{"gene":"ASAH1","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":2012,"finding":"ASAH1 (acid ceramidase) localizes to the nuclei of H295R adrenocortical cells and represses steroidogenic factor 1 (SF-1)-dependent gene transcription by directly binding to SF-1. ChIP assays showed ASAH1 is recruited to SF-1 target gene promoters (CYP17A1, StAR), where it co-occupies the same promoter regions as SF-1. cAMP signaling promotes nuclear sphingolipid metabolism in an ASAH1-dependent manner.","method":"Nuclear fractionation, co-immunoprecipitation, chromatin immunoprecipitation (ChIP), RNA interference","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, ChIP, subcellular fractionation, and RNAi knockdown in a single study with multiple orthogonal methods","pmids":["22927646"],"is_preprint":false},{"year":2009,"finding":"ACTH/cAMP signaling induces ASAH1 gene expression in H295R adrenocortical cells by stimulating CREB binding to multiple regions of the ASAH1 promoter, which in turn recruits coactivators CBP and p300 and increases H3K4 trimethylation at the ASAH1 promoter. CREB is indispensable for cAMP-induced ASAH1 transcription.","method":"ChIP assay, RNAi knockdown, reporter assay, histone modification analysis","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (ChIP, RNAi, histone marks) in a single study demonstrating transcriptional regulatory mechanism","pmids":["19298866"],"is_preprint":false},{"year":2018,"finding":"ASAH1 (acid ceramidase) controls the phenotypic switch between proliferative and invasive states in melanoma cells. Low ASAH1 expression drives invasive behavior via activation of integrin αvβ5-FAK signaling. ASAH1 was identified as a transcriptional target of MITF, linking sphingolipid metabolism to melanoma phenotypic plasticity.","method":"ASAH1 knockdown/overexpression, invasion assays, signaling pathway analysis, MITF reporter assays, human melanoma biopsy IHC","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — KD/OE with defined cellular phenotype and pathway placement (integrin αvβ5-FAK), single lab","pmids":["30254208"],"is_preprint":false},{"year":2018,"finding":"Overexpression of ASAH1 in ARPE19 retinal cells prevents ceramide and hexosyl-ceramide accumulation under hydrogen peroxide-induced oxidative stress, protecting cells from oxidative stress-induced death. ASAH1 hydrolyzes excess ceramide, and its induction reduces lipid death mediators.","method":"ASAH1 overexpression, lipidomic analysis (ceramide measurement), cell viability assays under oxidative stress","journal":"Journal of lipid research","confidence":"Medium","confidence_rationale":"Tier 2 — OE with defined biochemical and cellular phenotype, single lab with multiple readouts","pmids":["30413652"],"is_preprint":false},{"year":2020,"finding":"Podocyte-specific deletion of the ASAH1 gene (Asah1fl/fl/PodoCre mice) causes ceramide accumulation in glomeruli, leading to podocyte foot process effacement, proteinuria, and nephrotic syndrome. Double knockout of Asah1 and Smpd1 (acid sphingomyelinase, which generates ceramide from sphingomyelin) reduced glomerular ceramide and attenuated podocyte injury, confirming that lysosomal acid ceramidase is essential for ceramide homeostasis in podocytes.","method":"Conditional knockout mouse model, LC-MS/MS ceramide quantification, transmission electron microscopy, genetic epistasis (double knockout with Smpd1-/-)","journal":"The American journal of pathology","confidence":"High","confidence_rationale":"Tier 2 — conditional KO with defined phenotype, genetic epistasis, and biochemical (lipidomic) validation; multiple orthogonal methods","pmids":["32194052"],"is_preprint":false},{"year":2020,"finding":"ASAH1 deletion in podocytes suppresses lysosomal TRPML1 channel Ca2+ release, which reduces lysosome-multivesicular body (MVB) interaction and enhances exosome release. Sphingosine (the ASAH1 product) rescues TRPML1 channel activity and restores lysosome-MVB interaction, reducing exosome secretion. This identifies a sphingosine-TRPML1-exosome axis downstream of ASAH1 activity.","method":"Conditional knockout mouse model, GCaMP3 Ca2+ imaging, Port-a-Patch patch clamping of lysosomes, rescue with sphingosine, urinary exosome quantification","journal":"Biochimica et biophysica acta. Molecular and cell biology of lipids","confidence":"High","confidence_rationale":"Tier 1–2 — direct lysosomal electrophysiology, Ca2+ imaging, genetic rescue, and chemical rescue converge on a mechanistic pathway","pmids":["33221496"],"is_preprint":false},{"year":2020,"finding":"Smooth muscle cell-specific deletion of Asah1 (Asah1fl/fl/SMCre) impairs lysosomal TRPML1 channel activity and reduces lysosome-MVB interaction, leading to increased small extracellular vesicle (sEV) secretion, osteogenic phenotypic transition (upregulation of RUNX2, osteopontin), and arterial medial calcification. GW4869 (sEV release inhibitor) reduced calcification, confirming the sEV pathway as mechanistically downstream of ASAH1.","method":"Conditional knockout mouse model, GCaMP3 Ca2+ imaging, Port-a-Patch patch clamping of lysosomes, sEV inhibitor, immunostaining for osteogenic markers, calcium deposition assay","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 — conditional KO with mechanistic follow-up including direct lysosomal electrophysiology and pharmacological intervention; multiple orthogonal methods","pmids":["32015399"],"is_preprint":false},{"year":2019,"finding":"Endothelium-specific ASAH1 knockout (Asah1fl/fl/ECcre) enhances NLRP3 inflammasome formation/activation in coronary arterial endothelial cells and increases IL-1β-containing exosome release. AC deficiency decreases MVB-lysosome interaction, redirecting MVBs to exosome secretion rather than lysosomal degradation, thereby amplifying NLRP3 inflammasome product release during hyperglycemia.","method":"Endothelium-specific conditional KO mouse model, NLRP3 inflammasome assays, exosome isolation and characterization, confocal imaging of MVB-lysosome interaction","journal":"Biochimica et biophysica acta. Molecular and cell biology of lipids","confidence":"Medium","confidence_rationale":"Tier 2 — conditional KO with defined cellular phenotype and pathway placement, single lab","pmids":["31647995"],"is_preprint":false},{"year":2016,"finding":"A homozygous ASAH1 variant (c.124A>G; p.Thr42Ala) in patients with a slowly progressive non-5q SMA phenotype results in reduced ceramidase enzymatic activity and ceramide accumulation in cultured fibroblasts, directly linking ASAH1 loss of function to the SMA-PME phenotypic spectrum.","method":"ASAH1 gene sequencing, ceramidase enzyme activity assay in cultured fibroblasts, ceramide accumulation measurement","journal":"European journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 — enzyme activity assay and ceramide accumulation in patient-derived cells confirm loss of catalytic function","pmids":["27026573"],"is_preprint":false},{"year":2016,"finding":"Compound heterozygous mutations in ASAH1 (c.505T>C/p.Trp169Arg and c.760A>G/p.Arg254Gly) reduce acid ceramidase enzyme activity to ~8% of controls in patient fibroblasts, establishing ASAH1 loss-of-function as the cause of an adult-onset peripheral osteolysis phenotype (atypical Farber disease).","method":"Exome sequencing, Sanger sequencing, ceramidase enzyme activity assay in cultured fibroblasts","journal":"Arthritis & rheumatology","confidence":"Medium","confidence_rationale":"Tier 2 — direct enzyme activity assay in patient-derived cells corroborates genotype-phenotype link","pmids":["26945816"],"is_preprint":false},{"year":2013,"finding":"Novel ASAH1 mutations causing Farber lipogranulomatosis include a splice mutation (IVS6+4A>G) and a polypyrimidine tract deletion (IVS5-16delTTTTC) that result in skipping of exon 6, precluding cleavage of the enzyme precursor. A missense mutation (p.V198A) inactivates an exonic splicing enhancer, causing exon 8 skipping. These findings define the molecular processing requirements for ASAH1 activation.","method":"Mutation analysis, RT-PCR for splicing, ESE prediction and validation","journal":"Clinical genetics","confidence":"Medium","confidence_rationale":"Tier 2 — direct demonstration of splicing consequences with functional annotation of mutations affecting ASAH1 precursor cleavage","pmids":["24355074"],"is_preprint":false},{"year":2017,"finding":"A rare coding variant (c.1202T>C; p.Leu401Pro) in ASAH1 co-segregates with keloid formation in a large Yoruba family (LOD score 4.48), identifying ASAH1 as a susceptibility gene for familial keloids and implicating ceramide/sphingosine balance in abnormal scar formation.","method":"Whole-genome sequencing, exome