{"gene":"DBT","run_date":"2026-04-28T17:28:53","timeline":{"discoveries":[{"year":2006,"finding":"Drosophila DBT (doubletime, CKIε ortholog) directly phosphorylates and destabilizes the circadian transcription factor CLOCK (CLK) in a phase-specific manner in vivo, promoting CLK hyperphosphorylation and enhancing its degradation; DBT also evokes modest inhibition of CLK-dependent transactivation. DBT functions in dynamic equilibrium with protein phosphatase 2A to maintain balanced hypo- and hyperphosphorylated CLK isoforms, stabilizing CLK levels against stochastic fluctuations.","method":"In vivo genetic analysis in Drosophila, Drosophila S2 cell transfection assays, immunostaining for subcellular localization of CLK","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — in vivo and cell-based functional assays with multiple orthogonal readouts (phosphorylation, degradation, transcriptional activity, localization), replicated across contexts","pmids":["16603629"],"is_preprint":false},{"year":2007,"finding":"Enzymatically active DBT kinase activity is required for normal circadian rhythms in Drosophila. A kinase-dead DBT(K38R) mutant interacts with PER but cannot phosphorylate it; expression of DBT(K38R) in flies antagonizes PER phosphorylation and degradation, dampens PER oscillation, and produces long circadian periods or arrhythmicity in proportion to titration of endogenous DBT activity.","method":"Site-directed mutagenesis (K38R) abolishing kinase activity, in vitro kinase assay, S2 cell transfection, transgenic fly behavioral analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 — in vitro kinase assay with mutagenesis combined with in vivo genetic rescue and behavioral phenotyping","pmids":["17893330"],"is_preprint":false},{"year":2008,"finding":"DBT directly phosphorylates the Drosophila clock protein PER at specific sites. DBT-dependent phosphorylation at two adjoining sequence motifs acts in a switch-like manner to regulate PER stability and repressor function. The per(S) short-period mutation alters a key DBT phosphorylation target within PER, linking phosphorylation site identity to period length.","method":"In vitro kinase assay with purified proteins, phosphorylation site mapping by mutagenesis, S2 cell functional assays, in vivo behavioral analysis","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 1 — direct in vitro phosphorylation with site-specific mutagenesis validated in cell culture and in vivo","pmids":["18666831"],"is_preprint":false},{"year":2007,"finding":"PER, TIM, and DBT form physical interactions in Drosophila cells; live-cell imaging revealed dynamic patterns of DBT, PER, and TIM stability and localization consistent with a cytoplasmic interval timer that regulates nuclear translocation of PER and TIM once per day.","method":"Live-cell video microscopy with GFP-tagged proteins in cultured Drosophila cells, co-immunoprecipitation","journal":"Cold Spring Harbor symposia on quantitative biology","confidence":"Medium","confidence_rationale":"Tier 2 — live imaging with GFP fusion proteins in single cells, consistent with in vivo data, but single lab","pmids":["18419263"],"is_preprint":false},{"year":2013,"finding":"The non-canonical FK506-binding protein BRIDE OF DOUBLETIME (BDBT/CG17282) physically interacts with DBT kinase. BDBT enhances DBT-dependent PER degradation in S2 cells; RNAi knockdown of BDBT produces behavioral arrhythmicity and elevated hypophosphorylated nuclear PER and phosphorylated DBT. Structural analysis showed BDBT contains an inactive peptide prolyl-isomerase domain that binds DBT and tetratricopeptide repeats that may scaffold larger complexes.","method":"Proteomic identification of DBT interactors, reciprocal co-IP, RNAi knockdown with behavioral and molecular phenotyping, S2 cell overexpression assays, structural analysis","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1–2 — proteomic discovery combined with reciprocal co-IP, functional cell assays, in vivo genetic phenotyping, and structural analysis","pmids":["24210908"],"is_preprint":false},{"year":2015,"finding":"Drosophila DBT undergoes C-terminal autophosphorylation at six serine/threonine residues identified by mass spectrometry. Mutation of these sites (DBT(C/ala)) prevents autophosphorylation-dependent DBT turnover in S2 cells. Unlike vertebrate CKIδ, DBT autophosphorylation does not reduce in vitro kinase activity and is not required for circadian clock function. However, DBT autophosphorylation is required for protection against UV-induced apoptosis: wild-type DBT protects S2 cells and larvae from UV-induced apoptosis and is degraded by the proteasome after UV exposure, while DBT(C/ala) does not protect. The HSP90 co-chaperone SPAG antagonizes DBT autophosphorylation in S2 cells.","method":"Mass spectrometry for phosphosite mapping, site-directed mutagenesis, in vitro kinase assay, S2 cell UV apoptosis assay, proteasome inhibitor studies, transgenic fly behavioral analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 — mass spectrometry-based site mapping combined with mutagenesis, in vitro and in vivo functional validation, multiple orthogonal assays","pmids":["25939385"],"is_preprint":false},{"year":2022,"finding":"DBT (BDBT) foci in Drosophila eye photoreceptors require both CRYPTOCHROME and RHODOPSIN-1 visual photoreceptor pathways for light-induced disappearance; arrestin mutants (arr1, arr2) that affect rhodopsin quenching eliminated BDBT foci in darkness and caused increased nuclear PER. Knockdown of BDBT specifically in the eye produced constitutively nuclear PER and constitutively cytosolic DBT, demonstrating that BDBT is required for co-transport of DBT and PER into the nucleus.","method":"Genetic analysis with circadian and visual pathway mutants, tissue-specific RNAi knockdown, immunofluorescence localization","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis and immunofluorescence localization with functional consequence (nuclear PER changes), single lab","pmids":["36994075"],"is_preprint":false},{"year":2022,"finding":"Reduction of DBT kinase in Drosophila circadian neurons increases sleep loss at night (via adult clock function), while reduction in non-circadian neurons produces increased daytime sleep (via developmental effects). PER protein is involved in DBT-mediated sleep regulation independently of the neuronal context.","method":"CRISPR-Cas9 knock-in of GAL4 at dbt locus, targeted RNAi in neuron subsets, sleep behavioral assays","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 — genetic manipulation with defined neuronal specificity and behavioral phenotyping, single lab","pmids":["35139068"],"is_preprint":false},{"year":1993,"finding":"Two novel loss-of-function mutations in the human DBT (E2) gene cause MSUD: a 2-bp (AT) deletion in exon 2 causing a frameshift in the mitochondrial targeting presequence, and a G-to-T nonsense mutation in exon 6 (E163*). Transfection of the E163* construct into an E2-deficient cell line showed that the truncated E2 protein cannot assemble into the native 24-mer cubic structure and is rapidly degraded, establishing the structural requirement for the cubic core in DBT protein stability.","method":"Site-directed mutation, transfection into E2-deficient MSUD cell line, protein assembly assay, degradation analysis","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 1 — cell-based reconstitution demonstrating failure of assembly and degradation of mutant E2, plus genetic characterization of patient alleles","pmids":["8430702"],"is_preprint":false},{"year":1995,"finding":"Autoantibodies to BCOADC-E2 (DBT) in primary biliary cirrhosis recognize a conformational epitope located within amino acids 1–227 of the mature protein that includes the lipoic acid-binding region. Full-length protein (aa 1–421) is required to absorb all detectable anti-BCOADC-E2 reactivity. Antibody binding is not dependent on the presence of lipoic acid on the antigen.","method":"Immunoblotting, ELISA, and selective absorption of patient sera with defined recombinant protein fragments spanning the full DBT/BCOADC-E2 sequence","journal":"Hepatology (Baltimore, Md.)","confidence":"High","confidence_rationale":"Tier 2 — systematic epitope mapping with multiple overlapping fragments and orthogonal serological methods, replicated across patient cohorts","pmids":["7543435"],"is_preprint":false},{"year":1991,"finding":"The human DBT gene (encoding the E2/transacylase subunit of the BCKDH complex) was localized to chromosome 1 by somatic cell hybrid analysis and regionally assigned to chromosome band 1p31 by in situ hybridization.","method":"Human × mouse somatic cell hybrid panel analysis with PCR-amplified E2 cDNA probe, in situ hybridization","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 2 — direct chromosomal mapping by two independent methods (somatic cell hybrids and in situ hybridization)","pmids":["1889817"],"is_preprint":false},{"year":2015,"finding":"Peroxiredoxin V (PrdxV) interacts with DBT (dihydrolipoamide branched chain transacylase E2) in mouse kidney under hypoxic stress. This interaction is enhanced under hypoxia compared to normoxia. Hypoxic conditions also increase DBT enzymatic activity. The peroxidatic cysteine residue (Cys48) of PrdxV is responsible for the interaction with DBT. Enhanced colocalization of PrdxV and DBT was observed in vitro under hypoxic conditions.","method":"Immunoprecipitation coupled with nano-UPLC-MS shotgun proteomics, comparative interactomics under normoxia vs. hypoxia, co-localization imaging, enzymatic activity assay","journal":"Proteome science","confidence":"Medium","confidence_rationale":"Tier 2/3 — mass spectrometry-based interactomics with enzymatic activity measurement, but functional consequence of interaction not deeply characterized","pmids":["25670924"],"is_preprint":false},{"year":2023,"finding":"DBT (dihydrolipoamide branched chain transacylase E2) interacts with ANXA2 (annexin A2) through its lipoyl-binding domain to activate Hippo signaling, resulting in decreased nuclear localization of YAP and transcriptional repression of lipogenic genes. DBT downregulation in ccRCC is caused by METTL3-mediated m6A modification. DBT acts as a tumor suppressor by inhibiting tumor progression and correcting lipid metabolism disorder in ccRCC.","method":"Luciferase reporter assay, immunoprecipitation, mass spectrometry, mutational studies of the lipoyl-binding domain, gain/loss-of-function assays in vitro and in vivo","journal":"Cancer communications (London, England)","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP with domain mapping, mass spectrometry, and functional assays, single lab","pmids":["36860124"],"is_preprint":false},{"year":2024,"finding":"Loss of DBT (dihydrolipoamide branched chain transacylase E2) protects against proteasome inhibition-associated cell death by promoting clearance of ubiquitinated proteins. Loss of DBT alters cellular metabolic and energetic status, activating autophagy through an AMPK-dependent mechanism when the proteasome is inhibited. DBT loss protects against proteotoxicity from ALS-linked mutant TDP-43 in both Drosophila and mammalian neurons. DBT is upregulated in ALS patient tissues, positioning it as a metabolic switch controlling protein quality control pathways.","method":"Genome-wide CRISPR screen, genetic loss-of-function in Drosophila and mammalian neurons, AMPK pathway activation assays, ubiquitinated protein clearance assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1–2 — genome-wide CRISPR screen identification combined with mechanistic pathway dissection (AMPK-autophagy axis) validated in multiple model systems","pmids":["39255192"],"is_preprint":false},{"year":2024,"finding":"The lipoyl domain of BCOADC-E2 (DBT) is critical for autoantibody recognition in primary biliary cholangitis. The folding conformation of the lipoyl β-sheet, specifically the glutamic acid at position 4 and isoleucine at position 13, are necessary for recognition by anti-BCOADC-E2 autoantibodies. Multi-site mutations of these residues reduce reactivity with patient sera, and EPR spectroscopy confirmed the conformational integrity of these positions is maintained in the wild-type protein.","method":"Site-directed mutagenesis of lipoyl domain, ELISA with patient sera, MTSSL spin-labeling and EPR spectroscopy","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 1/2 — mutagenesis combined with structural EPR spectroscopy and serological validation, single lab","pmids":["39769438"],"is_preprint":false},{"year":2022,"finding":"Homozygous deletion of exon 2 (delEx2) of the DBT gene results in complete absence of DBT protein in hepatocytes (confirmed by Western blot), while compound heterozygous delEx2/p.Ser306Pro produces decreased DBT protein. Both variants cause failure of branched-chain amino acid catabolism, with accumulation of branched-chain amino acids and alpha-ketoacids in explanted hepatocytes demonstrated by UPLC-MS/MS, establishing the functional requirement of the DBT E2 subunit for BCKDH complex activity.","method":"Western blot of patient-derived liver cells, UPLC-tandem mass spectrometry of hepatocyte metabolites, Sanger sequencing","journal":"American journal of medical genetics. Part A","confidence":"Medium","confidence_rationale":"Tier 2 — direct protein-level confirmation with functional metabolic assay in patient-derived cells","pmids":["35799415"],"is_preprint":false}],"current_model":"Human DBT (dihydrolipoamide branched chain transacylase E2) is the E2 core subunit of the mitochondrial BCKDH complex that catalyzes branched-chain α-ketoacid catabolism via its lipoyl-binding domain; loss-of-function mutations cause MSUD by preventing BCKDH complex assembly and activity; DBT also functions as a metabolic switch that, when lost, activates AMPK-dependent autophagy to compensate for proteasomal impairment and protect against proteotoxicity in ALS models, and in ccRCC its lipoyl-binding domain engages ANXA2 to activate Hippo/YAP signaling and suppress lipogenesis; the Drosophila ortholog Doubletime (DBT/CKIε) directly phosphorylates PER and CLK at defined sites to drive circadian feedback loop dynamics, with its activity regulated by autophosphorylation, the co-chaperone SPAG, and the scaffold protein BDBT which facilitates nuclear co-transport of DBT and PER."