions.\",\n      \"method\": \"Co-immunoprecipitation, overexpression and knockdown in HUVECs, in vitro shear stress model, in vivo partial carotid ligation mouse model, western blotting, immunofluorescence\",\n      \"journal\": \"Cardiovascular therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP plus in vitro and in vivo gain/loss-of-function with quantified molecular readouts; single lab\",\n      \"pmids\": [\"40313652\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FBXO38 is an F-box-containing E3 ubiquitin ligase that acts as the substrate receptor for SCF(FBXO38) complexes to mediate Lys48-linked ubiquitination and proteasomal degradation of multiple substrates including ZXDA/B (controlling centromere integrity), FGL1, and Nox1; it also stabilizes KIF20B (required for cytokinesis) independently of SCF, is itself stabilized by the deubiquitylase USP7, functions as a transcriptional coactivator of KLF7 with nucleocytoplasmic shuttling regulated by distinct NLS and NES elements, and plays cell-type-specific roles in T cells, NK cells, macrophages, and Sertoli cells to regulate immune checkpoints and reproductive function—though whether FBXO38 directly degrades PD-1 in T cells remains contested.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FBXO38 is an F-box protein that serves as the substrate receptor of SCF(FBXO38) E3 ubiquitin ligase complexes, directing Lys48-linked poly-ubiquitination and proteasomal degradation of multiple substrates and thereby governing centromere integrity, immune cell function, and vascular homeostasis [#5, #8]. As a degradation receptor it directly ubiquitylates the zinc-finger proteins ZXDA and ZXDB, restraining CENP-A/CENP-B-positive centromeric chromatin, a function that is required for Sertoli cell maturation and spermatogonial differentiation in vivo [#5, #6]. The same degradative activity targets the LAG-3 ligand FGL1 and the NADPH oxidase Nox1, linking FBXO38 to CD8+ T cell-mediated immune surveillance and to endothelial redox balance under shear stress [#8, #12]. Beyond canonical SCF activity, FBXO38 is itself stabilized by the deubiquitylase USP7 and acts non-degradatively to stabilize the cytokinesis kinesin KIF20B at the midbody, such that loss of either USP7 or FBXO38 causes cytokinetic defects [#4]. Independently of ubiquitin ligase function, FBXO38 (MoKA) is a nucleocytoplasmic shuttling transcriptional coactivator of KLF7 that stimulates target genes including p21(WAF1/Cip1), an activity disrupted by the p.Cys206Arg mutation associated with impaired motor neuron neurite outgrowth [#0, #2]. At the organismal level FBXO38 exerts cell-type-specific control over immune responses, promoting M2-like macrophage polarization via MAPK/IRF4 signaling and supporting IL-15 responsiveness of NK cells by restraining TGF-\\u03b2/Smad signaling [#7, #11]. Its reported role in degrading PD-1 in T cells [#3] has been contradicted by genetic re-examination finding FBXO38 dispensable for PD-1 regulation [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established the first molecular function of FBXO38 (MoKA) as a transcriptional coactivator, defining a partner and a downstream target before its ubiquitin ligase role was known.\",\n      \"evidence\": \"Y2H, GST pull-down, Co-IP, ChIP and reporter assays linking FBXO38 to KLF7 and p21 transcription\",\n      \"pmids\": [\"14729953\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address how coactivation relates to any ubiquitin ligase activity\", \"Domain basis of KLF7 interaction not resolved structurally\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Resolved how FBXO38 traffics between compartments, mapping discrete NLS, CRM1-dependent and CRM1-independent export signals and the acidic activation domain controlling its transcriptional function.\",\n      \"evidence\": \"Fusion protein localization, leptomycin B treatment, deletion/mutation analysis and GAL4 chimeric reporter assays in mammalian cells\",\n      \"pmids\": [\"16990251\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not connect shuttling regulation to substrate degradation\", \"Physiological signals regulating shuttling not identified\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connected a disease-associated missense variant to loss of KLF7 coactivation, providing the first genotype-phenotype link for the transcriptional function.\",\n      \"evidence\": \"Reporter assays and patient-derived fibroblasts plus primary motor neuron neurite outgrowth assay for the p.Cys206Arg mutation\",\n      \"pmids\": [\"24207122\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which the mutation impairs coactivation not defined\", \"Single lab; effect on ligase function not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Reframed FBXO38 as an E3 ubiquitin ligase by reporting Lys48-linked ubiquitination and degradation of PD-1, with a tumor immunity phenotype in conditional knockout mice.