{"gene":"ACR","run_date":"2026-06-09T22:02:39","timeline":{"discoveries":[{"year":1989,"finding":"The human preproacrosin gene (ACR) was mapped to chromosomal region 22q13-qter using somatic cell hybrid panels, establishing it as a single-copy gene on chromosome 22.","method":"Somatic cell hybrid segregation analysis with Southern blotting; restriction fragment length polymorphism (RFLP) with SstI","journal":"Human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct chromosomal mapping by somatic cell hybrids with translocation panel; single lab but two complementary methods (segregation + RFLP)","pmids":["2606479"],"is_preprint":false},{"year":1991,"finding":"The rat proacrosin gene (ACR) was assigned to rat chromosome 7 by analysis of mouse × rat somatic cell hybrids, confirming orthologous chromosomal localization in rodents.","method":"Somatic cell hybrid segregation analysis","journal":"Cytogenetics and cell genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single method (somatic cell hybrid segregation), single lab, chromosomal assignment only with no functional follow-up","pmids":["1906796"],"is_preprint":false},{"year":2010,"finding":"ACR (acrosin) and PRSS21 together provide trypsin-like serine protease activity required for sperm penetration through cumulus matrix and zona pellucida (ZP); double-knockout male mice were subfertile, and double-knockout epididymal sperm failed to undergo acrosomal exocytosis on the ZP surface and could not traverse the ZP in vitro, demonstrating that ACR's protease activity is essential for in vitro fertilization but partially compensated by the female reproductive tract in vivo.","method":"Double-knockout mouse generation (ACR and PRSS21 null); in vitro fertilization assays; intrauterine sperm injection; acrosomal exocytosis assay on ZP","journal":"Biology of reproduction","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic knockout with multiple orthogonal functional readouts (in vitro fertilization, acrosomal exocytosis, cumulus penetration, intrauterine rescue experiment) in a single rigorous study","pmids":["20484738"],"is_preprint":false},{"year":2019,"finding":"Fluoride exposure selectively downregulated ACR protein expression in the rat epididymis (but not testis), correlating with reduced sperm ability to penetrate the egg cumulus cell layer, indicating that epididymal ACR protein contributes to sperm fertilizing capacity at the cumulus penetration step.","method":"In vivo fluoride exposure (NaF via drinking water); western blot; immunofluorescence; RT-PCR; sperm-egg binding assay","journal":"Journal of agricultural and food chemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — correlation between ACR downregulation and functional deficit without direct genetic rescue; single lab, observational toxicology design","pmids":["31008594"],"is_preprint":false}],"current_model":"Human ACR encodes proacrosin/acrosin, a sperm-specific trypsin-like serine protease localized to the acrosome; genetic evidence from mouse double-knockout studies (ACR/PRSS21) establishes that acrosin's proteolytic activity is required for sperm penetration through the cumulus matrix and zona pellucida during fertilization in vitro, while the female reproductive tract can partially compensate for its loss in vivo, and the gene maps to human chromosome 22q13-qter."},"narrative":{"mechanistic_narrative":"ACR encodes proacrosin/acrosin, a sperm protease that, together with PRSS21, provides the trypsin-like serine protease activity required for sperm penetration through the cumulus matrix and zona pellucida during fertilization [PMID:20484738]. Genetic ablation in mice demonstrates that this proteolytic activity is essential for acrosomal exocytosis on the zona pellucida surface and for traversal of the zona pellucida in vitro, while loss is partially compensated by the female reproductive tract in vivo [PMID:20484738]. The protein contributes to fertilizing capacity at the cumulus-penetration step, with epididymal ACR expression correlating with this function [PMID:31008594]. The human gene is a single-copy locus on chromosome 22q13-qter [PMID:2606479]. Beyond these functional and mapping data, no further mechanistic detail on substrate specificity or structural regulation has been characterized in the available corpus.","teleology":[{"year":1989,"claim":"Establishing the human ACR locus answered where the preproacrosin gene resides in the genome and confirmed it as a single-copy gene, a prerequisite for genetic and clinical follow-up.","evidence":"Somatic cell hybrid segregation analysis with Southern blotting and SstI RFLP in human cell panels","pmids":["2606479"],"confidence":"Medium","gaps":["No functional characterization of the gene product","Mapping resolution limited to 22q13-qter band region"]},{"year":1991,"claim":"Mapping the rodent ortholog confirmed conserved chromosomal localization of proacrosin across mammals, supporting cross-species relevance of the locus.","evidence":"Mouse × rat somatic cell hybrid segregation analysis","pmids":["1906796"],"confidence":"Low","gaps":["Chromosomal assignment only, no functional follow-up","Single method, single lab"]},{"year":2010,"claim":"Whether acrosin's protease activity is genuinely required for fertilization was resolved by double-knockout genetics, distinguishing an essential in vitro role from in vivo compensation.","evidence":"ACR/PRSS21 double-knockout mice with in vitro fertilization, acrosomal exocytosis on ZP, cumulus penetration, and intrauterine sperm injection assays","pmids":["20484738"],"confidence":"High","gaps":["Redundancy between ACR and PRSS21 not fully partitioned to individual contributions","Molecular substrates cleaved during ZP traversal not identified","Mechanism of female-tract compensation in vivo unknown"]},{"year":2019,"claim":"Linking epididymal ACR protein levels to cumulus-penetration capacity addressed whether post-testicular ACR expression contributes functionally to sperm fertilizing ability.","evidence":"In vivo fluoride exposure with western blot, immunofluorescence, RT-PCR, and sperm-egg binding assays in rat","pmids":["31008594"],"confidence":"Low","gaps":["Correlative toxicology design without genetic rescue","Cannot exclude off-target effects of fluoride on other sperm proteins","Single lab observational study"]},{"year":null,"claim":"The molecular substrates of acrosin during zona pellucida penetration and the structural basis of proacrosin activation remain undefined in the available corpus.","evidence":"","pmids":[],"confidence":"Low","gaps":["No identified physiological substrates","No structural model of proacrosin activation","Mechanism of in vivo compensation uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[2]}],"localization":[],"pathway":[{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[2]}],"complexes":[],"partners":["PRSS21"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P10323","full_name":"Acrosin","aliases":[],"length_aa":421,"mass_kda":45.8,"function":"Acrosin is the major protease of mammalian spermatozoa. It is a serine protease of trypsin-like cleavage specificity, it is synthesized in a zymogen form, proacrosin and stored in the acrosome","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/P10323/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ACR","classification":"Not Classified","n_dependent_lines":32,"n_total_lines":1208,"dependency_fraction":0.026490066225165563},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ACR","total_profiled":1310},"omim":[{"mim_id":"620500","title":"SPERMATOGENIC FAILURE 87; SPGF87","url":"https://www.omim.org/entry/620500"},{"mim_id":"620376","title":"AUTOINFLAMMATORY DISEASE, SYSTEMIC, WITH VASCULITIS; SAIDV","url":"https://www.omim.org/entry/620376"},{"mim_id":"615538","title":"CHROMOSOME 22q13 DUPLICATION SYNDROME","url":"https://www.omim.org/entry/615538"},{"mim_id":"608537","title":"VON HIPPEL-LINDAU TUMOR SUPPRESSOR; VHL","url":"https://www.omim.org/entry/608537"},{"mim_id":"606426","title":"EGL9 FAMILY HYPOXIA-INDUCIBLE FACTOR 