},"narrative":{"teleology":[{"year":1991,"claim":"Chromosomal mapping of DBT to 1p31 established its genomic context and enabled subsequent mutation screening in MSUD families.","evidence":"Somatic cell hybrid analysis and in situ hybridization in human cells","pmids":["1889817"],"confidence":"High","gaps":["No functional characterization performed at this stage","Regulatory elements not defined"]},{"year":1993,"claim":"Demonstration that truncating DBT mutations prevent assembly of the 24-mer E2 cubic core and cause rapid protein degradation established the structural basis of MSUD pathogenesis.","evidence":"Transfection of mutant E2 constructs into E2-deficient MSUD cell line with assembly and degradation assays","pmids":["8430702"],"confidence":"High","gaps":["Only two mutations characterized; spectrum of pathogenic variants not surveyed","No rescue experiment with wild-type cDNA reported"]},{"year":1995,"claim":"Mapping of the conformational autoantibody epitope to the N-terminal lipoyl-binding region (aa 1–227) of DBT linked this domain to autoimmune recognition in primary biliary cirrhosis, independent of lipoic acid attachment.","evidence":"ELISA and immunoblot absorption with recombinant domain fragments against PBC patient sera","pmids":["7543435"],"confidence":"High","gaps":["Mechanism by which tolerance to this epitope is broken remains unknown","No structural resolution of the antibody–antigen interface"]},{"year":2015,"claim":"Identification of a hypoxia-enhanced interaction between peroxiredoxin V and DBT, with increased DBT enzymatic activity under hypoxia, suggested redox-dependent regulation of BCKDH activity.","evidence":"Immunoprecipitation–mass spectrometry interactomics in mouse kidney under normoxia versus hypoxia, enzymatic activity assay","pmids":["25670924"],"confidence":"Medium","gaps":["Functional consequence of the PrdxV–DBT interaction on BCAA catabolism not established","Interaction not validated by reciprocal pulldown or in additional tissues","Mechanism linking Cys48 of PrdxV to DBT activity unclear"]},{"year":2022,"claim":"Patient-derived hepatocyte studies confirmed that complete loss or reduction of DBT protein abolishes BCKDH complex activity and causes accumulation of branched-chain amino acids and α-ketoacids, directly linking genotype to metabolic phenotype at the cellular level.","evidence":"Western blot of patient liver cells with homozygous exon 2 deletion and compound heterozygous mutations, UPLC-MS/MS metabolite profiling","pmids":["35799415"],"confidence":"Medium","gaps":["No BCKDH complex assembly assay performed on these specific alleles","Residual E2 protein from the Ser306Pro allele not functionally characterized in isolation"]},{"year":2023,"claim":"Discovery that the DBT lipoyl-binding domain interacts with ANXA2 to activate Hippo signaling and repress YAP-driven lipogenic transcription revealed a non-canonical tumor-suppressive role for DBT in ccRCC, with its downregulation mediated by METTL3-dependent m6A modification.","evidence":"Co-IP with lipoyl domain mutants, mass spectrometry, luciferase reporters, and gain/loss-of-function assays in ccRCC models in vitro and in vivo","pmids":["36860124"],"confidence":"Medium","gaps":["Single-lab finding; independent replication needed","Structural basis of lipoyl domain–ANXA2 interaction unresolved","Extent of this mechanism in other cancer types unknown"]},{"year":2024,"claim":"A genome-wide CRISPR screen revealed that DBT loss activates AMPK-dependent autophagy to compensate for proteasomal impairment, protecting against proteotoxicity from ALS-linked mutant TDP-43 across species, repositioning DBT as a metabolic switch governing protein quality control.","evidence":"CRISPR screen in mammalian cells, genetic loss-of-function in Drosophila and mammalian neurons, AMPK pathway and ubiquitinated protein clearance assays","pmids":["39255192"],"confidence":"High","gaps":["Precise metabolite(s) linking DBT loss to AMPK activation not identified","Whether this protective mechanism operates in human ALS patients is untested","Potential detrimental effects of chronic DBT loss on BCAA metabolism not addressed"]},{"year":2024,"claim":"Fine-mapping of the autoantibody epitope in PBC to specific residues (Glu4, Ile13) in the lipoyl β-sheet of DBT, with structural validation by EPR spectroscopy, refined understanding of conformational determinants of autoimmune recognition.","evidence":"Site-directed mutagenesis of lipoyl domain, ELISA with PBC patient sera, MTSSL spin-labeling and EPR spectroscopy","pmids":["39769438"],"confidence":"Medium","gaps":["Crystal structure of the autoantibody–lipoyl domain complex not solved","Whether these residues drive pathogenic T-cell responses is unknown"]},{"year":null,"claim":"The metabolic signals linking DBT loss to AMPK activation and the structural basis of DBT's interaction with ANXA2 in Hippo pathway regulation remain undefined, as does whether the proteotoxicity-protective mechanism of DBT loss can be therapeutically exploited without disrupting BCAA homeostasis.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of full-length human DBT in complex context","Metabolite mediator of DBT loss → AMPK axis not identified","Therapeutic window for DBT modulation unexplored"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[8,15]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[8,15]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[8,15,11]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[8,9,14,15]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[13]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[12]}],"complexes":["BCKDH complex (branched-chain α-keto acid dehydrogenase complex)"],"partners":["ANXA2","PRDX5"],"other_free_text":[]},"mechanistic_narrative":"DBT encodes the dihydrolipoamide branched-chain transacylase (E2) core subunit of the mitochondrial branched-chain α-keto acid dehydrogenase (BCKDH) complex, which catalyzes an essential step in branched-chain amino acid catabolism; its 24-meric cubic core structure is required for complex assembly, and truncating mutations cause rapid E2 degradation and loss of BCKDH activity, resulting in maple syrup urine disease (MSUD) [PMID:8430702, PMID:35799415]. Beyond its canonical metabolic role, the DBT lipoyl-binding domain engages ANXA2 to activate Hippo/YAP signaling and suppress lipogenesis in clear-cell renal cell carcinoma, functioning as a tumor suppressor [PMID:36860124]. Loss of DBT shifts cellular energy status to activate AMPK-dependent autophagy, compensating for proteasomal impairment and protecting against TDP-43 proteotoxicity in ALS models across Drosophila and mammalian neurons [PMID:39255192]. The lipoyl domain is also the principal conformational epitope recognized by autoantibodies in primary biliary cholangitis [PMID:7543435, PMID:39769438]."},"prefetch_data":{"uniprot":{"accession":"P11182","full_name":"Lipoamide acyltransferase component of branched-chain alpha-keto acid dehydrogenase complex, mitochondrial","aliases":["52 kDa mitochondrial autoantigen of primary biliary cirrhosis","Branched chain 2-oxo-acid dehydrogenase complex component E2","BCOADC-E2","Branched-chain alpha-keto acid dehydrogenase complex component E2","BCKAD-E2","BCKADE2","BCKDH-E2","Dihydrolipoamide acetyltransferase component of branched-chain alpha-keto acid dehydrogenase complex","Dihydrolipoamide branched chain transacylase","Dihydrolipoyllysine-residue (2-methylpropanoyl)transferase"],"length_aa":482,"mass_kda":53.5,"function":"The branched-chain alpha-keto dehydrogenase complex catalyzes the overall conversion of alpha-keto acids to acyl-CoA and CO(2). It contains multiple copies of three enzymatic components: branched-chain alpha-keto acid decarboxylase (E1), lipoamide acyltransferase (E2) and lipoamide dehydrogenase (E3). Within this complex, the catalytic function of this enzyme is to accept, and to transfer to coenzyme A, acyl groups that are generated by the branched-chain alpha-keto acid decarboxylase component","subcellular_location":"Mitochondrion matrix","url":"https://www.uniprot.org/uniprotkb/P11182/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DBT","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/DBT","total_profiled":1310},"omim":[{"mim_id":"620699","title":"MAPLE SYRUP URINE DISEASE, TYPE II; MSUD2","url":"https://www.omim.org/entry/620699"},{"mim_id":"620698","title":"MAPLE SYRUP URINE DISEASE, TYPE IB; MSUD1B","url":"https://www.omim.org/entry/620698"},{"mim_id":"611065","title":"PROTEIN PHOSPHATASE, MAGNESIUM/MANGANESE-DEPENDENT, 1K; PPM1K","url":"https://www.omim.org/entry/611065"},{"mim_id":"610783","title":"MICRO RNA 29B1; MIR29B1","url":"https://www.omim.org/entry/610783"},{"mim_id":"610284","title":"LIPOYLTRANSFERASE 1; LIPT1","url":"https://www.omim.org/entry/610284"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Mitochondria","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/DBT"},"hgnc":{"alias_symbol":["BCOADC-E2","BCKAD-E2","BCKDH-E2"],"prev_symbol":[]},"alphafold":{"accession":"P11182","domains":[{"cath_id":"2.40.50.100","chopping":"64-141","consensus_level":"high","plddt":90.0428,"start":64,"end":141},{"cath_id":"4.10.320.10","chopping":"176-212","consensus_level":"high","plddt":89.1916,"start":176,"end":212},{"cath_id":"3.30.559.10","chopping":"273-481","consensus_level":"high","plddt":95.0325,"start":273,"end":481}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P11182","model_url":"https://alphafold.ebi.ac.uk/files/AF-P11182-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P11182-F1-predicted_aligned_error_v6.png","plddt_mean":78.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DBT","jax_strain_url":"https://www.jax.org/strain/search?query=DBT"},"sequence":{"accession":"P11182","fasta_url":"https://rest.uniprot.org/uniprotkb/P11182.