\",\n      \"evidence\": \"In vitro ubiquitination with linkage specificity, T cell-specific conditional knockout, tumor growth and anti-PD-1 rescue\",\n      \"pmids\": [\"30487606\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrate relationship later contradicted by genetic re-examination\", \"SCF complex requirement for PD-1 not dissected here\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined the upstream stabilizer of FBXO38 and a non-degradative output, showing USP7 protects FBXO38 which in turn stabilizes KIF20B for cytokinesis independently of SCF.\",\n      \"evidence\": \"AP-MS, BioID, Co-IP, siRNA knockdown, proteasome inhibition and cytokinesis rescue experiments\",\n      \"pmids\": [\"30804394\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of SCF-independent KIF20B stabilization unknown\", \"How USP7 selectively targets FBXO38 not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified bona fide SCF(FBXO38) substrates ZXDA/B and linked their degradation to centromeric chromatin control, both in cells and in a Sertoli cell/fertility context.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, proteasome inhibition, ChIP, and Fbxo38 conditional knockout mice with testis phenotyping\",\n      \"pmids\": [\"35813202\", \"35769260\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct enzymatic reconstitution of SCF(FBXO38) on ZXDA/B not shown\", \"Link between centromeric chromatin changes and the spermatogenic phenotype is correlative\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended FBXO38 substrate range to FGL1 and assigned a macrophage-intrinsic role in M2 polarization, broadening its immunoregulatory functions.\",\n      \"evidence\": \"Co-IP/ubiquitination with siRNA and tumor models for FGL1; macrophage-specific knockout with tumor and DSS colitis models and MAPK/IRF4 pathway analysis\",\n      \"pmids\": [\"37938970\", \"37821621\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether macrophage M2 effect is ubiquitination-dependent not established\", \"Direct substrate in the MAPK/IRF4 axis not identified\", \"Single lab for each finding\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Challenged the original PD-1 model and added new degradation-independent and lysosomal mechanisms, indicating FBXO38 outputs are context- and substrate-specific.\",\n      \"evidence\": \"Genetic re-examination in T cells (PD-1); lysosome vs proteasome inhibitor dissection of STING; NK-cell conditional knockout dissecting the TGF-\\u03b2/Smad/Eomes/IL15R axis\",\n      \"pmids\": [\"39266770\", \"38277817\", \"38990095\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Source of discrepancy in PD-1 regulation unresolved\", \"Mechanism by which FBXO38 affects STING lysosomal turnover unclear\", \"Direct substrate in the NK TGF-\\u03b2 axis not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed FBXO38 degrades Nox1 to limit endothelial ROS, linking shear-stress-regulated FBXO38 abundance to vascular oxidative stress and apoptosis.\",\n      \"evidence\": \"Co-IP, gain/loss-of-function in HUVECs, in vitro shear stress model and in vivo partial carotid ligation\",\n      \"pmids\": [\"40313652\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitin linkage specificity on Nox1 not characterized\", \"Mechanism reducing FBXO38 under oscillatory shear not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved which FBXO38 functions require SCF-dependent ubiquitination versus degradation-independent or transcriptional activities, and how substrate selection is partitioned across cell types.\",\n      \"evidence\": \"No single study integrates the ligase, stabilizer, lysosomal, and coactivator activities under a unified mechanistic framework\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of substrate recognition by SCF(FBXO38)\", \"Unknown determinants of substrate-specific proteasomal vs lysosomal routing\", \"Reconciliation of the contested PD-1 phenotype outstanding\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [3, 5, 8, 12]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [3, 5]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [5, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [3, 5, 8]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [7, 8, 11]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\"SCF(FBXO38)\"],\n    \"partners\": [\"KLF7\", \"USP7\", \"KIF20B\", \"ZXDA\", \"ZXDB\", \"FGL1\", \"NOX1\", \"PDCD1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}