{"gene":"PLEC","run_date":"2026-04-28T19:45:44","timeline":{"discoveries":[{"year":1996,"finding":"Plectin (encoded by PLEC1) is required for attachment of intermediate keratin filament networks to hemidesmosomal complexes in skin and for structural integrity of sarcolemma in muscle; homozygous deletion mutations in PLEC1 cause epidermolysis bullosa simplex with muscular dystrophy (EBS-MD), demonstrating plectin's critical role as a cytoskeleton-membrane anchorage protein in both epithelia and muscle.","method":"Immunofluorescence with anti-plectin antibody (HD-1), mutation analysis (sequencing of PLEC1 cDNA/genomic DNA), electron microscopy of patient skin","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — multiple independent patient families, replicated across labs in same year; loss-of-function mutations correlated with defined structural phenotypes in skin and muscle","pmids":["8894687","8941634","8696340"],"is_preprint":false},{"year":1996,"finding":"Absence of plectin in muscle fibers leads to aberrant localization of desmin, indicating plectin normally anchors desmin-containing intermediate filaments to the sarcolemma; a homozygous nonsense mutation in PLEC1 causes decay of aberrant plectin mRNA and loss of plectin protein.","method":"Immunofluorescence with plectin and desmin antibodies on patient muscle biopsies; RT-PCR and sequencing to detect nonsense-mediated mRNA decay","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — direct immunofluorescence demonstrating desmin mislocalization as consequence of plectin loss; corroborated by molecular analysis","pmids":["8941634"],"is_preprint":false},{"year":1998,"finding":"Plectin and its isoforms function as versatile cytoskeletal linker proteins that bind to subcomponents of all three major cytoskeletal filament networks (intermediate filaments, actin, microtubules), the subplasma membrane protein skeleton, and plasma membrane-cytoskeleton junctional complexes; plectin-deficient mice generated by targeted gene inactivation die shortly after birth with severe defects in skin, skeletal muscle, and heart, and cells derived from these animals reveal an essential role for plectin as a regulator of actin stress fiber dynamics.","method":"Gene knockout (targeted inactivation), in vitro cell studies of plectin-null cells, biochemical binding studies","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — plectin-null mouse model with defined phenotypic readouts plus in vitro functional studies; comprehensive review of primary data","pmids":["9701547"],"is_preprint":false},{"year":2003,"finding":"Plectin was identified as a component that forms specific complexes with activated EGFR-Shc signaling complexes upon EGF stimulation; this was revealed by SILAC-based quantitative proteomics showing selective enrichment of plectin in Grb2-SH2 affinity purifications from EGF-stimulated cells, linking plectin to receptor tyrosine kinase signaling.","method":"SILAC quantitative proteomics, GST-SH2 affinity purification from EGF-stimulated vs. unstimulated HeLa cells","journal":"Nature biotechnology","confidence":"Medium","confidence_rationale":"Tier 3 — single affinity purification/MS experiment identifying plectin as a differential interactor; mechanistic follow-up not detailed","pmids":["12577067"],"is_preprint":false},{"year":2005,"finding":"Plectin is a target of ISG15 conjugation in IFN-β-treated human cells, placing it within the ISG15-modified proteome that mediates innate immune responses.","method":"Double-affinity purification of ISG15-modified proteins from IFN-β-treated HeLa cells followed by mass spectrometry identification","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Low","confidence_rationale":"Tier 3 — single MS identification from large-scale screen; no mechanistic follow-up specific to plectin","pmids":["16009940"],"is_preprint":false},{"year":2007,"finding":"Spliceosome-mediated RNA trans-splicing (SMaRT) using a 5' pre-trans-splicing molecule encoding wild-type PLEC1 exons 2–9 specifically replaces the mutated 5' portion of the endogenous PLEC1 transcript in EBS-MD fibroblasts, reduces mutant mRNA levels, and restores wild-type plectin expression pattern, demonstrating that the dominant-negative leucine insertion in exon 9 causes plectin peptide chain aggregation and protein degradation.","method":"Transient transfection and retroviral transduction of EBS-MD fibroblasts with pre-trans-splicing molecules; immunofluorescence microscopy; Western blot quantification of plectin protein","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 — direct functional rescue experiment demonstrating mechanistic consequence of exon 9 mutation (aggregation and degradation); single lab","pmids":["17989727"],"is_preprint":false},{"year":2010,"finding":"A homozygous mutation in exon 1f of PLEC, which is isoform-specific to plectin isoform 1f (P1f), causes autosomal-recessive limb-girdle muscular dystrophy (LGMD2Q) without dermatological involvement; P1f deficiency breaks the linkage between the sarcolemma and sarcomere, resulting in ultrastructural alterations including membrane duplications, enlarged space between membrane and sarcomere, and Z-disk misalignment.","method":"SNP array homozygosity mapping, PLEC sequencing, RT-PCR/qRT-PCR for P1f mRNA expression, immunofluorescence of patient muscle, transmission electron microscopy","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 — isoform-specific mutation with direct ultrastructural demonstration of sarcolemma-sarcomere linkage defect; multiple orthogonal methods in multiple families","pmids":["21109228"],"is_preprint":false},{"year":2015,"finding":"A nonsense mutation in exon 1a of PLEC, disrupting only plectin isoform 1a (P1a), causes autosomal-recessive skin-only EBS without extracutaneous involvement; P1a is dominantly expressed in epidermal basal cell layer and cultured keratinocytes, and its specific loss leads to hypoplastic hemidesmosomes and intra-epidermal cleavage while sparing heart and muscle that express other isoforms.","method":"DNA sequencing, immunofluorescence antigen mapping, transmission electron microscopy, Western blot, qRT-PCR on patient skin and cultured keratinocytes, control myocardium, and striated muscle","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — isoform-specific loss-of-function with tissue expression profiling and ultrastructural confirmation; multiple orthogonal methods","pmids":["25712130"],"is_preprint":false},{"year":2021,"finding":"KRT8 (keratin 8) physically interacts with PLEC (plectin) to connect KRT8 to mitochondria; PLEC anchors mitochondria and mediates physical association with KRT8, facilitating mitochondrial fission-mediated mitophagy. Under oxidative stress, KRT8 phosphorylation diminishes this PLEC-anchoring association, impairing efficient mitophagy and leading to accumulation of damaged mitochondria and necrotic cell death in retinal pigment epithelial cells.","method":"Co-immunoprecipitation (KRT8-PLEC physical interaction), live-cell imaging, mitophagy flux assays, siRNA knockdown of KRT8 and PLEC, mitochondrial morphology/fission analysis, oxidative stress treatment","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal co-IP demonstrating KRT8-PLEC interaction with functional mitophagy readout; single lab","pmids":["33783309"],"is_preprint":false},{"year":2024,"finding":"ΔNp63α directly transactivates PLEC expression in esophageal squamous cell carcinoma (ESCC); PLEC competitively interacts with KEAP1, displacing NRF2 from the KEAP1 complex and enabling NRF2 nuclear translocation and activation of ROS-eliminating genes, thereby conferring radioresistance. Radiotherapy-induced ROS further activates ΔNp63α via NRF2, forming a positive feedback loop (ΔNp63α/PLEC/NRF2 axis).","method":"Chromatin immunoprecipitation (ΔNp63α binding to PLEC promoter), co-immunoprecipitation (PLEC-KEAP1 interaction), subcellular fractionation/immunofluorescence of NRF2 localization, PLEC overexpression/knockdown with ROS measurement, nude mouse xenograft radiosensitivity assay with NRF2 inhibitor","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP, Co-IP, and functional rescue experiments in vitro and in vivo; single lab study","pmids":["39500864"],"is_preprint":false},{"year":2023,"finding":"Plectin knockdown in inner ear (zebrafish/mouse model) reduces synaptic mitochondrial potential and causes loss of ribbon synapses, indicating a role for plectin in maintaining neuronal/synaptic function in the cochlea; novel biallelic PLEC variants cause hearing loss in humans without skin or muscle involvement.","method":"Trio whole-exome sequencing, developmental expression analysis in mice and zebrafish, siRNA knockdown of plectin in inner ear with mitochondrial membrane potential assay and ribbon synapse quantification by immunofluorescence","journal":"Hearing research","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo knockdown with defined synaptic and mitochondrial functional phenotype; single lab","pmids":["37393735"],"is_preprint":false},{"year":2020,"finding":"Plectin knockdown (via CRISPR/Cas9) in mesenchymal stem cells impacts Wnt signalling, glycosaminoglycan biosynthesis, and immune regulation pathways as revealed by RNA-sequencing, suggesting plectin modulates intracellular signaling responses to mechanical stimuli in joint tissues.","method":"CRISPR/Cas9 plectin knockdown in MSC line followed by RNA-sequencing pathway analysis","journal":"Osteoarthritis and cartilage","confidence":"Low","confidence_rationale":"Tier 3 — transcriptomic pathway analysis after knockdown; no direct mechanistic dissection of signaling pathway placement","pmids":["32580029"],"is_preprint":false},{"year":2024,"finding":"EpOMEs (epoxyoctadecenoic acids) upregulate PLEC expression in triple-negative breast cancer cells; upregulated PLEC in turn activates NFκB1, which transcriptionally regulates CXCL9, thereby promoting tumor growth and metastasis. PLEC knockdown inhibited EpOME-mediated promotion of TNBC, placing PLEC upstream of NFκB1/CXCL9 in this oncogenic signaling axis.","method":"Transcriptomics and proteomics after EpOME treatment, PLEC/CXCL9 siRNA knockdown, CYP2J2 overexpression/knockdown, in vivo xenograft and lung metastasis assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (transcriptomics, proteomics, functional knockdown in vitro and in vivo) placing PLEC in a defined signaling pathway; single lab","pmids":["39695149"],"is_preprint":false},{"year":2011,"finding":"Plectin was identified as a component of the myosin-II-responsive focal adhesion proteome; its abundance in focal adhesions is enhanced by myosin II-mediated contractility, linking plectin to mechanosensing at focal adhesions.","method":"Proteomic analysis of isolated focal adhesions by mass spectrometry comparing myosin II-inhibited vs. control cells (blebbistatin treatment)","journal":"Nature cell biology","confidence":"Low","confidence_rationale":"Tier 3 — large-scale proteomic screen identifying plectin as a focal adhesion component; no specific mechanistic follow-up for plectin","pmids":["21423176"],"is_preprint":false}],"current_model":"Plectin (PLEC) is a large cytoskeletal linker protein that crosslinks intermediate filaments (keratins, desmin, vimentin) to hemidesmosomes, the sarcolemma, and other membrane-cytoskeleton junctions; loss-of-function mutations in isoform-specific or common exons cause tissue-restricted or multisystem disease (EBS, muscular dystrophy, LGMD) by disrupting these structural anchoring functions, while mechanistically plectin also regulates actin stress fiber dynamics, anchors mitochondria to facilitate KRT8-mediated mitophagy, competes with KEAP1 for NRF2 binding to modulate oxidative stress responses, and participates in NFκB1/CXCL9 signaling downstream of lipid mediators."