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P11182/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P11182"}},"corpus_meta":[{"pmid":"16603629","id":"PMC_16603629","title":"Balance between DBT/CKIepsilon kinase and protein phosphatase activities regulate phosphorylation and stability of Drosophila CLOCK protein.","date":"2006","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/16603629","citation_count":107,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7543435","id":"PMC_7543435","title":"Autoantibodies to BCOADC-E2 in patients with primary biliary cirrhosis recognize a conformational epitope.","date":"1995","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/7543435","citation_count":97,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17893330","id":"PMC_17893330","title":"Drosophila DBT lacking protein kinase activity produces long-period and arrhythmic circadian behavioral and molecular rhythms.","date":"2007","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17893330","citation_count":75,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18666831","id":"PMC_18666831","title":"Activating PER repressor through a DBT-directed phosphorylation switch.","date":"2008","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/18666831","citation_count":70,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"184329","id":"PMC_184329","title":"Mouse hepatitis virus (MHV-2). Plaque assay and propagation in mouse cell line DBT cells.","date":"1976","source":"Japanese journal of microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/184329","citation_count":69,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"14654871","id":"PMC_14654871","title":"Practice-based outcomes of dialectical behaviour therapy (DBT) targeting anger and violence, with male forensic patients: a pragmatic and non-contemporaneous comparison.","date":"2003","source":"Criminal behaviour and mental health : CBMH","url":"https://pubmed.ncbi.nlm.nih.gov/14654871","citation_count":52,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8430702","id":"PMC_8430702","title":"Occurrence of a 2-bp (AT) deletion allele and a nonsense (G-to-T) mutant allele at the E2 (DBT) locus of six patients with maple syrup urine disease: multiple-exon skipping as a secondary effect of the mutations.","date":"1993","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/8430702","citation_count":47,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36860124","id":"PMC_36860124","title":"N6-methyladenosine-modified DBT alleviates lipid accumulation and inhibits tumor progression in clear cell renal cell carcinoma through the ANXA2/YAP axis-regulated Hippo pathway.","date":"2023","source":"Cancer communications (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/36860124","citation_count":46,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28841194","id":"PMC_28841194","title":"PSFM-DBT: Identifying DNA-Binding Proteins by Combing Position Specific Frequency Matrix and Distance-Bigram Transformation.","date":"2017","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/28841194","citation_count":44,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28120003","id":"PMC_28120003","title":"PET imaging of α7 nicotinic acetylcholine receptors: a comparative study of [18F]ASEM and [18F]DBT-10 in nonhuman primates, and further evaluation of [18F]ASEM in humans.","date":"2017","source":"European journal of nuclear medicine and molecular imaging","url":"https://pubmed.ncbi.nlm.nih.gov/28120003","citation_count":43,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16232672","id":"PMC_16232672","title":"Purification and characterization of dibenzothiophene (DBT) sulfone monooxygenase, an enzyme involved in DBT desulfurization, from Rhodococcus erythropolis D-1.","date":"1999","source":"Journal of bioscience and bioengineering","url":"https://pubmed.ncbi.nlm.nih.gov/16232672","citation_count":35,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"6278888","id":"PMC_6278888","title":"Persistent infection with mouse hepatitis virus, JHM strain in DBT cell culture.","date":"1981","source":"Advances in experimental medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/6278888","citation_count":29,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16905217","id":"PMC_16905217","title":"Biodesulfurization of DBT in tetradecane and crude oil by a facultative thermophilic bacterium Mycobacterium goodii X7B.","date":"2006","source":"Journal of biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/16905217","citation_count":29,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20950683","id":"PMC_20950683","title":"Tributyltin (TBT) and dibutyltin (DBT) differently inhibit the mitochondrial Mg-ATPase activity in mussel digestive gland.","date":"2010","source":"Toxicology in vitro : an international journal published in association with BIBRA","url":"https://pubmed.ncbi.nlm.nih.gov/20950683","citation_count":26,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22066220","id":"PMC_22066220","title":"Desulfurization of dibenzothiophene (DBT) by a novel strain Lysinibacillus sphaericus DMT-7 isolated from diesel contaminated soil.","date":"2011","source":"Journal of environmental sciences (China)","url":"https://pubmed.ncbi.nlm.nih.gov/22066220","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23534342","id":"PMC_23534342","title":"In vitro approaches to evaluate toxicity induced by organotin compounds tributyltin (TBT), dibutyltin (DBT), and monobutyltin (MBT) in neuroblastoma cells.","date":"2013","source":"Journal of agricultural and food chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23534342","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12192519","id":"PMC_12192519","title":"Recombinant Rhodococcus sp. strain T09 can desulfurize DBT in the presence of inorganic sulfate.","date":"2002","source":"Current microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/12192519","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10385636","id":"PMC_10385636","title":"In situ nucleic acid detection of PDC-E2, BCOADC-E2, OGDC-E2, PDC-E1alpha, BCOADC-E1alpha, OGDC-E1, and the E3 binding protein (protein X) in primary biliary cirrhosis.","date":"1999","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/10385636","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32762677","id":"PMC_32762677","title":"A randomized controlled trial comparing the clinical efficacy and cost-effectiveness of eye movement desensitization and reprocessing (EMDR) and integrated EMDR-Dialectical Behavioural Therapy (DBT) in the treatment of patients with post-traumatic stress disorder and comorbid (Sub)clinical borderline personality disorder: study design.","date":"2020","source":"BMC psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/32762677","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24210908","id":"PMC_24210908","title":"Noncanonical FK506-binding protein BDBT binds DBT to enhance its circadian function and forms foci at night.","date":"2013","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/24210908","citation_count":21,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30228974","id":"PMC_30228974","title":"Fourteen new mutations of BCKDHA, BCKDHB and DBT genes associated with maple syrup urine disease (MSUD) in Malaysian population.","date":"2018","source":"Molecular genetics and metabolism reports","url":"https://pubmed.ncbi.nlm.nih.gov/30228974","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18419263","id":"PMC_18419263","title":"A PER/TIM/DBT interval timer for Drosophila's circadian clock.","date":"2007","source":"Cold Spring Harbor symposia on quantitative biology","url":"https://pubmed.ncbi.nlm.nih.gov/18419263","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26453840","id":"PMC_26453840","title":"Eleven novel mutations of the BCKDHA, BCKDHB and DBT genes associated with maple syrup urine disease in the Chinese population: Report on eight cases.","date":"2015","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26453840","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27663817","id":"PMC_27663817","title":"CBT/DBT skills training for adults with attention deficit hyperactivity disorder (ADHD).","date":"2016","source":"Psychiatria Danubina","url":"https://pubmed.ncbi.nlm.nih.gov/27663817","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10604255","id":"PMC_10604255","title":"Evidence for a separate genetic origin of the partial D phenotype DBT in a Japanese family.","date":"1999","source":"Transfusion","url":"https://pubmed.ncbi.nlm.nih.gov/10604255","citation_count":16,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28417071","id":"PMC_28417071","title":"Twenty novel mutations in BCKDHA, BCKDHB and DBT genes in a cohort of 52 Saudi Arabian patients with maple syrup urine disease.","date":"2017","source":"Molecular genetics and metabolism reports","url":"https://pubmed.ncbi.nlm.nih.gov/28417071","citation_count":16,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26455500","id":"PMC_26455500","title":"PET imaging evaluation of [(18)F]DBT-10, a novel radioligand specific to α7 nicotinic acetylcholine receptors, in nonhuman primates.","date":"2015","source":"European journal of nuclear medicine and molecular imaging","url":"https://pubmed.ncbi.nlm.nih.gov/26455500","citation_count":16,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30881","id":"PMC_30881","title":"Physico-chemical properties of mouse hepatitis virus (MHV-2) grown on DBT cell culture.","date":"1978","source":"Microbiology and immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30881","citation_count":16,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25670924","id":"PMC_25670924","title":"Interaction of peroxiredoxin V with dihydrolipoamide branched chain transacylase E2 (DBT) in mouse kidney under hypoxia.","date":"2015","source":"Proteome science","url":"https://pubmed.ncbi.nlm.nih.gov/25670924","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"1889817","id":"PMC_1889817","title":"Regional assignment of two genes of the human branched-chain alpha-keto acid dehydrogenase complex: the E1 beta gene (BCKDHB) to chromosome 6p21-22 and the E2 gene (DBT) to chromosome 1p31.","date":"1991","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/1889817","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"14508502","id":"PMC_14508502","title":"Maple syrup urine disease in the Austronesian aboriginal tribe Paiwan of Taiwan: a novel DBT (E2) gene 4.7 kb founder deletion caused by a nonhomologous recombination between LINE-1 and Alu and the carrier-frequency determination.","date":"2003","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/14508502","citation_count":13,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30443799","id":"PMC_30443799","title":"Impact on mindfulness, emotion regulation, and emotional overeating of a DBT skills training group: a pilot study.","date":"2018","source":"Eating and weight disorders : EWD","url":"https://pubmed.ncbi.nlm.nih.gov/30443799","citation_count":12,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32624797","id":"PMC_32624797","title":"DBT desulfurization by decorating Rhodococcus erythropolis IGTS8 using magnetic Fe3O4 nanoparticles in a bioreactor.","date":"2016","source":"Engineering in life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32624797","citation_count":12,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20167346","id":"PMC_20167346","title":"CYP1A expression in liver and gills of rainbow trout (Oncorhynchus mykiss) after short-term exposure to dibenzothiophene (DBT).","date":"2010","source":"Chemosphere","url":"https://pubmed.ncbi.nlm.nih.gov/20167346","citation_count":9,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8593285","id":"PMC_8593285","title":"Characterization of DBT cell clones derived from cells persistently infected with the JHM strain of mouse hepatitis virus.","date":"1995","source":"The Journal of veterinary medical science","url":"https://pubmed.ncbi.nlm.nih.gov/8593285","citation_count":8,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10433090","id":"PMC_10433090","title":"Detection of anti-branched chain 2-oxo acid dehydrogenase complex (BCOADC)-E2 antibody in primary biliary cirrhosis by ELISA using recombinant fusion protein.","date":"1999","source":"Autoimmunity","url":"https://pubmed.ncbi.nlm.nih.gov/10433090","citation_count":6,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29306928","id":"PMC_29306928","title":"Four novel mutations of the BCKDHA, BCKDHB and DBT genes in Iranian patients with maple syrup urine disease.","date":"2018","source":"Journal of pediatric endocrinology & metabolism : JPEM","url":"https://pubmed.ncbi.nlm.nih.gov/29306928","citation_count":6,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25369245","id":"PMC_25369245","title":"DBT- and DBTO2-induced dysplasia and their associated proteomic alterations in the small intestines of Wistar rats.","date":"2014","source":"Journal of proteome research","url":"https://pubmed.ncbi.nlm.nih.gov/25369245","citation_count":5,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22583489","id":"PMC_22583489","title":"Oxidation of dibenzothiophene (DBT) by Serratia marcescens UCP 1549 formed biphenyl as final product.","date":"2012","source":"Biotechnology for biofuels","url":"https://pubmed.ncbi.nlm.nih.gov/22583489","citation_count":5,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35799415","id":"PMC_35799415","title":"Genomic and biochemical analysis of repeatedly observed variants in DBT in individuals with maple syrup urine disease of Central American ancestry.","date":"2022","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/35799415","citation_count":5,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16232847","id":"PMC_16232847","title":"Identification of the gene encoding a NAD(P)H-flavin oxidoreductase coupling with dibenzothiophene (DBT)-desulfurizing enzymes from the DBT-nondesulfurizing bacterium Paenibacillus polymyxa A-1.","date":"2000","source":"Journal of bioscience and bioengineering","url":"https://pubmed.ncbi.nlm.nih.gov/16232847","citation_count":5,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38305803","id":"PMC_38305803","title":"Underlying mechanisms of novel cuproptosis-related dihydrolipoamide branched-chain transacylase E2 (DBT) signature in sunitinib-resistant clear-cell renal cell carcinoma.","date":"2024","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/38305803","citation_count":5,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35657820","id":"PMC_35657820","title":"Pathogenic Homozygous Mutations in the DBT Gene (c.1174A>C) Result in Maple Syrup Urine Disease in a rs12021720 Carrier.","date":"2022","source":"Laboratory medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35657820","citation_count":4,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"6302351","id":"PMC_6302351","title":"Heterologous response of antiserum-treated cell clones from a persistently infected DBT cell line to mouse hepatitis virus.","date":"1982","source":"The Japanese journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/6302351","citation_count":4,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"2004553","id":"PMC_2004553","title":"Localization of the dihydrolipoamide branched-chain transacylase gene (DBT) of the human branched-chain keto acid dehydrogenase complex to chromosome 1.","date":"1991","source":"Cytogenetics and cell genetics","url":"https://pubmed.ncbi.nlm.nih.gov/2004553","citation_count":4,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33862173","id":"PMC_33862173","title":"Dibutyltin (DBT) inhibits in vitro androgen biosynthesis of rat immature Leydig cells.","date":"2021","source":"Toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/33862173","citation_count":4,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18022671","id":"PMC_18022671","title":"Dibenzothiophene oxidation by horseradish peroxidase in organic media: effect of the DBT:H2O2 molar ratio and H2O2 addition mode.","date":"2007","source":"Chemosphere","url":"https://pubmed.ncbi.nlm.nih.gov/18022671","citation_count":4,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35139068","id":"PMC_35139068","title":"DBT affects sleep in both circadian and non-circadian neurons.","date":"2022","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35139068","citation_count":3,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31830945","id":"PMC_31830945","title":"Case report: maple syrup urine disease with a novel DBT gene mutation.","date":"2019","source":"BMC pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/31830945","citation_count":3,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35959297","id":"PMC_35959297","title":"Impaired fasting glucose, oxidative distress, and cognitive impairment. Is this the starting point on DBT cognitive decline?","date":"2022","source":"Frontiers in aging neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/35959297","citation_count":3,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25939385","id":"PMC_25939385","title":"Drosophila DBT Autophosphorylation of Its C-Terminal Domain Antagonized by SPAG and Involved in UV-Induced Apoptosis.","date":"2015","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/25939385","citation_count":3,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23686744","id":"PMC_23686744","title":"Identification of aldolase and ferredoxin reductase within the dbt operon of Burkholderia fungorum DBT1.","date":"2013","source":"Journal of basic microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/23686744","citation_count":3,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36994075","id":"PMC_36994075","title":"Visual and circadian regulation of Drosophila BDBT and BDBT effects on DBT and PER localization.","date":"2023","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/36994075","citation_count":3,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39748703","id":"PMC_39748703","title":"Comparative analysis of biodesulfurization of dibenzothiophene (DBT) and 4,6-dimethyl dibenzothiophene (4,6-DMDBT) by 4S pathway using molecular simulations.","date":"2025","source":"Preparative biochemistry & biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/39748703","citation_count":2,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9873825","id":"PMC_9873825","title":"Expression of a recombinant branched chain alpha-oxo acid dehydrogenase complex E2 (BCOADC-E2) in insect cells and its immunoreactivity to autoimmune sera.","date":"1998","source":"Experimental & molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/9873825","citation_count":2,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39255192","id":"PMC_39255192","title":"DBT is a metabolic switch for maintenance of proteostasis under proteasomal impairment.","date":"2024","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/39255192","citation_count":2,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39769438","id":"PMC_39769438","title":"Probing the Effects of Multisite Mutations in the Lipoic Acid Region of the BCOADC-E2 Protein.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39769438","citation_count":1,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31683506","id":"PMC_31683506","title":"The Gas-Phase Formation Mechanism of Dibenzofuran (DBF), Dibenzothiophene (DBT), and Carbazole (CA) from Benzofuran (BF), Benzothiophene (BT), and Indole (IN) with Cyclopentadienyl Radical.","date":"2019","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31683506","citation_count":1,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34883003","id":"PMC_34883003","title":"Three novel mutations of the BCKDHA, BCKDHB and DBT genes in Chinese children with maple syrup urine disease.","date":"2021","source":"Journal of pediatric endocrinology & metabolism : JPEM","url":"https://pubmed.ncbi.nlm.nih.gov/34883003","citation_count":1,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"40932091","id":"PMC_40932091","title":"Boosting Dibenzothiophene Biodesulfurization Through Implantation of a Refactored DBT Pathway in a Tailored Pseudomonas putida Chassis.","date":"2025","source":"Microbial biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/40932091","citation_count":1,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37745492","id":"PMC_37745492","title":"DBT is a metabolic switch for maintenance of proteostasis under proteasomal impairment.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/37745492","citation_count":1,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"41086491","id":"PMC_41086491","title":"Exogenous DBT and overexpression of deoR improved the waste tire rubber desulfurization ability of a newly isolated Escherichia sp. strain.","date":"2025","source":"Journal of hazardous materials","url":"https://pubmed.ncbi.nlm.nih.gov/41086491","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"41749528","id":"PMC_41749528","title":"DBT-K for Adolescents: Feasibility and Preliminary Outcomes of a Creative Eight-Week, DBT-Based Transdiagnostic Skills Group.","date":"2026","source":"Children (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/41749528","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"41802175","id":"PMC_41802175","title":"Enhancing the Clinical Feasibility of Morita Therapy in China Through the Integration of ACT and DBT: A Theoretical Framework and Implementation Protocol.","date":"2026","source":"Journal of evaluation in clinical practice","url":"https://pubmed.ncbi.nlm.nih.gov/41802175","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39432007","id":"PMC_39432007","title":"[Pilot study on the effect of an effective anger management group based on Dialectical Behavior Therapy (DBT)].","date":"2024","source":"Vertex (Buenos Aires, Argentina)","url":"https://pubmed.ncbi.nlm.nih.gov/39432007","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9271448","id":"PMC_9271448","title":"Resistance to infection with mouse hepatitis virus (MHV) in the cell clones derived from persistently infected DBT cells with the JHM strain of MHV.","date":"1997","source":"The Journal of veterinary medical science","url":"https://pubmed.ncbi.nlm.nih.gov/9271448","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39908659","id":"PMC_39908659","title":"Alloanti-D induction in a rare RhD variant (DBT-2) case: Insights from serological and molecular biological testing.","date":"2025","source":"Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis","url":"https://pubmed.ncbi.nlm.nih.gov/39908659","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"41225620","id":"PMC_41225620","title":"The mediating role of social connectedness between inflexibility, the suppression of emotional expression, and symptoms of eating disorders and depression in adolescents with restrictive eating disorders referred for radically open dialectical behaviour therapy (RO DBT).","date":"2025","source":"Journal of eating disorders","url":"https://pubmed.ncbi.nlm.nih.gov/41225620","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":null,"id":"bio_10.1101_2025.11.18.25340531","title":"A protocol for MIndfulness-based Neurofeedback to augment DBT psychotherapy for adults with Borderline Personality Disorder (MIND-BPD)","date":"2025-11-19","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.18.25340531","citation_count":0,"is_preprint":true,"source_track":"pubmed_title"},{"pmid":null,"id":"bio_10.1101_2025.10.07.25337533","title":"Multilevel associations between skills use, engagement, and treatment outcome in self-guided internet-delivered dialectical behavior therapy for substance use disorders","date":"2025-10-09","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.07.25337533","citation_count":0,"is_preprint":true,"source_track":"pubmed_title"},{"pmid":null,"id":"bio_10.1101_2025.11.04.25339393","title":"Selective interoception impairments and treatment effects in Borderline Personality Disorder","date":"2025-11-06","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.04.25339393","citation_count":0,"is_preprint":true,"source_track":"pubmed_title"},{"pmid":null,"id":"bio_10.1101_2025.09.12.675962","title":"Response-optimised training improves learning of a complex motor task and closely related motor tasks","date":"2025-09-17","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.12.675962","citation_count":0,"is_preprint":true,"source_track":"pubmed_title"},{"pmid":null,"id":"bio_10.1101_2025.08.05.25333061","title":"Novel autoantibodies in patients with systemic sclerosis and gastrointestinal dysfunction provide insight into disease pathogenesis","date":"2025-08-07","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.05.25333061","citation_count":0,"is_preprint":true,"source_track":"pubmed_title"},{"pmid":null,"id":"bio_10.1101_2025.08.19.25334013","title":"Qualitative Review of a Dialectical Behavior Therapy – Skills Training Intervention for Cigarette Smoking by Patients with Cancer","date":"2025-08-24","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.19.25334013","citation_count":0,"is_preprint":true,"source_track":"pubmed_title"},{"pmid":null,"id":"bio_10.1101_2025.05.14.25327662","title":"Antidiabetic Activity of a Ghanaian Herbal Product, DBT-57A: An Observational Study","date":"2025-05-28","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.14.25327662","citation_count":0,"is_preprint":true,"source_track":"pubmed_title"},{"pmid":"12477932","id":"PMC_12477932","title":"Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12477932","citation_count":1479,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19615732","id":"PMC_19615732","title":"Defining the human deubiquitinating enzyme interaction landscape.","date":"2009","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/19615732","citation_count":1282,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26186194","id":"PMC_26186194","title":"The BioPlex Network: A Systematic Exploration of the Human Interactome.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26186194","citation_count":1118,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28514442","id":"PMC_28514442","title":"Architecture of the human interactome defines protein communities and disease networks.","date":"2017","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/28514442","citation_count":1085,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26496610","id":"PMC_26496610","title":"A human interactome in three quantitative dimensions organized by stoichiometries and abundances.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26496610","citation_count":1015,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14743216","id":"PMC_14743216","title":"A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway.","date":"2004","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/14743216","citation_count":841,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"17353931","id":"PMC_17353931","title":"Large-scale mapping of human protein-protein interactions by mass spectrometry.","date":"2007","source":"Molecular systems biology","url":"https://pubmed.ncbi.nlm.nih.gov/17353931","citation_count":733,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33961781","id":"PMC_33961781","title":"Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.","date":"2021","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/33961781","citation_count":705,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22939629","id":"PMC_22939629","title":"A census of human soluble protein complexes.","date":"2012","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/22939629","citation_count":689,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21873635","id":"PMC_21873635","title":"Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium.","date":"2011","source":"Briefings in bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/21873635","citation_count":656,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15489334","id":"PMC_15489334","title":"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).","date":"2004","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/15489334","citation_count":438,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26638075","id":"PMC_26638075","title":"A Dynamic Protein Interaction Landscape of the Human Centrosome-Cilium Interface.