{"gene":"NACA","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2004,"finding":"Integrin-linked kinase (ILK) directly phosphorylates alpha-NAC on serine-43 upon cell adhesion to fibronectin; this phosphorylation event is necessary and sufficient for nuclear accumulation of alpha-NAC and is required for alpha-NAC to potentiate ILK-dependent c-Jun-mediated transcription. A phosphoacceptor-dead S43A mutant remained cytoplasmic and could not enhance c-Jun-dependent transcription.","method":"Co-expression of constitutively active and dominant-negative ILK with alpha-NAC; site-directed mutagenesis (S43A); subcellular localization by immunofluorescence; transcriptional reporter assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro kinase assay combined with mutagenesis, localization assay, and functional transcription assay in single rigorous study","pmids":["15299025"],"is_preprint":false},{"year":2004,"finding":"GSK3β directly phosphorylates alpha-NAC on threonine-159 in vitro and in vivo; this phosphorylation targets alpha-NAC for degradation by the 26S proteasome. Inhibition of GSK3β (by dominant-negative mutant, pharmacological inhibitor, or T159 mutation) stabilizes alpha-NAC, promotes its nuclear accumulation, and increases its coactivation potency.","method":"In vitro kinase assay with GSK3β and alpha-NAC; site-directed mutagenesis (T159); proteasome inhibitors (lactacystin, MG-132, epoxomicin); dominant-negative GSK3β; metabolic stability and subcellular localization assays","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro kinase assay plus mutagenesis plus pharmacological validation and functional coactivation assay in single study","pmids":["15005626"],"is_preprint":false},{"year":2010,"finding":"Nuclear translocation of alpha-NAC (dependent on ILK-mediated S43 phosphorylation) is required for osteocalcin gene transcription and alpha(1)(I) collagen gene transcription in osteoblasts. S43A knock-in mice exhibit reduced nuclear alpha-NAC, decreased osteocalcin and collagen mRNA, reduced osteoid, accelerated matrix mineralization, and an osteopenic phenotype with immature woven bone. ChIP confirmed reduced alpha-NAC occupancy at the osteocalcin promoter.","method":"S43A knock-in mouse model; chromatin immunoprecipitation (ChIP); transient transfection reporter assays; histomorphometry; osteoblast isolation and culture","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic model combined with ChIP and cell-autonomous assays, replicating the ILK–S43 phosphorylation mechanism","pmids":["19884350"],"is_preprint":false},{"year":2010,"finding":"Crystal structure of the human NAC domain (formed by NACA and NACB subunits) was solved, revealing the dimerization interface. A nucleic acid-binding region was identified within the NAC domain of the NACA subunit; this region is blocked by a helix from the beta-subunit in the heterodimeric complex.","method":"X-ray crystallography of human NAC domain; structural analysis of nucleic acid-binding region","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with functional mapping of nucleic acid-binding region, single rigorous structural study","pmids":["20214399"],"is_preprint":false},{"year":2015,"finding":"In zebrafish, NACA deficiency does not impair haematopoietic stem/progenitor cells (HSPCs) intrinsically, but specifically disrupts maturation of somite-derived caudal haematopoietic tissue (CHT) stromal cells; NACA-deficient stromal cell progenitors fail to mature into reticular cells, rendering the niche unable to support HSPC maintenance, expansion, and differentiation.","method":"Zebrafish naca mutant analysis; live imaging of CHT niche formation; cell transplantation to distinguish HSPC-intrinsic vs niche defect; immunostaining of stromal and sinusoidal markers","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function in vivo with cell-transplantation epistasis distinguishing niche vs HSPC defect","pmids":["26411530"],"is_preprint":false},{"year":2009,"finding":"skNAC, a muscle-specific alternatively spliced isoform of NACA (containing an extra 815 aa exon), is required for myofibril assembly in zebrafish skeletal muscle. Antisense knockdown of sknac produced paralyzed embryos with disorganized thick and thin filaments and significantly reduced myosin protein levels, while the nascent polypeptide chaperone function of skNAC is implicated in proper sarcomeric protein folding/assembly.","method":"Antisense morpholino knockdown in zebrafish; immunostaining of sarcomeric proteins; Western blot; histology; behavioral analysis (paralysis phenotype)","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean loss-of-function knockdown with defined myofibril assembly phenotype in vivo, single lab, morpholino approach","pmids":["19211926"],"is_preprint":false}],"current_model":"NACA (alpha-NAC) is a cytoplasmic chaperone subunit of the nascent polypeptide-associated complex that also shuttles to the nucleus to act as a transcriptional coactivator: integrin-linked kinase phosphorylates NACA at Ser-43 upon fibronectin adhesion, driving nuclear translocation and potentiation of c-Jun/AP-1-dependent gene transcription (including osteocalcin and type I collagen); conversely, GSK3β phosphorylates NACA at Thr-159, targeting it for proteasomal degradation and restricting its nuclear activity. Structurally, the NACA subunit harbors a nucleic acid-binding region within its NAC domain that is occluded when in the heterodimeric complex with the beta-subunit. In vivo, nuclear NACA is required for osteoblast maturation and bone matrix quality, a muscle-specific isoform (skNAC) is essential for myofibril assembly, and NACA is required in haematopoietic niche stromal cells for HSPC maintenance."