sequencing, linkage analysis, Sanger sequencing for co-segregation","journal":"European journal of human genetics","confidence":"Low","confidence_rationale":"Tier 3 — genetic linkage and variant co-segregation only; no functional/biochemical validation of the variant in the paper","pmids":["28905881"],"is_preprint":false},{"year":2024,"finding":"Hepatocyte-specific deletion of Asah1 in mice results in ceramide and cholesterol accumulation in hepatocytes, increased ER stress, impaired chaperone-mediated autophagy, and augmented lipid droplet biogenesis, leading to exacerbated hepatic steatosis and fibrotic NASH on a paigen diet. Asah1 knockdown broadly impacts lipogenesis, fatty acid uptake/oxidation, and lipid transport pathways.","method":"Hepatocyte-specific conditional knockout (Asah1fl/fl/Albcre), ceramide/cholesterol quantification, ER stress markers, autophagy assays, transcriptomic analysis","journal":"The American journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 — conditional KO with multiple biochemical and cellular phenotypic readouts, single lab","pmids":["39719015"],"is_preprint":false}],"current_model":"ASAH1 encodes lysosomal acid ceramidase, which hydrolyzes ceramide into sphingosine and fatty acids; its activity controls ceramide homeostasis in lysosomes, regulates lysosomal TRPML1 Ca2+ channel activity and thereby lysosome-MVB interactions and exosome secretion, and in the nucleus directly binds and represses the steroidogenic transcription factor SF-1, while its deficiency across multiple cell types (podocytes, smooth muscle cells, endothelium, hepatocytes) leads to ceramide accumulation, impaired lysosomal trafficking, and downstream pathological signaling including NLRP3 inflammasome activation, arterial calcification, nephrotic syndrome, and steatohepatitis."},"narrative":{"teleology":[{"year":2009,"claim":"ASAH1 transcription was shown to be directly controlled by ACTH/cAMP–CREB signaling, establishing how the gene is induced in steroidogenic cells and linking its expression to hormonal regulation.","evidence":"ChIP, RNAi knockdown, reporter assays, and histone modification analysis in H295R adrenocortical cells","pmids":["19298866"],"confidence":"High","gaps":["Whether CREB-dependent ASAH1 induction operates in non-adrenal tissues","Downstream consequences of ASAH1 induction on adrenal ceramide pools were not quantified"]},{"year":2012,"claim":"Discovery that ASAH1 has a non-catalytic nuclear function—directly binding SF-1 on steroidogenic gene promoters and repressing transcription—revealed a dual lysosomal/nuclear role for the enzyme.","evidence":"Nuclear fractionation, reciprocal co-immunoprecipitation, ChIP, and RNAi in H295R cells","pmids":["22927646"],"confidence":"High","gaps":["Whether the nuclear role requires catalytic activity or is purely scaffolding","Mechanism of ASAH1 nuclear import is unknown","Whether nuclear ASAH1 represses SF-1 targets in tissues other than adrenal cortex"]},{"year":2013,"claim":"Characterization of splice-disrupting ASAH1 mutations defined the precursor cleavage requirement for enzyme activation, explaining how specific variants abolish function and cause Farber lipogranulomatosis.","evidence":"RT-PCR splice analysis and exonic splicing enhancer prediction/validation in patient-derived cells","pmids":["24355074"],"confidence":"Medium","gaps":["No structural model of ASAH1 precursor cleavage site","Residual enzyme activity for each splice variant was not quantified"]},{"year":2016,"claim":"Direct measurement of ceramidase activity in patient fibroblasts linked ASAH1 loss-of-function mutations to both Farber disease and the SMA-PME phenotypic spectrum, expanding the clinical impact of ASAH1 deficiency beyond lipogranulomatosis.","evidence":"Ceramidase enzyme activity assays and ceramide quantification in patient-derived fibroblasts, combined with exome/Sanger sequencing","pmids":["26945816","27026573"],"confidence":"Medium","gaps":["The cell-type–specific basis for neuronal versus connective tissue manifestations of ASAH1 deficiency is unresolved","Rescue experiments with wild-type ASAH1 were not performed"]},{"year":2018,"claim":"ASAH1 was positioned as a metabolic effector of melanoma phenotypic switching, with low ASAH1 promoting invasion via integrin αvβ5–FAK signaling, and as a protector against oxidative stress-induced ceramide accumulation in retinal cells.","evidence":"ASAH1 knockdown/overexpression with invasion assays and signaling pathway analysis in melanoma; lipidomic analysis under oxidative stress in ARPE19 cells","pmids":["30254208","30413652"],"confidence":"Medium","gaps":["Whether ceramide species specificity determines ASAH1's pro-survival versus phenotype-switching roles","In vivo melanoma models were not used for validation"]},{"year":2019,"claim":"Endothelium-specific ASAH1 deletion demonstrated that acid ceramidase deficiency redirects MVBs from lysosomal degradation to exosome secretion, amplifying NLRP3 inflammasome-derived IL-1β release, providing a mechanistic link between ceramide metabolism and vascular inflammation.","evidence":"Endothelium-specific conditional KO mouse model with NLRP3 inflammasome assays, exosome isolation, and confocal imaging of MVB–lysosome interaction","pmids":["31647995"],"confidence":"Medium","gaps":["Direct measurement of TRPML1 activity in endothelial cells was not performed in this study","Whether inflammasome activation is ceramide-species specific is unresolved"]},{"year":2020,"claim":"A convergent mechanism was established across podocytes and smooth muscle cells: ASAH1-derived sphingosine activates the lysosomal TRPML1 Ca²⁺ channel, which promotes lysosome–MVB fusion; loss of ASAH1 suppresses this axis, increasing exosome release and causing tissue-specific pathology (nephrotic syndrome in podocytes, arterial calcification in smooth muscle).","evidence":"Conditional KO mouse models (podocyte-specific and SMC-specific), lysosomal patch clamp (Port-a-Patch), GCaMP3 Ca²⁺ imaging, sphingosine rescue, genetic epistasis with Smpd1, sEV inhibitor (GW4869)","pmids":["32194052","33221496","32015399"],"confidence":"High","gaps":["Whether sphingosine directly binds TRPML1 or acts through an intermediate","Structural basis for TRPML1 activation by sphingosine is unknown","Whether the sphingosine–TRPML1 axis operates in non-lysosomal compartments"]},{"year":2024,"claim":"Hepatocyte-specific Asah1 deletion revealed that acid ceramidase is required for hepatic ceramide and cholesterol homeostasis, with its absence driving ER stress, impaired chaperone-mediated autophagy, lipid droplet biogenesis, and progression to steatohepatitis.","evidence":"Hepatocyte-specific conditional KO (Asah1fl/fl/Albcre), ceramide/cholesterol quantification, ER stress markers, autophagy assays, transcriptomic analysis","pmids":["39719015"],"confidence":"Medium","gaps":["Mechanism linking ceramide accumulation to impaired chaperone-mediated autophagy is not fully delineated","Whether TRPML1 suppression underlies the hepatic phenotype was not tested","Therapeutic rescue with exogenous acid ceramidase was not attempted"]},{"year":null,"claim":"Key unresolved questions include the structural mechanism of ASAH1 precursor auto-cleavage and activation, whether sphingosine directly binds TRPML1, how ASAH1 is imported into the nucleus, and whether its catalytic and nuclear scaffolding functions are separable.","evidence":"","pmids":[],"confidence":"High","gaps":["No high-resolution structure of human ASAH1 in active or precursor form","Separation-of-function mutants distinguishing catalytic versus nuclear roles have not been generated","Direct biophysical evidence for sphingosine–TRPML1 binding is lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[3,4,5,6,8,9,10,12]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[4,5,6,7,12]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[3,4,5,6,12]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[5,6,7]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[7]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[8,9,10]}],"complexes":[],"partners":["NR5A1","MCOLN1","SMPD1"],"other_free_text":[]},"mechanistic_narrative":"ASAH1 encodes lysosomal acid ceramidase, which hydrolyzes ceramide into sphingosine and free fatty acids and thereby maintains ceramide homeostasis across diverse cell types including podocytes, vascular smooth muscle cells, endothelial cells, and hepatocytes [PMID:32194052, PMID:32015399, PMID:39719015]. The sphingosine product of ASAH1 activates the lysosomal TRPML1 Ca²⁺ channel, promoting lysosome–multivesicular body (MVB) fusion and directing MVB cargo to lysosomal degradation rather than exosome secretion; loss of ASAH1 therefore augments exosome release and, in specific contexts, drives arterial calcification via osteogenic extracellular vesicles or amplifies NLRP3 inflammasome signaling [PMID:33221496, PMID:32015399, PMID:31647995]. Beyond its lysosomal catalytic role, ASAH1 localizes to the nucleus in adrenocortical cells, where it directly binds steroidogenic factor 1 (SF-1) on target gene promoters (CYP17A1, StAR) and represses SF-1-dependent transcription in a cAMP-regulated manner [PMID:22927646, PMID:19298866]. Loss-of-function mutations in ASAH1 cause Farber lipogranulomatosis and the SMA-PME phenotypic spectrum, with disease-causing variants reducing ceramidase activity and disrupting precursor processing through splicing or missense defects [PMID:26945816, PMID:27026573, PMID:24355074]."