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26638075","citation_count":433,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16344560","id":"PMC_16344560","title":"Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes.","date":"2005","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/16344560","citation_count":409,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26344197","id":"PMC_26344197","title":"Panorama of ancient metazoan macromolecular complexes.","date":"2015","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/26344197","citation_count":407,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21642987","id":"PMC_21642987","title":"IFIT1 is an antiviral protein that recognizes 5'-triphosphate RNA.","date":"2011","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/21642987","citation_count":405,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"18063578","id":"PMC_18063578","title":"The layered structure of human mitochondrial DNA nucleoids.","date":"2007","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18063578","citation_count":340,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"34079125","id":"PMC_34079125","title":"A proximity-dependent biotinylation map of a human cell.","date":"2021","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/34079125","citation_count":339,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"27342126","id":"PMC_27342126","title":"Identification of Zika Virus and Dengue Virus Dependency Factors using Functional Genomics.","date":"2016","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/27342126","citation_count":306,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19167051","id":"PMC_19167051","title":"Importin 8 is a gene silencing factor that targets argonaute proteins to distinct mRNAs.","date":"2009","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/19167051","citation_count":281,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21532586","id":"PMC_21532586","title":"WWP2 is an E3 ubiquitin ligase for PTEN.","date":"2011","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/21532586","citation_count":266,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"35031058","id":"PMC_35031058","title":"EWSR1-induced circNEIL3 promotes glioma progression and exosome-mediated macrophage immunosuppressive polarization via stabilizing IGF2BP3.","date":"2022","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/35031058","citation_count":257,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"34800366","id":"PMC_34800366","title":"Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.","date":"2021","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/34800366","citation_count":239,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"27499296","id":"PMC_27499296","title":"Mitochondrial Protein Interaction Mapping Identifies Regulators of Respiratory Chain Function.","date":"2016","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/27499296","citation_count":220,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25281560","id":"PMC_25281560","title":"Proximity biotinylation and affinity purification are complementary approaches for the interactome mapping of chromatin-associated protein complexes.","date":"2014","source":"Journal of proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/25281560","citation_count":215,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28973437","id":"PMC_28973437","title":"Quantitative proteomics reveals that long non-coding RNA MALAT1 interacts with DBC1 to regulate p53 acetylation.","date":"2017","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/28973437","citation_count":148,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32877691","id":"PMC_32877691","title":"A High-Density Human Mitochondrial Proximity Interaction Network.","date":"2020","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/32877691","citation_count":148,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"31871319","id":"PMC_31871319","title":"Mapping the proximity interaction network of the Rho-family GTPases reveals signalling pathways and regulatory mechanisms.","date":"2019","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/31871319","citation_count":137,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"35140242","id":"PMC_35140242","title":"Human transcription factor protein interaction networks.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/35140242","citation_count":123,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28718761","id":"PMC_28718761","title":"The human cytoplasmic dynein interactome reveals novel activators of motility.","date":"2017","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/28718761","citation_count":118,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"18029348","id":"PMC_18029348","title":"Toward a confocal subcellular atlas of the human proteome.","date":"2007","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/18029348","citation_count":114,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":37314,"output_tokens":3491,"usd":0.082154},"stage2":{"model":"claude-opus-4-6","input_tokens":6877,"output_tokens":3309,"usd":0.175665},"total_usd":0.516035,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":49149,"output_tokens":5327,"usd":0.113676},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":8212,"output_tokens":2212,"usd":0.14454}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"DBT (Drosophila CKIε homolog) directly phosphorylates CLOCK (CLK) in vivo and in cultured Drosophila cells, causing its hyperphosphorylation, enhanced degradation, and modest inhibition of CLK-dependent transactivation; DBT functions in dynamic equilibrium with protein phosphatase 2A to balance hypo- and hyperphosphorylated CLK isoforms.\",\n      \"method\": \"Cultured Drosophila cell assays, in vivo phosphorylation analysis, circadian promoter transactivation assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (cell-based assays, in vivo analysis, transactivation assays) in a highly cited study\",\n      \"pmids\": [\"16603629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"DBT kinase activity is required for normal circadian rhythms; a kinase-dead DBT(K38R) mutant interacts with PER protein but lacks kinase activity, antagonizes PER phosphorylation and degradation, and dampens PER oscillation in vivo, demonstrating that reduced DBT kinase activity produces long periods or arrhythmicity rather than short periods.\",\n      \"method\": \"In vitro kinase assays with K38R mutation, cell culture overexpression, in vivo fly behavioral and molecular analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — active-site mutagenesis combined with in vitro assay and in vivo genetic analysis\",\n      \"pmids\": [\"17893330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"DBT directly phosphorylates the Drosophila clock protein PER at multiple specific sites; a DBT-directed phosphorylation switch at the per(S) mutation site (short-period allele) and neighboring residues controls PER stability and repressor function in an integrated fashion, with alternative phosphorylations of two adjoining motifs producing switch-like changes.\",\n      \"method\": \"In vitro phosphorylation assays with enzymatically active DBT, identification of phosphorylation sites, mutational analysis in cultured cells and in vivo\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct in vitro phosphorylation with site identification, mutagenesis, and in vivo validation\",\n      \"pmids\": [\"18666831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PER, TIM, and DBT form a physical complex that acts as a cytoplasmic interval timer; dynamic interactions among DBT, PER, and TIM regulate nuclear translocation timing, as observed by live cell video microscopy with GFP-tagged proteins in cultured Drosophila cells.\",\n      \"method\": \"Live cell video microscopy, GFP tagging, single-cell imaging of cultured Drosophila cells\",\n      \"journal\": \"Cold Spring Harbor symposia on quantitative biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct live-imaging localization study with functional context, single lab\",\n      \"pmids\": [\"18419263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"BRIDE OF DOUBLETIME (BDBT/CG17282), a noncanonical FK506-binding protein with an inactive peptidyl-prolyl isomerase domain, physically binds DBT and enhances DBT-dependent PER degradation; structural analysis showed BDBT uses tetratricopeptide repeats to promote larger protein complex assembly; BDBT accumulates rhythmically in PER- and DBT-dependent cytosolic foci in photoreceptors.\",\n      \"method\": \"Proteomic pulldown/mass spectrometry, RNAi knockdown, S2 cell overexpression assays, structural analysis, immunofluorescence\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including proteomics, structural analysis, genetic knockdown, and cell-based functional assays\",\n      \"pmids\": [\"24210908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"DBT undergoes C-terminal autophosphorylation at 6 serine/threonine residues identified by mass spectrometry; autophosphorylation regulates DBT turnover and electrophoretic mobility but is not required for circadian clock function; instead, DBT autophosphorylation protects cells from UV-induced apoptosis and is antagonized by the HSP-90 cochaperone spaghetti protein (SPAG).\",\n      \"method\": \"Mass spectrometry identification of phosphorylation sites, C-terminal truncation analysis, S2 cell overexpression and UV apoptosis assays, in vitro kinase assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mass spectrometry site identification plus mutagenesis, in vitro assays, and functional cell-based validation\",\n      \"pmids\": [\"25939385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DBT affects sleep in both circadian and non-circadian neurons; reduction of DBT in circadian neurons produces less sleep at night (adult-stage effect), while reduction in non-circadian neurons increases sleep during the day (developmental effect); PER protein is involved in DBT-mediated sleep regulation.\",\n      \"method\": \"CRISPR-Cas9 DBT-GAL4 knock-in, targeted RNAi in neuron subsets, behavioral sleep analysis in Drosophila\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis and neuron-specific knockdown with defined behavioral phenotypes, single lab\",\n      \"pmids\": [\"35139068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"BDBT is necessary for co-transport of DBT and PER into the nucleus; knockdown of BDBT specifically in the eye produced constitutively nuclear PER and constitutively cytosolic DBT; BDBT foci formation and nuclear translocation are regulated by light-dependent mechanisms involving CRYPTOCHROME and RHODOPSIN-1 pathways and rhodopsin-quenching arrestins.\",\n      \"method\": \"Targeted RNAi, immunofluorescence localization in Drosophila photoreceptors, genetic analysis of cry, ninaE, arr1, arr2 mutants\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockdown with direct localization readout, multiple genetic backgrounds tested, single lab\",\n      \"pmids\": [\"36994075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Peroxiredoxin V (Prdx V) interacts with DBT (dihydrolipoamide branched chain transacylase E2) in mouse kidney under hypoxia; the interaction is enhanced under hypoxic stress, the peroxidatic cysteine residue Cys48 of Prdx V is responsible for binding DBT, and hypoxic kidney exhibits altered DBT enzymatic activity compared to normoxia.\",\n      \"method\": \"Immunoprecipitation, nano-UPLC-MS shotgun proteomics, enzymatic activity assays, colocalization by immunofluorescence\",\n      \"journal\": \"Proteome science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP confirmed by mass spectrometry and enzymatic assay, but site identification by mutagenesis is limited, single lab\",\n      \"pmids\": [\"25670924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Loss of DBT (dihydrolipoamide branched chain transacylase E2) protects against proteasome inhibition-associated cell death by promoting clearance of ubiquitinated proteins; DBT loss alters metabolic and energetic status and activates autophagy via an AMPK-dependent mechanism; loss of DBT also protects against proteotoxicity from ALS-linked mutant TDP-43 in Drosophila and mammalian neurons.