},"narrative":{"mechanistic_narrative":"NACA (alpha-NAC) is a dual-function protein that operates both as a nascent-chain-associated chaperone subunit and as a signal-regulated transcriptional coactivator, integrating adhesion signaling with tissue-specific gene expression programs [PMID:15299025, PMID:19884350]. Its subcellular distribution and activity are governed by opposing phosphorylation events: integrin-linked kinase phosphorylates NACA at Ser-43 upon cell adhesion to fibronectin, an event necessary and sufficient for nuclear accumulation and for potentiation of c-Jun-dependent transcription, whereas GSK3β phosphorylates NACA at Thr-159 to target it for 26S proteasomal degradation and thereby restrict its nuclear coactivator function [PMID:15299025, PMID:15005626]. In osteoblasts, ILK–Ser-43-driven nuclear NACA is required for osteocalcin and α(1)(I) collagen transcription, and mice bearing a phospho-dead S43A allele show reduced promoter occupancy, decreased matrix gene expression, and an osteopenic phenotype with immature woven bone [PMID:19884350]. Structurally, NACA forms a heterodimeric NAC domain with the beta-subunit; a nucleic acid-binding region within the NACA NAC domain is occluded by a beta-subunit helix in the complex, providing a structural basis for regulated nucleic acid engagement [PMID:20214399]. Beyond transcriptional control, NACA function is required non-cell-autonomously in haematopoietic niche stromal cells for maturation of reticular cells supporting HSPCs, and a muscle-specific isoform, skNAC, is required for myofibril assembly and sarcomeric protein accumulation [PMID:26411530, PMID:19211926].","teleology":[{"year":2004,"claim":"Established how alpha-NAC is directed to the nucleus and licensed as a coactivator, linking adhesion signaling to transcription.","evidence":"ILK kinase assays, S43A mutagenesis, immunofluorescence localization, and transcriptional reporter assays in cultured cells","pmids":["15299025"],"confidence":"High","gaps":["Does not identify the nuclear import machinery recognizing phospho-S43 NACA","Direct DNA/promoter contacts of nuclear NACA not resolved"]},{"year":2004,"claim":"Defined the counter-regulatory arm controlling nuclear alpha-NAC levels, showing degradation as a brake on its coactivation potency.","evidence":"In vitro GSK3β kinase assay, T159 mutagenesis, proteasome inhibitors, and metabolic stability/localization assays","pmids":["15005626"],"confidence":"High","gaps":["E3 ligase coupling Thr-159 phosphorylation to proteasomal turnover not identified","Crosstalk between S43 and T159 phosphorylation events untested"]},{"year":2010,"claim":"Demonstrated in vivo that the ILK–S43 nuclear-translocation mechanism drives osteoblast matrix gene programs and bone quality.","evidence":"S43A knock-in mouse, ChIP at the osteocalcin promoter, reporter assays, and histomorphometry","pmids":["19884350"],"confidence":"High","gaps":["Full set of NACA-regulated osteoblast target genes not delineated","Whether NACA acts directly on DNA or via c-Jun tethering at these promoters not resolved"]},{"year":2010,"claim":"Provided the structural basis for NACA's nucleic acid-binding activity and its masking within the heterodimer.","evidence":"X-ray crystallography of the human NAC domain with mapping of the nucleic acid-binding region","pmids":["20214399"],"confidence":"High","gaps":["Does not show what triggers release of the beta-subunit helix to expose the binding region in vivo","Sequence specificity and physiological nucleic acid ligand not defined"]},{"year":2009,"claim":"Identified a tissue-specific role for the skNAC isoform in sarcomere assembly, extending NACA function to muscle structural integrity.","evidence":"Morpholino knockdown of sknac in zebrafish with sarcomeric immunostaining, Western blot, and paralysis phenotyping","pmids":["19211926"],"confidence":"Medium","gaps":["Morpholino-based knockdown without genetic mutant confirmation","Direct chaperone substrates among sarcomeric proteins not identified"]},{"year":2015,"claim":"Showed NACA acts non-cell-autonomously in the haematopoietic niche, distinguishing a stromal maturation requirement from an HSPC-intrinsic role.","evidence":"Zebrafish naca mutant analysis with live imaging and cell-transplantation epistasis distinguishing niche versus HSPC defects","pmids":["26411530"],"confidence":"High","gaps":["Molecular targets of NACA driving stromal reticular-cell maturation not identified","Whether the niche role uses the chaperone or transcriptional function unresolved"]},{"year":null,"claim":"How NACA's chaperone, nucleic acid-binding, and signal-regulated coactivator activities are mechanistically coordinated within a single molecule across tissues remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking NAC-domain chaperone function to nuclear transcriptional role","Direct transcriptional target spectrum and DNA-binding mode of nuclear NACA undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,2]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[3]},{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[5]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,2]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,2]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,4,5]}],"complexes":["nascent