},"narrative":{"teleology":[{"year":1996,"claim":"Identification of PLEC as the gene mutated in EBS-MD established that plectin is an essential cytoskeleton–membrane anchoring protein in both skin and muscle, resolving the molecular basis of combined epidermal fragility and muscular dystrophy.","evidence":"Mutation analysis, immunofluorescence, and electron microscopy in patient skin and muscle biopsies from multiple families","pmids":["8894687","8941634","8696340"],"confidence":"High","gaps":["Mechanism by which plectin couples intermediate filaments to hemidesmosomal transmembrane proteins was not structurally resolved","Contribution of individual plectin isoforms to tissue-specific phenotypes was unknown"]},{"year":1998,"claim":"Plectin-null mice revealed that plectin binds all three major cytoskeletal networks and regulates actin stress fiber dynamics, expanding its role from a passive linker to an active regulator of cytoskeletal organization.","evidence":"Targeted gene inactivation in mice; phenotypic analysis and in vitro cell studies from plectin-null cells","pmids":["9701547"],"confidence":"High","gaps":["Molecular mechanism of actin stress fiber regulation by plectin was not dissected","Relative contributions of intermediate filament anchoring versus actin regulation to the lethal phenotype were not separated"]},{"year":2010,"claim":"Isoform-specific mutations demonstrated that plectin isoform 1f (P1f) links the sarcolemma to the sarcomere, and its selective loss causes LGMD2Q without skin disease, proving that isoform diversity explains tissue-restricted pathology.","evidence":"Homozygosity mapping, PLEC sequencing, isoform-specific qRT-PCR, immunofluorescence, and TEM in patient muscle from multiple families","pmids":["21109228"],"confidence":"High","gaps":["Structural basis for P1f-specific sarcolemma–sarcomere anchoring was not determined","Whether P1f loss also impairs signaling at the sarcolemma was not assessed"]},{"year":2015,"claim":"Disruption of plectin isoform 1a (P1a) alone caused skin-only EBS with hypoplastic hemidesmosomes, completing the isoform–tissue specificity map by showing P1a is the dominant epidermal basal cell isoform.","evidence":"DNA sequencing, immunofluorescence antigen mapping, TEM, and isoform expression profiling in patient skin and control tissues","pmids":["25712130"],"confidence":"High","gaps":["Whether P1a-specific residues mediate unique protein–protein interactions at hemidesmosomes was not resolved","Functional compensation among isoforms in tissues co-expressing P1a and other variants was not tested"]},{"year":2021,"claim":"Discovery that plectin physically anchors mitochondria to keratin 8 and facilitates fission-mediated mitophagy revealed a non-structural role, explaining how plectin loss can cause mitochondrial dysfunction and necrotic cell death under oxidative stress.","evidence":"Reciprocal co-immunoprecipitation, siRNA knockdown of PLEC and KRT8, mitophagy flux assays, and live-cell imaging in retinal pigment epithelial cells","pmids":["33783309"],"confidence":"Medium","gaps":["Domain on plectin responsible for mitochondrial anchoring was not mapped","Whether this mitochondrial-anchoring function is relevant in muscle or skin disease has not been tested","Confirmation in additional cell types is lacking"]},{"year":2023,"claim":"Plectin knockdown in the inner ear reduced synaptic mitochondrial potential and caused ribbon synapse loss, extending plectin's mitochondrial-support function to cochlear neurons and identifying biallelic PLEC variants as a cause of isolated hearing loss.","evidence":"Whole-exome sequencing in hearing-loss families, plectin knockdown in zebrafish and mouse inner ear, mitochondrial membrane potential assay, and ribbon synapse quantification","pmids":["37393735"],"confidence":"Medium","gaps":["Specific plectin isoform(s) mediating cochlear function are unknown","Mechanism linking plectin to mitochondrial membrane potential at synapses was not dissected"]},{"year":2024,"claim":"Plectin was shown to competitively bind KEAP1 and displace NRF2, enabling NRF2 nuclear translocation and antioxidant gene activation, establishing plectin as a direct modulator of the oxidative stress response and radioresistance in ESCC.","evidence":"ChIP (ΔNp63α on PLEC promoter), co-IP (PLEC–KEAP1), subcellular fractionation, PLEC overexpression/knockdown with ROS measurement, and xenograft radiosensitivity assay","pmids":["39500864"],"confidence":"Medium","gaps":["KEAP1-binding domain on plectin has not been mapped","Generalizability of the PLEC/KEAP1/NRF2 axis to non-cancer contexts is untested","Single-lab finding awaits independent replication"]},{"year":2024,"claim":"Placement of plectin upstream of NFκB1/CXCL9 in lipid-mediator-driven breast cancer signaling revealed yet another signaling axis influenced by plectin, beyond its structural and NRF2 roles.","evidence":"Transcriptomics/proteomics after EpOME treatment, PLEC siRNA knockdown, and in vivo xenograft/metastasis assays in TNBC models","pmids":["39695149"],"confidence":"Medium","gaps":["Direct physical interaction between plectin and NFκB1 pathway components has not been demonstrated","Mechanism by which plectin activates NFκB1 is undefined","Single-lab study in one cancer type"]},{"year":null,"claim":"How plectin's structural scaffolding, mitochondrial anchoring, and newly discovered signaling roles (NRF2, NFκB1) are coordinated across tissues and whether they are functionally coupled or independent remain major open questions.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of full-length plectin or its isoform-specific domains exists","Domain-level separation of structural versus signaling functions has not been achieved","In vivo isoform-specific knockout models for signaling readouts are lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,1,2,6,7,8]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,2,6,7]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[9,12]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,1,2,6,7,13]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,6,7]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[8,10]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,9]}],"pathway":[{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[0,6,7]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[8]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[8,9,10]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[9,12]},{"term_id":"R-HSA-397014","term_label":"Muscle contraction","supporting_discovery_ids":[1,6]}],"complexes":["Hemidesmosome"],"partners":["KRT8","KEAP1","ITGB4","DST","VIM","DES"],"other_free_text":[]},"mechanistic_narrative":"Plectin is a giant cytoskeletal linker protein that bridges intermediate filament networks (keratins, desmin, vimentin) to hemidesmosomes, the sarcolemma, and other membrane–cytoskeleton junctions, thereby maintaining mechanical integrity in skin, skeletal muscle, and heart [PMID:8894687, PMID:9701547]. Loss-of-function mutations in common exons cause epidermolysis bullosa simplex with muscular dystrophy (EBS-MD), whereas isoform-specific mutations in exon 1f cause limb-girdle muscular dystrophy (LGMD2Q) and mutations in exon 1a cause skin-only EBS, demonstrating that distinct plectin isoforms fulfill tissue-restricted anchoring roles [PMID:21109228, PMID:25712130]. Beyond structural scaffolding, plectin regulates actin stress fiber dynamics, anchors mitochondria to keratin 8 to facilitate mitophagy, and competitively displaces NRF2 from KEAP1 to activate antioxidant gene expression [PMID:9701547, PMID:33783309, PMID:39500864]. Plectin also participates in NFκB1/CXCL9 signaling downstream of lipid mediator stimulation in breast cancer cells [PMID:39695149]."},"prefetch_data":{"uniprot":{"accession":"Q15149","full_name":"Plectin","aliases":["Hemidesmosomal protein 1","HD1","Plectin-1"],"length_aa":4684,"mass_kda":531.8,"function":"Interlinks intermediate filaments with microtubules and microfilaments and anchors intermediate filaments to desmosomes or hemidesmosomes. Could also bind muscle proteins such as actin to membrane complexes in muscle. May be involved not only in the filaments network, but also in the regulation of their dynamics. Structural component of muscle. Isoform 9 plays a major role in the maintenance of myofiber integrity","subcellular_location":"Cytoplasm, cytoskeleton; Cell junction, hemidesmosome; Cell projection, podosome","url":"https://www.uniprot.org/uniprotkb/Q15149/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PLEC","classification":"Not Classified","n_dependent_lines":41,"n_total_lines":1208,"dependency_fraction":0.03394039735099338},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CTTN","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PLEC","total_profiled":1310},"omim":[{"mim_id":"616807","title":"FAS-BINDING FACTOR 1; FBF1","url":"https://www.omim.org/entry/616807"},{"mim_id":"616487","title":"EPIDERMOLYSIS BULLOSA SIMPLEX 5D, GENERALIZED INTERMEDIATE, AUTOSOMAL RECESSIVE; EBS5D","url":"https://www.omim.org/entry/616487"},{"mim_id":"613723","title":"MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 17; LGMDR17","url":"https://www.omim.org/entry/613723"},{"mim_id":"612138","title":"EPIDERMOLYSIS BULLOSA SIMPLEX 5C, WITH PYLORIC ATRESIA; EBS5C","url":"https://www.omim.org/entry/612138"},{"mim_id":"601282","title":"PLECTIN; PLEC","url":"https://www.omim.org/entry/601282"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Intermediate filaments","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"},{"location":"Focal adhesion sites","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skeletal muscle","ntpm":229.5}],"url":"https://www.proteinatlas.org/search/PLEC"},"hgnc":{"alias_symbol":["PCN","PLTN"],"prev_symbol":["EBS1","PLEC1"]},"alphafold":{"accession":"Q15149","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15149","model_url":"","pae_url":"","plddt_mean":null},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PLEC","jax_strain_url":"https://www.jax.org/strain/search?query=PLEC"},"sequence":{"accession":"Q15149","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15149.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15149/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15149"}},"corpus_meta":[{"pmid":"8894687","id":"PMC_8894687","title":"Homozygous deletion mutations in the plectin gene (PLEC1) in patients with epidermolysis bullosa simplex associated with late-onset muscular dystrophy.","date":"1996","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/8894687","citation_count":134,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11513122","id":"PMC_11513122","title":"Formation of PCDF, PCDD, PCB, and PCN in de novo synthesis from PAH: mechanistic aspects and correlation to fluidized bed incinerators.","date":"2001","source":"Chemosphere","url":"https://pubmed.ncbi.nlm.nih.gov/11513122","citation_count":126,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30202917","id":"PMC_30202917","title":"Development of a protein-ligand extended connectivity (PLEC) fingerprint and its application for binding affinity predictions.","date":"2019","source":"Bioinformatics (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/30202917","citation_count":111,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12581350","id":"PMC_12581350","title":"The Caulobacter crescentus polar organelle development protein PodJ is differentially localized and is required for polar targeting of the PleC development regulator.","date":"2003","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/12581350","citation_count":94,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8941634","id":"PMC_8941634","title":"A homozygous nonsense mutation in the PLEC1 gene in patients with epidermolysis bullosa simplex with muscular dystrophy.","date":"1996","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/8941634","citation_count":91,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21109228","id":"PMC_21109228","title":"Mutation in exon 1f of PLEC, leading to disruption of plectin isoform 1f, causes autosomal-recessive limb-girdle muscular dystrophy.","date":"2010","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21109228","citation_count":83,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24747385","id":"PMC_24747385","title":"Reducing NO and N₂O emission during aerobic denitrification by newly isolated Pseudomonas stutzeri PCN-1.","date":"2014","source":"Bioresource technology","url":"https://pubmed.ncbi.nlm.nih.gov/24747385","citation_count":79,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"2536661","id":"PMC_2536661","title":"Turning off flagellum rotation requires the pleiotropic gene pleD: pleA, pleC, and pleD define two morphogenic pathways in Caulobacter crescentus.","date":"1989","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/2536661","citation_count":77,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36622022","id":"PMC_36622022","title":"Self-Driven Electron Transfer Biomimetic Enzymatic Catalysis of Bismuth-Doped PCN-222 MOF for Rapid Therapy of Bacteria-Infected Wounds.","date":"2023","source":"ACS nano","url":"https://pubmed.ncbi.nlm.nih.gov/36622022","citation_count":76,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29050564","id":"PMC_29050564","title":"A Missense Variant in PLEC Increases Risk of Atrial Fibrillation.","date":"2017","source":"Journal of the American College of Cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/29050564","citation_count":68,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28376383","id":"PMC_28376383","title":"Effect of sulfamethoxazole on aerobic denitrification by strain Pseudomonas stutzeri PCN-1.","date":"2017","source":"Bioresource technology","url":"https://pubmed.ncbi.nlm.nih.gov/28376383","citation_count":63,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34035286","id":"PMC_34035286","title":"Understanding disorder and linker deficiency in porphyrinic zirconium-based metal-organic frameworks by resolving the Zr8O6 cluster conundrum in PCN-221.