{"gene":"CADPS","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":1997,"finding":"CAPS (rat homolog of UNC-31) was purified as a 145-kDa cytosolic protein required for the Ca2+-dependent triggering step of dense-core vesicle exocytosis in permeable PC12 cells. Recombinant CAPS substituted for cytosol in the Ca2+ triggering step and exhibited moderate affinity Ca2+ binding (Kd = 270 µM, 2 mol Ca2+/mol CAPS dimer), consistent with a role as a Ca2+-regulated factor in vesicle fusion.","method":"Protein purification, in vitro exocytosis reconstitution in permeable PC12 cells, recombinant protein substitution assay, Ca2+ binding measurement","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified recombinant protein, direct Ca2+ binding measurement, functional substitution assay","pmids":["9289490"],"is_preprint":false},{"year":1998,"finding":"CAPS localizes selectively to plasma membranes and dense-core vesicles (DCVs) but not to small clear synaptic vesicles in brain homogenates. CAPS is a peripherally membrane-associated protein that binds DCVs via bilayer phospholipids with high affinity and saturable binding. Specific CAPS antibodies inhibit Ca2+-activated norepinephrine release from lysed synaptosomes, indicating that membrane-bound CAPS is essential for neural DCV exocytosis.","method":"Subcellular fractionation, membrane binding assay, phospholipid binding characterization, antibody inhibition of DCV exocytosis from synaptosomes","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct fractionation with functional antibody inhibition assay, multiple orthogonal methods in one study","pmids":["9697858"],"is_preprint":false},{"year":2003,"finding":"Human CADPS contains a C2 domain, a known protein motif involved in calcium and phospholipid interactions. CADPS expression is restricted to neural and endocrine tissues. The C2 domain identification supports a role for CADPS as a calcium sensor in regulated exocytosis.","method":"Full-length cDNA cloning, domain analysis, tissue expression profiling","journal":"Genomics","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational domain identification and expression profiling only, no functional validation of the C2 domain in this study","pmids":["12659812"],"is_preprint":false},{"year":2007,"finding":"C. elegans UNC-31 (CAPS ortholog) is required for dense-core vesicle (DCV) exocytosis and evoked peptide release in cultured neurons, but is not required for stimulated synaptic vesicle recycling. Conversely, UNC-13 is essential for synaptic vesicle but not DCV exocytosis, indicating parallel and dedicated roles for these proteins.","method":"Novel in vivo peptide release assay (prepro-ANF-GFP fusion), FM4-64 dye uptake for synaptic vesicle recycling in cultured C. elegans neurons, genetic loss-of-function analysis","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal assays (in vivo release, vesicle recycling, cultured neuron electrophysiology), genetic dissection with parallel control (UNC-13), replicated across assays","pmids":["17553987"],"is_preprint":false},{"year":2005,"finding":"C. elegans UNC-31 acts upstream of the neuronal Gαs pathway to regulate locomotion. Genetic epistasis shows UNC-31 and Gαs are in the same pathway, distinct from the Gαq pathway. UNC-31 functions in cholinergic motor neurons and is concentrated at or near active zones, suggesting that DCV exocytosis locally activates Gαs signaling near synaptic active zones.","method":"Genetic epistasis analysis, cell-specific rescue with promoters, immunostaining for UNC-31 localization","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — rigorous epistasis with cell-specific rescue and localization data, single lab study","pmids":["16272411"],"is_preprint":false},{"year":2007,"finding":"UNC-31 is required for docking of dense-core vesicles (DCVs) at the plasma membrane in C. elegans neurons, as shown by direct electrophysiological (membrane capacitance, amperometry) and total internal reflection fluorescence microscopy assays. The DCV docking defect in unc-31 mutants is fully rescued by PKA activation. UNC-31 is also required for UNC-13-mediated augmentation of DCV exocytosis.","method":"Primary cultured C. elegans neuron electrophysiology (membrane capacitance, amperometry), TIRF microscopy of single DCV docking/fusion, PKA activation rescue experiment, genetic mutant analysis","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple direct functional assays (electrophysiology, single-vesicle imaging), PKA rescue experiment, rigorous controls","pmids":["18031683"],"is_preprint":false},{"year":2004,"finding":"C. elegans CeIA-2 (IA-2 homolog, encoded by ida-1) has a specific genetic interaction with UNC-31/CAPS, suggesting CeIA-2 is an important factor in dense-core vesicle cargo release. Double mutant analysis indicated that CeIA-2 and UNC-31 function in the same process of neurosecretory vesicle release.","method":"Genetic interaction analysis using null alleles of ida-1 and unc-31 in C. elegans","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with two independent null alleles, single lab","pmids":["15044551"],"is_preprint":false},{"year":2010,"finding":"Domain deletion analysis of UNC-31 in C. elegans revealed that the C2, PH, and DCV-binding domains (DCVBD) are each required for Ca2+-evoked DCV secretion, vesicle docking, and tethering. The MHD (MUN/UNC-13 homology domain) deletion partially retained function. These domains support