polypeptide-associated complex (NAC)"],"partners":["ILK","GSK3B","JUN","NACB"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13765","full_name":"Nascent polypeptide-associated complex subunit alpha","aliases":["Alpha-NAC"],"length_aa":215,"mass_kda":23.4,"function":"Prevents inappropriate targeting of non-secretory polypeptides to the endoplasmic reticulum (ER). Binds to nascent polypeptide chains as they emerge from the ribosome and blocks their interaction with the signal recognition particle (SRP), which normally targets nascent secretory peptides to the ER. Also reduces the inherent affinity of ribosomes for protein translocation sites in the ER membrane (M sites). May act as a specific coactivator for JUN, binding to DNA and stabilizing the interaction of JUN homodimers with target gene promoters","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q13765/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/NACA","classification":"Common Essential","n_dependent_lines":1190,"n_total_lines":1208,"dependency_fraction":0.9850993377483444},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"BTF3","stoichiometry":10.0},{"gene":"ENY2","stoichiometry":4.0},{"gene":"ATG13","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"DNM1L","stoichiometry":0.2},{"gene":"EMC9","stoichiometry":0.2},{"gene":"NCAPH","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/NACA","total_profiled":1310},"omim":[{"mim_id":"619419","title":"NAC-ALPHA DOMAIN-CONTAINING PROTEIN; NACAD","url":"https://www.omim.org/entry/619419"},{"mim_id":"617603","title":"RNA-BINDING MOTIF PROTEIN 24; RBM24","url":"https://www.omim.org/entry/617603"},{"mim_id":"609751","title":"ACYL-CoA OXIDASE 1, PALMITOYL; ACOX1","url":"https://www.omim.org/entry/609751"},{"mim_id":"609274","title":"NASCENT POLYPEPTIDE-ASSOCIATED COMPLEX, ALPHA POLYPEPTIDE, 2; NACA2","url":"https://www.omim.org/entry/609274"},{"mim_id":"602542","title":"BASIC TRANSCRIPTION FACTOR 3; BTF3","url":"https://www.omim.org/entry/602542"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/NACA"},"hgnc":{"alias_symbol":["NACA1","Alpha-NAC"],"prev_symbol":[]},"alphafold":{"accession":"Q13765","domains":[{"cath_id":"2.20.70.30","chopping":"70-132","consensus_level":"high","plddt":93.5022,"start":70,"end":132},{"cath_id":"1.10.8","chopping":"172-215","consensus_level":"medium","plddt":91.2552,"start":172,"end":215}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13765","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13765-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13765-F1-predicted_aligned_error_v6.png","plddt_mean":72.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NACA","jax_strain_url":"https://www.jax.org/strain/search?query=NACA"},"sequence":{"accession":"Q13765","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13765.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13765/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13765"}},"corpus_meta":[{"pmid":"3945347","id":"PMC_3945347","title":"Na-Ca 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amide (NACA) prevents retinal degeneration by up-regulating reduced glutathione production and reversing lipid peroxidation.","date":"2011","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/21457933","citation_count":51,"is_preprint":false},{"pmid":"7432497","id":"PMC_7432497","title":"Parathyroid hormone stimulates bone resorption via a Na-Ca exchange mechanism.","date":"1980","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/7432497","citation_count":51,"is_preprint":false},{"pmid":"16242149","id":"PMC_16242149","title":"Isoproterenol does not enhance Ca-dependent Na/Ca exchange current in intact rabbit ventricular myocytes.","date":"2005","source":"Journal of molecular and cellular cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/16242149","citation_count":50,"is_preprint":false},{"pmid":"6776149","id":"PMC_6776149","title":"Evidence for the involvement of Na/Ca exchange in glucose-induced insulin release from rat pancreatic 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Sciences","url":"https://pubmed.ncbi.nlm.nih.gov/17446473","citation_count":44,"is_preprint":false},{"pmid":"12031969","id":"PMC_12031969","title":"Na/Ca exchanger overexpression induces endoplasmic reticulum-related apoptosis and caspase-12 activation in insulin-releasing BRIN-BD11 cells.","date":"2002","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/12031969","citation_count":44,"is_preprint":false},{"pmid":"16781745","id":"PMC_16781745","title":"Potentiation of lead-induced cell death in PC12 cells by glutamate: protection by N-acetylcysteine amide (NACA), a novel thiol antioxidant.","date":"2006","source":"Toxicology and applied pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/16781745","citation_count":42,"is_preprint":false},{"pmid":"1694586","id":"PMC_1694586","title":"Inward current generated by Na-Ca exchange during the action potential in single atrial cells of the rabbit.","date":"1990","source":"Proceedings of the Royal Society of London. Series B, Biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/1694586","citation_count":42,"is_preprint":false},{"pmid":"3029391","id":"PMC_3029391","title":"Sarcolemmal Na-Ca exchange and sarcoplasmic reticulum