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/34035286","citation_count":58,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17989727","id":"PMC_17989727","title":"5' trans-splicing repair of the PLEC1 gene.","date":"2007","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/17989727","citation_count":57,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25795449","id":"PMC_25795449","title":"Interaction of Cr(VI) reduction and denitrification by strain Pseudomonas aeruginosa PCN-2 under aerobic conditions.","date":"2015","source":"Bioresource technology","url":"https://pubmed.ncbi.nlm.nih.gov/25795449","citation_count":57,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15681471","id":"PMC_15681471","title":"Epidermolysis bullosa simplex associated with pyloric atresia is a novel clinical subtype caused by mutations in the plectin gene (PLEC1).","date":"2005","source":"The Journal of molecular diagnostics : JMD","url":"https://pubmed.ncbi.nlm.nih.gov/15681471","citation_count":56,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"2818616","id":"PMC_2818616","title":"Human fetal and adult liver metabolism of ethylmorphine. Relation to immunodetected cytochrome P-450 PCN and interactions with important fetal corticosteroids.","date":"1989","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/2818616","citation_count":54,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23909720","id":"PMC_23909720","title":"The DivJ, CbrA and PleC system controls DivK phosphorylation and symbiosis in Sinorhizobium meliloti.","date":"2013","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/23909720","citation_count":52,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18978058","id":"PMC_18978058","title":"The Anaplasma phagocytophilum PleC histidine kinase and PleD diguanylate cyclase two-component system and role of cyclic Di-GMP in host cell infection.","date":"2008","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/18978058","citation_count":47,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36701949","id":"PMC_36701949","title":"A novel CRISPR/Cas14a-based electrochemical biosensor for ultrasensitive detection of Burkholderia pseudomallei with PtPd@PCN-224 nanoenzymes for signal amplification.","date":"2023","source":"Biosensors & bioelectronics","url":"https://pubmed.ncbi.nlm.nih.gov/36701949","citation_count":46,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30730609","id":"PMC_30730609","title":"Prioritization of PLEC and GRINA as Osteoarthritis Risk Genes Through the Identification and Characterization of Novel Methylation Quantitative Trait Loci.","date":"2019","source":"Arthritis & rheumatology (Hoboken, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/30730609","citation_count":43,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25712130","id":"PMC_25712130","title":"Mutation in exon 1a of PLEC, leading to disruption of plectin isoform 1a, causes autosomal-recessive skin-only epidermolysis bullosa simplex.","date":"2015","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25712130","citation_count":41,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27853857","id":"PMC_27853857","title":"Effects of heavy metals on aerobic denitrification by strain Pseudomonas stutzeri PCN-1.","date":"2016","source":"Applied microbiology and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/27853857","citation_count":39,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23289980","id":"PMC_23289980","title":"Epidermolysis bullosa simplex with PLEC mutations: new phenotypes and new mutations.","date":"2013","source":"The British journal of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/23289980","citation_count":36,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32580029","id":"PMC_32580029","title":"Multi-tissue epigenetic analysis of the osteoarthritis susceptibility locus mapping to the plectin gene PLEC.","date":"2020","source":"Osteoarthritis and cartilage","url":"https://pubmed.ncbi.nlm.nih.gov/32580029","citation_count":35,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21175599","id":"PMC_21175599","title":"Congenital myasthenic syndrome associated with epidermolysis bullosa caused by homozygous mutations in PLEC1 and CHRNE.","date":"2010","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21175599","citation_count":34,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20624679","id":"PMC_20624679","title":"Congenital muscular dystrophy, myasthenic symptoms and epidermolysis bullosa simplex (EBS) associated with mutations in the PLEC1 gene encoding plectin.","date":"2010","source":"Neuromuscular disorders : NMD","url":"https://pubmed.ncbi.nlm.nih.gov/20624679","citation_count":33,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33783309","id":"PMC_33783309","title":"KRT8 (keratin 8) attenuates necrotic cell death by facilitating mitochondrial fission-mediated mitophagy through interaction with PLEC (plectin).","date":"2021","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/33783309","citation_count":33,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"2725470","id":"PMC_2725470","title":"Evidence for a PCN-P450 enzyme in chickens and comparison of its development with that of other phenobarbital-inducible forms.","date":"1989","source":"Molecular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/2725470","citation_count":30,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27469045","id":"PMC_27469045","title":"Potential application of aerobic denitrifying bacterium Pseudomonas aeruginosa PCN-2 in nitrogen oxides (NOx) removal from flue gas.","date":"2016","source":"Journal of hazardous materials","url":"https://pubmed.ncbi.nlm.nih.gov/27469045","citation_count":29,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28500885","id":"PMC_28500885","title":"Effects of ZnO nanoparticles on aerobic denitrification by strain Pseudomonas stutzeri PCN-1.","date":"2017","source":"Bioresource technology","url":"https://pubmed.ncbi.nlm.nih.gov/28500885","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22813907","id":"PMC_22813907","title":"Repeated dose toxicity and relative potency of 1,2,3,4,6,7-hexachloronaphthalene (PCN 66) 1,2,3,5,6,7-hexachloronaphthalene (PCN 67) compared to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) for induction of CYP1A1, CYP1A2 and thymic atrophy in female Harlan Sprague-Dawley rats.","date":"2012","source":"Toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/22813907","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12167307","id":"PMC_12167307","title":"Expression of rat Multidrug Resistance Protein 2 (Mrp2) in male and female rats during normal and pregnenolone-16alpha-carbonitrile (PCN)-induced postnatal ontogeny.","date":"2002","source":"Toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/12167307","citation_count":27,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35852837","id":"PMC_35852837","title":"A New Paradigm in Pincer Iridium Chemistry: PCN Complexes for (De)Hydrogenation Catalysis and Beyond.","date":"2022","source":"Accounts of chemical research","url":"https://pubmed.ncbi.nlm.nih.gov/35852837","citation_count":26,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15201439","id":"PMC_15201439","title":"Promotion of thyroid tumors in rats by pregnenolone-16alpha-carbonitrile (PCN) and polychlorinated biphenyl (PCB).","date":"2004","source":"Toxicological sciences : an official journal of the Society of Toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/15201439","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9294444","id":"PMC_9294444","title":"Roles of the histidine protein kinase pleC in Caulobacter crescentus motility and chemotaxis.","date":"1997","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/9294444","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"3986963","id":"PMC_3986963","title":"Age- and sex-dependent induction of liver microsomal benzo[a]pyrene hydroxylase activity in rats treated with pregnenolone-16 alpha-carbonitrile (PCN).","date":"1985","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/3986963","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29761480","id":"PMC_29761480","title":"Whole exome sequencing identifies PLEC, EXO5 and DNAH7 as novel susceptibility genes in testicular cancer.","date":"2018","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/29761480","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25454730","id":"PMC_25454730","title":"Left ventricular non-compaction cardiomyopathy associated with epidermolysis bullosa simplex with muscular dystrophy and PLEC1 mutation.","date":"2014","source":"Neuromuscular disorders : NMD","url":"https://pubmed.ncbi.nlm.nih.gov/25454730","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25820140","id":"PMC_25820140","title":"Phenazine-1-carboxamide (PCN) from Pseudomonas sp. strain PUP6 selectively induced apoptosis in lung (A549) and breast (MDA MB-231) cancer cells by inhibition of antiapoptotic Bcl-2 family proteins.","date":"2015","source":"Apoptosis : an international journal on programmed cell death","url":"https://pubmed.ncbi.nlm.nih.gov/25820140","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"3264502","id":"PMC_3264502","title":"Monoclonal antibody directed detection of cytochrome P-450 (PCN) in human fetal liver.","date":"1988","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/3264502","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34977888","id":"PMC_34977888","title":"Insights into the Interaction between Immobilized Biocatalysts and Metal-Organic Frameworks: A Case Study of PCN-333.","date":"2021","source":"JACS Au","url":"https://pubmed.ncbi.nlm.nih.gov/34977888","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33165537","id":"PMC_33165537","title":"An S-ribonuclease binding protein EBS1 and brassinolide signaling are specifically required for Arabidopsis tolerance to bicarbonate.","date":"2021","source":"Journal of experimental botany","url":"https://pubmed.ncbi.nlm.nih.gov/33165537","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35124010","id":"PMC_35124010","title":"Regulation of the activity of the bacterial histidine kinase PleC by the scaffolding protein PodJ.","date":"2022","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/35124010","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28824526","id":"PMC_28824526","title":"Glu20Ter Variant in PLEC 1f Isoform Causes Limb-Girdle Muscle Dystrophy with Lung Injury.","date":"2017","source":"Frontiers in neurology","url":"https://pubmed.ncbi.nlm.nih.gov/28824526","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38599073","id":"PMC_38599073","title":"Highly sensitive and selective demethylase FTO detection using a DNAzyme-mediated CRISPR/Cas12a signal cascade amplification electrochemiluminescence biosensor with C-CN/PCNV heterojunction as emitter.","date":"2024","source":"Biosensors & bioelectronics","url":"https://pubmed.ncbi.nlm.nih.gov/38599073","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32605089","id":"PMC_32605089","title":"Four Individuals with a Homozygous Mutation in Exon 1f of the PLEC Gene and Associated Myasthenic Features.","date":"2020","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/32605089","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35815343","id":"PMC_35815343","title":"Mutation update: The spectra of PLEC sequence variants and related plectinopathies.","date":"2022","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/35815343","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27878870","id":"PMC_27878870","title":"Epidermolysis bullosa simplex in sibling Eurasier dogs is caused by a PLEC non-sense variant.","date":"2016","source":"Veterinary dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/27878870","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29352809","id":"PMC_29352809","title":"A novel PLEC nonsense homozygous mutation (c.7159G > T; p.Glu2387*) causes epidermolysis bullosa simplex with muscular dystrophy and diffuse alopecia: a case report.","date":"2018","source":"BMC dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/29352809","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34225215","id":"PMC_34225215","title":"Circular RNA PLEC acts as a sponge of microRNA-198 to promote gastric carcinoma cell resistance to paclitaxel and tumorigenesis.","date":"2021","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/34225215","citation_count":13,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26693059","id":"PMC_26693059","title":"Germline copy number loss of UGT2B28 and gain of PLEC contribute to increased human esophageal squamous cell carcinoma risk in Southwest China.","date":"2015","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/26693059","citation_count":13,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29440732","id":"PMC_29440732","title":"Matrimid-JUC-62 and Matrimid-PCN-250 mixed matrix membranes displaying light-responsive gas separation and beneficial ageing characteristics for CO2/N2 separation.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29440732","citation_count":12,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38194287","id":"PMC_38194287","title":"Sustainable Gold Nanoparticle (Au-NP) Growth within Interspaces of Porphyrinic Zirconium-Based Metal-Organic Frameworks: Green Synthesis of PCN-224/Au-NPs and Its Anticancer Effect on Colorectal Cancer Cells Assay.","date":"2024","source":"ACS applied materials & interfaces","url":"https://pubmed.ncbi.nlm.nih.gov/38194287","citation_count":12,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28447722","id":"PMC_28447722","title":"Novel compound heterozygous PLEC mutations lead to early‑onset limb‑girdle muscular dystrophy 2Q.","date":"2017","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/28447722","citation_count":11,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37318099","id":"PMC_37318099","title":"Reprogramming of the tumor microenvironment using a PCN-224@IrNCs/D-Arg nanoplatform for the synergistic PDT, NO, and radiosensitization therapy of breast cancer and improving anti-tumor immunity.","date":"2023","source":"Nanoscale","url":"https://pubmed.ncbi.nlm.nih.gov/37318099","citation_count":11,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38199125","id":"PMC_38199125","title":"A Zn-modified PCN-224 fluorescent nanoprobe for selective and sensitive turn-on detection of glutathione.","date":"2024","source":"Talanta","url":"https://pubmed.ncbi.nlm.nih.gov/38199125","citation_count":11,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38520931","id":"PMC_38520931","title":"Strong cathode electroluminescence biosensor based on CeO2 functionalized PCN-222@Ag NPs for sensitive detection of p-Tau-181 protein.","date":"2024","source":"Journal of colloid and interface science","url":"https://pubmed.ncbi.nlm.nih.gov/38520931","citation_count":11,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27501765","id":"PMC_27501765","title":"Differences in the action of lower and higher chlorinated polychlorinated naphthalene (PCN) congeners on estrogen dependent breast cancer cell line viability and apoptosis, and its correlation with Ahr and CYP1A1 expression.","date":"2016","source":"Toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/27501765","citation_count":11,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"40382627","id":"PMC_40382627","title":"Novel Pt@PCN-Cu-induced cuproptosis amplifies αPD-L1 immunotherapy in pancreatic ductal adenocarcinoma through mitochondrial HK2-mediated PD-L1 upregulation.","date":"2025","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/40382627","citation_count":10,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35234827","id":"PMC_35234827","title":"Evaluation of Systemic Gentamicin as Translational Readthrough Therapy for a Patient With Epidermolysis Bullosa Simplex With Muscular Dystrophy Owing to PLEC1 Pathogenic Nonsense Variants.","date":"2022","source":"JAMA dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/35234827","citation_count":10,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37758018","id":"PMC_37758018","title":"Pharmacological profiles and anti-inflammatory activity of pCN-diEPP and mCN-diEPP, new alpha9alpha10 nicotinic receptor ligands.","date":"2023","source":"Neuropharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/37758018","citation_count":10,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35799364","id":"PMC_35799364","title":"PCN-Miner: an open-source extensible tool for the analysis of Protein Contact Networks.","date":"2022","source":"Bioinformatics (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/35799364","citation_count":10,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26874276","id":"PMC_26874276","title":"Reduction of PCN biosynthesis by NO in Pseudomonas aeruginosa.","date":"2015","source":"Redox biology","url":"https://pubmed.ncbi.nlm.nih.gov/26874276","citation_count":10,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34861485","id":"PMC_34861485","title":"Disposable biosensor based on novel ternary Ru-PEI@PCN-333(Al) self-enhanced electrochemiluminescence system for on-site determination of caspase-3 activity.","date":"2021","source":"Talanta","url":"https://pubmed.ncbi.nlm.nih.gov/34861485","citation_count":10,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25209331","id":"PMC_25209331","title":"Compound heterozygous PLEC mutations in a patient of consanguineous parentage with epidermolysis bullosa simplex with muscular dystrophy and diffuse alopecia.","date":"2014","source":"International journal of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/25209331","citation_count":10,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34947511","id":"PMC_34947511","title":"PCN-224 Nanoparticle/Polyacrylonitrile Nanofiber Membrane for Light-Driven Bacterial Inactivation.","date":"2021","source":"Nanomaterials (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/34947511","citation_count":10,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27237601","id":"PMC_27237601","title":"Identification of Candidate Target Cyp Genes for microRNAs Whose Expression Is Altered by PCN and TCPOBOP, Representative Ligands of PXR and CAR.","date":"2016","source":"Biological & pharmaceutical bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/27237601","citation_count":10,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38067002","id":"PMC_38067002","title":"Effects of Copy Number Variations in the Plectin (PLEC) Gene on the Growth Traits and Meat Quality of Leizhou Black Goats.","date":"2023","source":"Animals : an open access journal from MDPI","url":"https://pubmed.ncbi.nlm.nih.gov/38067002","citation_count":9,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29848313","id":"PMC_29848313","title":"Cell cycle accumulation of the proliferating cell nuclear antigen PCN-1 transitions from continuous in the adult germline to intermittent in the early embryo of C. elegans.","date":"2018","source":"BMC developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/29848313","citation_count":9,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35775960","id":"PMC_35775960","title":"Highly water-dispersible PCN nanosheets as light-controlled lysosome self-promoting escape type non-cationic gene carriers for tumor therapy.","date":"2022","source":"Journal of materials chemistry. B","url":"https://pubmed.ncbi.nlm.nih.gov/35775960","citation_count":9,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33058999","id":"PMC_33058999","title":"Cellular evaluation of the metal-organic framework PCN-224 associated with inflammation and autophagy.","date":"2020","source":"Toxicology in vitro : an international journal published in association with BIBRA","url":"https://pubmed.ncbi.nlm.nih.gov/33058999","citation_count":9,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39500864","id":"PMC_39500864","title":"ΔNp63α promotes radioresistance in esophageal squamous cell carcinoma through the PLEC-KEAP1-NRF2 feedback loop.","date":"2024","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/39500864","citation_count":8,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26186202","id":"PMC_26186202","title":"Dynamical Localization of DivL and PleC in the Asymmetric Division Cycle of Caulobacter crescentus: A Theoretical Investigation of Alternative Models.","date":"2015","source":"PLoS computational biology","url":"https://pubmed.ncbi.nlm.nih.gov/26186202","citation_count":8,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36493888","id":"PMC_36493888","title":"Insight into sulfamethoxazole effects on aerobic denitrification by strain Pseudomonas aeruginosa PCN-2: From simultaneous degradation performance to transcriptome analysis.","date":"2022","source":"Chemosphere","url":"https://pubmed.ncbi.nlm.nih.gov/36493888","citation_count":8,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39695149","id":"PMC_39695149","title":"Epoxy metabolites of linoleic acid promote the development of breast cancer via orchestrating PLEC/NFκB1/CXCL9-mediated tumor growth and metastasis.","date":"2024","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/39695149","citation_count":7,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24243113","id":"PMC_24243113","title":"Role of helical constraints of the EBS1-IBS1 duplex of a group II intron on demarcation of the 5' splice site.","date":"2013","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/24243113","citation_count":7,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38606488","id":"PMC_38606488","title":"Metal-Organic Framework PCN-224 Combined Cobalt Oxide Nanoparticles for Hypoxia Relief and Synergistic Photodynamic/Chemodynamic Therapy.","date":"2024","source":"Chemistry (Weinheim an der Bergstrasse, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/38606488","citation_count":6,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27766310","id":"PMC_27766310","title":"Epidermolysis bullosa simplex with muscular dystrophy associated with PLEC deletion mutation.","date":"2016","source":"Neurology. Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27766310","citation_count":5,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31388680","id":"PMC_31388680","title":"Epigenetic Memory Is Involved in the Persistent Alterations of Drug-Processing Genes in Adult Mice Due to PCN-Activated PXR During Early Life.","date":"2019","source":"Toxicological sciences : an official journal of the Society of Toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/31388680","citation_count":5,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35432467","id":"PMC_35432467","title":"Epidermolysis Bullosa With Congenital Absence of Skin: Congenital Corneal Cloudiness and Esophagogastric Obstruction Including Extended Genotypic Spectrum of PLEC, LAMC2, ITGB4 and COL7A1.","date":"2022","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35432467","citation_count":4,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37578169","id":"PMC_37578169","title":"\"Gold-plated\" PCN-222(Fe) and superconductive carbon black-based sandwich-type immunosensor for detecting CYFRA21-1.","date":"2023","source":"Journal of materials chemistry. B","url":"https://pubmed.ncbi.nlm.nih.gov/37578169","citation_count":4,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36598843","id":"PMC_36598843","title":"Delivery of Immobilized IFN-γ With PCN-333 and Its Effect on Human Mesenchymal Stem Cells.","date":"2023","source":"ACS biomaterials science & engineering","url":"https://pubmed.ncbi.nlm.nih.gov/36598843","citation_count":4,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35773338","id":"PMC_35773338","title":"Long-term treatment with the mPXR agonist PCN promotes hepatomegaly and lipid accumulation without hepatocyte proliferation in mice.","date":"2022","source":"Acta pharmacologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/35773338","citation_count":4,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34702657","id":"PMC_34702657","title":"Congenital myopathy and epidermolysis bullosa due to PLEC variant.","date":"2021","source":"Neuromuscular disorders : NMD","url":"https://pubmed.ncbi.nlm.nih.gov/34702657","citation_count":4,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37470104","id":"PMC_37470104","title":"Exploring the role of sandwich-type polyoxometalates in {K10(PW9O34)2M4(H2O)2}@PCN-222 (M = Mn, Ni, Zn) for electroreduction of CO2 to CO.","date":"2023","source":"Dalton transactions (Cambridge, England : 2003)","url":"https://pubmed.ncbi.nlm.nih.gov/37470104","citation_count":4,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39934406","id":"PMC_39934406","title":"A split-type photoelectrochemical sensor based on In2S3/PCN-224 Z-scheme heterojunction for ultrasensitive detection of ampicillin.","date":"2025","source":"Mikrochimica acta","url":"https://pubmed.ncbi.nlm.nih.gov/39934406","citation_count":4,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22544908","id":"PMC_22544908","title":"Functional analysis of the single Est1/Ebs1 homologue in Kluyveromyces lactis reveals roles in both telomere maintenance and rapamycin resistance.","date":"2012","source":"Eukaryotic cell","url":"https://pubmed.ncbi.nlm.nih.gov/22544908","citation_count":3,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"970082","id":"PMC_970082","title":"Effect of pregnenolone-16alpha-carbonitrile (PCN) on rat liver.","date":"1976","source":"Acta hepato-gastroenterologica","url":"https://pubmed.ncbi.nlm.nih.gov/970082","citation_count":3,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"40054254","id":"PMC_40054254","title":"Self-driven charge transfer mechanism of Bi NPs/PCN-224 for enhanced photodynamic antimicrobial chemotherapy effect.","date":"2025","source":"Journal of colloid and interface science","url":"https://pubmed.ncbi.nlm.nih.gov/40054254","citation_count":3,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37393735","id":"PMC_37393735","title":"Novel biallelic variants in the PLEC gene are associated with severe hearing loss.","date":"2023","source":"Hearing research","url":"https://pubmed.ncbi.nlm.nih.gov/37393735","citation_count":2,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35996939","id":"PMC_35996939","title":"Novel compound heterozygous mutations in the PLEC gene in a neonate with epidermolysis bullosa simplex with pyloric atresia.","date":"2022","source":"The Journal of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/35996939","citation_count":2,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19322062","id":"PMC_19322062","title":"Exclusion of EGFR, HRAS, DSP, JUP, CTNNB1, PLEC1, and EPPK1 as functional candidate genes in 7 families with syndromic diarrhoea.","date":"2009","source":"Journal of pediatric gastroenterology and nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/19322062","citation_count":2,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35656234","id":"PMC_35656234","title":"Epidermolysis Bullosa: A Report of Three Cases with Novel Heterozygous Deletions in PLEC and Homozygous Non sense Mutations in COL7A1 Genes.","date":"2022","source":"Indian journal of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/35656234","citation_count":2,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39733955","id":"PMC_39733955","title":"Prioritising relevant polychlorinated naphthalene (PCN) congeners for human dietary exposure studies.","date":"2025","source":"Chemosphere","url":"https://pubmed.ncbi.nlm.nih.gov/39733955","citation_count":2,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38055169","id":"PMC_38055169","title":"Nitrogen-doped Zn/Fe@PCN derived from metal-organic frameworks activating persulfate to efficiently degrade rhodamine B.","date":"2023","source":"Environmental science and pollution research international","url":"https://pubmed.ncbi.nlm.nih.gov/38055169","citation_count":2,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31793579","id":"PMC_31793579","title":"Rational modifications of PCN-700 to induce electrical conductivity: a computational study.","date":"2019","source":"Dalton transactions (Cambridge, England : 2003)","url":"https://pubmed.ncbi.nlm.nih.gov/31793579","citation_count":2,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37453957","id":"PMC_37453957","title":"Identification of genes governing resistance to PCN (Globodera rostochiensis) through transcriptome analysis in Solanum tuberosum.","date":"2023","source":"Functional & integrative genomics","url":"https://pubmed.ncbi.nlm.nih.gov/37453957","citation_count":1,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"3325990","id":"PMC_3325990","title":"Effect of age on the induction of in vitro drug metabolism by pregnenolone-16 alpha-carbonitrile (PCN); effect of age and PCN on immune responses.","date":"1987","source":"Die Pharmazie","url":"https://pubmed.ncbi.nlm.nih.gov/3325990","citation_count":1,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"41143710","id":"PMC_41143710","title":"A review on multi-enzyme activity of ZIF, PBA, PCN and MIL MOF-derived cascade nano-enzymes for catalytic applications.","date":"2025","source":"Nanoscale","url":"https://pubmed.ncbi.nlm.nih.gov/41143710","citation_count":1,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17546391","id":"PMC_17546391","title":"[Construction and verification of the dual-promoter plasmid pCN-SSISG as bivalent anti-caries DNA vaccine].","date":"2007","source":"Shanghai kou qiang yi xue = Shanghai journal of stomatology","url":"https://pubmed.ncbi.nlm.nih.gov/17546391","citation_count":1,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20686565","id":"PMC_20686565","title":"Biological, clinical and population relevance of 95 loci for blood lipids.","date":"2010","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/20686565","citation_count":2873,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"17081983","id":"PMC_17081983","title":"Global, in vivo, and site-specific phosphorylation dynamics in signaling networks.","date":"2006","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/17081983","citation_count":2861,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"24097068","id":"PMC_24097068","title":"Discovery and refinement of loci associated with lipid levels.","date":"2013","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24097068","citation_count":2409,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22658674","id":"PMC_22658674","title":"Insights into RNA biology from an atlas of mammalian mRNA-binding proteins.","date":"2012","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/22658674","citation_count":1718,"is_preprint":false,"source_track":"gene2pubmed"},{"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":"15302935","id":"PMC_15302935","title":"Large-scale characterization of HeLa cell nuclear phosphoproteins.","date":"2004","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/15302935","citation_count":1159,"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":"15635413","id":"PMC_15635413","title":"Nucleolar proteome dynamics.","date":"2005","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/15635413","citation_count":934,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15592455","id":"PMC_15592455","title":"Immunoaffinity profiling of tyrosine phosphorylation in cancer cells.","date":"2004","source":"Nature biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/15592455","citation_count":916,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"29507755","id":"PMC_29507755","title":"VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation.","date":"2018","source":"Cell discovery","url":"https://pubmed.ncbi.nlm.nih.gov/29507755","citation_count":829,"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":"12577067","id":"PMC_12577067","title":"A proteomics strategy to elucidate functional protein-protein interactions applied to EGF signaling.","date":"2003","source":"Nature biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/12577067","citation_count":558,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21423176","id":"PMC_21423176","title":"Analysis of the myosin-II-responsive focal adhesion proteome reveals a role for β-Pix in negative regulation of focal adhesion maturation.","date":"2011","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/21423176","citation_count":490,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32051585","id":"PMC_32051585","title":"Mechanical regulation of glycolysis via cytoskeleton architecture.","date":"2020","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/32051585","citation_count":445,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15951569","id":"PMC_15951569","title":"Time-resolved mass spectrometry of tyrosine phosphorylation sites in the epidermal growth factor receptor signaling network reveals dynamic modules.","date":"2005","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/15951569","citation_count":434,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"35271311","id":"PMC_35271311","title":"OpenCell: Endogenous tagging for the cartography of human cellular organization.","date":"2022","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/35271311","citation_count":432,"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":"8889548","id":"PMC_8889548","title":"Normalization and subtraction: two approaches to facilitate gene discovery.","date":"1996","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/8889548","citation_count":401,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16009940","id":"PMC_16009940","title":"Human ISG15 conjugation targets both IFN-induced and constitutively expressed proteins functioning in diverse cellular pathways.","date":"2005","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/16009940","citation_count":383,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26414014","id":"PMC_26414014","title":"Proteome-wide profiling of protein assemblies by cross-linking mass spectrometry.","date":"2015","source":"Nature methods","url":"https://pubmed.ncbi.nlm.nih.gov/26414014","citation_count":370,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"9701547","id":"PMC_9701547","title":"Role of plectin in cytoskeleton organization and dynamics.","date":"1998","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/9701547","citation_count":343,"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":"22139419","id":"PMC_22139419","title":"New gene functions in megakaryopoiesis and platelet formation.","date":"2011","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/22139419","citation_count":332,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21145461","id":"PMC_21145461","title":"Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics.","date":"2010","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/21145461","citation_count":318,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"8696340","id":"PMC_8696340","title":"Plectin deficiency results in muscular dystrophy with epidermolysis bullosa.","date":"1996","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/8696340","citation_count":314,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50308,"output_tokens":2525,"usd":0.094399},"stage2":{"model":"claude-opus-4-6","input_tokens":5858,"output_tokens":2441,"usd":0.135472},"total_usd":0.508817,"stage1_batch_id":"msgbatch_01SUR8NDzVrNmyszWyJeCct7","stage2_batch_id":"msgbatch_01G7Yfutko3cDWzejrwH5AMx","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":62309,"output_tokens":3804,"usd":0.121994},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":7462,"output_tokens":2693,"usd":0.156952}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"Homozygous deletion mutations in PLEC1 abolish plectin protein in hemidesmosomes, demonstrating that plectin is required for attachment of the intermediate keratin filament network to hemidesmosomal complexes in basal keratinocytes, and its absence in sarcolemma correlates with muscular dystrophy.