},"prefetch_data":{"uniprot":{"accession":"Q13510","full_name":"Acid ceramidase","aliases":["Acylsphingosine deacylase","Glycosylceramide deacylase","N-acylethanolamine hydrolase ASAH1","N-acylsphingosine amidohydrolase","Putative 32 kDa heart protein","PHP32"],"length_aa":395,"mass_kda":44.7,"function":"Lysosomal ceramidase that hydrolyzes sphingolipid ceramides into sphingosine and free fatty acids at acidic pH (PubMed:10610716, PubMed:11451951, PubMed:15655246, PubMed:26898341, PubMed:36752535, PubMed:7744740, PubMed:7852294). Ceramides, sphingosine, and its phosphorylated form sphingosine-1-phosphate are bioactive lipids that mediate cellular signaling pathways regulating several biological processes including cell proliferation, apoptosis and differentiation (PubMed:10610716). Has a higher catalytic efficiency towards C12-ceramides versus other ceramides (PubMed:15655246, PubMed:7744740). Also catalyzes the reverse reaction allowing the synthesis of ceramides from fatty acids and sphingosine (PubMed:12764132, PubMed:12815059). For the reverse synthetic reaction, the natural sphingosine D-erythro isomer is more efficiently utilized as a substrate compared to D-erythro-dihydrosphingosine and D-erythro-phytosphingosine, while the fatty acids with chain lengths of 12 or 14 carbons are the most efficiently used (PubMed:12764132). Also has an N-acylethanolamine hydrolase activity (PubMed:15655246). By regulating the levels of ceramides, sphingosine and sphingosine-1-phosphate in the epidermis, mediates the calcium-induced differentiation of epidermal keratinocytes (PubMed:17713573). Also indirectly regulates tumor necrosis factor/TNF-induced apoptosis (By similarity). By regulating the intracellular balance between ceramides and sphingosine, in adrenocortical cells, probably also acts as a regulator of steroidogenesis (PubMed:22261821) May directly regulate steroidogenesis by binding the nuclear receptor NR5A1 and negatively regulating its transcriptional activity","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q13510/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ASAH1","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CANX","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ASAH1","total_profiled":1310},"omim":[{"mim_id":"618773","title":"LYMPHATIC MALFORMATION 8; LMPHM8","url":"https://www.omim.org/entry/618773"},{"mim_id":"613468","title":"N-ACYLSPHINGOSINE AMIDOHYDROLASE 1; ASAH1","url":"https://www.omim.org/entry/613468"},{"mim_id":"607469","title":"N-ACYLETHANOLAMINE ACID AMIDASE; NAAA","url":"https://www.omim.org/entry/607469"},{"mim_id":"606897","title":"LYSOSOMAL TRAFFICKING REGULATOR; LYST","url":"https://www.omim.org/entry/606897"},{"mim_id":"606890","title":"GALACTOSYLCERAMIDASE; GALC","url":"https://www.omim.org/entry/606890"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"heart muscle","ntpm":537.2}],"url":"https://www.proteinatlas.org/search/ASAH1"},"hgnc":{"alias_symbol":["AC","PHP32","FLJ21558","ACDase"],"prev_symbol":["ASAH"]},"alphafold":{"accession":"Q13510","domains":[{"cath_id":"3.60.60.10","chopping":"27-52_139-387","consensus_level":"high","plddt":95.6988,"start":27,"end":387},{"cath_id":"-","chopping":"57-135","consensus_level":"medium","plddt":92.0373,"start":57,"end":135}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13510","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13510-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13510-F1-predicted_aligned_error_v6.png","plddt_mean":91.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ASAH1","jax_strain_url":"https://www.jax.org/strain/search?query=ASAH1"},"sequence":{"accession":"Q13510","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13510.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13510/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13510"}},"corpus_meta":[{"pmid":"23374351","id":"PMC_23374351","title":"LBR and lamin A/C sequentially tether peripheral heterochromatin and inversely regulate differentiation.","date":"2013","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/23374351","citation_count":625,"is_preprint":false},{"pmid":"1312981","id":"PMC_1312981","title":"Molecular analysis of Ac transposition and DNA replication.","date":"1992","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/1312981","citation_count":94,"is_preprint":false},{"pmid":"33316938","id":"PMC_33316938","title":"Lamin A/C: Function in Normal and Tumor Cells.","date":"2020","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/33316938","citation_count":80,"is_preprint":false},{"pmid":"30011792","id":"PMC_30011792","title":"Role of Damage Associated Molecular Pattern Molecules (DAMPs) in Aneurysmal Subarachnoid Hemorrhage (aSAH).","date":"2018","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30011792","citation_count":76,"is_preprint":false},{"pmid":"17148436","id":"PMC_17148436","title":"Third activity of Bordetella adenylate cyclase (AC) toxin-hemolysin. Membrane translocation of AC domain polypeptide promotes calcium influx into CD11b+ monocytes independently of the catalytic and hemolytic activities.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17148436","citation_count":62,"is_preprint":false},{"pmid":"16601451","id":"PMC_16601451","title":"Lamin A/C and cardiac diseases.","date":"2006","source":"Current opinion in cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/16601451","citation_count":56,"is_preprint":false},{"pmid":"32456328","id":"PMC_32456328","title":"Lamin A/C Mechanotransduction in Laminopathies.","date":"2020","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/32456328","citation_count":56,"is_preprint":false},{"pmid":"31647095","id":"PMC_31647095","title":"Lamin A/C promotes DNA base excision repair.","date":"2019","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/31647095","citation_count":56,"is_preprint":false},{"pmid":"30410928","id":"PMC_30410928","title":"AC-YVAD-CMK Inhibits Pyroptosis and Improves Functional Outcome after Intracerebral Hemorrhage.","date":"2018","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/30410928","citation_count":55,"is_preprint":false},{"pmid":"18366013","id":"PMC_18366013","title":"Lamin A/C, laminopathies and premature ageing.","date":"2008","source":"Histology and histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/18366013","citation_count":49,"is_preprint":false},{"pmid":"21047144","id":"PMC_21047144","title":"Grassypeptolides A-C, cytotoxic bis-thiazoline containing marine cyclodepsipeptides.","date":"2010","source":"The Journal of organic chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21047144","citation_count":49,"is_preprint":false},{"pmid":"2556713","id":"PMC_2556713","title":"Chromosome-breaking structure in maize involving a fractured Ac element.","date":"1989","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/2556713","citation_count":47,"is_preprint":false},{"pmid":"34064048","id":"PMC_34064048","title":"Neuroprotective Strategies in Aneurysmal Subarachnoid Hemorrhage (aSAH).","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34064048","citation_count":44,"is_preprint":false},{"pmid":"36099415","id":"PMC_36099415","title":"Lamin A/C impairments cause mitochondrial dysfunction by attenuating PGC1α and the NAMPT-NAD+ pathway.","date":"2022","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/36099415","citation_count":44,"is_preprint":false},{"pmid":"15520264","id":"PMC_15520264","title":"Distribution of Activator (Ac) throughout the maize genome for use in regional mutagenesis.","date":"2004","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15520264","citation_count":44,"is_preprint":false},{"pmid":"16142468","id":"PMC_16142468","title":"A novel thermoacidophilic endoglucanase, Ba-EGA, from a new cellulose-degrading bacterium, Bacillus sp.AC-1.","date":"2005","source":"Applied microbiology