calcium uptake in developing chick heart.","date":"1986","source":"Journal of molecular and cellular cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/3029391","citation_count":42,"is_preprint":false},{"pmid":"9349392","id":"PMC_9349392","title":"The role of L-type Ca2+ current and Na+ current-stimulated Na/Ca exchange in triggering SR calcium release in guinea-pig cardiac ventricular myocytes.","date":"1997","source":"Cardiovascular research","url":"https://pubmed.ncbi.nlm.nih.gov/9349392","citation_count":41,"is_preprint":false},{"pmid":"18448127","id":"PMC_18448127","title":"Effects of N-acetylcysteine amide (NACA), a thiol antioxidant on radiation-induced cytotoxicity in Chinese hamster ovary cells.","date":"2008","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/18448127","citation_count":40,"is_preprint":false},{"pmid":"9836518","id":"PMC_9836518","title":"Contribution of Na/Ca exchange to Ca2+ outflow and entry in the rat pancreatic beta-cell: studies with antisense oligonucleotides.","date":"1998","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/9836518","citation_count":40,"is_preprint":false},{"pmid":"10096898","id":"PMC_10096898","title":"Significance of Na/Ca exchange for Ca2+ buffering and electrical activity in mouse pancreatic beta-cells.","date":"1999","source":"Biophysical journal","url":"https://pubmed.ncbi.nlm.nih.gov/10096898","citation_count":40,"is_preprint":false},{"pmid":"10405185","id":"PMC_10405185","title":"Reversal of mitochondrial Na/Ca exchange during metabolic inhibition in rat cardiomyocytes.","date":"1999","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/10405185","citation_count":39,"is_preprint":false},{"pmid":"2362183","id":"PMC_2362183","title":"Asymmetrical properties of the Na-Ca exchanger in voltage-clamped, internally dialyzed squid axons under symmetrical ionic conditions.","date":"1990","source":"The Journal of general physiology","url":"https://pubmed.ncbi.nlm.nih.gov/2362183","citation_count":39,"is_preprint":false},{"pmid":"10456229","id":"PMC_10456229","title":"Inhibition of Na/Ca exchange by external Ni in guinea-pig ventricular myocytes at 37 degrees C, dialysed internally with cAMP-free and cAMP-containing solutions.","date":"1999","source":"Cell calcium","url":"https://pubmed.ncbi.nlm.nih.gov/10456229","citation_count":39,"is_preprint":false},{"pmid":"2315011","id":"PMC_2315011","title":"Is potassium co-transported by the cardiac Na-Ca exchange?","date":"1990","source":"Pflugers Archiv : European journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/2315011","citation_count":39,"is_preprint":false},{"pmid":"20973764","id":"PMC_20973764","title":"The role of T-cell reactivity towards the autoantigen α-NAC in atopic dermatitis.","date":"2011","source":"The British journal of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/20973764","citation_count":38,"is_preprint":false},{"pmid":"26962231","id":"PMC_26962231","title":"α-NAC-Specific Autoreactive CD8+ T Cells in Atopic Dermatitis Are of an Effector Memory Type and Secrete IL-4 and IFN-γ.","date":"2016","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/26962231","citation_count":38,"is_preprint":false},{"pmid":"7750570","id":"PMC_7750570","title":"Specific inhibition of Na-Ca exchange function by antisense oligodeoxynucleotides.","date":"1995","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/7750570","citation_count":38,"is_preprint":false},{"pmid":"8218911","id":"PMC_8218911","title":"Activation of Na-Ca exchange current by photolysis of \"caged calcium\".","date":"1993","source":"Biophysical journal","url":"https://pubmed.ncbi.nlm.nih.gov/8218911","citation_count":37,"is_preprint":false},{"pmid":"17446486","id":"PMC_17446486","title":"Role of Na/Ca exchange and the plasma membrane Ca2+-ATPase in beta cell function and death.","date":"2007","source":"Annals of the New York Academy of Sciences","url":"https://pubmed.ncbi.nlm.nih.gov/17446486","citation_count":36,"is_preprint":false},{"pmid":"6491635","id":"PMC_6491635","title":"Changes in external Na induce a membrane current related to the Na-Ca exchange in cesium-loaded frog heart cells.","date":"1984","source":"The Journal of general physiology","url":"https://pubmed.ncbi.nlm.nih.gov/6491635","citation_count":36,"is_preprint":false},{"pmid":"21145953","id":"PMC_21145953","title":"Comparative evaluation of N-acetylcysteine (NAC) and N-acetylcysteine amide (NACA) on glutamate and lead-induced toxicity in CD-1 mice.","date":"2010","source":"Toxicology letters","url":"https://pubmed.ncbi.nlm.nih.gov/21145953","citation_count":35,"is_preprint":false},{"pmid":"15005626","id":"PMC_15005626","title":"GSK3 beta-dependent phosphorylation of the alpha NAC coactivator regulates its nuclear translocation and proteasome-mediated degradation.","date":"2004","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15005626","citation_count":35,"is_preprint":false},{"pmid":"8729058","id":"PMC_8729058","title":"Functional coupling between sarcoplasmic reticulum and Na/Ca exchange in single myocytes of guinea-pig and rat heart.","date":"1996","source":"Journal of molecular and cellular cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/8729058","citation_count":35,"is_preprint":false},{"pmid":"9000424","id":"PMC_9000424","title":"The peptide \"FRCRCFa\", dialysed intracellularly, inhibits the Na/Ca exchange in rabbit ventricular myocytes with high affinity.","date":"1997","source":"Pflugers