\",\n      \"method\": \"Genome-wide CRISPR screen, AMPK pathway analysis, autophagy assays, Drosophila and mammalian neuron TDP-43 toxicity models, metabolic profiling\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide unbiased screen confirmed with mechanistic follow-up (AMPK pathway, autophagy, cross-species validation), multiple orthogonal methods\",\n      \"pmids\": [\"39255192\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DBT (dihydrolipoamide branched chain transacylase E2) interacts with ANXA2 (annexin A2) through its lipoyl-binding domain; this interaction activates Hippo signaling, leading to decreased nuclear localization of YAP and transcriptional repression of lipogenic genes; METTL3-mediated m6A modification suppresses DBT expression in ccRCC.\",\n      \"method\": \"Immunoprecipitation, mass spectrometry, luciferase reporter assay, mutational studies, gain/loss-of-function assays in vitro and in vivo, nuclear fractionation\",\n      \"journal\": \"Cancer communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with domain mapping, reporter assay, and functional mutational analysis, single lab\",\n      \"pmids\": [\"36860124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"A nonsense mutation (E163*) in the DBT (E2) gene produces a truncated E2 subunit that cannot assemble into the normal 24-mer cubic structure of the BCKDH complex and is degraded in the cell; a 2-bp deletion causes a frameshift in the mitochondrial targeting presequence.\",\n      \"method\": \"Transfection of mutant constructs into E2-deficient MSUD cell line, cell biology analysis of protein assembly and stability\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct cell-based functional demonstration of assembly failure with defined mutations\",\n      \"pmids\": [\"8430702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A deletion of exon 2 (delEx2) in the human DBT gene results in absence of protein product in homozygous hepatocytes, and compound heterozygosity with p.Ser306Pro results in decreased protein; both variants cause accumulation of branched-chain amino acids and alpha-ketoacids in explanted hepatocytes, confirming loss of BCKDH complex function.\",\n      \"method\": \"Western blot, UPLC-tandem mass spectrometry of explanted hepatocytes\",\n      \"journal\": \"American journal of medical genetics. Part A\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct biochemical demonstration in patient-derived hepatocytes\",\n      \"pmids\": [\"35799415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Autoantibodies to BCOADC-E2 (DBT) in primary biliary cirrhosis recognize a conformational epitope within residues 1-227 of the mature protein that includes the lipoic acid binding region; the full-length protein (residues 1-421) is required to absorb all anti-BCOADC-E2 reactivity, and antibody binding is not dependent on the presence of lipoic acid.\",\n      \"method\": \"Immunoblotting, ELISA, selective absorption with expressed protein fragments spanning the full BCOADC-E2 sequence\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — systematic epitope mapping with recombinant fragments, multiple orthogonal methods, highly cited\",\n      \"pmids\": [\"7543435\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DBT (dihydrolipoamide branched chain transacylase E2) functions as the E2 subunit of the branched-chain alpha-ketoacid dehydrogenase (BCKDH) complex, where its lipoyl-binding domain is essential for complex assembly; in Drosophila, the orthologous DBT (DOUBLETIME/CKIε) kinase directly phosphorylates PER and CLK at defined sites to drive circadian feedback loop dynamics, acts in equilibrium with PP2A phosphatase, requires the co-factor BDBT for nuclear co-transport of DBT/PER, and undergoes SPAG-antagonized C-terminal autophosphorylation that regulates apoptosis; in mammalian cells, loss of DBT enzymatic activity activates AMPK-dependent autophagy to compensate for proteasomal impairment, and DBT interacts with ANXA2 to activate Hippo/YAP signaling and suppress lipogenesis.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll systematically classify each paper before extracting discoveries.\n\n**Classification:**\n\nThe canonical DBT gene is *dihydrolipoamide branched chain transacylase E2* (the E2 subunit of the BCKDH complex, involved in MSUD). However, \"DBT\" is also the symbol for Drosophila's *doubletime* kinase (CKIε ortholog). Both are legitimate KEEP targets — Drosophila DBT is a clear ortholog of vertebrate CKIε/δ and the papers describe conserved circadian kinase function.\n\n**KEEP:**\n- Papers about human DBT (BCKDH E2 subunit): [2], [7], [8], [18], [21], [23], [26], [29], [30], [31], [36], [37], [40], [41] (gene2pubmed), [42], [43], [45], [49], [55], [56], [57], [59], [61] (preprint of 56)\n- Papers about Drosophila DBT (doubletime kinase, CKIε ortholog): [1], [3], [4], [20], [22], [48], [51], [53]\n- gene2pubmed papers describing DBT protein interactions/localization: [3 (BioPlex)], [4 (BioPlex2)], [8 (BioPlex3)], [9], [16], [17], [22], [26 (mitochondrial BioID)], [30 (subcellular atlas)]\n\n**EXCLUDE (alias collisions or irrelevant):**\n- Papers about dibenzothiophene (chemical): [11], [13], [15], [17 (bacteria)], [33], [34], [38], [39], [41 (bacteria)], [47], [52], [54], [58], [60], [62]\n- Papers about DBT as dialectical behavior therapy: [6], [19], [24], [32], [50 (DBT2=diabetes)], [63], [64], [65], [68], [69], [70], [71], [72 (balance training)], [74], [75]\n- DBT as PET radioligand: [10], [27]\n- DBT as RhD blood group variant: [25], [67]\n- DBT as organotins (dibutyltin): [14], [16 (organotin)], [46]\n- MHV in DBT cell line (DBT = cell line name, not gene): [5], [12], [28], [35], [44], [66]\n- Papers about circNEIL3, MALAT1, etc. (alt-locus): gene2pubmed [21], [25]\n- General interactome/proteome papers (gene2pubmed) where DBT appears only as a detected protein: [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [18], [19], [20], [24], [27], [28], [29] — these are large-scale screens; I'll keep ones where DBT is specifically mentioned in context.\n\nLet me be more precise about gene2pubmed large-scale papers — these detected DBT as part of broad screens but contain no specific mechanistic findings about DBT itself. I'll exclude them as they add no DBT-specific discoveries.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"Drosophila DBT (doubletime, CKIε ortholog) directly phosphorylates and destabilizes the circadian transcription factor CLOCK (CLK) in a phase-specific manner in vivo, promoting CLK hyperphosphorylation and enhancing its degradation; DBT also evokes modest inhibition of CLK-dependent transactivation. DBT functions in dynamic equilibrium with protein phosphatase 2A to maintain balanced hypo- and hyperphosphorylated CLK isoforms, stabilizing CLK levels against stochastic fluctuations.\",\n      \"method\": \"In vivo genetic analysis in Drosophila, Drosophila S2 cell transfection assays, immunostaining for subcellular localization of CLK\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo and cell-based functional assays with multiple orthogonal readouts (phosphorylation, degradation, transcriptional activity, localization), replicated across contexts\",\n      \"pmids\": [\"16603629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Enzymatically active DBT kinase activity is required for normal circadian rhythms in Drosophila. A kinase-dead DBT(K38R) mutant interacts with PER but cannot phosphorylate it; expression of DBT(K38R) in flies antagonizes PER phosphorylation and degradation, dampens PER oscillation, and produces long circadian periods or arrhythmicity in proportion to titration of endogenous DBT activity.\",\n      \"method\": \"Site-directed mutagenesis (K38R) abolishing kinase activity, in vitro kinase assay, S2 cell transfection, transgenic fly behavioral analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinase assay with mutagenesis combined with in vivo genetic rescue and behavioral phenotyping\",\n      \"pmids\": [\"17893330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"DBT directly phosphorylates the Drosophila clock protein PER at specific sites. DBT-dependent phosphorylation at two adjoining sequence motifs acts in a switch-like manner to regulate PER stability and repressor function. The per(S) short-period mutation alters a key DBT phosphorylation target within PER, linking phosphorylation site identity to period length.\",\n      \"method\": \"In vitro kinase assay with purified proteins, phosphorylation site mapping by mutagenesis, S2 cell functional assays, in vivo behavioral analysis\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct in vitro phosphorylation with site-specific mutagenesis validated in cell culture and in vivo\",\n      \"pmids\": [\"18666831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PER, TIM, and DBT form physical interactions in Drosophila cells; live-cell imaging revealed dynamic patterns of DBT, PER, and TIM stability and localization consistent with a cytoplasmic interval timer that regulates nuclear translocation of PER and TIM once per day.\",\n      \"method\": \"Live-cell video microscopy with GFP-tagged proteins in cultured Drosophila cells, co-immunoprecipitation\",\n      \"journal\": \"Cold Spring Harbor symposia on quantitative biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — live imaging with GFP fusion proteins in single cells, consistent with in vivo data, but single lab\",\n      \"pmids\": [\"18419263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The non-canonical FK506-binding protein BRIDE OF DOUBLETIME (BDBT/CG17282) physically interacts with DBT kinase. BDBT enhances DBT-dependent PER degradation in S2 cells; RNAi knockdown of BDBT produces behavioral arrhythmicity and elevated hypophosphorylated nuclear PER and phosphorylated DBT. Structural analysis showed BDBT contains an inactive peptide prolyl-isomerase domain that binds DBT and tetratricopeptide repeats that may scaffold larger complexes.\",\n      \"method\": \"Proteomic identification of DBT interactors, reciprocal co-IP, RNAi knockdown with behavioral and molecular phenotyping, S2 cell overexpression assays, structural analysis\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — proteomic discovery combined with reciprocal co-IP, functional cell assays, in vivo genetic phenotyping, and structural analysis\",\n      \"pmids\": [\"24210908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Drosophila DBT undergoes C-terminal autophosphorylation at six serine/threonine residues identified by mass spectrometry. Mutation of these sites (DBT(C/ala)) prevents autophosphorylation-dependent DBT turnover in S2 cells. Unlike vertebrate CKIδ, DBT autophosphorylation does not reduce in vitro kinase activity and is not required for circadian clock function. However, DBT autophosphorylation is required for protection against UV-induced apoptosis: wild-type DBT protects S2 cells and larvae from UV-induced apoptosis and is degraded by the proteasome after UV exposure, while DBT(C/ala) does not protect. The HSP90 co-chaperone SPAG antagonizes DBT autophosphorylation in S2 cells.\",\n      \"method\": \"Mass spectrometry for phosphosite mapping, site-directed mutagenesis, in vitro kinase assay, S2 cell UV apoptosis assay, proteasome inhibitor studies, transgenic fly behavioral analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mass spectrometry-based site mapping combined with mutagenesis, in vitro and in vivo functional validation, multiple orthogonal assays\",\n      \"pmids\": [\"25939385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DBT (BDBT) foci in Drosophila eye photoreceptors require both CRYPTOCHROME and RHODOPSIN-1 visual photoreceptor pathways for light-induced disappearance; arrestin mutants (arr1, arr2) that affect rhodopsin quenching eliminated BDBT foci in darkness and caused increased nuclear PER. Knockdown of BDBT specifically in the eye produced constitutively nuclear PER and constitutively cytosolic DBT, demonstrating that BDBT is required for co-transport of DBT and PER into the nucleus.\",\n      \"method\": \"Genetic analysis with circadian and visual pathway mutants, tissue-specific RNAi knockdown, immunofluorescence localization\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis and immunofluorescence localization with functional consequence (nuclear PER changes), single lab\",\n      \"pmids\": [\"36994075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Reduction of DBT kinase in Drosophila circadian neurons increases sleep loss at night (via adult clock function), while reduction in non-circadian neurons produces increased daytime sleep (via developmental effects). PER protein is involved in DBT-mediated sleep regulation independently of the neuronal context.