and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/16142468","citation_count":42,"is_preprint":false},{"pmid":"23325228","id":"PMC_23325228","title":"Temperature integration at the AC thermosensory neurons in Drosophila.","date":"2013","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/23325228","citation_count":41,"is_preprint":false},{"pmid":"1454542","id":"PMC_1454542","title":"RecA-AC: single-site cleavage of plasmids and chromosomes at any predetermined restriction site.","date":"1992","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/1454542","citation_count":41,"is_preprint":false},{"pmid":"24499164","id":"PMC_24499164","title":"Aspewentins A-C, norditerpenes from a cryptic pathway in an algicolous strain of Aspergillus wentii.","date":"2014","source":"Journal of natural products","url":"https://pubmed.ncbi.nlm.nih.gov/24499164","citation_count":40,"is_preprint":false},{"pmid":"18674907","id":"PMC_18674907","title":"Double dissociation of PKC and AC manipulations on operant and classical learning in Drosophila.","date":"2008","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/18674907","citation_count":37,"is_preprint":false},{"pmid":"24787317","id":"PMC_24787317","title":"Parameters characterization and optimization of activated carbon (AC) cathodes for microbial fuel cell application.","date":"2014","source":"Bioresource technology","url":"https://pubmed.ncbi.nlm.nih.gov/24787317","citation_count":36,"is_preprint":false},{"pmid":"30254208","id":"PMC_30254208","title":"Lysosomal acid ceramidase ASAH1 controls the transition between invasive and proliferative phenotype in melanoma cells.","date":"2018","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/30254208","citation_count":36,"is_preprint":false},{"pmid":"31427614","id":"PMC_31427614","title":"A flow through device for simultaneous dielectrophoretic cell trapping and AC electroporation.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31427614","citation_count":36,"is_preprint":false},{"pmid":"34181406","id":"PMC_34181406","title":"Argicyclamides A-C Unveil Enzymatic Basis for Guanidine Bis-prenylation.","date":"2021","source":"Journal of the American Chemical Society","url":"https://pubmed.ncbi.nlm.nih.gov/34181406","citation_count":36,"is_preprint":false},{"pmid":"32194052","id":"PMC_32194052","title":"Podocytopathy and Nephrotic Syndrome in Mice with Podocyte-Specific Deletion of the Asah1 Gene: Role of Ceramide Accumulation in Glomeruli.","date":"2020","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/32194052","citation_count":35,"is_preprint":false},{"pmid":"34196752","id":"PMC_34196752","title":"Cyclotron production of 225Ac from an electroplated 226Ra target.","date":"2021","source":"European journal of nuclear medicine and molecular imaging","url":"https://pubmed.ncbi.nlm.nih.gov/34196752","citation_count":34,"is_preprint":false},{"pmid":"33772332","id":"PMC_33772332","title":"Preclinical evaluation of [225Ac]Ac-DOTA-TATE for treatment of lung neuroendocrine neoplasms.","date":"2021","source":"European journal of nuclear medicine and molecular imaging","url":"https://pubmed.ncbi.nlm.nih.gov/33772332","citation_count":33,"is_preprint":false},{"pmid":"23609092","id":"PMC_23609092","title":"Enantioselective synthesis of tatanans A-C and reinvestigation of their glucokinase-activating properties.","date":"2013","source":"Nature chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23609092","citation_count":32,"is_preprint":false},{"pmid":"30413652","id":"PMC_30413652","title":"Overexpression of acid ceramidase (ASAH1) protects retinal cells (ARPE19) from oxidative stress.","date":"2018","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/30413652","citation_count":32,"is_preprint":false},{"pmid":"32015399","id":"PMC_32015399","title":"Arterial Medial Calcification through Enhanced small Extracellular Vesicle Release in Smooth Muscle-Specific Asah1 Gene Knockout Mice.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/32015399","citation_count":31,"is_preprint":false},{"pmid":"33835779","id":"PMC_33835779","title":"Optimization of Metabolic Oligosaccharide Engineering with Ac4GalNAlk and Ac4GlcNAlk by an Engineered Pyrophosphorylase.","date":"2021","source":"ACS chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/33835779","citation_count":31,"is_preprint":false},{"pmid":"30354563","id":"PMC_30354563","title":"A Small Peptide Ac-SDKP Inhibits Radiation-Induced Cardiomyopathy.","date":"2018","source":"Circulation. Heart failure","url":"https://pubmed.ncbi.nlm.nih.gov/30354563","citation_count":31,"is_preprint":false},{"pmid":"19693367","id":"PMC_19693367","title":"Long-range and superfast trapping of DNA molecules in an ac electrokinetic funnel.","date":"2008","source":"Biomicrofluidics","url":"https://pubmed.ncbi.nlm.nih.gov/19693367","citation_count":30,"is_preprint":false},{"pmid":"28299614","id":"PMC_28299614","title":"Lamin A/C Cardiomyopathies: Current Understanding and Novel Treatment Strategies.","date":"2017","source":"Current treatment options in cardiovascular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28299614","citation_count":29,"is_preprint":false},{"pmid":"8696369","id":"PMC_8696369","title":"Use of Ac as an insertional mutagen in Arabidopsis.","date":"1996","source":"The Plant journal : for cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/8696369","citation_count":29,"is_preprint":false},{"pmid":"26558750","id":"PMC_26558750","title":"AC Electrothermal Circulatory Pumping Chip for Cell Culture.","date":"2015","source":"ACS applied materials & interfaces","url":"https://pubmed.ncbi.nlm.nih.gov/26558750","citation_count":29,"is_preprint":false},{"pmid":"11695562","id":"PMC_11695562","title":"The Tg.AC (v-Ha-ras) transgenic mouse: nature of the model.","date":"2001","source":"Toxicologic pathology","url":"https://pubmed.ncbi.nlm.nih.gov/11695562","citation_count":29,"is_preprint":false},{"pmid":"21443171","id":"PMC_21443171","title":"Ferruginenes A-C from Rhododendron ferrugineum and their cytotoxic evaluation.","date":"2011","source":"Journal of natural products","url":"https://pubmed.ncbi.nlm.nih.gov/21443171","citation_count":28,"is_preprint":false},{"pmid":"2562396","id":"PMC_2562396","title":"A comparative study of Tam3 and Ac transposition in transgenic tobacco and petunia plants.","date":"1989","source":"Plant molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/2562396","citation_count":27,"is_preprint":false},{"pmid":"37218714","id":"PMC_37218714","title":"The five types of glomerulonephritis classified by pathogenesis, activity and chronicity (GN-AC).","date":"2023","source":"Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association","url":"https://pubmed.ncbi.nlm.nih.gov/37218714","citation_count":25,"is_preprint":false},{"pmid":"28905881","id":"PMC_28905881","title":"Identification of ASAH1 as a susceptibility gene for familial keloids.","date":"2017","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/28905881","citation_count":25,"is_preprint":false},{"pmid":"23918421","id":"PMC_23918421","title":"Molecular biology of maize Ac/Ds elements: an overview.","date":"2013","source":"Methods in molecular biology (Clifton, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/23918421","citation_count":25,"is_preprint":false},{"pmid":"10722149","id":"PMC_10722149","title":"AC voltammetric carbon paste-based enzyme immunosensors.","date":"2000","source":"Biosensors & bioelectronics","url":"https://pubmed.ncbi.nlm.nih.gov/10722149","citation_count":25,"is_preprint":false},{"pmid":"22562933","id":"PMC_22562933","title":"A hyperactive transposase of the maize transposable element activator (Ac).","date":"2012","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22562933","citation_count":25,"is_preprint":false},{"pmid":"22927646","id":"PMC_22927646","title":"Acid ceramidase (ASAH1) represses steroidogenic factor 1-dependent gene transcription in H295R human adrenocortical cells by binding to the receptor.","date":"2012","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/22927646","citation_count":24,"is_preprint":false},{"pmid":"25584783","id":"PMC_25584783","title":"Thiasporines A-C, thiazine and thiazole derivatives from a marine-derived Actinomycetospora chlora.","date":"2015","source":"Journal of natural products","url":"https://pubmed.ncbi.nlm.nih.gov/25584783","citation_count":24,"is_preprint":false},{"pmid":"19298866","id":"PMC_19298866","title":"The cAMP-responsive element binding protein (CREB) regulates the expression of acid ceramidase (ASAH1) in H295R human adrenocortical cells.","date":"2009","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/19298866","citation_count":23,"is_preprint":false},{"pmid":"29665450","id":"PMC_29665450","title":"Lamin