3; EGLN3","url":"https://www.omim.org/entry/606426"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"testis","ntpm":80.9}],"url":"https://www.proteinatlas.org/search/ACR"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P10323","domains":[{"cath_id":"2.40.10.10","chopping":"58-159_283-299","consensus_level":"medium","plddt":95.821,"start":58,"end":299},{"cath_id":"2.40.10.10","chopping":"177-280","consensus_level":"medium","plddt":93.1426,"start":177,"end":280}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P10323","model_url":"https://alphafold.ebi.ac.uk/files/AF-P10323-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P10323-F1-predicted_aligned_error_v6.png","plddt_mean":79.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ACR","jax_strain_url":"https://www.jax.org/strain/search?query=ACR"},"sequence":{"accession":"P10323","fasta_url":"https://rest.uniprot.org/uniprotkb/P10323.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P10323/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P10323"}},"corpus_meta":[{"pmid":"37635643","id":"PMC_37635643","title":"The 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medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28409015","citation_count":24,"is_preprint":false},{"pmid":"24793039","id":"PMC_24793039","title":"ACR appropriateness criteria post-treatment follow-up of renal cell carcinoma.","date":"2014","source":"Journal of the American College of Radiology : JACR","url":"https://pubmed.ncbi.nlm.nih.gov/24793039","citation_count":23,"is_preprint":false},{"pmid":"9606719","id":"PMC_9606719","title":"ACR-3, a Caenorhabditis elegans nicotinic acetylcholine receptor subunit. Molecular cloning and functional expression.","date":"1997","source":"Receptors & channels","url":"https://pubmed.ncbi.nlm.nih.gov/9606719","citation_count":23,"is_preprint":false},{"pmid":"7766418","id":"PMC_7766418","title":"Cloning and partial characterization of the cDNA encoding the fox sperm protein FSA-Acr.1 with similarities to the SP-10 antigen.","date":"1995","source":"Molecular reproduction and development","url":"https://pubmed.ncbi.nlm.nih.gov/7766418","citation_count":22,"is_preprint":false},{"pmid":"1906796","id":"PMC_1906796","title":"Chromosomal assignment of four rat genes coding for the spermatid-specific proteins proacrosin (ACR), transition proteins 1 (TNP1) and 2 (TNP2), and protamine 1 (PRM1).","date":"1991","source":"Cytogenetics and cell genetics","url":"https://pubmed.ncbi.nlm.nih.gov/1906796","citation_count":22,"is_preprint":false},{"pmid":"29724415","id":"PMC_29724415","title":"ACR Appropriateness Criteria® Orbits Vision and Visual Loss.","date":"2018","source":"Journal of the American College of Radiology : JACR","url":"https://pubmed.ncbi.nlm.nih.gov/29724415","citation_count":21,"is_preprint":false},{"pmid":"31054741","id":"PMC_31054741","title":"ACR Appropriateness Criteria® Neck Mass-Adenopathy.","date":"2019","source":"Journal of the American College of Radiology : JACR","url":"https://pubmed.ncbi.nlm.nih.gov/31054741","citation_count":20,"is_preprint":false},{"pmid":"16784488","id":"PMC_16784488","title":"Usefulness of acr expression for monitoring latent Mycobacterium tuberculosis bacilli in 'in vitro' and 'in vivo' experimental models.","date":"2006","source":"Scandinavian journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/16784488","citation_count":20,"is_preprint":false},{"pmid":"22574210","id":"PMC_22574210","title":"The features of the synovium in early rheumatoid arthritis according to the 2010 ACR/EULAR classification criteria.