\",\n      \"method\": \"CRISPR-Cas9 knock-in of GAL4 at dbt locus, targeted RNAi in neuron subsets, sleep behavioral assays\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic manipulation with defined neuronal specificity and behavioral phenotyping, single lab\",\n      \"pmids\": [\"35139068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"Two novel loss-of-function mutations in the human DBT (E2) gene cause MSUD: a 2-bp (AT) deletion in exon 2 causing a frameshift in the mitochondrial targeting presequence, and a G-to-T nonsense mutation in exon 6 (E163*). Transfection of the E163* construct into an E2-deficient cell line showed that the truncated E2 protein cannot assemble into the native 24-mer cubic structure and is rapidly degraded, establishing the structural requirement for the cubic core in DBT protein stability.\",\n      \"method\": \"Site-directed mutation, transfection into E2-deficient MSUD cell line, protein assembly assay, degradation analysis\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cell-based reconstitution demonstrating failure of assembly and degradation of mutant E2, plus genetic characterization of patient alleles\",\n      \"pmids\": [\"8430702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Autoantibodies to BCOADC-E2 (DBT) in primary biliary cirrhosis recognize a conformational epitope located within amino acids 1–227 of the mature protein that includes the lipoic acid-binding region. Full-length protein (aa 1–421) is required to absorb all detectable anti-BCOADC-E2 reactivity. Antibody binding is not dependent on the presence of lipoic acid on the antigen.\",\n      \"method\": \"Immunoblotting, ELISA, and selective absorption of patient sera with defined recombinant protein fragments spanning the full DBT/BCOADC-E2 sequence\",\n      \"journal\": \"Hepatology (Baltimore, Md.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — systematic epitope mapping with multiple overlapping fragments and orthogonal serological methods, replicated across patient cohorts\",\n      \"pmids\": [\"7543435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"The human DBT gene (encoding the E2/transacylase subunit of the BCKDH complex) was localized to chromosome 1 by somatic cell hybrid analysis and regionally assigned to chromosome band 1p31 by in situ hybridization.\",\n      \"method\": \"Human × mouse somatic cell hybrid panel analysis with PCR-amplified E2 cDNA probe, in situ hybridization\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct chromosomal mapping by two independent methods (somatic cell hybrids and in situ hybridization)\",\n      \"pmids\": [\"1889817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Peroxiredoxin V (PrdxV) interacts with DBT (dihydrolipoamide branched chain transacylase E2) in mouse kidney under hypoxic stress. This interaction is enhanced under hypoxia compared to normoxia. Hypoxic conditions also increase DBT enzymatic activity. The peroxidatic cysteine residue (Cys48) of PrdxV is responsible for the interaction with DBT. Enhanced colocalization of PrdxV and DBT was observed in vitro under hypoxic conditions.\",\n      \"method\": \"Immunoprecipitation coupled with nano-UPLC-MS shotgun proteomics, comparative interactomics under normoxia vs. hypoxia, co-localization imaging, enzymatic activity assay\",\n      \"journal\": \"Proteome science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — mass spectrometry-based interactomics with enzymatic activity measurement, but functional consequence of interaction not deeply characterized\",\n      \"pmids\": [\"25670924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DBT (dihydrolipoamide branched chain transacylase E2) interacts with ANXA2 (annexin A2) through its lipoyl-binding domain to activate Hippo signaling, resulting in decreased nuclear localization of YAP and transcriptional repression of lipogenic genes. DBT downregulation in ccRCC is caused by METTL3-mediated m6A modification. DBT acts as a tumor suppressor by inhibiting tumor progression and correcting lipid metabolism disorder in ccRCC.\",\n      \"method\": \"Luciferase reporter assay, immunoprecipitation, mass spectrometry, mutational studies of the lipoyl-binding domain, gain/loss-of-function assays in vitro and in vivo\",\n      \"journal\": \"Cancer communications (London, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with domain mapping, mass spectrometry, and functional assays, single lab\",\n      \"pmids\": [\"36860124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Loss of DBT (dihydrolipoamide branched chain transacylase E2) protects against proteasome inhibition-associated cell death by promoting clearance of ubiquitinated proteins. Loss of DBT alters cellular metabolic and energetic status, activating autophagy through an AMPK-dependent mechanism when the proteasome is inhibited. DBT loss protects against proteotoxicity from ALS-linked mutant TDP-43 in both Drosophila and mammalian neurons. DBT is upregulated in ALS patient tissues, positioning it as a metabolic switch controlling protein quality control pathways.\",\n      \"method\": \"Genome-wide CRISPR screen, genetic loss-of-function in Drosophila and mammalian neurons, AMPK pathway activation assays, ubiquitinated protein clearance assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — genome-wide CRISPR screen identification combined with mechanistic pathway dissection (AMPK-autophagy axis) validated in multiple model systems\",\n      \"pmids\": [\"39255192\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The lipoyl domain of BCOADC-E2 (DBT) is critical for autoantibody recognition in primary biliary cholangitis. The folding conformation of the lipoyl β-sheet, specifically the glutamic acid at position 4 and isoleucine at position 13, are necessary for recognition by anti-BCOADC-E2 autoantibodies. Multi-site mutations of these residues reduce reactivity with patient sera, and EPR spectroscopy confirmed the conformational integrity of these positions is maintained in the wild-type protein.\",\n      \"method\": \"Site-directed mutagenesis of lipoyl domain, ELISA with patient sera, MTSSL spin-labeling and EPR spectroscopy\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1/2 — mutagenesis combined with structural EPR spectroscopy and serological validation, single lab\",\n      \"pmids\": [\"39769438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Homozygous deletion of exon 2 (delEx2) of the DBT gene results in complete absence of DBT protein in hepatocytes (confirmed by Western blot), while compound heterozygous delEx2/p.Ser306Pro produces decreased DBT protein. Both variants cause failure of branched-chain amino acid catabolism, with accumulation of branched-chain amino acids and alpha-ketoacids in explanted hepatocytes demonstrated by UPLC-MS/MS, establishing the functional requirement of the DBT E2 subunit for BCKDH complex activity.\",\n      \"method\": \"Western blot of patient-derived liver cells, UPLC-tandem mass spectrometry of hepatocyte metabolites, Sanger sequencing\",\n      \"journal\": \"American journal of medical genetics. Part A\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct protein-level confirmation with functional metabolic assay in patient-derived cells\",\n      \"pmids\": [\"35799415\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Human DBT (dihydrolipoamide branched chain transacylase E2) is the E2 core subunit of the mitochondrial BCKDH complex that catalyzes branched-chain α-ketoacid catabolism via its lipoyl-binding domain; loss-of-function mutations cause MSUD by preventing BCKDH complex assembly and activity; DBT also functions as a metabolic switch that, when lost, activates AMPK-dependent autophagy to compensate for proteasomal impairment and protect against proteotoxicity in ALS models, and in ccRCC its lipoyl-binding domain engages ANXA2 to activate Hippo/YAP signaling and suppress lipogenesis; the Drosophila ortholog Doubletime (DBT/CKIε) directly phosphorylates PER and CLK at defined sites to drive circadian feedback loop dynamics, with its activity regulated by autophosphorylation, the co-chaperone SPAG, and the scaffold protein BDBT which facilitates nuclear co-transport of DBT and PER.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"DBT encodes the E2 (dihydrolipoamide branched chain transacylase) subunit of the mitochondrial branched-chain alpha-ketoacid dehydrogenase (BCKDH) complex, where its lipoyl-binding domain is essential for 24-mer core assembly, branched-chain amino acid catabolism, and interaction with ANXA2 to activate Hippo/YAP signaling and suppress lipogenesis [PMID:8430702, PMID:35799415, PMID:36860124]. Loss of DBT enzymatic activity alters cellular metabolic and energetic status, activating AMPK-dependent autophagy that compensates for proteasomal impairment and protects against proteotoxicity from ALS-linked mutant TDP-43 in both Drosophila and mammalian neurons [PMID:39255192]. Mutations in DBT cause maple syrup urine disease (MSUD) type II, as nonsense and frameshift mutations produce truncated E2 subunits that fail to assemble into the BCKDH complex and are degraded, while compound heterozygous loss-of-function variants cause accumulation of branched-chain amino acids and alpha-ketoacids in patient hepatocytes [PMID:8430702, PMID:35799415]. DBT is also a major autoantigen in primary biliary cirrhosis, where autoantibodies recognize a conformational epitope within the lipoic acid-binding region of the mature protein [PMID:7543435].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Establishing that DBT E2 mutations cause BCKDH assembly failure resolved a key question about how loss-of-function at the E2 subunit produces maple syrup urine disease: truncated E2 cannot form the 24-mer core and is degraded.\",\n      \"evidence\": \"Transfection of nonsense (E163*) and frameshift mutant constructs into E2-deficient MSUD cell lines with protein assembly analysis\",\n      \"pmids\": [\"8430702\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural resolution of the 24-mer assembly interface\",\n        \"Only two mutations characterized; spectrum of pathogenic variants not established\"\n      ]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Mapping the autoantibody epitope in primary biliary cirrhosis to the lipoyl-binding region (residues 1–227) of DBT established that this domain is an immunodominant target, independent of lipoic acid attachment.\",\n      \"evidence\": \"Immunoblotting, ELISA, and selective absorption with recombinant protein fragments spanning the full BCOADC-E2 sequence\",\n      \"pmids\": [\"7543435\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which tolerance to DBT is broken in PBC is unknown\",\n        \"Whether autoantibody binding affects BCKDH enzymatic function in vivo is not addressed\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Studies from 2006–2008 demonstrated that Drosophila DBT (CKIε/DOUBLETIME) directly phosphorylates the clock proteins PER and CLK at defined sites, with a phosphorylation switch at the per(S) site controlling PER stability and repressor function, while DBT acts in dynamic equilibrium with PP2A to regulate CLK isoform balance.\",\n      \"evidence\": \"In vitro kinase assays with site identification, kinase-dead K38R mutagenesis, cell-based transactivation and phosphorylation assays, in vivo fly behavioral and molecular analysis\",\n      \"pmids\": [\"16603629\", \"17893330\", \"18666831\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis for substrate recognition by DBT kinase domain not resolved\",\n        \"Quantitative kinetics of the DBT-PP2A equilibrium on CLK not measured\"\n      ]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Live imaging of PER/TIM/DBT complexes showed these proteins form a cytoplasmic interval timer whose dynamic interactions regulate nuclear translocation timing, providing a cell-biological framework for the Drosophila circadian delay.\",\n      \"evidence\": \"Live cell video microscopy with GFP-tagged proteins in cultured Drosophila cells\",\n      \"pmids\": [\"18419263\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single imaging system in cultured cells; not confirmed in intact clock neurons\",\n        \"Stoichiometry and structure of the PER/TIM/DBT complex not determined\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identification of BDBT as a dedicated DBT cofactor that uses TPR repeats to scaffold DBT-dependent PER degradation answered how DBT activity is organized into cytosolic foci and amplified in clock cells.\",\n      \"evidence\": \"Proteomic pulldown/mass spectrometry, RNAi knockdown, S2 cell overexpression, structural analysis, immunofluorescence in Drosophila photoreceptors\",\n      \"pmids\": [\"24210908\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Atomic-resolution structure of the DBT–BDBT interface not available\",\n        \"Whether BDBT ortholog exists in mammalian clock is unknown\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Discovery that DBT undergoes C-terminal autophosphorylation at six sites—antagonized by the HSP-90 cochaperone SPAG—separated DBT's clock function from a distinct role in UV-induced apoptosis protection.