Archiv : European journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/9000424","citation_count":34,"is_preprint":false},{"pmid":"8203501","id":"PMC_8203501","title":"Effects of vanadate on MgATP stimulation of Na-Ca exchange support kinase-phosphatase modulation in squid axons.","date":"1994","source":"The American journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/8203501","citation_count":34,"is_preprint":false},{"pmid":"9003795","id":"PMC_9003795","title":"A novel 13 kDa cytoplasmic soluble protein is required for the nucleotide (MgATP) modulation of the Na/Ca exchange in squid nerve fibers.","date":"1997","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/9003795","citation_count":34,"is_preprint":false},{"pmid":"19007774","id":"PMC_19007774","title":"Ankyrin-B is required for coordinated expression of beta-2-spectrin, the Na/K-ATPase and the Na/Ca exchanger in the inner segment of rod photoreceptors.","date":"2008","source":"Experimental eye research","url":"https://pubmed.ncbi.nlm.nih.gov/19007774","citation_count":33,"is_preprint":false},{"pmid":"2594475","id":"PMC_2594475","title":"Na/Ca exchangers in collecting cells of rat kidney. A single tubule fura-2 study.","date":"1989","source":"Pflugers Archiv : European journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/2594475","citation_count":33,"is_preprint":false},{"pmid":"19884350","id":"PMC_19884350","title":"Nuclear alpha NAC influences bone matrix mineralization and osteoblast maturation in vivo.","date":"2010","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/19884350","citation_count":32,"is_preprint":false},{"pmid":"9105728","id":"PMC_9105728","title":"Identification, expression pattern and potential activity of Na/Ca exchanger isoforms in rat pancreatic B-cells.","date":"1997","source":"Cell calcium","url":"https://pubmed.ncbi.nlm.nih.gov/9105728","citation_count":32,"is_preprint":false},{"pmid":"20214399","id":"PMC_20214399","title":"The crystal structure of the human nascent polypeptide-associated complex domain reveals a nucleic acid-binding region on the NACA subunit .","date":"2010","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20214399","citation_count":31,"is_preprint":false},{"pmid":"10320357","id":"PMC_10320357","title":"cDNA cloning and functional expression of the dolphin retinal rod Na-Ca+K exchanger NCKX1: comparison with the functionally silent bovine NCKX1.","date":"1999","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10320357","citation_count":30,"is_preprint":false},{"pmid":"10336850","id":"PMC_10336850","title":"Quantitation of Na/Ca exchanger function in single ventricular myocytes.","date":"1999","source":"Journal of molecular and cellular cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/10336850","citation_count":30,"is_preprint":false},{"pmid":"8424825","id":"PMC_8424825","title":"A role for Na/Ca exchange in the pancreatic B cell. Studies with thapsigargin and caffeine.","date":"1993","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/8424825","citation_count":30,"is_preprint":false},{"pmid":"11179087","id":"PMC_11179087","title":"In vivo regulation of Na/Ca exchanger expression by adrenergic effectors.","date":"2001","source":"American journal of physiology. Heart and circulatory physiology","url":"https://pubmed.ncbi.nlm.nih.gov/11179087","citation_count":29,"is_preprint":false},{"pmid":"11241183","id":"PMC_11241183","title":"NCX1 Na/Ca exchanger splice variants in pancreatic islet cells.","date":"2001","source":"The Journal of endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/11241183","citation_count":29,"is_preprint":false},{"pmid":"7478945","id":"PMC_7478945","title":"[Ca2+]i-dependent membrane currents in guinea-pig ventricular cells in the absence of Na/Ca exchange.","date":"1995","source":"Pflugers Archiv : European journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/7478945","citation_count":29,"is_preprint":false},{"pmid":"7288663","id":"PMC_7288663","title":"The electrogenic Na-Ca exchange and the cardiac electrical activity. I--Simulation on Purkinje fibre action potential.","date":"1981","source":"Journal de physiologie","url":"https://pubmed.ncbi.nlm.nih.gov/7288663","citation_count":29,"is_preprint":false},{"pmid":"34481041","id":"PMC_34481041","title":"Emerging therapeutic opportunities of novel thiol-amides, NAC-amide (AD4/NACA) and thioredoxin mimetics (TXM-Peptides) for neurodegenerative-related disorders.","date":"2021","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34481041","citation_count":28,"is_preprint":false},{"pmid":"24441101","id":"PMC_24441101","title":"Cytokine effects induced by the human autoallergen α-NAC.","date":"2014","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/24441101","citation_count":28,"is_preprint":false},{"pmid":"9398501","id":"PMC_9398501","title":"A conservation principle and its effect on the formulation of Na-Ca exchanger current in cardiac cells.","date":"1997","source":"Journal of theoretical biology","url":"https://pubmed.ncbi.nlm.nih.gov/9398501","citation_count":28,"is_preprint":false},{"pmid":"11508998","id":"PMC_11508998","title":"A new Na/Ca exchanger splicing pattern identified in situ leads to a functionally active 70kDa NH(2)-terminal protein.","date":"2001","source":"Cell calcium","url":"https://pubmed.ncbi.nlm.nih.gov/11508998","citation_count":27,"is_preprint":false},{"pmid":"9478004","id":"PMC_9478004","title":"cDNA