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22574210","citation_count":20,"is_preprint":false},{"pmid":"23351035","id":"PMC_23351035","title":"Nicotine-motivated behavior in Caenorhabditis elegans requires the nicotinic acetylcholine receptor subunits acr-5 and acr-15.","date":"2013","source":"The European journal of neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/23351035","citation_count":19,"is_preprint":false},{"pmid":"26045887","id":"PMC_26045887","title":"The advantages of PD1 activating chimeric receptor (PD1-ACR) engineered lymphocytes for PDL1(+) cancer therapy.","date":"2015","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/26045887","citation_count":19,"is_preprint":false},{"pmid":"40447498","id":"PMC_40447498","title":"EULAR/ACR risk stratification criteria for development of rheumatoid arthritis in the risk stage of arthralgia.","date":"2025","source":"Annals of the rheumatic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/40447498","citation_count":18,"is_preprint":false},{"pmid":"37913913","id":"PMC_37913913","title":"Hesperidin ameliorates Amyloid-β toxicity and enhances oxidative stress resistance and lifespan of Caenorhabditis elegans through acr-16 mediated activation of the autophagy pathway.","date":"2023","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37913913","citation_count":18,"is_preprint":false},{"pmid":"23675907","id":"PMC_23675907","title":"Expression analysis of MND1/GAJ, SPATA22, GAPDHS and ACR genes in testicular biopsies from non-obstructive azoospermia (NOA) patients.","date":"2013","source":"Reproductive biology and endocrinology : RB&E","url":"https://pubmed.ncbi.nlm.nih.gov/23675907","citation_count":18,"is_preprint":false},{"pmid":"25093695","id":"PMC_25093695","title":"A novel antigen-carrier system: the Mycobacterium tuberculosis Acr protein carried by raw starch microparticles.","date":"2014","source":"International journal of pharmaceutics","url":"https://pubmed.ncbi.nlm.nih.gov/25093695","citation_count":18,"is_preprint":false},{"pmid":"22970690","id":"PMC_22970690","title":"Xenopus laevis RIC-3 enhances the functional expression of the C. elegans homomeric nicotinic receptor, ACR-16, in Xenopus oocytes.","date":"2012","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22970690","citation_count":17,"is_preprint":false},{"pmid":"33311451","id":"PMC_33311451","title":"Correlation between urine ACR and 24-h proteinuria in a real-world cohort of systemic AL amyloidosis patients.","date":"2020","source":"Blood cancer journal","url":"https://pubmed.ncbi.nlm.nih.gov/33311451","citation_count":17,"is_preprint":false},{"pmid":"38040469","id":"PMC_38040469","title":"ACR Appropriateness Criteria® Staging and Post-Therapy Assessment of Head and Neck Cancer.","date":"2023","source":"Journal of the American College of Radiology : JACR","url":"https://pubmed.ncbi.nlm.nih.gov/38040469","citation_count":16,"is_preprint":false},{"pmid":"28528783","id":"PMC_28528783","title":"Revelation and cloning of valinomycin synthetase genes in Streptomyces lavendulae ACR-DA1 and their expression analysis under different fermentation and elicitation conditions.","date":"2017","source":"Journal of biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/28528783","citation_count":16,"is_preprint":false},{"pmid":"16287924","id":"PMC_16287924","title":"Interleukin-10 gene polymorphisms are associated with the SLICC/ACR Damage Index in systemic lupus erythematosus.","date":"2005","source":"Rheumatology (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/16287924","citation_count":15,"is_preprint":false},{"pmid":"21786421","id":"PMC_21786421","title":"Topography-induced cell adhesion to Acr-sP(EO-stat-PO) hydrogels: the role of protein adsorption.","date":"2011","source":"Macromolecular bioscience","url":"https://pubmed.ncbi.nlm.nih.gov/21786421","citation_count":15,"is_preprint":false},{"pmid":"34794595","id":"PMC_34794595","title":"ACR Appropriateness Criteria® Noncerebral Vasculitis.","date":"2021","source":"Journal of the American College of Radiology : JACR","url":"https://pubmed.ncbi.nlm.nih.gov/34794595","citation_count":14,"is_preprint":false},{"pmid":"27131050","id":"PMC_27131050","title":"ACR Appropriateness criteria® for nasopharyngeal carcinoma.","date":"2016","source":"Head & neck","url":"https://pubmed.ncbi.nlm.nih.gov/27131050","citation_count":14,"is_preprint":false},{"pmid":"27330003","id":"PMC_27330003","title":"ACR Appropriateness Criteria(®) Locoregional therapy for resectable oropharyngeal squamous cell carcinomas.","date":"2016","source":"Head & neck","url":"https://pubmed.ncbi.nlm.nih.gov/27330003","citation_count":14,"is_preprint":false},{"pmid":"27054065","id":"PMC_27054065","title":"The Ascaris suum nicotinic receptor, ACR-16, as a drug target: Four novel negative allosteric modulators from virtual screening.","date":"2016","source":"International journal for parasitology. Drugs and drug resistance","url":"https://pubmed.ncbi.nlm.nih.gov/27054065","citation_count":14,"is_preprint":false},{"pmid":"23890874","id":"PMC_23890874","title":"ACR appropriateness criteria nonsurgical treatment for non-small-cell lung cancer: poor performance status or palliative intent.","date":"2013","source":"Journal of the American College of Radiology : JACR","url":"https://pubmed.ncbi.nlm.nih.gov/23890874","citation_count":14,"is_preprint":false},{"pmid":"31685101","id":"PMC_31685101","title":"ACR Appropriateness Criteria® Acute Respiratory Illness in Immunocompromised Patients.","date":"2019","source":"Journal of the American College of Radiology : JACR","url":"https://pubmed.ncbi.nlm.nih.gov/31685101","citation_count":13,"is_preprint":false},{"pmid":"25180631","id":"PMC_25180631","title":"ACR appropriateness Criteria® early-stage non-small-cell lung cancer.","date":"2014","source":"American journal of clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/25180631","citation_count":13,"is_preprint":false},{"pmid":"37598876","id":"PMC_37598876","title":"Performance of the new 2022 ACR/EULAR classification criteria for giant cell arteritis in clinical practice in relation to its clinical phenotypes.","date":"2023","source":"Autoimmunity reviews","url":"https://pubmed.ncbi.nlm.nih.gov/37598876","citation_count":13,"is_preprint":false},{"pmid":"35625691","id":"PMC_35625691","title":"Thyroid Cancer Detection in a Routine Clinical Setting: Performance of ACR TI-RADS, FNAC, and Molecular Testing in Prospective Cohort Study.","date":"2022","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/35625691","citation_count":13,"is_preprint":false},{"pmid":"39966038","id":"PMC_39966038","title":"EULAR/ACR classification criteria for paediatric chronic nonbacterial osteomyelitis (CNO).","date":"2025","source":"Annals of the rheumatic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/39966038","citation_count":12,"is_preprint":false},{"pmid":"37633353","id":"PMC_37633353","title":"Should ACR/EULAR criteria be revised changing the RF and ACPA scores?","date":"2023","source":"Autoimmunity reviews","url":"https://pubmed.ncbi.nlm.nih.gov/37633353","citation_count":12,"is_preprint":false},{"pmid":"35068450","id":"PMC_35068450","title":"Comparison of diagnostic value of SWE, FNA and BRAF gene detection in ACR TI-RADS 4 and 5 thyroid nodules.","date":"2022","source":"Clinical hemorheology and microcirculation","url":"https://pubmed.ncbi.nlm.nih.gov/35068450","citation_count":12,"is_preprint":false},{"pmid":"23872794","id":"PMC_23872794","title":"ACR Appropriateness Criteria® management of locoregionally advanced squamous cell carcinoma of the vulva.","date":"2013","source":"American journal of clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/23872794","citation_count":12,"is_preprint":false},{"pmid":"23511336","id":"PMC_23511336","title":"ACR Appropriateness Criteria® radiation therapy for small-cell lung cancer.","date":"2013","source":"American journal of clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/23511336","citation_count":12,"is_preprint":false},{"pmid":"37507207","id":"PMC_37507207","title":"External validation of the 2022 ACR/EULAR classification criteria in patients with suspected giant cell arteritis in a Dutch fast-track clinic.","date":"2023","source":"RMD open","url":"https://pubmed.ncbi.nlm.nih.gov/37507207","citation_count":12,"is_preprint":false},{"pmid":"29468340","id":"PMC_29468340","title":"Phrasing of the patient global assessment in the rheumatoid arthritis ACR/EULAR remission criteria: an analysis of 967 patients from two databases of early and established rheumatoid arthritis patients.","date":"2018","source":"Clinical rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/29468340","citation_count":12,"is_preprint":false},{"pmid":"38040459","id":"PMC_38040459","title":"ACR Appropriateness Criteria® Breast Implant Evaluation: 2023 Update.","date":"2023","source":"Journal of the American College of Radiology : JACR","url":"https://pubmed.ncbi.nlm.nih.gov/38040459","citation_count":11,"is_preprint":false},{"pmid":"38040462","id":"PMC_38040462","title":"ACR Appropriateness Criteria® Imaging After Total Hip Arthroplasty.","date":"2023","source":"Journal of the American College of Radiology : JACR","url":"https://pubmed.ncbi.nlm.nih.gov/38040462","citation_count":11,"is_preprint":false},{"pmid":"31685108","id":"PMC_31685108","title":"ACR Appropriateness Criteria® Post-Treatment Follow-up and Active Surveillance of Clinically Localized Renal Cell Cancer.","date":"2019","source":"Journal of the American College of Radiology : JACR","url":"https://pubmed.ncbi.nlm.nih.gov/31685108","citation_count":11,"is_preprint":false},{"pmid":"27374781","id":"PMC_27374781","title":"ACR Appropriateness Criteria Fever Without Source or Unknown Origin-Child.","date":"2016","source":"Journal of the American College of Radiology : JACR","url":"https://pubmed.ncbi.nlm.nih.gov/27374781","citation_count":11,"is_preprint":false},{"pmid":"20541060","id":"PMC_20541060","title":"ACR Appropriateness Criteria: nonsurgical treatment for non-small-cell lung cancer: good performance status/definitive intent.","date":"2010","source":"Current problems in cancer","url":"https://pubmed.ncbi.nlm.nih.gov/20541060","citation_count":11,"is_preprint":false},{"pmid":"21033738","id":"PMC_21033738","title":"Combined influence of substrate stiffness and surface topography on the antiadhesive properties of Acr-sP(EO-stat-PO) hydrogels.","date":"2010","source":"Biomacromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/21033738","citation_count":11,"is_preprint":false},{"pmid":"31685109","id":"PMC_31685109","title":"ACR Appropriateness Criteria® Post-Treatment Surveillance of Bladder Cancer.","date":"2019","source":"Journal of the American College of Radiology : JACR","url":"https://pubmed.ncbi.nlm.nih.gov/31685109","citation_count":10,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50725,"output_tokens":1911,"usd":0.09042,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7568,"output_tokens":1529,"usd":0.038032,"stage2_stop_reason":"end_turn"},"total_usd":0.128452,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to identify papers about the human/mammalian gene ACR (acrosin, the sperm serine protease). Let me classify each paper:\n\n- Papers 1-2, 5-7, 10-11, 17-21, 24-26, 28-32, 34-35, 37-41, 44-48, 50-54, 56-58, 62-68, 72-79, 82-100: ACR = \"American College of Rheumatology\" or \"American College of Radiology\" — NOT the gene. Skip.\n- Paper 3: Mycobacterium tuberculosis Acr protein (alpha-crystallin homolog) — not the human ACR gene. Skip.\n- Paper 4: circRNA ACR — non-protein locus product. Skip.\n- Paper 8: C. elegans acr-16 — symbol collision (different gene family, nematode nicotinic receptor). Not ortholog of human ACR (acrosin).\n- Paper 9: C. elegans acr-16/cam-1 — same, skip.\n- Paper 12-13: M. tuberculosis acr gene — not human ACR. Skip.\n- Paper 14: Mouse ACR (acrosin) + PRSS21 double-knockout — this IS an ortholog of human ACR (acrosin serine protease). Include.\n- Paper 15: Alternaria alternata ACR-toxin — symbol collision (fungal toxin). Skip.\n- Paper 22-23, 36, 37, 49, 51, 55, 59, 66, 69, 72, 81: C. elegans acr genes — these are nicotinic receptor subunit genes, NOT orthologs of human ACR (acrosin). Skip.\n- Paper 27: \"Glc-N-AcR\" — just notation, not ACR gene. Skip.\n- Paper 38: F4ab/acR- pigs — F4 receptor negative pigs, not ACR gene. Skip.\n- Paper 41-42, 64, 71: M. tuberculosis acr — not human ACR. Skip.\n- Paper 43: Alternaria ACRTS2 for ACR-toxin — fungal, skip.\n- Paper 44: ACR protein in rat epididymis (fluoride effect on SPAM1, ACR, PRSS21) — this IS about mammalian ACR (acrosin). Include.