\",\n      \"method\": \"Mutation analysis (sequencing), immunofluorescence with anti-plectin antibody, electron microscopy of patient skin\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function mutations with direct protein localization readout, replicated across two independent patients\",\n      \"pmids\": [\"8894687\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"A homozygous nonsense mutation in PLEC1 leads to absence of plectin protein, causing failure of keratin filaments to connect to the plasma membrane via hemidesmosomes in skin, and aberrant localization of desmin in muscle fibers.\",\n      \"method\": \"Mutation analysis (sequencing), immunofluorescence, mRNA decay analysis\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — orthogonal methods (sequencing, IF, mRNA analysis) establishing mechanistic link between plectin loss and cytoskeletal disconnection\",\n      \"pmids\": [\"8941634\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Mutation in exon 1f of PLEC specifically disrupts plectin isoform 1f expression, breaking the linkage between the sarcolemma and sarcomere in skeletal muscle and causing LGMD without dermatological involvement, establishing an isoform-specific structural role for plectin 1f at the sarcolemma-sarcomere interface.\",\n      \"method\": \"Homozygosity mapping, DNA sequencing, qRT-PCR, transmission electron microscopy, immunofluorescence of patient muscle\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods showing isoform-specific loss with defined ultrastructural phenotype\",\n      \"pmids\": [\"21109228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Mutation in exon 1a of PLEC specifically disrupts plectin isoform 1a, causing skin-only epidermolysis bullosa simplex with hypoplastic hemidesmosomes but no muscle or cardiac involvement, demonstrating that isoform 1a is the dominant plectin isoform in epidermal basal cells and keratinocytes.\",\n      \"method\": \"Sequencing, immunofluorescence antigen mapping, transmission electron microscopy, western blot, qRT-PCR on patient skin and keratinocytes\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods establishing isoform-specific tissue expression and function\",\n      \"pmids\": [\"25712130\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Plectin physically interacts with KRT8 (keratin 8) to anchor mitochondria, and this PLEC-mitochondria association facilitates mitochondrial fission-mediated mitophagy; KRT8 phosphorylation under oxidative stress reduces the KRT8-PLEC association, regulating mitophagy flux and protecting retinal pigment epithelial cells from necrotic cell death.\",\n      \"method\": \"Co-immunoprecipitation (physical interaction), live imaging, knockdown experiments with specific phenotypic readouts (mitophagy flux, cell death)\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — co-IP plus functional KD phenotype in single study\",\n      \"pmids\": [\"33783309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ΔNP63α directly transactivates PLEC expression; plectin then competitively interacts with KEAP1, displacing NRF2 from KEAP1 and enabling NRF2 nuclear translocation to activate antioxidant gene expression, thereby reducing ROS and promoting radioresistance in esophageal squamous cell carcinoma.\",\n      \"method\": \"ChIP/transactivation assays, co-immunoprecipitation (PLEC-KEAP1 interaction), subcellular fractionation (NRF2 nuclear translocation), loss-of-function knockdown, in vivo mouse model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal interaction assays plus pathway epistasis with defined functional readout, single study\",\n      \"pmids\": [\"39500864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"PLEC1 mutations outside the muscular dystrophy-associated rod domain (including nonsense and splice-site mutations causing aberrant splicing) cause EBS associated with pyloric atresia, with absent plectin in hemidesmosomes, establishing that plectin function is required in epithelial tissues beyond skin.\",\n      \"method\": \"Immunohistochemistry, exon-trapping for splice-site mutation, sequencing, electron microscopy\",\n      \"journal\": \"The Journal of molecular diagnostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — exon trapping plus IF and EM in patient tissue; single study but multiple orthogonal methods\",\n      \"pmids\": [\"15681471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Spliceosome-mediated RNA trans-splicing (SMaRT) of PLEC1 mRNA can replace the mutated 5' portion of the endogenous PLEC1 transcript, reduce mutant mRNA levels, and restore wild-type plectin protein expression (58.7% increase in full-length protein after retroviral correction) in EBS-MD patient fibroblasts.\",\n      \"method\": \"Transient transfection, retroviral transduction, immunofluorescence microscopy, quantification of plectin protein\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional rescue experiment with protein-level readout; single study\",\n      \"pmids\": [\"17989727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Biallelic PLEC variants cause severe hearing loss; plectin knockdown in animal models reduces synaptic mitochondrial potential and causes loss of ribbon synapses in the inner ear, revealing a role for plectin in maintaining neuronal/synaptic function at the cochlear ribbon synapse.\",\n      \"method\": \"Whole-exome sequencing, plectin knockdown in mice and zebrafish, synaptic mitochondrial potential assay, ribbon synapse quantification\",\n      \"journal\": \"Hearing research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — knockdown in two model organisms with defined synaptic phenotype; single study\",\n      \"pmids\": [\"37393735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Gentamicin (translational readthrough) treatment suppresses PLEC1 premature termination codons and restores plectin expression in skin of an EBS-MD patient with nonsense variants, demonstrating that PLEC1 nonsense variants can be partially rescued by readthrough pharmacology.\",\n      \"method\": \"Translational readthrough drug treatment, immunofluorescence of patient skin, clinical functional scales\",\n      \"journal\": \"JAMA dermatology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single patient case report with protein expression readout, no mechanistic controls\",\n      \"pmids\": [\"35234827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"EpOMEs (epoxy metabolites of linoleic acid produced by CYP2J2) upregulate PLEC expression in triple-negative breast cancer; elevated PLEC in turn upregulates NFκB1, which acts as a transcription regulator of CXCL9, thereby promoting TNBC tumor growth and metastasis.\",\n      \"method\": \"Transcriptomics, proteomics, CYP2J2 knockdown/overexpression, PLEC knockdown, CXCL9 knockdown, EpOME treatment, in vivo mouse model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple omics approaches plus functional KD experiments placing PLEC in a defined signaling axis; single study\",\n      \"pmids\": [\"39695149\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Plectin (PLEC) is a large cytoskeletal cross-linker that tethers intermediate filaments (keratins in epithelium, desmin in muscle) to plasma membrane attachment complexes (hemidesmosomes, sarcolemma), with tissue-specific isoforms (e.g., 1a in keratinocytes, 1f at the sarcolemma-sarcomere interface) dictating organ-specific disease when mutated; it also anchors mitochondria to facilitate mitophagy via KRT8 interaction, competitively binds KEAP1 to release and activate NRF2, and supports ribbon synapse integrity and neuronal transmission in the inner ear.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"Plectin (encoded by PLEC1) is required for attachment of intermediate keratin filament networks to hemidesmosomal complexes in skin and for structural integrity of sarcolemma in muscle; homozygous deletion mutations in PLEC1 cause epidermolysis bullosa simplex with muscular dystrophy (EBS-MD), demonstrating plectin's critical role as a cytoskeleton-membrane anchorage protein in both epithelia and muscle.\",\n      \"method\": \"Immunofluorescence with anti-plectin antibody (HD-1), mutation analysis (sequencing of PLEC1 cDNA/genomic DNA), electron microscopy of patient skin\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple independent patient families, replicated across labs in same year; loss-of-function mutations correlated with defined structural phenotypes in skin and muscle\",\n      \"pmids\": [\"8894687\", \"8941634\", \"8696340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Absence of plectin in muscle fibers leads to aberrant localization of desmin, indicating plectin normally anchors desmin-containing intermediate filaments to the sarcolemma; a homozygous nonsense mutation in PLEC1 causes decay of aberrant plectin mRNA and loss of plectin protein.\",\n      \"method\": \"Immunofluorescence with plectin and desmin antibodies on patient muscle biopsies; RT-PCR and sequencing to detect nonsense-mediated mRNA decay\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct immunofluorescence demonstrating desmin mislocalization as consequence of plectin loss; corroborated by molecular analysis\",\n      \"pmids\": [\"8941634\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Plectin and its isoforms function as versatile cytoskeletal linker proteins that bind to subcomponents of all three major cytoskeletal filament networks (intermediate filaments, actin, microtubules), the subplasma membrane protein skeleton, and plasma membrane-cytoskeleton junctional complexes; plectin-deficient mice generated by targeted gene inactivation die shortly after birth with severe defects in skin, skeletal muscle, and heart, and cells derived from these animals reveal an essential role for plectin as a regulator of actin stress fiber dynamics.\",\n      \"method\": \"Gene knockout (targeted inactivation), in vitro cell studies of plectin-null cells, biochemical binding studies\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — plectin-null mouse model with defined phenotypic readouts plus in vitro functional studies; comprehensive review of primary data\",\n      \"pmids\": [\"9701547\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Plectin was identified as a component that forms specific complexes with activated EGFR-Shc signaling complexes upon EGF stimulation; this was revealed by SILAC-based quantitative proteomics showing selective enrichment of plectin in Grb2-SH2 affinity purifications from EGF-stimulated cells, linking plectin to receptor tyrosine kinase signaling.\",\n      \"method\": \"SILAC quantitative proteomics, GST-SH2 affinity purification from EGF-stimulated vs. unstimulated HeLa cells\",\n      \"journal\": \"Nature biotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single affinity purification/MS experiment identifying plectin as a differential interactor; mechanistic follow-up not detailed\",\n      \"pmids\": [\"12577067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Plectin is a target of ISG15 conjugation in IFN-β-treated human cells, placing it within the ISG15-modified proteome that mediates innate immune responses.\",\n      \"method\": \"Double-affinity purification of ISG15-modified proteins from IFN-β-treated HeLa cells followed by mass spectrometry identification\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single MS identification from large-scale screen; no mechanistic follow-up specific to plectin\",\n      \"pmids\": [\"16009940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Spliceosome-mediated RNA trans-splicing (SMaRT) using a 5' pre-trans-splicing molecule encoding wild-type PLEC1 exons 2–9 specifically replaces the mutated 5' portion of the endogenous PLEC1 transcript in EBS-MD fibroblasts, reduces mutant mRNA levels, and restores wild-type plectin expression pattern, demonstrating that the dominant-negative leucine insertion in exon 9 causes plectin peptide chain aggregation and protein degradation.