cloning of the human retinal rod Na-Ca + K exchanger: comparison with a revised bovine sequence.","date":"1998","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/9478004","citation_count":27,"is_preprint":false},{"pmid":"19211926","id":"PMC_19211926","title":"skNAC (skeletal Naca), a muscle-specific isoform of Naca (nascent polypeptide-associated complex alpha), is required for myofibril organization.","date":"2009","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/19211926","citation_count":26,"is_preprint":false},{"pmid":"11827683","id":"PMC_11827683","title":"Cytosolic free magnesium modulates Na/Ca exchange currents in pig myocytes.","date":"2002","source":"Cardiovascular research","url":"https://pubmed.ncbi.nlm.nih.gov/11827683","citation_count":26,"is_preprint":false},{"pmid":"1887874","id":"PMC_1887874","title":"Mn and Cd transport by the Na-Ca exchanger of ferret red blood cells.","date":"1991","source":"The American journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/1887874","citation_count":26,"is_preprint":false},{"pmid":"1590356","id":"PMC_1590356","title":"A discrete Na-Ca exchange-dependent Ca compartment in rat ventricular cells: exchange and localization.","date":"1992","source":"The American journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/1590356","citation_count":26,"is_preprint":false},{"pmid":"12232005","id":"PMC_12232005","title":"Kinematics and Dynamics of Sorghum (Sorghum bicolor L.) Leaf Development at Various Na/Ca Salinities (I. Elongation Growth).","date":"1993","source":"Plant physiology","url":"https://pubmed.ncbi.nlm.nih.gov/12232005","citation_count":26,"is_preprint":false},{"pmid":"11733942","id":"PMC_11733942","title":"Regulation by endothelin-1 of Na+-Ca2+ exchange current (I(NaCa)) from guinea-pig isolated ventricular myocytes.","date":"2001","source":"Cell calcium","url":"https://pubmed.ncbi.nlm.nih.gov/11733942","citation_count":25,"is_preprint":false},{"pmid":"30261225","id":"PMC_30261225","title":"HIV-1 Tat and methamphetamine co-induced oxidative cellular injury is mitigated by N-acetylcysteine amide (NACA) through rectifying mTOR signaling.","date":"2018","source":"Toxicology letters","url":"https://pubmed.ncbi.nlm.nih.gov/30261225","citation_count":25,"is_preprint":false},{"pmid":"12037007","id":"PMC_12037007","title":"Mutated alleles of the rod and cone Na-Ca+K-exchanger genes in patients with retinal diseases.","date":"2002","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/12037007","citation_count":24,"is_preprint":false},{"pmid":"11812743","id":"PMC_11812743","title":"Overexpression of the Na/Ca exchanger shapes stimulus-induced cytosolic Ca(2+) oscillations in insulin-producing BRIN-BD11 cells.","date":"2002","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/11812743","citation_count":24,"is_preprint":false},{"pmid":"1858856","id":"PMC_1858856","title":"Na-Ca exchange: evidence against a ping-pong mechanism and against a Ca pool in ferret red blood cells.","date":"1991","source":"The American journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/1858856","citation_count":24,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49534,"output_tokens":2346,"usd":0.091896,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8775,"output_tokens":2453,"usd":0.0526,"stage2_stop_reason":"end_turn"},"total_usd":0.144496,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking through the corpus, I need to identify papers about the canonical NACA gene (nascent polypeptide-associated complex alpha subunit, also known as Alpha-NAC). The vast majority of papers (1-24, 26-45, 50-61, 63-67, 70-75, 77, 79-85, 88-90, 92-96, 98-100) are about Na/Ca exchangers (NCX, NCKX) — completely different proteins unrelated to NACA. Papers 25, 43, 51, 55, 68, 86, 97 are about N-acetylcysteine amide (NACA), a chemical compound, not the NACA gene.\n\nPapers about the canonical NACA gene:\n- PMID 15299025: ILK phosphorylates alpha-NAC on Ser-43, regulating nuclear entry and c-Jun coactivation\n- PMID 15005626: GSK3β phosphorylates alpha-NAC on Thr-159, directing it to proteasome degradation\n- PMID 26411530: NACA deficiency in zebrafish — stromal cell niche role in haematopoiesis\n- PMID 20214399: Crystal structure of human NAC domain, identifies nucleic acid-binding region on NACA subunit\n- PMID 19884350: Nuclear alpha-NAC (ILK-phosphorylated at S43) acts as AP-1 coactivator for osteocalcin and collagen genes\n- PMID 19211926: skNAC (muscle-specific NACA isoform) required for myofibril organization in zebrafish\n- PMID 20973764: T-cell reactivity to alpha-NAC in atopic dermatitis (mostly immunological/clinical — limited mechanistic content)\n- PMID 26962231: CD8+ T cells specific for alpha-NAC in AD (immunological)\n- PMID 24441101: Cytokine effects of alpha-NAC (immunological)\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"Integrin-linked kinase (ILK) directly phosphorylates alpha-NAC on serine-43 upon cell adhesion to fibronectin; this phosphorylation event is necessary and sufficient for nuclear accumulation of alpha-NAC and is required for alpha-NAC to potentiate ILK-dependent c-Jun-mediated transcription. A phosphoacceptor-dead S43A mutant remained cytoplasmic and could not enhance c-Jun-dependent transcription.