\",\n      \"evidence\": \"Mass spectrometry site identification, C-terminal truncation analysis, S2 cell UV apoptosis assays, in vitro kinase assays\",\n      \"pmids\": [\"25939385\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Downstream apoptotic pathway targets of autophosphorylated DBT not identified\",\n        \"Whether SPAG regulation of DBT autophosphorylation occurs in mammalian CKIε is untested\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstration that Peroxiredoxin V interacts with DBT E2 under hypoxia via its peroxidatic Cys48 and modulates BCKDH enzymatic activity linked DBT to redox-sensitive metabolic regulation in kidney.\",\n      \"evidence\": \"Immunoprecipitation, nano-UPLC-MS shotgun proteomics, enzymatic activity assays, and colocalization by immunofluorescence in mouse kidney\",\n      \"pmids\": [\"25670924\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No reciprocal validation or structural characterization of the Prdx V–DBT interface\",\n        \"Functional consequence of altered DBT activity under hypoxia for BCAA metabolism not measured\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Neuron-subset-specific DBT knockdown in Drosophila separated circadian from non-circadian sleep roles: DBT in clock neurons regulates nighttime sleep (adult effect), while DBT in non-clock neurons regulates daytime sleep (developmental effect).\",\n      \"evidence\": \"CRISPR-Cas9 DBT-GAL4 knock-in, targeted RNAi, behavioral sleep analysis\",\n      \"pmids\": [\"35139068\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Molecular substrates of DBT in non-circadian sleep-regulating neurons are unknown\",\n        \"Developmental mechanism by which DBT loss increases daytime sleep is uncharacterized\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Biochemical analysis of patient-derived hepatocytes carrying DBT exon 2 deletion and S306P variants confirmed that compound heterozygous loss of DBT protein causes BCAA and alpha-ketoacid accumulation, directly linking genotype to metabolite phenotype in MSUD type II.\",\n      \"evidence\": \"Western blot and UPLC-tandem mass spectrometry of explanted patient hepatocytes\",\n      \"pmids\": [\"35799415\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether residual E2 activity in S306P heterozygotes supports partial complex assembly is not assessed\",\n        \"Only hepatocytes studied; tissue-specific metabolic consequences not explored\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"BDBT was shown to be necessary for co-transport of DBT and PER into the nucleus, with light-input pathways (CRY, Rh1, arrestins) controlling BDBT foci dynamics—resolving how DBT nuclear entry is gated by light.\",\n      \"evidence\": \"Targeted RNAi and immunofluorescence localization in Drosophila photoreceptors, genetic analysis of cry, ninaE, arr1, arr2 mutants\",\n      \"pmids\": [\"36994075\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single tissue (photoreceptors); generality to pacemaker neurons not tested\",\n        \"Molecular mechanism of light-dependent BDBT foci formation not resolved\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identification of the DBT–ANXA2 interaction via the lipoyl-binding domain, which activates Hippo signaling to suppress YAP nuclear localization and lipogenesis, uncovered a non-metabolic signaling role for the E2 subunit in cancer cells.\",\n      \"evidence\": \"Reciprocal Co-IP with domain mapping, luciferase reporter, gain/loss-of-function in vitro and xenograft, nuclear fractionation in ccRCC models\",\n      \"pmids\": [\"36860124\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether DBT–ANXA2 interaction occurs in non-cancer tissues is unknown\",\n        \"Structural basis for lipoyl domain recognition of ANXA2 not determined\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"A genome-wide CRISPR screen revealed that DBT loss activates AMPK-dependent autophagy to clear ubiquitinated proteins when the proteasome is impaired, and this mechanism protects against TDP-43 proteotoxicity across species—establishing a metabolic-to-proteostasis link.\",\n      \"evidence\": \"Genome-wide CRISPR screen, AMPK pathway analysis, autophagy assays, Drosophila and mammalian neuron TDP-43 models, metabolic profiling\",\n      \"pmids\": [\"39255192\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Precise metabolite(s) linking BCKDH loss to AMPK activation not identified\",\n        \"Therapeutic potential of DBT inhibition for neurodegeneration is unexplored in mammalian in vivo models\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of DBT E2 24-mer assembly and its interface with ANXA2, the identity of the metabolite signal linking BCKDH loss to AMPK activation, and whether DBT's non-metabolic signaling roles (Hippo pathway, apoptosis protection) are physiologically relevant in normal tissues.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No high-resolution structure of the human DBT E2 24-mer core\",\n        \"Metabolic intermediate linking BCKDH loss to AMPK activation not identified\",\n        \"Physiological significance of DBT–ANXA2/Hippo axis outside cancer is untested\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [8, 11, 12]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [8, 9, 11, 12]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [11, 12, 13]}\n    ],\n    \"complexes\": [\n      \"BCKDH complex (branched-chain alpha-ketoacid dehydrogenase)\"\n    ],\n    \"partners\": [\n      \"ANXA2\",\n      \"PRDX5\",\n      \"BDBT\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"DBT encodes the dihydrolipoamide branched-chain transacylase (E2) core subunit of the mitochondrial branched-chain α-keto acid dehydrogenase (BCKDH) complex, which catalyzes an essential step in branched-chain amino acid catabolism; its 24-meric cubic core structure is required for complex assembly, and truncating mutations cause rapid E2 degradation and loss of BCKDH activity, resulting in maple syrup urine disease (MSUD) [PMID:8430702, PMID:35799415]. Beyond its canonical metabolic role, the DBT lipoyl-binding domain engages ANXA2 to activate Hippo/YAP signaling and suppress lipogenesis in clear-cell renal cell carcinoma, functioning as a tumor suppressor [PMID:36860124]. Loss of DBT shifts cellular energy status to activate AMPK-dependent autophagy, compensating for proteasomal impairment and protecting against TDP-43 proteotoxicity in ALS models across Drosophila and mammalian neurons [PMID:39255192]. The lipoyl domain is also the principal conformational epitope recognized by autoantibodies in primary biliary cholangitis [PMID:7543435, PMID:39769438].\",\n  \"teleology\": [\n    {\n      \"year\": 1991,\n      \"claim\": \"Chromosomal mapping of DBT to 1p31 established its genomic context and enabled subsequent mutation screening in MSUD families.\",\n      \"evidence\": \"Somatic cell hybrid analysis and in situ hybridization in human cells\",\n      \"pmids\": [\"1889817\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No functional characterization performed at this stage\", \"Regulatory elements not defined\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Demonstration that truncating DBT mutations prevent assembly of the 24-mer E2 cubic core and cause rapid protein degradation established the structural basis of MSUD pathogenesis.\",\n      \"evidence\": \"Transfection of mutant E2 constructs into E2-deficient MSUD cell line with assembly and degradation assays\",\n      \"pmids\": [\"8430702\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Only two mutations characterized; spectrum of pathogenic variants not surveyed\", \"No rescue experiment with wild-type cDNA reported\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Mapping of the conformational autoantibody epitope to the N-terminal lipoyl-binding region (aa 1–227) of DBT linked this domain to autoimmune recognition in primary biliary cirrhosis, independent of lipoic acid attachment.\",\n      \"evidence\": \"ELISA and immunoblot absorption with recombinant domain fragments against PBC patient sera\",\n      \"pmids\": [\"7543435\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which tolerance to this epitope is broken remains unknown\", \"No structural resolution of the antibody–antigen interface\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identification of a hypoxia-enhanced interaction between peroxiredoxin V and DBT, with increased DBT enzymatic activity under hypoxia, suggested redox-dependent regulation of BCKDH activity.\",\n      \"evidence\": \"Immunoprecipitation–mass spectrometry interactomics in mouse kidney under normoxia versus hypoxia, enzymatic activity assay\",\n      \"pmids\": [\"25670924\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the PrdxV–DBT interaction on BCAA catabolism not established\", \"Interaction not validated by reciprocal pulldown or in additional tissues\", \"Mechanism linking Cys48 of PrdxV to DBT activity unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Patient-derived hepatocyte studies confirmed that complete loss or reduction of DBT protein abolishes BCKDH complex activity and causes accumulation of branched-chain amino acids and α-ketoacids, directly linking genotype to metabolic phenotype at the cellular level.\",\n      \"evidence\": \"Western blot of patient liver cells with homozygous exon 2 deletion and compound heterozygous mutations, UPLC-MS/MS metabolite profiling\",\n      \"pmids\": [\"35799415\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No BCKDH complex assembly assay performed on these specific alleles\", \"Residual E2 protein from the Ser306Pro allele not functionally characterized in isolation\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Discovery that the DBT lipoyl-binding domain interacts with ANXA2 to activate Hippo signaling and repress YAP-driven lipogenic transcription revealed a non-canonical tumor-suppressive role for DBT in ccRCC, with its downregulation mediated by METTL3-dependent m6A modification.\",\n      \"evidence\": \"Co-IP with lipoyl domain mutants, mass spectrometry, luciferase reporters, and gain/loss-of-function assays in ccRCC models in vitro and in vivo\",\n      \"pmids\": [\"36860124\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding; independent replication needed\", \"Structural basis of lipoyl domain–ANXA2 interaction unresolved\", \"Extent of this mechanism in other cancer types unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"A genome-wide CRISPR screen revealed that DBT loss activates AMPK-dependent autophagy to compensate for proteasomal impairment, protecting against proteotoxicity from ALS-linked mutant TDP-43 across species, repositioning DBT as a metabolic switch governing protein quality control.\",\n      \"evidence\": \"CRISPR screen in mammalian cells, genetic loss-of-function in Drosophila and mammalian neurons, AMPK pathway and ubiquitinated protein clearance assays\",\n      \"pmids\": [\"39255192\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise metabolite(s) linking DBT loss to AMPK activation not identified\", \"Whether this protective mechanism operates in human ALS patients is untested\", \"Potential detrimental effects of chronic DBT loss on BCAA metabolism not addressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Fine-mapping of the autoantibody epitope in PBC to specific residues (Glu4, Ile13) in the lipoyl β-sheet of DBT, with structural validation by EPR spectroscopy, refined understanding of conformational determinants of autoimmune recognition.\",\n      \"evidence\": \"Site-directed mutagenesis of lipoyl domain, ELISA with PBC patient sera, MTSSL spin-labeling and EPR spectroscopy\",\n      \"pmids\": [\"39769438\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Crystal structure of the autoantibody–lipoyl domain complex not solved\", \"Whether these residues drive pathogenic T-cell responses is unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The metabolic signals linking DBT loss to AMPK activation and the structural basis of DBT's interaction with ANXA2 in Hippo pathway regulation remain undefined, as does whether the proteotoxicity-protective mechanism of DBT loss can be therapeutically exploited without disrupting BCAA homeostasis.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of full-length human DBT in complex context\", \"Metabolite mediator of DBT loss → AMPK axis not identified\", \"Therapeutic window for DBT modulation unexplored\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [8, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [8, 15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [8, 15, 11]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [8, 9, 14, 15]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"complexes\": [\n      \"BCKDH complex (branched-chain α-keto acid dehydrogenase complex)\"\n    ],\n    \"partners\": [\n      \"ANXA2\",\n      \"PRDX5\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}