\",\n      \"method\": \"Transient transfection and retroviral transduction of EBS-MD fibroblasts with pre-trans-splicing molecules; immunofluorescence microscopy; Western blot quantification of plectin protein\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct functional rescue experiment demonstrating mechanistic consequence of exon 9 mutation (aggregation and degradation); single lab\",\n      \"pmids\": [\"17989727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"A homozygous mutation in exon 1f of PLEC, which is isoform-specific to plectin isoform 1f (P1f), causes autosomal-recessive limb-girdle muscular dystrophy (LGMD2Q) without dermatological involvement; P1f deficiency breaks the linkage between the sarcolemma and sarcomere, resulting in ultrastructural alterations including membrane duplications, enlarged space between membrane and sarcomere, and Z-disk misalignment.\",\n      \"method\": \"SNP array homozygosity mapping, PLEC sequencing, RT-PCR/qRT-PCR for P1f mRNA expression, immunofluorescence of patient muscle, transmission electron microscopy\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — isoform-specific mutation with direct ultrastructural demonstration of sarcolemma-sarcomere linkage defect; multiple orthogonal methods in multiple families\",\n      \"pmids\": [\"21109228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"A nonsense mutation in exon 1a of PLEC, disrupting only plectin isoform 1a (P1a), causes autosomal-recessive skin-only EBS without extracutaneous involvement; P1a is dominantly expressed in epidermal basal cell layer and cultured keratinocytes, and its specific loss leads to hypoplastic hemidesmosomes and intra-epidermal cleavage while sparing heart and muscle that express other isoforms.\",\n      \"method\": \"DNA sequencing, immunofluorescence antigen mapping, transmission electron microscopy, Western blot, qRT-PCR on patient skin and cultured keratinocytes, control myocardium, and striated muscle\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — isoform-specific loss-of-function with tissue expression profiling and ultrastructural confirmation; multiple orthogonal methods\",\n      \"pmids\": [\"25712130\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KRT8 (keratin 8) physically interacts with PLEC (plectin) to connect KRT8 to mitochondria; PLEC anchors mitochondria and mediates physical association with KRT8, facilitating mitochondrial fission-mediated mitophagy. Under oxidative stress, KRT8 phosphorylation diminishes this PLEC-anchoring association, impairing efficient mitophagy and leading to accumulation of damaged mitochondria and necrotic cell death in retinal pigment epithelial cells.\",\n      \"method\": \"Co-immunoprecipitation (KRT8-PLEC physical interaction), live-cell imaging, mitophagy flux assays, siRNA knockdown of KRT8 and PLEC, mitochondrial morphology/fission analysis, oxidative stress treatment\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP demonstrating KRT8-PLEC interaction with functional mitophagy readout; single lab\",\n      \"pmids\": [\"33783309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ΔNp63α directly transactivates PLEC expression in esophageal squamous cell carcinoma (ESCC); PLEC competitively interacts with KEAP1, displacing NRF2 from the KEAP1 complex and enabling NRF2 nuclear translocation and activation of ROS-eliminating genes, thereby conferring radioresistance. Radiotherapy-induced ROS further activates ΔNp63α via NRF2, forming a positive feedback loop (ΔNp63α/PLEC/NRF2 axis).\",\n      \"method\": \"Chromatin immunoprecipitation (ΔNp63α binding to PLEC promoter), co-immunoprecipitation (PLEC-KEAP1 interaction), subcellular fractionation/immunofluorescence of NRF2 localization, PLEC overexpression/knockdown with ROS measurement, nude mouse xenograft radiosensitivity assay with NRF2 inhibitor\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP, Co-IP, and functional rescue experiments in vitro and in vivo; single lab study\",\n      \"pmids\": [\"39500864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Plectin knockdown in inner ear (zebrafish/mouse model) reduces synaptic mitochondrial potential and causes loss of ribbon synapses, indicating a role for plectin in maintaining neuronal/synaptic function in the cochlea; novel biallelic PLEC variants cause hearing loss in humans without skin or muscle involvement.\",\n      \"method\": \"Trio whole-exome sequencing, developmental expression analysis in mice and zebrafish, siRNA knockdown of plectin in inner ear with mitochondrial membrane potential assay and ribbon synapse quantification by immunofluorescence\",\n      \"journal\": \"Hearing research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo knockdown with defined synaptic and mitochondrial functional phenotype; single lab\",\n      \"pmids\": [\"37393735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Plectin knockdown (via CRISPR/Cas9) in mesenchymal stem cells impacts Wnt signalling, glycosaminoglycan biosynthesis, and immune regulation pathways as revealed by RNA-sequencing, suggesting plectin modulates intracellular signaling responses to mechanical stimuli in joint tissues.\",\n      \"method\": \"CRISPR/Cas9 plectin knockdown in MSC line followed by RNA-sequencing pathway analysis\",\n      \"journal\": \"Osteoarthritis and cartilage\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — transcriptomic pathway analysis after knockdown; no direct mechanistic dissection of signaling pathway placement\",\n      \"pmids\": [\"32580029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"EpOMEs (epoxyoctadecenoic acids) upregulate PLEC expression in triple-negative breast cancer cells; upregulated PLEC in turn activates NFκB1, which transcriptionally regulates CXCL9, thereby promoting tumor growth and metastasis. PLEC knockdown inhibited EpOME-mediated promotion of TNBC, placing PLEC upstream of NFκB1/CXCL9 in this oncogenic signaling axis.\",\n      \"method\": \"Transcriptomics and proteomics after EpOME treatment, PLEC/CXCL9 siRNA knockdown, CYP2J2 overexpression/knockdown, in vivo xenograft and lung metastasis assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (transcriptomics, proteomics, functional knockdown in vitro and in vivo) placing PLEC in a defined signaling pathway; single lab\",\n      \"pmids\": [\"39695149\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Plectin was identified as a component of the myosin-II-responsive focal adhesion proteome; its abundance in focal adhesions is enhanced by myosin II-mediated contractility, linking plectin to mechanosensing at focal adhesions.\",\n      \"method\": \"Proteomic analysis of isolated focal adhesions by mass spectrometry comparing myosin II-inhibited vs. control cells (blebbistatin treatment)\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — large-scale proteomic screen identifying plectin as a focal adhesion component; no specific mechanistic follow-up for plectin\",\n      \"pmids\": [\"21423176\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Plectin (PLEC) is a large cytoskeletal linker protein that crosslinks intermediate filaments (keratins, desmin, vimentin) to hemidesmosomes, the sarcolemma, and other membrane-cytoskeleton junctions; loss-of-function mutations in isoform-specific or common exons cause tissue-restricted or multisystem disease (EBS, muscular dystrophy, LGMD) by disrupting these structural anchoring functions, while mechanistically plectin also regulates actin stress fiber dynamics, anchors mitochondria to facilitate KRT8-mediated mitophagy, competes with KEAP1 for NRF2 binding to modulate oxidative stress responses, and participates in NFκB1/CXCL9 signaling downstream of lipid mediators.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"Plectin is a giant cytoskeletal cross-linker that tethers intermediate filament networks to membrane attachment sites, with tissue-specific first-exon isoforms dictating organ-specific functions: isoform 1a anchors keratin filaments to hemidesmosomes in epidermal basal cells, while isoform 1f links the sarcolemma to the sarcomere in skeletal muscle [PMID:8894687, PMID:25712130, PMID:21109228]. Loss-of-function mutations in PLEC cause epidermolysis bullosa simplex with muscular dystrophy (EBS-MD) and, when isoform-restricted, isolated skin fragility or limb-girdle muscular dystrophy, establishing plectin as essential for mechanical integrity in both epithelial and muscle tissues [PMID:8941634, PMID:15681471]. Beyond structural cross-linking, plectin interacts with KRT8 to anchor mitochondria and regulate mitophagy flux, and competitively binds KEAP1 to liberate NRF2 for antioxidant gene activation [PMID:33783309, PMID:39500864]. Plectin also maintains ribbon synapse integrity and synaptic mitochondrial function in the cochlea, and biallelic PLEC variants cause severe hearing loss [PMID:37393735].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Establishing that plectin is the essential physical linker between keratin intermediate filaments and hemidesmosomes in skin and between desmin and sarcolemma in muscle resolved why its loss simultaneously causes skin blistering and muscular dystrophy.\",\n      \"evidence\": \"Homozygous deletion and nonsense mutations in PLEC1 analyzed by sequencing, immunofluorescence, and electron microscopy in patient skin and muscle\",\n      \"pmids\": [\"8894687\", \"8941634\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular basis of how plectin binds both integrin α6β4 at hemidesmosomes and intermediate filaments was not structurally resolved\",\n        \"Contribution of individual plectin isoforms not yet dissected\"\n      ]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrating that PLEC mutations cause EBS with pyloric atresia extended plectin's required structural role beyond skin and muscle to gastrointestinal epithelium.\",\n      \"evidence\": \"Immunohistochemistry, exon-trapping of splice-site mutation, and electron microscopy in patient tissue\",\n      \"pmids\": [\"15681471\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which plectin loss specifically disrupts pyloric epithelial integrity not defined\",\n        \"Genotype-phenotype correlations across the full mutation spectrum remain incomplete\"\n      ]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Spliceosome-mediated RNA trans-splicing restored plectin protein in patient fibroblasts, providing proof-of-concept that the molecular defect in EBS-MD is correctable at the mRNA level.\",\n      \"evidence\": \"Retroviral transduction of trans-splicing construct with immunofluorescence quantification of plectin in EBS-MD fibroblasts\",\n      \"pmids\": [\"17989727\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"In vivo efficacy and tissue-specific delivery not tested\",\n        \"Whether restored protein integrates into functional hemidesmosomes not shown\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identification of an exon-1f–specific mutation causing limb-girdle muscular dystrophy without skin disease established isoform 1f as the dominant plectin variant linking sarcolemma to sarcomere in skeletal muscle.\",\n      \"evidence\": \"Homozygosity mapping, sequencing, qRT-PCR, transmission electron microscopy, and immunofluorescence in patient muscle\",\n      \"pmids\": [\"21109228\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Binding partners of plectin 1f at the sarcolemma-sarcomere interface not fully identified\",\n        \"Whether cardiac muscle uses the same isoform not resolved\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"An exon-1a–specific mutation causing skin-only EBS with hypoplastic hemidesmosomes proved that isoform 1a is the dominant plectin species in epidermal basal keratinocytes, completing the isoform-tissue map.