sequential molecular actions including vesicle tethering, docking, and SNARE complex initiation.","method":"Domain deletion mutant rescue in unc-31 null C. elegans (locomotion assay, pharmacological NMJ assay, in vivo neuropeptide release, capacitance measurements in ALA neurons, vesicle docking analysis)","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple domain mutants with multiple functional readouts, single lab","pmids":["20515653"],"is_preprint":false},{"year":2022,"finding":"Endogenously tagged UNC-31 is expressed in major ganglia and nerve cords from late embryonic stages through adulthood in C. elegans. Auxin-inducible postembryonic degradation of UNC-31 from the hermaphrodite nervous system caused defects in egg laying, locomotion, and vesicle release comparable to null mutants. Depletion specifically from BAG sensory neurons increased intestinal fat storage, indicating a spatially specific role in neuropeptide-regulated fat metabolism.","method":"Endogenous tagging, auxin-inducible degradation system, live imaging for localization, behavioral and physiological assays (egg laying, locomotion, vesicle release, fat storage)","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct subcellular/temporal localization with conditional loss-of-function and functional phenotype, single lab","pmids":["36302635"],"is_preprint":false},{"year":2022,"finding":"CADPS variants identified in bipolar disorder patients resulted in lower protein abundance or partial impairment of neuronal exocytosis, synaptic plasticity, and vesicular transporter-dependent uptake of catecholamines. Heterozygous Cadps+/- mice showed manic-like behaviors, altered BDNF levels, and hypersensitivity to stress, which were rescued by lithium treatment.","method":"Patient mutation screening, functional assays of mutant CADPS in neuronal exocytosis and catecholamine uptake, heterozygous mouse model behavioral analysis, lithium rescue experiment","journal":"Molecular psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays (exocytosis, vesicular uptake, mouse behavioral phenotype with rescue), single lab","pmids":["35169262"],"is_preprint":false},{"year":2024,"finding":"Loss of UNC-31 in C. elegans reduces evoked acetylcholine transmission at the NMJ but paradoxically results in enhanced muscle contraction and Ca2+ transients in response to presynaptic stimulation. Compensatory postsynaptic homeostatic scaling involves upregulation of the muscular L-type voltage-gated Ca2+ channel EGL-19 (CaV1). Specific neuropeptides from cholinergic and GABAergic neurons (FLP-6, NLP-9, NLP-21, NLP-38, FLP-15, NLP-15) normally mediate NMJ transmission, and their absence prevents neurons from upregulating transmitter output in response to increased cAMP.","method":"Electrophysiology at C. elegans NMJ, Ca2+ imaging, expression profiling, genetic analysis of neuropeptide and proprotein convertase mutants, EGL-19 expression analysis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — electrophysiology and Ca2+ imaging with genetic dissection, preprint not yet peer-reviewed","pmids":[],"is_preprint":true},{"year":2025,"finding":"Fasting ameliorates locomotion defects in unc-31/CAPS mutant C. elegans via upregulation of Gαq (EGL-30) signaling and its downstream effectors. A gain-of-function mutation in egl-30 suppresses unc-31 locomotion defects. Exogenous octopamine treatment activates EGL-30/Gαq signaling and mimics the fasting response, restoring locomotion in an EGL-30-dependent manner, revealing a compensatory octopamine-Gαq pathway downstream of UNC-31 loss.","method":"Forward genetic screen, transcriptomic analysis, octopamine pharmacology, genetic epistasis (egl-30 gain-of-function in unc-31 null background)","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — genetic and pharmacological epistasis in a preprint, single lab, no biochemical mechanism established","pmids":[],"is_preprint":true}],"current_model":"CADPS/CAPS (UNC-31 in C. elegans) is a peripherally membrane-associated cytosolic protein that selectively localizes to dense-core vesicles (DCVs) and the plasma membrane, where it acts as a Ca2+-regulated priming and docking factor specifically required for DCV exocytosis—but not synaptic vesicle exocytosis—by binding phospholipids via its C2 and PH domains, facilitating SNARE complex formation, and acting upstream of the Gαs signaling pathway; loss of CADPS impairs catecholamine/neuropeptide secretion and synaptic plasticity, and is associated with neuropsychiatric phenotypes including manic-like behavior and stress hypersensitivity."},"narrative":{"mechanistic_narrative":"CADPS/CAPS (UNC-31 in C. elegans) is a Ca2+-regulated cytosolic factor that is selectively required for the exocytosis of dense-core vesicles (DCVs), and not small clear synaptic vesicles, in neural and endocrine cells [PMID:9289490, PMID:9697858, PMID:17553987]. Originally purified as a 145-kDa protein that reconstitutes the Ca2+-triggering step of DCV fusion in permeable PC12 cells and binds Ca2+ with moderate affinity [PMID:9289490], it associates peripherally with membranes, localizing specifically to plasma membranes and DCVs through high-affinity phospholipid binding, where it is essential for Ca2+-activated catecholamine and neuropeptide release [PMID:9697858]. Mechanistically, CADPS acts at the docking and priming steps: in C. elegans neurons UNC-31 is required for DCV docking at the plasma membrane and for UNC-13-mediated