\",\n      \"method\": \"Co-expression of constitutively active and dominant-negative ILK with alpha-NAC; site-directed mutagenesis (S43A); subcellular localization by immunofluorescence; transcriptional reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro kinase assay combined with mutagenesis, localization assay, and functional transcription assay in single rigorous study\",\n      \"pmids\": [\"15299025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"GSK3β directly phosphorylates alpha-NAC on threonine-159 in vitro and in vivo; this phosphorylation targets alpha-NAC for degradation by the 26S proteasome. Inhibition of GSK3β (by dominant-negative mutant, pharmacological inhibitor, or T159 mutation) stabilizes alpha-NAC, promotes its nuclear accumulation, and increases its coactivation potency.\",\n      \"method\": \"In vitro kinase assay with GSK3β and alpha-NAC; site-directed mutagenesis (T159); proteasome inhibitors (lactacystin, MG-132, epoxomicin); dominant-negative GSK3β; metabolic stability and subcellular localization assays\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro kinase assay plus mutagenesis plus pharmacological validation and functional coactivation assay in single study\",\n      \"pmids\": [\"15005626\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Nuclear translocation of alpha-NAC (dependent on ILK-mediated S43 phosphorylation) is required for osteocalcin gene transcription and alpha(1)(I) collagen gene transcription in osteoblasts. S43A knock-in mice exhibit reduced nuclear alpha-NAC, decreased osteocalcin and collagen mRNA, reduced osteoid, accelerated matrix mineralization, and an osteopenic phenotype with immature woven bone. ChIP confirmed reduced alpha-NAC occupancy at the osteocalcin promoter.\",\n      \"method\": \"S43A knock-in mouse model; chromatin immunoprecipitation (ChIP); transient transfection reporter assays; histomorphometry; osteoblast isolation and culture\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic model combined with ChIP and cell-autonomous assays, replicating the ILK–S43 phosphorylation mechanism\",\n      \"pmids\": [\"19884350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Crystal structure of the human NAC domain (formed by NACA and NACB subunits) was solved, revealing the dimerization interface. A nucleic acid-binding region was identified within the NAC domain of the NACA subunit; this region is blocked by a helix from the beta-subunit in the heterodimeric complex.\",\n      \"method\": \"X-ray crystallography of human NAC domain; structural analysis of nucleic acid-binding region\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with functional mapping of nucleic acid-binding region, single rigorous structural study\",\n      \"pmids\": [\"20214399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In zebrafish, NACA deficiency does not impair haematopoietic stem/progenitor cells (HSPCs) intrinsically, but specifically disrupts maturation of somite-derived caudal haematopoietic tissue (CHT) stromal cells; NACA-deficient stromal cell progenitors fail to mature into reticular cells, rendering the niche unable to support HSPC maintenance, expansion, and differentiation.\",\n      \"method\": \"Zebrafish naca mutant analysis; live imaging of CHT niche formation; cell transplantation to distinguish HSPC-intrinsic vs niche defect; immunostaining of stromal and sinusoidal markers\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function in vivo with cell-transplantation epistasis distinguishing niche vs HSPC defect\",\n      \"pmids\": [\"26411530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"skNAC, a muscle-specific alternatively spliced isoform of NACA (containing an extra 815 aa exon), is required for myofibril assembly in zebrafish skeletal muscle. Antisense knockdown of sknac produced paralyzed embryos with disorganized thick and thin filaments and significantly reduced myosin protein levels, while the nascent polypeptide chaperone function of skNAC is implicated in proper sarcomeric protein folding/assembly.\",\n      \"method\": \"Antisense morpholino knockdown in zebrafish; immunostaining of sarcomeric proteins; Western blot; histology; behavioral analysis (paralysis phenotype)\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean loss-of-function knockdown with defined myofibril assembly phenotype in vivo, single lab, morpholino approach\",\n      \"pmids\": [\"19211926\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NACA (alpha-NAC) is a cytoplasmic chaperone subunit of the nascent polypeptide-associated complex that also shuttles to the nucleus to act as a transcriptional coactivator: integrin-linked kinase phosphorylates NACA at Ser-43 upon fibronectin adhesion, driving nuclear translocation and potentiation of c-Jun/AP-1-dependent gene transcription (including osteocalcin and type I collagen); conversely, GSK3β phosphorylates NACA at Thr-159, targeting it for proteasomal degradation and restricting its nuclear activity. Structurally, the NACA subunit harbors a nucleic acid-binding region within its NAC domain that is occluded when in the heterodimeric complex with the beta-subunit. In vivo, nuclear NACA is required for osteoblast maturation and bone matrix quality, a muscle-specific isoform (skNAC) is essential for myofibril assembly, and NACA is required in haematopoietic niche stromal cells for HSPC maintenance.