A/C might be involved in the EMT signalling pathway.","date":"2018","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/29665450","citation_count":23,"is_preprint":false},{"pmid":"8038181","id":"PMC_8038181","title":"Forces on biological cells due to applied alternating (AC) electric fields. I. Dielectrophoresis.","date":"1994","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/8038181","citation_count":22,"is_preprint":false},{"pmid":"30355655","id":"PMC_30355655","title":"Early serum miR-1297 is an indicator of poor neurological outcome in patients with aSAH.","date":"2018","source":"Bioscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/30355655","citation_count":22,"is_preprint":false},{"pmid":"31647995","id":"PMC_31647995","title":"Endothelial acid ceramidase in exosome-mediated release of NLRP3 inflammasome products during hyperglycemia: Evidence from endothelium-specific deletion of Asah1 gene.","date":"2019","source":"Biochimica et biophysica acta. Molecular and cell biology of lipids","url":"https://pubmed.ncbi.nlm.nih.gov/31647995","citation_count":22,"is_preprint":false},{"pmid":"32485621","id":"PMC_32485621","title":"Elevated level of cerebrospinal fluid and systemic chemokine CCL5 is a predictive biomarker of clinical outcome after aneurysmal subarachnoid hemorrhage (aSAH).","date":"2020","source":"Cytokine","url":"https://pubmed.ncbi.nlm.nih.gov/32485621","citation_count":22,"is_preprint":false},{"pmid":"27026573","id":"PMC_27026573","title":"ASAH1 variant causing a mild SMA phenotype with no myoclonic epilepsy: a clinical, biochemical and molecular study.","date":"2016","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/27026573","citation_count":22,"is_preprint":false},{"pmid":"16215681","id":"PMC_16215681","title":"Prostaglandins and activation of AC/cAMP prevents anoikis in IEC-18.","date":"2005","source":"Apoptosis : an international journal on programmed cell death","url":"https://pubmed.ncbi.nlm.nih.gov/16215681","citation_count":22,"is_preprint":false},{"pmid":"33198403","id":"PMC_33198403","title":"Evaluation of Actinium-225 Labeled Minigastrin Analogue [225Ac]Ac-DOTA-PP-F11N for Targeted Alpha Particle Therapy.","date":"2020","source":"Pharmaceutics","url":"https://pubmed.ncbi.nlm.nih.gov/33198403","citation_count":22,"is_preprint":false},{"pmid":"31641717","id":"PMC_31641717","title":"Activate capture and digital counting (AC + DC) assay for protein biomarker detection integrated with a self-powered microfluidic cartridge.","date":"2019","source":"Lab on a chip","url":"https://pubmed.ncbi.nlm.nih.gov/31641717","citation_count":21,"is_preprint":false},{"pmid":"10699317","id":"PMC_10699317","title":"Gene-transfer systems for human endothelial cells. stewart.martin@nottingham.ac.uk.","date":"2000","source":"Advanced drug delivery reviews","url":"https://pubmed.ncbi.nlm.nih.gov/10699317","citation_count":21,"is_preprint":false},{"pmid":"33743782","id":"PMC_33743782","title":"Epigenetic evidence of an Ac/Dc axis by VPA and SAHA.","date":"2021","source":"Clinical epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/33743782","citation_count":20,"is_preprint":false},{"pmid":"38139806","id":"PMC_38139806","title":"Targeted Alpha Therapy: All We Need to Know about 225Ac's Physical Characteristics and Production as a Potential Theranostic Radionuclide.","date":"2023","source":"Pharmaceuticals (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/38139806","citation_count":20,"is_preprint":false},{"pmid":"21714531","id":"PMC_21714531","title":"Schicagenins A-C: three cagelike nortriterpenoids from leaves and stems of Schisandra chinensis.","date":"2011","source":"Organic letters","url":"https://pubmed.ncbi.nlm.nih.gov/21714531","citation_count":20,"is_preprint":false},{"pmid":"32087459","id":"PMC_32087459","title":"Dimensionality changes actin network through lamin A/C and zyxin.","date":"2020","source":"Biomaterials","url":"https://pubmed.ncbi.nlm.nih.gov/32087459","citation_count":20,"is_preprint":false},{"pmid":"8138163","id":"PMC_8138163","title":"Distribution of unlinked receptor sites for transposed Ac elements from the bz-m2(Ac) allele in maize.","date":"1994","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/8138163","citation_count":20,"is_preprint":false},{"pmid":"14501064","id":"PMC_14501064","title":"Transposon tagging using Activator (Ac) in maize.","date":"2003","source":"Methods in molecular biology (Clifton, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/14501064","citation_count":20,"is_preprint":false},{"pmid":"33221496","id":"PMC_33221496","title":"Abnormal podocyte TRPML1 channel activity and exosome release in mice with podocyte-specific Asah1 gene deletion.","date":"2020","source":"Biochimica et biophysica acta. Molecular and cell biology of lipids","url":"https://pubmed.ncbi.nlm.nih.gov/33221496","citation_count":19,"is_preprint":false},{"pmid":"37459599","id":"PMC_37459599","title":"Lamin A/C and Vimentin as a Coordinated Regulator during Amoeboid Migration in Microscale Confined Microenvironments.","date":"2023","source":"Nano letters","url":"https://pubmed.ncbi.nlm.nih.gov/37459599","citation_count":19,"is_preprint":false},{"pmid":"30529453","id":"PMC_30529453","title":"Temporal profile of serum mitochondrial DNA (mtDNA) in patients with aneurysmal subarachnoid hemorrhage (aSAH).","date":"2018","source":"Mitochondrion","url":"https://pubmed.ncbi.nlm.nih.gov/30529453","citation_count":18,"is_preprint":false},{"pmid":"22132901","id":"PMC_22132901","title":"The complete Ac/Ds transposon family of maize.","date":"2011","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/22132901","citation_count":18,"is_preprint":false},{"pmid":"33613288","id":"PMC_33613288","title":"Clinical Pharmacology of Clazosentan, a Selective Endothelin A Receptor Antagonist for the Prevention and Treatment of aSAH-Related Cerebral Vasospasm.","date":"2021","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/33613288","citation_count":17,"is_preprint":false},{"pmid":"37870290","id":"PMC_37870290","title":"Initial Findings on the Use of [225Ac]Ac-DOTATATE Therapy as a Theranostic Application in Patients with Neuroendocrine Tumors.","date":"2023","source":"Molecular imaging and radionuclide therapy","url":"https://pubmed.ncbi.nlm.nih.gov/37870290","citation_count":17,"is_preprint":false},{"pmid":"39008063","id":"PMC_39008063","title":"Evaluating [225Ac]Ac-FAPI-46 for the treatment of soft-tissue sarcoma in mice.","date":"2024","source":"European journal of nuclear medicine and molecular imaging","url":"https://pubmed.ncbi.nlm.nih.gov/39008063","citation_count":16,"is_preprint":false},{"pmid":"29182911","id":"PMC_29182911","title":"Electrode-based AC electrokinetics of proteins: A mini-review.","date":"2017","source":"Bioelectrochemistry (Amsterdam, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/29182911","citation_count":16,"is_preprint":false},{"pmid":"29320752","id":"PMC_29320752","title":"The value of detection of S100A8 and ASAH1 in predicting the chemotherapy response for breast cancer patients.","date":"2018","source":"Human pathology","url":"https://pubmed.ncbi.nlm.nih.gov/29320752","citation_count":16,"is_preprint":false},{"pmid":"32872553","id":"PMC_32872553","title":"Tetrapeptide Ac-HAEE-NH2 Protects α4β2 nAChR from Inhibition by Aβ.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32872553","citation_count":16,"is_preprint":false},{"pmid":"32571981","id":"PMC_32571981","title":"SPANX Control of Lamin A/C Modulates Nuclear Architecture and Promotes Melanoma Growth.","date":"2020","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/32571981","citation_count":16,"is_preprint":false},{"pmid":"25578555","id":"PMC_25578555","title":"Uniparental disomy as a cause of spinal muscular atrophy and progressive myoclonic epilepsy: phenotypic homogeneity due to the homozygous c.125C>T mutation in ASAH1.","date":"2014","source":"Neuromuscular disorders : NMD","url":"https://pubmed.ncbi.nlm.nih.gov/25578555","citation_count":16,"is_preprint":false},{"pmid":"16631311","id":"PMC_16631311","title":"Adenosine 2b receptor (A2bR) signals through adenylate cyclase (AC) 6 isoform in the intestinal epithelial cells.","date":"2006","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/16631311","citation_count":16,"is_preprint":false},{"pmid":"32449975","id":"PMC_32449975","title":"ASAH1 pathogenic variants associated with acid ceramidase deficiency: Farber disease and spinal muscular atrophy with progressive myoclonic epilepsy.","date":"2020","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/32449975","citation_count":15,"is_preprint":false},{"pmid":"1311405","id":"PMC_1311405","title":"Transactivation