augmentation of DCV exocytosis, and its docking defect is rescued by PKA activation [PMID:18031683]. Its C2, PH, and DCV-binding domains are each required for Ca2+-evoked secretion, docking, and tethering, consistent with sequential roles in vesicle tethering, docking, and SNARE complex initiation [PMID:20515653]. Functionally, DCV release through UNC-31 acts upstream of neuronal Gαs signaling near synaptic active zones to control locomotion [PMID:16272411], and through a parallel pathway controls neuropeptide-regulated fat metabolism [PMID:36302635]. In humans, CADPS variants that reduce protein abundance and impair neuronal exocytosis, synaptic plasticity, and vesicular catecholamine uptake are linked to bipolar disorder, and heterozygous Cadps+/- mice display lithium-responsive manic-like behavior and stress hypersensitivity [PMID:35169262].","teleology":[{"year":1997,"claim":"Established that a dedicated cytosolic factor is required for the Ca2+-triggering step of dense-core vesicle fusion, defining CAPS as a Ca2+-regulated exocytosis factor rather than a generic cytosolic component.","evidence":"Protein purification and in vitro exocytosis reconstitution with recombinant protein substitution in permeable PC12 cells, plus direct Ca2+ binding measurement","pmids":["9289490"],"confidence":"High","gaps":["Did not resolve which domain mediates Ca2+ binding","No structural mechanism for how Ca2+ binding triggers fusion"]},{"year":1998,"claim":"Resolved where CAPS acts by showing it is a peripheral membrane protein selectively associated with DCVs and plasma membrane via phospholipid binding, and functionally required for neural DCV exocytosis.","evidence":"Subcellular fractionation, phospholipid binding assays, and antibody inhibition of norepinephrine release from synaptosomes","pmids":["9697858"],"confidence":"High","gaps":["Phospholipid species/domain specificity not defined","No direct demonstration of the molecular step blocked by antibody"]},{"year":2003,"claim":"Identified the human CADPS C2 domain and neural/endocrine-restricted expression, supporting a calcium-sensor role in regulated exocytosis.","evidence":"Full-length cDNA cloning, computational domain analysis, and tissue expression profiling","pmids":["12659812"],"confidence":"Low","gaps":["No functional validation of the C2 domain in this study","Domain function inferred computationally only"]},{"year":2004,"claim":"Placed UNC-31 in a genetic network for neurosecretory vesicle release by demonstrating a specific interaction with the IA-2 homolog CeIA-2 in the same DCV release process.","evidence":"Genetic interaction analysis with null alleles of ida-1 and unc-31 in C. elegans","pmids":["15044551"],"confidence":"Medium","gaps":["No physical interaction demonstrated","Molecular role of CeIA-2 in the release step unresolved"]},{"year":2005,"claim":"Connected DCV exocytosis to downstream signaling by showing UNC-31 acts upstream of neuronal Gαs near active zones to regulate locomotion, distinct from the Gαq pathway.","evidence":"Genetic epistasis, cell-specific promoter rescue, and immunostaining for UNC-31 localization in C. elegans","pmids":["16272411"],"confidence":"Medium","gaps":["Identity of the released signal activating Gαs not defined","Single-lab epistasis"]},{"year":2007,"claim":"Demonstrated the pathway specificity and step of action: UNC-31 is dedicated to DCV exocytosis and docking but dispensable for synaptic vesicle recycling, opposite to UNC-13.","evidence":"In vivo peptide release assay, FM4-64 dye uptake, cultured C. elegans neuron assays, electrophysiology, TIRF single-DCV imaging, and PKA rescue","pmids":["17553987","18031683"],"confidence":"High","gaps":["Biochemical relationship between UNC-31 docking and UNC-13 augmentation not resolved","Mechanism by which PKA bypasses the docking defect unknown"]},{"year":2010,"claim":"Assigned distinct functions to UNC-31 domains, showing C2, PH, and DCV-binding domains are each required for evoked secretion, docking, and tethering while the MUN/UNC-13 homology domain is partially dispensable.","evidence":"Domain deletion mutant rescue in unc-31 null C. elegans with locomotion, NMJ, neuropeptide release, capacitance, and docking readouts","pmids":["20515653"],"confidence":"Medium","gaps":["Direct binding partners of each domain not mapped","Temporal ordering of tethering/docking/SNARE steps inferred, not directly measured"]},{"year":2022,"claim":"Defined the temporal and spatial requirement for CADPS in vivo and extended its role to neuropeptide-regulated physiology, including fat metabolism via specific sensory neurons.","evidence":"Endogenous tagging, auxin-inducible degradation, live imaging, and behavioral/physiological assays in C. elegans","pmids":["36302635"],"confidence":"Medium","gaps":["Identity of the BAG-neuron neuropeptide controlling fat storage not established","Single-lab study"]},{"year":2022,"claim":"Linked CADPS dysfunction to human bipolar disorder by showing patient variants impair exocytosis, synaptic plasticity, and catecholamine uptake, with a lithium-responsive manic phenotype in heterozygous mice.","evidence":"Patient mutation screening, functional exocytosis/uptake assays, and Cadps+/- mouse behavioral analysis with lithium rescue","pmids":["35169262"],"confidence":"Medium","gaps":["Causal mechanism linking reduced CADPS to manic behavior unresolved","Single-lab study without independent cohort replication"]},{"year":2024,"claim":"Revealed