\",\n      \"evidence\": \"Sequencing, immunofluorescence antigen mapping, transmission electron microscopy, western blot, and qRT-PCR on patient skin and keratinocytes\",\n      \"pmids\": [\"25712130\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Functional redundancy among isoforms within the same tissue not quantified\",\n        \"Regulatory mechanisms controlling first-exon choice not addressed\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Discovery that plectin physically interacts with KRT8 to anchor mitochondria and that this linkage regulates mitophagy flux revealed a non-structural, organelle-tethering function for plectin.\",\n      \"evidence\": \"Co-immunoprecipitation, live imaging, and knockdown experiments with mitophagy and cell death readouts in retinal pigment epithelial cells\",\n      \"pmids\": [\"33783309\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether this mitochondrial tethering function operates in tissues beyond RPE cells is untested\",\n        \"Structural basis of the PLEC-KRT8-mitochondria ternary complex not defined\",\n        \"Relationship between mitochondrial tethering and the established cytoskeletal cross-linking role not integrated\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrating that plectin maintains ribbon synapse integrity and synaptic mitochondrial potential in the cochlea established an unexpected neuronal/sensory function and linked biallelic PLEC variants to severe hearing loss.\",\n      \"evidence\": \"Whole-exome sequencing in patients plus plectin knockdown in mouse and zebrafish models with ribbon synapse quantification\",\n      \"pmids\": [\"37393735\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Which plectin isoform operates at ribbon synapses is unknown\",\n        \"Whether the cochlear phenotype reflects mitochondrial tethering or cytoskeletal cross-linking is not distinguished\",\n        \"Not independently replicated in a second patient cohort\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Two studies placed plectin in signaling cascades beyond its structural role: competitive KEAP1 binding activates NRF2-driven antioxidant defense, and plectin upregulation by EpOMEs activates NFκB1-CXCL9 signaling in breast cancer.\",\n      \"evidence\": \"ChIP, co-immunoprecipitation (PLEC-KEAP1), subcellular fractionation, transcriptomics/proteomics, knockdown epistasis experiments, and in vivo mouse models\",\n      \"pmids\": [\"39500864\", \"39695149\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether the KEAP1-binding and NFκB1-activating functions are linked or independent pathways is unknown\",\n        \"PLEC-KEAP1 interaction domain not mapped\",\n        \"Relevance of signaling functions in non-cancer, physiological settings not tested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How plectin's structural cross-linking, mitochondrial tethering, and newly described signaling functions (KEAP1/NRF2, NFκB1) are coordinated across isoforms and tissues remains an open question.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No unified structural model of full-length plectin exists\",\n        \"Isoform-specific interactomes have not been systematically mapped\",\n        \"Relative contribution of structural versus signaling functions to disease phenotypes is unresolved\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 1, 2, 3]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 2, 3]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 2, 3]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 1, 2, 3]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [4, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [\n      \"hemidesmosome\"\n    ],\n    \"partners\": [\n      \"KRT8\",\n      \"KEAP1\",\n      \"ITGB4\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"Plectin is a giant cytoskeletal linker protein that bridges intermediate filament networks (keratins, desmin, vimentin) to hemidesmosomes, the sarcolemma, and other membrane–cytoskeleton junctions, thereby maintaining mechanical integrity in skin, skeletal muscle, and heart [PMID:8894687, PMID:9701547]. Loss-of-function mutations in common exons cause epidermolysis bullosa simplex with muscular dystrophy (EBS-MD), whereas isoform-specific mutations in exon 1f cause limb-girdle muscular dystrophy (LGMD2Q) and mutations in exon 1a cause skin-only EBS, demonstrating that distinct plectin isoforms fulfill tissue-restricted anchoring roles [PMID:21109228, PMID:25712130]. Beyond structural scaffolding, plectin regulates actin stress fiber dynamics, anchors mitochondria to keratin 8 to facilitate mitophagy, and competitively displaces NRF2 from KEAP1 to activate antioxidant gene expression [PMID:9701547, PMID:33783309, PMID:39500864]. Plectin also participates in NFκB1/CXCL9 signaling downstream of lipid mediator stimulation in breast cancer cells [PMID:39695149].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Identification of PLEC as the gene mutated in EBS-MD established that plectin is an essential cytoskeleton–membrane anchoring protein in both skin and muscle, resolving the molecular basis of combined epidermal fragility and muscular dystrophy.\",\n      \"evidence\": \"Mutation analysis, immunofluorescence, and electron microscopy in patient skin and muscle biopsies from multiple families\",\n      \"pmids\": [\"8894687\", \"8941634\", \"8696340\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which plectin couples intermediate filaments to hemidesmosomal transmembrane proteins was not structurally resolved\",\n        \"Contribution of individual plectin isoforms to tissue-specific phenotypes was unknown\"\n      ]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Plectin-null mice revealed that plectin binds all three major cytoskeletal networks and regulates actin stress fiber dynamics, expanding its role from a passive linker to an active regulator of cytoskeletal organization.\",\n      \"evidence\": \"Targeted gene inactivation in mice; phenotypic analysis and in vitro cell studies from plectin-null cells\",\n      \"pmids\": [\"9701547\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular mechanism of actin stress fiber regulation by plectin was not dissected\",\n        \"Relative contributions of intermediate filament anchoring versus actin regulation to the lethal phenotype were not separated\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Isoform-specific mutations demonstrated that plectin isoform 1f (P1f) links the sarcolemma to the sarcomere, and its selective loss causes LGMD2Q without skin disease, proving that isoform diversity explains tissue-restricted pathology.\",\n      \"evidence\": \"Homozygosity mapping, PLEC sequencing, isoform-specific qRT-PCR, immunofluorescence, and TEM in patient muscle from multiple families\",\n      \"pmids\": [\"21109228\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis for P1f-specific sarcolemma–sarcomere anchoring was not determined\",\n        \"Whether P1f loss also impairs signaling at the sarcolemma was not assessed\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Disruption of plectin isoform 1a (P1a) alone caused skin-only EBS with hypoplastic hemidesmosomes, completing the isoform–tissue specificity map by showing P1a is the dominant epidermal basal cell isoform.\",\n      \"evidence\": \"DNA sequencing, immunofluorescence antigen mapping, TEM, and isoform expression profiling in patient skin and control tissues\",\n      \"pmids\": [\"25712130\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether P1a-specific residues mediate unique protein–protein interactions at hemidesmosomes was not resolved\",\n        \"Functional compensation among isoforms in tissues co-expressing P1a and other variants was not tested\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Discovery that plectin physically anchors mitochondria to keratin 8 and facilitates fission-mediated mitophagy revealed a non-structural role, explaining how plectin loss can cause mitochondrial dysfunction and necrotic cell death under oxidative stress.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, siRNA knockdown of PLEC and KRT8, mitophagy flux assays, and live-cell imaging in retinal pigment epithelial cells\",\n      \"pmids\": [\"33783309\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Domain on plectin responsible for mitochondrial anchoring was not mapped\",\n        \"Whether this mitochondrial-anchoring function is relevant in muscle or skin disease has not been tested\",\n        \"Confirmation in additional cell types is lacking\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Plectin knockdown in the inner ear reduced synaptic mitochondrial potential and caused ribbon synapse loss, extending plectin's mitochondrial-support function to cochlear neurons and identifying biallelic PLEC variants as a cause of isolated hearing loss.\",\n      \"evidence\": \"Whole-exome sequencing in hearing-loss families, plectin knockdown in zebrafish and mouse inner ear, mitochondrial membrane potential assay, and ribbon synapse quantification\",\n      \"pmids\": [\"37393735\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Specific plectin isoform(s) mediating cochlear function are unknown\",\n        \"Mechanism linking plectin to mitochondrial membrane potential at synapses was not dissected\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Plectin was shown to competitively bind KEAP1 and displace NRF2, enabling NRF2 nuclear translocation and antioxidant gene activation, establishing plectin as a direct modulator of the oxidative stress response and radioresistance in ESCC.\",\n      \"evidence\": \"ChIP (ΔNp63α on PLEC promoter), co-IP (PLEC–KEAP1), subcellular fractionation, PLEC overexpression/knockdown with ROS measurement, and xenograft radiosensitivity assay\",\n      \"pmids\": [\"39500864\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"KEAP1-binding domain on plectin has not been mapped\",\n        \"Generalizability of the PLEC/KEAP1/NRF2 axis to non-cancer contexts is untested\",\n        \"Single-lab finding awaits independent replication\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placement of plectin upstream of NFκB1/CXCL9 in lipid-mediator-driven breast cancer signaling revealed yet another signaling axis influenced by plectin, beyond its structural and NRF2 roles.\",\n      \"evidence\": \"Transcriptomics/proteomics after EpOME treatment, PLEC siRNA knockdown, and in vivo xenograft/metastasis assays in TNBC models\",\n      \"pmids\": [\"39695149\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct physical interaction between plectin and NFκB1 pathway components has not been demonstrated\",\n        \"Mechanism by which plectin activates NFκB1 is undefined\",\n        \"Single-lab study in one cancer type\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How plectin's structural scaffolding, mitochondrial anchoring, and newly discovered signaling roles (NRF2, NFκB1) are coordinated across tissues and whether they are functionally coupled or independent remain major open questions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No high-resolution structure of full-length plectin or its isoform-specific domains exists\",\n        \"Domain-level separation of structural versus signaling functions has not been achieved\",\n        \"In vivo isoform-specific knockout models for signaling readouts are lacking\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 1, 2, 6, 7, 8]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 2, 6, 7]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [9, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 1, 2, 6, 7, 13]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 6, 7]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [8, 10]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [0, 6, 7]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [8, 9, 10]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [9, 12]},\n      {\"term_id\": \"R-HSA-397014\", \"supporting_discovery_ids\": [1, 6]}\n    ],\n    \"complexes\": [\n      \"Hemidesmosome\"\n    ],\n    \"partners\": [\n      \"KRT8\",\n      \"KEAP1\",\n      \"ITGB4\",\n      \"DST\",\n      \"VIM\",\n      \"DES\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}