of Ds by Ac-transposase gene fusions in tobacco.","date":"1992","source":"Molecular & general genetics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/1311405","citation_count":15,"is_preprint":false},{"pmid":"34358076","id":"PMC_34358076","title":"Ac-EAZY! Towards GMP-Compliant Module Syntheses of 225Ac-Labeled Peptides for Clinical Application.","date":"2021","source":"Pharmaceuticals (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/34358076","citation_count":14,"is_preprint":false},{"pmid":"33296194","id":"PMC_33296194","title":"Penipyranicins A-C: Antibacterial Methylpyran Polyketides from a Hydrothermal Spring Sediment Penicillium sp.","date":"2020","source":"Journal of natural products","url":"https://pubmed.ncbi.nlm.nih.gov/33296194","citation_count":14,"is_preprint":false},{"pmid":"16196609","id":"PMC_16196609","title":"ac conductivity in a DNA charge transport model.","date":"2005","source":"Physical review. E, Statistical, nonlinear, and soft matter physics","url":"https://pubmed.ncbi.nlm.nih.gov/16196609","citation_count":14,"is_preprint":false},{"pmid":"29771282","id":"PMC_29771282","title":"AC-DIAMOND v1: accelerating large-scale DNA-protein alignment.","date":"2018","source":"Bioinformatics (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/29771282","citation_count":13,"is_preprint":false},{"pmid":"30854877","id":"PMC_30854877","title":"Tβ4-Ac-SDKP pathway: Any relevance for the cardiovascular system?","date":"2019","source":"Canadian journal of physiology and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/30854877","citation_count":13,"is_preprint":false},{"pmid":"26107527","id":"PMC_26107527","title":"Erylivingstone A-C with antioxidant and antibacterial activities from Erythrina livingstoniana.","date":"2015","source":"Fitoterapia","url":"https://pubmed.ncbi.nlm.nih.gov/26107527","citation_count":13,"is_preprint":false},{"pmid":"32400187","id":"PMC_32400187","title":"Euphopanes A-C, three new diterpenoids from Euphorbia pekinensis.","date":"2020","source":"Natural product research","url":"https://pubmed.ncbi.nlm.nih.gov/32400187","citation_count":13,"is_preprint":false},{"pmid":"11294974","id":"PMC_11294974","title":"Comparative xenobiotic metabolism between Tg.AC and p53+/- genetically altered mice and their respective wild types.","date":"2001","source":"Toxicological sciences : an official journal of the Society of Toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/11294974","citation_count":13,"is_preprint":false},{"pmid":"18612243","id":"PMC_18612243","title":"Lamin A/C and polymeric actin in genome organization.","date":"2008","source":"Molecules and cells","url":"https://pubmed.ncbi.nlm.nih.gov/18612243","citation_count":13,"is_preprint":false},{"pmid":"9193065","id":"PMC_9193065","title":"Increased Ac excision (iae): Arabidopsis thaliana mutations affecting Ac transposition.","date":"1997","source":"The Plant journal : for cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/9193065","citation_count":13,"is_preprint":false},{"pmid":"26945816","id":"PMC_26945816","title":"Brief Report: Peripheral Osteolysis in Adults Linked to ASAH1 (Acid Ceramidase) Mutations: A New Presentation of Farber's Disease.","date":"2016","source":"Arthritis & rheumatology (Hoboken, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/26945816","citation_count":13,"is_preprint":false},{"pmid":"18226546","id":"PMC_18226546","title":"Cloning and expression of chondroitinase AC from Bacteroides stercoris HJ-15.","date":"2007","source":"Protein expression and purification","url":"https://pubmed.ncbi.nlm.nih.gov/18226546","citation_count":12,"is_preprint":false},{"pmid":"22926043","id":"PMC_22926043","title":"Tabebuialdehydes A-C, cyclopentene dialdehyde derivatives from the roots of Tabebuia rosea.","date":"2012","source":"Fitoterapia","url":"https://pubmed.ncbi.nlm.nih.gov/22926043","citation_count":12,"is_preprint":false},{"pmid":"19178688","id":"PMC_19178688","title":"An Ac/Ds-mediated gene trap system for functional genomics in barley.","date":"2009","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/19178688","citation_count":12,"is_preprint":false},{"pmid":"33533408","id":"PMC_33533408","title":"Time and predictors of time to treatment for aneurysmal subarachnoid haemorrhage (aSAH): a systematic review.","date":"2021","source":"International journal for quality in health care : journal of the International Society for Quality in Health Care","url":"https://pubmed.ncbi.nlm.nih.gov/33533408","citation_count":11,"is_preprint":false},{"pmid":"29979997","id":"PMC_29979997","title":"Interstitial telomeric loops and implications of the interaction between TRF2 and lamin A/C.","date":"2018","source":"Differentiation; research in biological diversity","url":"https://pubmed.ncbi.nlm.nih.gov/29979997","citation_count":11,"is_preprint":false},{"pmid":"36942261","id":"PMC_36942261","title":"Expanding DdCBE-mediated targeting scope to aC motif preference in rat.","date":"2023","source":"Molecular therapy. Nucleic acids","url":"https://pubmed.ncbi.nlm.nih.gov/36942261","citation_count":11,"is_preprint":false},{"pmid":"12815547","id":"PMC_12815547","title":"Apoptosis and increased expression of Fas ligand after uniocular anterior chamber (AC) inoculation of HSV-1.","date":"2003","source":"Current eye research","url":"https://pubmed.ncbi.nlm.nih.gov/12815547","citation_count":11,"is_preprint":false},{"pmid":"22232216","id":"PMC_22232216","title":"Recent applications of AC electrokinetics in biomolecular analysis on microfluidic devices.","date":"2012","source":"Analytical sciences : the international journal of the Japan Society for Analytical Chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22232216","citation_count":11,"is_preprint":false},{"pmid":"24355074","id":"PMC_24355074","title":"Molecular analyses of novel ASAH1 mutations causing Farber lipogranulomatosis: analyses of exonic splicing enhancer inactivating mutation.","date":"2013","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24355074","citation_count":11,"is_preprint":false},{"pmid":"39719015","id":"PMC_39719015","title":"Ablation of Hepatic Asah1 Gene Disrupts Hepatic Lipid Homeostasis and Promotes Fibrotic Nonalcoholic Steatohepatitis in Mice.","date":"2024","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/39719015","citation_count":10,"is_preprint":false},{"pmid":"31614420","id":"PMC_31614420","title":"InGaN as a Substrate for AC Photoelectrochemical Imaging.","date":"2019","source":"Sensors (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/31614420","citation_count":10,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":45178,"output_tokens":3476,"usd":0.093837},"stage2":{"model":"claude-opus-4-6","input_tokens":6855,"output_tokens":2705,"usd":0.15285},"total_usd":0.246687,"stage1_batch_id":"msgbatch_01TqNM6p6FsoMBT2jzQTwKBr","stage2_batch_id":"msgbatch_01Ya473eco8sTHbvRymQaU8o","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"ASAH1 (acid ceramidase) localizes to the nuclei of H295R adrenocortical cells and represses steroidogenic factor 1 (SF-1)-dependent gene transcription by directly binding to SF-1. ChIP assays showed ASAH1 is recruited to SF-1 target gene promoters (CYP17A1, StAR), where it co-occupies the same promoter regions as SF-1. cAMP signaling promotes nuclear sphingolipid metabolism in an ASAH1-dependent manner.\",\n      \"method\": \"Nuclear fractionation, co-immunoprecipitation, chromatin immunoprecipitation (ChIP), RNA interference\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, ChIP, subcellular fractionation, and RNAi knockdown in a single study with multiple orthogonal methods\",\n      \"pmids\": [\"22927646\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ACTH/cAMP signaling induces ASAH1 gene expression in H295R adrenocortical cells by stimulating CREB binding to multiple regions of the ASAH1 promoter, which in turn recruits coactivators CBP and p300 and increases H3K4 trimethylation at the ASAH1 promoter. CREB is indispensable for cAMP-induced ASAH1 transcription.\",\n      \"method\": \"ChIP assay, RNAi knockdown, reporter assay, histone modification analysis\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (ChIP, RNAi, histone marks) in a single study demonstrating transcriptional regulatory mechanism\",\n      \"pmids\": [\"19298866\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ASAH1 (acid ceramidase) controls the phenotypic switch between proliferative and invasive states in melanoma cells. Low ASAH1 expression drives invasive behavior via activation of integrin αvβ5-FAK signaling. ASAH1 was identified as a transcriptional target of MITF, linking sphingolipid metabolism to melanoma phenotypic plasticity.