homeostatic and neuropeptide-dependent consequences of UNC-31 loss at the NMJ, including postsynaptic CaV1/EGL-19 upregulation and a requirement for specific neuropeptides in cAMP-driven transmitter output.","evidence":"NMJ electrophysiology, Ca2+ imaging, expression profiling, and genetic analysis of neuropeptide and convertase mutants in C. elegans (preprint)","pmids":[],"confidence":"Medium","gaps":["Preprint not yet peer-reviewed","Mechanism coupling neuropeptide loss to failed cAMP-driven scaling unclear"]},{"year":2025,"claim":"Identified a compensatory octopamine-Gαq pathway that bypasses UNC-31 loss, with fasting and egl-30 gain-of-function rescuing locomotion defects.","evidence":"Forward genetic screen, transcriptomics, octopamine pharmacology, and egl-30 gain-of-function epistasis in unc-31 null C. elegans (preprint)","pmids":[],"confidence":"Low","gaps":["Preprint, no biochemical mechanism established","Single lab, genetic/pharmacological epistasis only"]},{"year":null,"claim":"The structural basis by which CADPS couples Ca2+ and phospholipid binding to SNARE-dependent DCV docking and priming, and the direct molecular partners of its C2/PH/DCV-binding domains, remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of CADPS on the vesicle/plasma membrane","Direct SNARE-machinery interactions not biochemically mapped in human protein","Mechanistic link between exocytosis defect and neuropsychiatric phenotype unestablished"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0,1,7]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[0]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,5]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[1,3,5]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,1]}],"pathway":[],"complexes":[],"partners":["UNC13","IA-2/IDA-1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9ULU8","full_name":"Calcium-dependent secretion activator 1","aliases":["Calcium-dependent activator protein for secretion 1","CAPS-1"],"length_aa":1353,"mass_kda":152.8,"function":"Calcium-binding protein involved in exocytosis of vesicles filled with neurotransmitters and neuropeptides. Probably acts upstream of fusion in the biogenesis or maintenance of mature secretory vesicles. Regulates catecholamine loading of DCVs. May specifically mediate the Ca(2+)-dependent exocytosis of large dense-core vesicles (DCVs) and other dense-core vesicles by acting as a PtdIns(4,5)P2-binding protein that acts at prefusion step following ATP-dependent priming and participates in DCVs-membrane fusion. However, it may also participate in small clear synaptic vesicles (SVs) exocytosis and it is unclear whether its function is related to Ca(2+) triggering (By similarity)","subcellular_location":"Synapse; Cytoplasmic vesicle, secretory vesicle, neuronal dense core vesicle membrane","url":"https://www.uniprot.org/uniprotkb/Q9ULU8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CADPS","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CHMP2B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CADPS","total_profiled":1310},"omim":[{"mim_id":"612128","title":"RAS-LIKE, FAMILY 10, MEMBER B; RASL10B","url":"https://www.omim.org/entry/612128"},{"mim_id":"609978","title":"CALCIUM-DEPENDENT ACTIVATOR PROTEIN FOR SECRETION 2; CADPS2","url":"https://www.omim.org/entry/609978"},{"mim_id":"604667","title":"CALCIUM-DEPENDENT ACTIVATOR PROTEIN FOR SECRETION; CADPS","url":"https://www.omim.org/entry/604667"},{"mim_id":"603315","title":"NEURONAL CALCIUM SENSOR 1; NCS1","url":"https://www.omim.org/entry/603315"},{"mim_id":"602758","title":"PHOSPHATIDYLINOSITOL 4-KINASE, BETA; PI4KB","url":"https://www.omim.org/entry/602758"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":77.2},{"tissue":"retina","ntpm":170.8}],"url":"https://www.proteinatlas.org/search/CADPS"},"hgnc":{"alias_symbol":["CAPS","KIAA1121","CAPS1","UNC-31","CADPS1"],"prev_symbol":[]},"alphafold":{"accession":"Q9ULU8","domains":[{"cath_id":"2.60.40.150","chopping":"399-518","consensus_level":"medium","plddt":87.1967,"start":399,"end":518},{"cath_id":"2.30.29.30","chopping":"523-627","consensus_level":"medium","plddt":88.4372,"start":523,"end":627},{"cath_id":"-","chopping":"836-865_874-903_914-966","consensus_level":"medium","plddt":89.2964,"start":836,"end":966},{"cath_id":"1.10.1510","chopping":"151-266","consensus_level":"high","plddt":82.8028,"start":151,"end":266}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9ULU8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9ULU8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9ULU8-F1-predicted_aligned_error_v6.png","plddt_mean":77.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CADPS","jax_strain_url":"https://www.jax.org/strain/search?query=CADPS"},"sequence":{"accession":"Q9ULU8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9ULU8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9ULU8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9ULU8"}},"corpus_meta":[{"pmid":"17553987","id":"PMC_17553987","title":"UNC-31 (CAPS) is required for dense-core vesicle but not synaptic vesicle exocytosis in Caenorhabditis elegans.","date":"2007","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/17553987","citation_count":260,"is_preprint":false},{"pmid":"9289490","id":"PMC_9289490","title":"Novel Ca2+-binding protein (CAPS) related to UNC-31 required for Ca2+-activated