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NACA (alpha-NAC) is a dual-function protein that operates both as a nascent-chain-associated chaperone subunit and as a signal-regulated transcriptional coactivator, integrating adhesion signaling with tissue-specific gene expression programs [#0, #2]. Its subcellular distribution and activity are governed by opposing phosphorylation events: integrin-linked kinase phosphorylates NACA at Ser-43 upon cell adhesion to fibronectin, an event necessary and sufficient for nuclear accumulation and for potentiation of c-Jun-dependent transcription, whereas GSK3\\u03b2 phosphorylates NACA at Thr-159 to target it for 26S proteasomal degradation and thereby restrict its nuclear coactivator function [#0, #1]. In osteoblasts, ILK\\u2013Ser-43-driven nuclear NACA is required for osteocalcin and \\u03b1(1)(I) collagen transcription, and mice bearing a phospho-dead S43A allele show reduced promoter occupancy, decreased matrix gene expression, and an osteopenic phenotype with immature woven bone [#2]. Structurally, NACA forms a heterodimeric NAC domain with the beta-subunit; a nucleic acid-binding region within the NACA NAC domain is occluded by a beta-subunit helix in the complex, providing a structural basis for regulated nucleic acid engagement [#3]. Beyond transcriptional control, NACA function is required non-cell-autonomously in haematopoietic niche stromal cells for maturation of reticular cells supporting HSPCs, and a muscle-specific isoform, skNAC, is required for myofibril assembly and sarcomeric protein accumulation [#4, #5].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established how alpha-NAC is directed to the nucleus and licensed as a coactivator, linking adhesion signaling to transcription.\",\n      \"evidence\": \"ILK kinase assays, S43A mutagenesis, immunofluorescence localization, and transcriptional reporter assays in cultured cells\",\n      \"pmids\": [\"15299025\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not identify the nuclear import machinery recognizing phospho-S43 NACA\", \"Direct DNA/promoter contacts of nuclear NACA not resolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined the counter-regulatory arm controlling nuclear alpha-NAC levels, showing degradation as a brake on its coactivation potency.\",\n      \"evidence\": \"In vitro GSK3\\u03b2 kinase assay, T159 mutagenesis, proteasome inhibitors, and metabolic stability/localization assays\",\n      \"pmids\": [\"15005626\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase coupling Thr-159 phosphorylation to proteasomal turnover not identified\", \"Crosstalk between S43 and T159 phosphorylation events untested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated in vivo that the ILK\\u2013S43 nuclear-translocation mechanism drives osteoblast matrix gene programs and bone quality.\",\n      \"evidence\": \"S43A knock-in mouse, ChIP at the osteocalcin promoter, reporter assays, and histomorphometry\",\n      \"pmids\": [\"19884350\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full set of NACA-regulated osteoblast target genes not delineated\", \"Whether NACA acts directly on DNA or via c-Jun tethering at these promoters not resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Provided the structural basis for NACA's nucleic acid-binding activity and its masking within the heterodimer.\",\n      \"evidence\": \"X-ray crystallography of the human NAC domain with mapping of the nucleic acid-binding region\",\n      \"pmids\": [\"20214399\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not show what triggers release of the beta-subunit helix to expose the binding region in vivo\", \"Sequence specificity and physiological nucleic acid ligand not defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified a tissue-specific role for the skNAC isoform in sarcomere assembly, extending NACA function to muscle structural integrity.\",\n      \"evidence\": \"Morpholino knockdown of sknac in zebrafish with sarcomeric immunostaining, Western blot, and paralysis phenotyping\",\n      \"pmids\": [\"19211926\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Morpholino-based knockdown without genetic mutant confirmation\", \"Direct chaperone substrates among sarcomeric proteins not identified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed NACA acts non-cell-autonomously in the haematopoietic niche, distinguishing a stromal maturation requirement from an HSPC-intrinsic role.\",\n      \"evidence\": \"Zebrafish naca mutant analysis with live imaging and cell-transplantation epistasis distinguishing niche versus HSPC defects\",\n      \"pmids\": [\"26411530\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular targets of NACA driving stromal reticular-cell maturation not identified\", \"Whether the niche role uses the chaperone or transcriptional function unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How NACA's chaperone, nucleic acid-binding, and signal-regulated coactivator activities are mechanistically coordinated within a single molecule across tissues remains unresolved.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking NAC-domain chaperone function to nuclear transcriptional role\", \"Direct transcriptional target spectrum and DNA-binding mode of nuclear NACA undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 4, 5]}\n    ],\n    \"complexes\": [\"nascent polypeptide-associated complex (NAC)\"],\n    \"partners\": [\"ILK\", \"GSK3B\", \"JUN\", \"NACB\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}