\n- Paper 46: Salmonella acrAB efflux pump — symbol collision. Skip.\n- Paper 52: circRNA ACR — retracted, non-protein. Skip.\n- Paper 56: Human ACR gene chromosomal mapping. Include.\n- Paper 60: Fox sperm FSA-Acr.1 — acrosin-related sperm antigen, possibly related but it's about FSA-Acr.1 similarity to SP-10, not ACR directly. Borderline — it describes a different protein with homology. Skip.\n- Paper 61: Rat ACR chromosomal assignment. Include (mechanistic context minimal but chromosomal).\n- Paper 67: PD1-ACR chimeric antigen receptor — \"ACR\" here = \"Activating Chimeric Receptor,\" not the gene. Skip.\n- Paper 70: ACR gene expression in NOA patients — expression study, no mechanism. Skip.\n- Paper 75: Streptomyces ACR-DA1 — symbol collision. Skip.\n- Paper 77, 99: Acr-sP(EO-stat-PO) hydrogels — material science, not the gene. Skip.\n\nNow extracting mechanistic discoveries from qualifying papers (14, 44, 56, 61):\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1989,\n      \"finding\": \"The human preproacrosin gene (ACR) was mapped to chromosomal region 22q13-qter using somatic cell hybrid panels, establishing it as a single-copy gene on chromosome 22.\",\n      \"method\": \"Somatic cell hybrid segregation analysis with Southern blotting; restriction fragment length polymorphism (RFLP) with SstI\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct chromosomal mapping by somatic cell hybrids with translocation panel; single lab but two complementary methods (segregation + RFLP)\",\n      \"pmids\": [\"2606479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"The rat proacrosin gene (ACR) was assigned to rat chromosome 7 by analysis of mouse × rat somatic cell hybrids, confirming orthologous chromosomal localization in rodents.\",\n      \"method\": \"Somatic cell hybrid segregation analysis\",\n      \"journal\": \"Cytogenetics and cell genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single method (somatic cell hybrid segregation), single lab, chromosomal assignment only with no functional follow-up\",\n      \"pmids\": [\"1906796\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ACR (acrosin) and PRSS21 together provide trypsin-like serine protease activity required for sperm penetration through cumulus matrix and zona pellucida (ZP); double-knockout male mice were subfertile, and double-knockout epididymal sperm failed to undergo acrosomal exocytosis on the ZP surface and could not traverse the ZP in vitro, demonstrating that ACR's protease activity is essential for in vitro fertilization but partially compensated by the female reproductive tract in vivo.\",\n      \"method\": \"Double-knockout mouse generation (ACR and PRSS21 null); in vitro fertilization assays; intrauterine sperm injection; acrosomal exocytosis assay on ZP\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic knockout with multiple orthogonal functional readouts (in vitro fertilization, acrosomal exocytosis, cumulus penetration, intrauterine rescue experiment) in a single rigorous study\",\n      \"pmids\": [\"20484738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Fluoride exposure selectively downregulated ACR protein expression in the rat epididymis (but not testis), correlating with reduced sperm ability to penetrate the egg cumulus cell layer, indicating that epididymal ACR protein contributes to sperm fertilizing capacity at the cumulus penetration step.\",\n      \"method\": \"In vivo fluoride exposure (NaF via drinking water); western blot; immunofluorescence; RT-PCR; sperm-egg binding assay\",\n      \"journal\": \"Journal of agricultural and food chemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — correlation between ACR downregulation and functional deficit without direct genetic rescue; single lab, observational toxicology design\",\n      \"pmids\": [\"31008594\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Human ACR encodes proacrosin/acrosin, a sperm-specific trypsin-like serine protease localized to the acrosome; genetic evidence from mouse double-knockout studies (ACR/PRSS21) establishes that acrosin's proteolytic activity is required for sperm penetration through the cumulus matrix and zona pellucida during fertilization in vitro, while the female reproductive tract can partially compensate for its loss in vivo, and the gene maps to human chromosome 22q13-qter.