\",\n      \"method\": \"ASAH1 knockdown/overexpression, invasion assays, signaling pathway analysis, MITF reporter assays, human melanoma biopsy IHC\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD/OE with defined cellular phenotype and pathway placement (integrin αvβ5-FAK), single lab\",\n      \"pmids\": [\"30254208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Overexpression of ASAH1 in ARPE19 retinal cells prevents ceramide and hexosyl-ceramide accumulation under hydrogen peroxide-induced oxidative stress, protecting cells from oxidative stress-induced death. ASAH1 hydrolyzes excess ceramide, and its induction reduces lipid death mediators.\",\n      \"method\": \"ASAH1 overexpression, lipidomic analysis (ceramide measurement), cell viability assays under oxidative stress\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — OE with defined biochemical and cellular phenotype, single lab with multiple readouts\",\n      \"pmids\": [\"30413652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Podocyte-specific deletion of the ASAH1 gene (Asah1fl/fl/PodoCre mice) causes ceramide accumulation in glomeruli, leading to podocyte foot process effacement, proteinuria, and nephrotic syndrome. Double knockout of Asah1 and Smpd1 (acid sphingomyelinase, which generates ceramide from sphingomyelin) reduced glomerular ceramide and attenuated podocyte injury, confirming that lysosomal acid ceramidase is essential for ceramide homeostasis in podocytes.\",\n      \"method\": \"Conditional knockout mouse model, LC-MS/MS ceramide quantification, transmission electron microscopy, genetic epistasis (double knockout with Smpd1-/-)\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with defined phenotype, genetic epistasis, and biochemical (lipidomic) validation; multiple orthogonal methods\",\n      \"pmids\": [\"32194052\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ASAH1 deletion in podocytes suppresses lysosomal TRPML1 channel Ca2+ release, which reduces lysosome-multivesicular body (MVB) interaction and enhances exosome release. Sphingosine (the ASAH1 product) rescues TRPML1 channel activity and restores lysosome-MVB interaction, reducing exosome secretion. This identifies a sphingosine-TRPML1-exosome axis downstream of ASAH1 activity.\",\n      \"method\": \"Conditional knockout mouse model, GCaMP3 Ca2+ imaging, Port-a-Patch patch clamping of lysosomes, rescue with sphingosine, urinary exosome quantification\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular and cell biology of lipids\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct lysosomal electrophysiology, Ca2+ imaging, genetic rescue, and chemical rescue converge on a mechanistic pathway\",\n      \"pmids\": [\"33221496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Smooth muscle cell-specific deletion of Asah1 (Asah1fl/fl/SMCre) impairs lysosomal TRPML1 channel activity and reduces lysosome-MVB interaction, leading to increased small extracellular vesicle (sEV) secretion, osteogenic phenotypic transition (upregulation of RUNX2, osteopontin), and arterial medial calcification. GW4869 (sEV release inhibitor) reduced calcification, confirming the sEV pathway as mechanistically downstream of ASAH1.\",\n      \"method\": \"Conditional knockout mouse model, GCaMP3 Ca2+ imaging, Port-a-Patch patch clamping of lysosomes, sEV inhibitor, immunostaining for osteogenic markers, calcium deposition assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with mechanistic follow-up including direct lysosomal electrophysiology and pharmacological intervention; multiple orthogonal methods\",\n      \"pmids\": [\"32015399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Endothelium-specific ASAH1 knockout (Asah1fl/fl/ECcre) enhances NLRP3 inflammasome formation/activation in coronary arterial endothelial cells and increases IL-1β-containing exosome release. AC deficiency decreases MVB-lysosome interaction, redirecting MVBs to exosome secretion rather than lysosomal degradation, thereby amplifying NLRP3 inflammasome product release during hyperglycemia.\",\n      \"method\": \"Endothelium-specific conditional KO mouse model, NLRP3 inflammasome assays, exosome isolation and characterization, confocal imaging of MVB-lysosome interaction\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular and cell biology of lipids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with defined cellular phenotype and pathway placement, single lab\",\n      \"pmids\": [\"31647995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A homozygous ASAH1 variant (c.124A>G; p.Thr42Ala) in patients with a slowly progressive non-5q SMA phenotype results in reduced ceramidase enzymatic activity and ceramide accumulation in cultured fibroblasts, directly linking ASAH1 loss of function to the SMA-PME phenotypic spectrum.\",\n      \"method\": \"ASAH1 gene sequencing, ceramidase enzyme activity assay in cultured fibroblasts, ceramide accumulation measurement\",\n      \"journal\": \"European journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — enzyme activity assay and ceramide accumulation in patient-derived cells confirm loss of catalytic function\",\n      \"pmids\": [\"27026573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Compound heterozygous mutations in ASAH1 (c.505T>C/p.Trp169Arg and c.760A>G/p.Arg254Gly) reduce acid ceramidase enzyme activity to ~8% of controls in patient fibroblasts, establishing ASAH1 loss-of-function as the cause of an adult-onset peripheral osteolysis phenotype (atypical Farber disease).\",\n      \"method\": \"Exome sequencing, Sanger sequencing, ceramidase enzyme activity assay in cultured fibroblasts\",\n      \"journal\": \"Arthritis & rheumatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct enzyme activity assay in patient-derived cells corroborates genotype-phenotype link\",\n      \"pmids\": [\"26945816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Novel ASAH1 mutations causing Farber lipogranulomatosis include a splice mutation (IVS6+4A>G) and a polypyrimidine tract deletion (IVS5-16delTTTTC) that result in skipping of exon 6, precluding cleavage of the enzyme precursor. A missense mutation (p.V198A) inactivates an exonic splicing enhancer, causing exon 8 skipping. These findings define the molecular processing requirements for ASAH1 activation.\",\n      \"method\": \"Mutation analysis, RT-PCR for splicing, ESE prediction and validation\",\n      \"journal\": \"Clinical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct demonstration of splicing consequences with functional annotation of mutations affecting ASAH1 precursor cleavage\",\n      \"pmids\": [\"24355074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A rare coding variant (c.1202T>C; p.Leu401Pro) in ASAH1 co-segregates with keloid formation in a large Yoruba family (LOD score 4.48), identifying ASAH1 as a susceptibility gene for familial keloids and implicating ceramide/sphingosine balance in abnormal scar formation.\",\n      \"method\": \"Whole-genome sequencing, exome sequencing, linkage analysis, Sanger sequencing for co-segregation\",\n      \"journal\": \"European journal of human genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — genetic linkage and variant co-segregation only; no functional/biochemical validation of the variant in the paper\",\n      \"pmids\": [\"28905881\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Hepatocyte-specific deletion of Asah1 in mice results in ceramide and cholesterol accumulation in hepatocytes, increased ER stress, impaired chaperone-mediated autophagy, and augmented lipid droplet biogenesis, leading to exacerbated hepatic steatosis and fibrotic NASH on a paigen diet. Asah1 knockdown broadly impacts lipogenesis, fatty acid uptake/oxidation, and lipid transport pathways.