exocytosis.","date":"1997","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9289490","citation_count":150,"is_preprint":false},{"pmid":"9697858","id":"PMC_9697858","title":"CAPS (mammalian UNC-31) protein localizes to membranes involved in dense-core vesicle exocytosis.","date":"1998","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/9697858","citation_count":123,"is_preprint":false},{"pmid":"8325482","id":"PMC_8325482","title":"The Caenorhabditis elegans unc-31 gene affects multiple nervous system-controlled 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Journal canadien de genetique et de cytologie","url":"https://pubmed.ncbi.nlm.nih.gov/3161604","citation_count":14,"is_preprint":false},{"pmid":"35169262","id":"PMC_35169262","title":"CADPS functional mutations in patients with bipolar disorder increase the sensitivity to stress.","date":"2022","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/35169262","citation_count":3,"is_preprint":false},{"pmid":"40842820","id":"PMC_40842820","title":"Shared molecular profiles of post-laser vision correction ectasia and keratoconus with key differences in CADPS, CPT1B, CIITA, and TBC1D4.","date":"2025","source":"Frontiers in molecular biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/40842820","citation_count":1,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.04.19.649495","title":"Fasting Rescues Locomotion in Neuromodulation-Deficient  <i>C. elegans</i>  via Octopamine–Gαq Signaling","date":"2025-04-21","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.19.649495","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.09.10.612183","title":"Loss of neuropeptidergic regulation of cholinergic transmission induces CaV1-mediated homeostatic compensation in muscle cells","date":"2024-09-12","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.10.612183","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.03.19.644218","title":"Serotonergic signaling governs  <i>C. elegans</i>  sensory response to conflicting olfactory stimuli","date":"2025-03-19","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.19.644218","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.06.18.599456","title":"Glutamate, GABA, and dense-core vesicle secretion regulate predatory feeding in the nematode  <i>Pristionchus pacificus</i>","date":"2024-06-22","source":"bioRxiv","url":"https://doi.org/10.1101/2024.06.18.599456","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.07.21.604457","title":"Disposition of the chemosensory neurons in the neurotransmitter-release mutant  <i>unc-13</i>","date":"2024-07-23","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.21.604457","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11037,"output_tokens":3297,"usd":0.041283,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10861,"output_tokens":3707,"usd":0.07349,"stage2_stop_reason":"end_turn"},"total_usd":0.114773,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"CAPS (rat homolog of UNC-31) was purified as a 145-kDa cytosolic protein required for the Ca2+-dependent triggering step of dense-core vesicle exocytosis in permeable PC12 cells. Recombinant CAPS substituted for cytosol in the Ca2+ triggering step and exhibited moderate affinity Ca2+ binding (Kd = 270 µM, 2 mol Ca2+/mol CAPS dimer), consistent with a role as a Ca2+-regulated factor in vesicle fusion.\",\n      \"method\": \"Protein purification, in vitro exocytosis reconstitution in permeable PC12 cells, recombinant protein substitution assay, Ca2+ binding measurement\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified recombinant protein, direct Ca2+ binding measurement, functional substitution assay\",\n      \"pmids\": [\"9289490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"CAPS localizes selectively to plasma membranes and dense-core vesicles (DCVs) but not to small clear synaptic vesicles in brain homogenates. CAPS is a peripherally membrane-associated protein that binds DCVs via bilayer phospholipids with high affinity and saturable binding. Specific CAPS antibodies inhibit Ca2+-activated norepinephrine release from lysed synaptosomes, indicating that membrane-bound CAPS is essential for neural DCV exocytosis.\",\n      \"method\": \"Subcellular fractionation, membrane binding assay, phospholipid binding characterization, antibody inhibition of DCV exocytosis from synaptosomes\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct fractionation with functional antibody inhibition assay, multiple orthogonal methods in one study\",\n      \"pmids\": [\"9697858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Human CADPS contains a C2 domain, a known protein motif involved in calcium and phospholipid interactions. CADPS expression is restricted to neural and endocrine tissues. The C2 domain identification supports a role for CADPS as a calcium sensor in regulated exocytosis.\",\n      \"method\": \"Full-length cDNA cloning, domain analysis, tissue expression profiling\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational domain identification and expression profiling only, no functional validation of the C2 domain in this study\",\n      \"pmids\": [\"12659812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"C. elegans UNC-31 (CAPS ortholog) is required for dense-core vesicle (DCV) exocytosis and evoked peptide release in cultured neurons, but is not required for stimulated synaptic vesicle recycling. Conversely, UNC-13 is essential for synaptic vesicle but not DCV exocytosis, indicating parallel and dedicated roles for these proteins.