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ACR encodes proacrosin/acrosin, a sperm protease that, together with PRSS21, provides the trypsin-like serine protease activity required for sperm penetration through the cumulus matrix and zona pellucida during fertilization [#2]. Genetic ablation in mice demonstrates that this proteolytic activity is essential for acrosomal exocytosis on the zona pellucida surface and for traversal of the zona pellucida in vitro, while loss is partially compensated by the female reproductive tract in vivo [#2]. The protein contributes to fertilizing capacity at the cumulus-penetration step, with epididymal ACR expression correlating with this function [#3]. The human gene is a single-copy locus on chromosome 22q13-qter [#0]. Beyond these functional and mapping data, no further mechanistic detail on substrate specificity or structural regulation has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 1989,\n      \"claim\": \"Establishing the human ACR locus answered where the preproacrosin gene resides in the genome and confirmed it as a single-copy gene, a prerequisite for genetic and clinical follow-up.\",\n      \"evidence\": \"Somatic cell hybrid segregation analysis with Southern blotting and SstI RFLP in human cell panels\",\n      \"pmids\": [\"2606479\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional characterization of the gene product\", \"Mapping resolution limited to 22q13-qter band region\"]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Mapping the rodent ortholog confirmed conserved chromosomal localization of proacrosin across mammals, supporting cross-species relevance of the locus.\",\n      \"evidence\": \"Mouse \\u00d7 rat somatic cell hybrid segregation analysis\",\n      \"pmids\": [\"1906796\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Chromosomal assignment only, no functional follow-up\", \"Single method, single lab\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Whether acrosin's protease activity is genuinely required for fertilization was resolved by double-knockout genetics, distinguishing an essential in vitro role from in vivo compensation.\",\n      \"evidence\": \"ACR/PRSS21 double-knockout mice with in vitro fertilization, acrosomal exocytosis on ZP, cumulus penetration, and intrauterine sperm injection assays\",\n      \"pmids\": [\"20484738\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Redundancy between ACR and PRSS21 not fully partitioned to individual contributions\", \"Molecular substrates cleaved during ZP traversal not identified\", \"Mechanism of female-tract compensation in vivo unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linking epididymal ACR protein levels to cumulus-penetration capacity addressed whether post-testicular ACR expression contributes functionally to sperm fertilizing ability.\",\n      \"evidence\": \"In vivo fluoride exposure with western blot, immunofluorescence, RT-PCR, and sperm-egg binding assays in rat\",\n      \"pmids\": [\"31008594\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Correlative toxicology design without genetic rescue\", \"Cannot exclude off-target effects of fluoride on other sperm proteins\", \"Single lab observational study\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular substrates of acrosin during zona pellucida penetration and the structural basis of proacrosin activation remain undefined in the available corpus.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No identified physiological substrates\", \"No structural model of proacrosin activation\", \"Mechanism of in vivo compensation uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PRSS21\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}