\",\n      \"method\": \"Hepatocyte-specific conditional knockout (Asah1fl/fl/Albcre), ceramide/cholesterol quantification, ER stress markers, autophagy assays, transcriptomic analysis\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with multiple biochemical and cellular phenotypic readouts, single lab\",\n      \"pmids\": [\"39719015\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ASAH1 encodes lysosomal acid ceramidase, which hydrolyzes ceramide into sphingosine and fatty acids; its activity controls ceramide homeostasis in lysosomes, regulates lysosomal TRPML1 Ca2+ channel activity and thereby lysosome-MVB interactions and exosome secretion, and in the nucleus directly binds and represses the steroidogenic transcription factor SF-1, while its deficiency across multiple cell types (podocytes, smooth muscle cells, endothelium, hepatocytes) leads to ceramide accumulation, impaired lysosomal trafficking, and downstream pathological signaling including NLRP3 inflammasome activation, arterial calcification, nephrotic syndrome, and steatohepatitis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ASAH1 encodes lysosomal acid ceramidase, which hydrolyzes ceramide into sphingosine and free fatty acids and thereby maintains ceramide homeostasis across diverse cell types including podocytes, vascular smooth muscle cells, endothelial cells, and hepatocytes [PMID:32194052, PMID:32015399, PMID:39719015]. The sphingosine product of ASAH1 activates the lysosomal TRPML1 Ca²⁺ channel, promoting lysosome–multivesicular body (MVB) fusion and directing MVB cargo to lysosomal degradation rather than exosome secretion; loss of ASAH1 therefore augments exosome release and, in specific contexts, drives arterial calcification via osteogenic extracellular vesicles or amplifies NLRP3 inflammasome signaling [PMID:33221496, PMID:32015399, PMID:31647995]. Beyond its lysosomal catalytic role, ASAH1 localizes to the nucleus in adrenocortical cells, where it directly binds steroidogenic factor 1 (SF-1) on target gene promoters (CYP17A1, StAR) and represses SF-1-dependent transcription in a cAMP-regulated manner [PMID:22927646, PMID:19298866]. Loss-of-function mutations in ASAH1 cause Farber lipogranulomatosis and the SMA-PME phenotypic spectrum, with disease-causing variants reducing ceramidase activity and disrupting precursor processing through splicing or missense defects [PMID:26945816, PMID:27026573, PMID:24355074].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"ASAH1 transcription was shown to be directly controlled by ACTH/cAMP–CREB signaling, establishing how the gene is induced in steroidogenic cells and linking its expression to hormonal regulation.\",\n      \"evidence\": \"ChIP, RNAi knockdown, reporter assays, and histone modification analysis in H295R adrenocortical cells\",\n      \"pmids\": [\"19298866\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether CREB-dependent ASAH1 induction operates in non-adrenal tissues\",\n        \"Downstream consequences of ASAH1 induction on adrenal ceramide pools were not quantified\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Discovery that ASAH1 has a non-catalytic nuclear function—directly binding SF-1 on steroidogenic gene promoters and repressing transcription—revealed a dual lysosomal/nuclear role for the enzyme.\",\n      \"evidence\": \"Nuclear fractionation, reciprocal co-immunoprecipitation, ChIP, and RNAi in H295R cells\",\n      \"pmids\": [\"22927646\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether the nuclear role requires catalytic activity or is purely scaffolding\",\n        \"Mechanism of ASAH1 nuclear import is unknown\",\n        \"Whether nuclear ASAH1 represses SF-1 targets in tissues other than adrenal cortex\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Characterization of splice-disrupting ASAH1 mutations defined the precursor cleavage requirement for enzyme activation, explaining how specific variants abolish function and cause Farber lipogranulomatosis.\",\n      \"evidence\": \"RT-PCR splice analysis and exonic splicing enhancer prediction/validation in patient-derived cells\",\n      \"pmids\": [\"24355074\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural model of ASAH1 precursor cleavage site\",\n        \"Residual enzyme activity for each splice variant was not quantified\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Direct measurement of ceramidase activity in patient fibroblasts linked ASAH1 loss-of-function mutations to both Farber disease and the SMA-PME phenotypic spectrum, expanding the clinical impact of ASAH1 deficiency beyond lipogranulomatosis.\",\n      \"evidence\": \"Ceramidase enzyme activity assays and ceramide quantification in patient-derived fibroblasts, combined with exome/Sanger sequencing\",\n      \"pmids\": [\"26945816\", \"27026573\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The cell-type–specific basis for neuronal versus connective tissue manifestations of ASAH1 deficiency is unresolved\",\n        \"Rescue experiments with wild-type ASAH1 were not performed\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"ASAH1 was positioned as a metabolic effector of melanoma phenotypic switching, with low ASAH1 promoting invasion via integrin αvβ5–FAK signaling, and as a protector against oxidative stress-induced ceramide accumulation in retinal cells.\",\n      \"evidence\": \"ASAH1 knockdown/overexpression with invasion assays and signaling pathway analysis in melanoma; lipidomic analysis under oxidative stress in ARPE19 cells\",\n      \"pmids\": [\"30254208\", \"30413652\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether ceramide species specificity determines ASAH1's pro-survival versus phenotype-switching roles\",\n        \"In vivo melanoma models were not used for validation\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Endothelium-specific ASAH1 deletion demonstrated that acid ceramidase deficiency redirects MVBs from lysosomal degradation to exosome secretion, amplifying NLRP3 inflammasome-derived IL-1β release, providing a mechanistic link between ceramide metabolism and vascular inflammation.\",\n      \"evidence\": \"Endothelium-specific conditional KO mouse model with NLRP3 inflammasome assays, exosome isolation, and confocal imaging of MVB–lysosome interaction\",\n      \"pmids\": [\"31647995\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct measurement of TRPML1 activity in endothelial cells was not performed in this study\",\n        \"Whether inflammasome activation is ceramide-species specific is unresolved\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"A convergent mechanism was established across podocytes and smooth muscle cells: ASAH1-derived sphingosine activates the lysosomal TRPML1 Ca²⁺ channel, which promotes lysosome–MVB fusion; loss of ASAH1 suppresses this axis, increasing exosome release and causing tissue-specific pathology (nephrotic syndrome in podocytes, arterial calcification in smooth muscle).\",\n      \"evidence\": \"Conditional KO mouse models (podocyte-specific and SMC-specific), lysosomal patch clamp (Port-a-Patch), GCaMP3 Ca²⁺ imaging, sphingosine rescue, genetic epistasis with Smpd1, sEV inhibitor (GW4869)\",\n      \"pmids\": [\"32194052\", \"33221496\", \"32015399\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether sphingosine directly binds TRPML1 or acts through an intermediate\",\n        \"Structural basis for TRPML1 activation by sphingosine is unknown\",\n        \"Whether the sphingosine–TRPML1 axis operates in non-lysosomal compartments\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Hepatocyte-specific Asah1 deletion revealed that acid ceramidase is required for hepatic ceramide and cholesterol homeostasis, with its absence driving ER stress, impaired chaperone-mediated autophagy, lipid droplet biogenesis, and progression to steatohepatitis.\",\n      \"evidence\": \"Hepatocyte-specific conditional KO (Asah1fl/fl/Albcre), ceramide/cholesterol quantification, ER stress markers, autophagy assays, transcriptomic analysis\",\n      \"pmids\": [\"39719015\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism linking ceramide accumulation to impaired chaperone-mediated autophagy is not fully delineated\",\n        \"Whether TRPML1 suppression underlies the hepatic phenotype was not tested\",\n        \"Therapeutic rescue with exogenous acid ceramidase was not attempted\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural mechanism of ASAH1 precursor auto-cleavage and activation, whether sphingosine directly binds TRPML1, how ASAH1 is imported into the nucleus, and whether its catalytic and nuclear scaffolding functions are separable.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No high-resolution structure of human ASAH1 in active or precursor form\",\n        \"Separation-of-function mutants distinguishing catalytic versus nuclear roles have not been generated\",\n        \"Direct biophysical evidence for sphingosine–TRPML1 binding is lacking\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [3, 4, 5, 6, 8, 9, 10, 12]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [4, 5, 6, 7, 12]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [3, 4, 5, 6, 12]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [5, 6, 7]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [8, 9, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"NR5A1\",\n      \"MCOLN1\",\n      \"SMPD1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}