\",\n      \"method\": \"Novel in vivo peptide release assay (prepro-ANF-GFP fusion), FM4-64 dye uptake for synaptic vesicle recycling in cultured C. elegans neurons, genetic loss-of-function analysis\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal assays (in vivo release, vesicle recycling, cultured neuron electrophysiology), genetic dissection with parallel control (UNC-13), replicated across assays\",\n      \"pmids\": [\"17553987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"C. elegans UNC-31 acts upstream of the neuronal Gαs pathway to regulate locomotion. Genetic epistasis shows UNC-31 and Gαs are in the same pathway, distinct from the Gαq pathway. UNC-31 functions in cholinergic motor neurons and is concentrated at or near active zones, suggesting that DCV exocytosis locally activates Gαs signaling near synaptic active zones.\",\n      \"method\": \"Genetic epistasis analysis, cell-specific rescue with promoters, immunostaining for UNC-31 localization\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — rigorous epistasis with cell-specific rescue and localization data, single lab study\",\n      \"pmids\": [\"16272411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"UNC-31 is required for docking of dense-core vesicles (DCVs) at the plasma membrane in C. elegans neurons, as shown by direct electrophysiological (membrane capacitance, amperometry) and total internal reflection fluorescence microscopy assays. The DCV docking defect in unc-31 mutants is fully rescued by PKA activation. UNC-31 is also required for UNC-13-mediated augmentation of DCV exocytosis.\",\n      \"method\": \"Primary cultured C. elegans neuron electrophysiology (membrane capacitance, amperometry), TIRF microscopy of single DCV docking/fusion, PKA activation rescue experiment, genetic mutant analysis\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple direct functional assays (electrophysiology, single-vesicle imaging), PKA rescue experiment, rigorous controls\",\n      \"pmids\": [\"18031683\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"C. elegans CeIA-2 (IA-2 homolog, encoded by ida-1) has a specific genetic interaction with UNC-31/CAPS, suggesting CeIA-2 is an important factor in dense-core vesicle cargo release. Double mutant analysis indicated that CeIA-2 and UNC-31 function in the same process of neurosecretory vesicle release.\",\n      \"method\": \"Genetic interaction analysis using null alleles of ida-1 and unc-31 in C. elegans\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with two independent null alleles, single lab\",\n      \"pmids\": [\"15044551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Domain deletion analysis of UNC-31 in C. elegans revealed that the C2, PH, and DCV-binding domains (DCVBD) are each required for Ca2+-evoked DCV secretion, vesicle docking, and tethering. The MHD (MUN/UNC-13 homology domain) deletion partially retained function. These domains support sequential molecular actions including vesicle tethering, docking, and SNARE complex initiation.\",\n      \"method\": \"Domain deletion mutant rescue in unc-31 null C. elegans (locomotion assay, pharmacological NMJ assay, in vivo neuropeptide release, capacitance measurements in ALA neurons, vesicle docking analysis)\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple domain mutants with multiple functional readouts, single lab\",\n      \"pmids\": [\"20515653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Endogenously tagged UNC-31 is expressed in major ganglia and nerve cords from late embryonic stages through adulthood in C. elegans. Auxin-inducible postembryonic degradation of UNC-31 from the hermaphrodite nervous system caused defects in egg laying, locomotion, and vesicle release comparable to null mutants. Depletion specifically from BAG sensory neurons increased intestinal fat storage, indicating a spatially specific role in neuropeptide-regulated fat metabolism.\",\n      \"method\": \"Endogenous tagging, auxin-inducible degradation system, live imaging for localization, behavioral and physiological assays (egg laying, locomotion, vesicle release, fat storage)\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct subcellular/temporal localization with conditional loss-of-function and functional phenotype, single lab\",\n      \"pmids\": [\"36302635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CADPS variants identified in bipolar disorder patients resulted in lower protein abundance or partial impairment of neuronal exocytosis, synaptic plasticity, and vesicular transporter-dependent uptake of catecholamines. Heterozygous Cadps+/- mice showed manic-like behaviors, altered BDNF levels, and hypersensitivity to stress, which were rescued by lithium treatment.\",\n      \"method\": \"Patient mutation screening, functional assays of mutant CADPS in neuronal exocytosis and catecholamine uptake, heterozygous mouse model behavioral analysis, lithium rescue experiment\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays (exocytosis, vesicular uptake, mouse behavioral phenotype with rescue), single lab\",\n      \"pmids\": [\"35169262\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Loss of UNC-31 in C. elegans reduces evoked acetylcholine transmission at the NMJ but paradoxically results in enhanced muscle contraction and Ca2+ transients in response to presynaptic stimulation. Compensatory postsynaptic homeostatic scaling involves upregulation of the muscular L-type voltage-gated Ca2+ channel EGL-19 (CaV1). Specific neuropeptides from cholinergic and GABAergic neurons (FLP-6, NLP-9, NLP-21, NLP-38, FLP-15, NLP-15) normally mediate NMJ transmission, and their absence prevents neurons from upregulating transmitter output in response to increased cAMP.\",\n      \"method\": \"Electrophysiology at C. elegans NMJ, Ca2+ imaging, expression profiling, genetic analysis of neuropeptide and proprotein convertase mutants, EGL-19 expression analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — electrophysiology and Ca2+ imaging with genetic dissection, preprint not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Fasting ameliorates locomotion defects in unc-31/CAPS mutant C. elegans via upregulation of Gαq (EGL-30) signaling and its downstream effectors. A gain-of-function mutation in egl-30 suppresses unc-31 locomotion defects. Exogenous octopamine treatment activates EGL-30/Gαq signaling and mimics the fasting response, restoring locomotion in an EGL-30-dependent manner, revealing a compensatory octopamine-Gαq pathway downstream of UNC-31 loss.\",\n      \"method\": \"Forward genetic screen, transcriptomic analysis, octopamine pharmacology, genetic epistasis (egl-30 gain-of-function in unc-31 null background)\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — genetic and pharmacological epistasis in a preprint, single lab, no biochemical mechanism established\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"CADPS/CAPS (UNC-31 in C. elegans) is a peripherally membrane-associated cytosolic protein that selectively localizes to dense-core vesicles (DCVs) and the plasma membrane, where it acts as a Ca2+-regulated priming and docking factor specifically required for DCV exocytosis—but not synaptic vesicle exocytosis—by binding phospholipids via its C2 and PH domains, facilitating SNARE complex formation, and acting upstream of the Gαs signaling pathway; loss of CADPS impairs catecholamine/neuropeptide secretion and synaptic plasticity, and is associated with neuropsychiatric phenotypes including manic-like behavior and stress hypersensitivity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CADPS/CAPS (UNC-31 in C. elegans) is a Ca2+-regulated cytosolic factor that is selectively required for the exocytosis of dense-core vesicles (DCVs), and not small clear synaptic vesicles, in neural and endocrine cells [#0, #1, #3]. Originally purified as a 145-kDa protein that reconstitutes the Ca2+-triggering step of DCV fusion in permeable PC12 cells and binds Ca2+ with moderate affinity [#0], it associates peripherally with membranes, localizing specifically to plasma membranes and DCVs through high-affinity phospholipid binding, where it is essential for Ca2+-activated catecholamine and neuropeptide release [#1]. Mechanistically, CADPS acts at the docking and priming steps: in C. elegans neurons UNC-31 is required for DCV docking at the plasma membrane and for UNC-13-mediated augmentation of DCV exocytosis, and its docking defect is rescued by PKA activation [#5]. Its C2, PH, and DCV-binding domains are each required for Ca2+-evoked secretion, docking, and tethering, consistent with sequential roles in vesicle tethering, docking, and SNARE complex initiation [#7]. Functionally, DCV release through UNC-31 acts upstream of neuronal G\\u03b1s signaling near synaptic active zones to control locomotion [#4], and through a parallel pathway controls neuropeptide-regulated fat metabolism [#8]. In humans, CADPS variants that reduce protein abundance and impair neuronal exocytosis, synaptic plasticity, and vesicular catecholamine uptake are linked to bipolar disorder, and heterozygous Cadps+/- mice display lithium-responsive manic-like behavior and stress hypersensitivity [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established that a dedicated cytosolic factor is required for the Ca2+-triggering step of dense-core vesicle fusion, defining CAPS as a Ca2+-regulated exocytosis factor rather than a generic cytosolic component.\",\n      \"evidence\": \"Protein purification and in vitro exocytosis reconstitution with recombinant protein substitution in permeable PC12 cells, plus direct Ca2+ binding measurement\",\n      \"pmids\": [\"9289490\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which domain mediates Ca2+ binding\", \"No structural mechanism for how Ca2+ binding triggers fusion\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Resolved where CAPS acts by showing it is a peripheral membrane protein selectively associated with DCVs and plasma membrane via phospholipid binding, and functionally required for neural DCV exocytosis.\",\n      \"evidence\": \"Subcellular fractionation, phospholipid binding assays, and antibody inhibition of norepinephrine release from synaptosomes\",\n      \"pmids\": [\"9697858\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phospholipid species/domain specificity not defined\", \"No direct demonstration of the molecular step blocked by antibody\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identified the human CADPS C2 domain and neural/endocrine-restricted expression, supporting a calcium-sensor role in regulated exocytosis.\",\n      \"evidence\": \"Full-length cDNA cloning, computational domain analysis, and tissue expression profiling\",\n      \"pmids\": [\"12659812\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No functional validation of the C2 domain in this study\", \"Domain function inferred computationally only\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Placed UNC-31 in a genetic network for neurosecretory vesicle release by demonstrating a specific interaction with the IA-2 homolog CeIA-2 in the same DCV release process.\",\n      \"evidence\": \"Genetic interaction analysis with null alleles of ida-1 and unc-31 in C. elegans\",\n      \"pmids\": [\"15044551\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No physical interaction demonstrated\", \"Molecular role of CeIA-2 in the release step unresolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Connected DCV exocytosis to downstream signaling by showing UNC-31 acts upstream of neuronal G\\u03b1s near active zones to regulate locomotion, distinct from the G\\u03b1q pathway.\",\n      \"evidence\": \"Genetic epistasis, cell-specific promoter rescue, and immunostaining for UNC-31 localization in C. elegans\",\n      \"pmids\": [\"16272411\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the released signal activating G\\u03b1s not defined\", \"Single-lab epistasis\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrated the pathway specificity and step of action: UNC-31 is dedicated to DCV exocytosis and docking but dispensable for synaptic vesicle recycling, opposite to UNC-13.\",\n      \"evidence\": \"In vivo peptide release assay, FM4-64 dye uptake, cultured C. elegans neuron assays, electrophysiology, TIRF single-DCV imaging, and PKA rescue\",\n      \"pmids\": [\"17553987\", \"18031683\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biochemical relationship between UNC-31 docking and UNC-13 augmentation not resolved\", \"Mechanism by which PKA bypasses the docking defect unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Assigned distinct functions to UNC-31 domains, showing C2, PH, and DCV-binding domains are each required for evoked secretion, docking, and tethering while the MUN/UNC-13 homology domain is partially dispensable.\",\n      \"evidence\": \"Domain deletion mutant rescue in unc-31 null C. elegans with locomotion, NMJ, neuropeptide release, capacitance, and docking readouts\",\n      \"pmids\": [\"20515653\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding partners of each domain not mapped\", \"Temporal ordering of tethering/docking/SNARE steps inferred, not directly measured\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined the temporal and spatial requirement for CADPS in vivo and extended its role to neuropeptide-regulated physiology, including fat metabolism via specific sensory neurons.\",\n      \"evidence\": \"Endogenous tagging, auxin-inducible degradation, live imaging, and behavioral/physiological assays in C. elegans\",\n      \"pmids\": [\"36302635\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the BAG-neuron neuropeptide controlling fat storage not established\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked CADPS dysfunction to human bipolar disorder by showing patient variants impair exocytosis, synaptic plasticity, and catecholamine uptake, with a lithium-responsive manic phenotype in heterozygous mice.\",\n      \"evidence\": \"Patient mutation screening, functional exocytosis/uptake assays, and Cadps+/- mouse behavioral analysis with lithium rescue\",\n      \"pmids\": [\"35169262\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal mechanism linking reduced CADPS to manic behavior unresolved\", \"Single-lab study without independent cohort replication\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed homeostatic and neuropeptide-dependent consequences of UNC-31 loss at the NMJ, including postsynaptic CaV1/EGL-19 upregulation and a requirement for specific neuropeptides in cAMP-driven transmitter output.\",\n      \"evidence\": \"NMJ electrophysiology, Ca2+ imaging, expression profiling, and genetic analysis of neuropeptide and convertase mutants in C. elegans (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint not yet peer-reviewed\", \"Mechanism coupling neuropeptide loss to failed cAMP-driven scaling unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified a compensatory octopamine-G\\u03b1q pathway that bypasses UNC-31 loss, with fasting and egl-30 gain-of-function rescuing locomotion defects.\",\n      \"evidence\": \"Forward genetic screen, transcriptomics, octopamine pharmacology, and egl-30 gain-of-function epistasis in unc-31 null C. elegans (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Preprint, no biochemical mechanism established\", \"Single lab, genetic/pharmacological epistasis only\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis by which CADPS couples Ca2+ and phospholipid binding to SNARE-dependent DCV docking and priming, and the direct molecular partners of its C2/PH/DCV-binding domains, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of CADPS on the vesicle/plasma membrane\", \"Direct SNARE-machinery interactions not biochemically mapped in human protein\", \"Mechanistic link between exocytosis defect and neuropsychiatric phenotype unestablished\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 1, 7]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [1, 3, 5]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005793\", \"supporting_discovery_ids\": []}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"UNC13\", \"IA-2/ida-1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}