{"gene":"NES","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2013,"finding":"A novel short nestin isoform, Nes-S, was identified in rat dorsal root ganglia (DRG) neurons. Nes-S cannot form filaments by itself in cytoplasmic intermediate filament-free SW13 cells, but co-assembles into filaments with vimentin in vimentin+ SW13 cells, and co-assembles with peripherin and neurofilament proteins in N2a cells and in primary DRG neurons. Knockdown of endogenous Nes-S impairs survival of DRG neurons in primary culture, and exogenous Nes-S enhances viability in N2a cells, establishing a cytoprotective function for this isoform.","method":"Transfection into SW13 (IF-free) and N2a cells, co-assembly assays, immunofluorescence, siRNA knockdown with cell viability readout","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD/KO with defined cellular phenotype and co-assembly assays across multiple cell systems in a single lab","pmids":["23319587"],"is_preprint":false},{"year":2013,"finding":"A second nestin isoform, Nes-SΔ₁₀₇₋₂₅₄, was identified in rat DRG neurons. Unlike Nes-S, this rod domain-truncated isoform is assembly-compromised, forms aggregates, and does not exert cytoprotective effects. Expression of EGFP-Nes-SΔ₁₀₇₋₂₅₄ in HEK293T cells elevated caspase-3 activation, indicating cytotoxicity.","method":"Transfection into SW13 and N2a cells, co-assembly assays, caspase-3 activation assay","journal":"Neuroscience letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single paper, limited mechanistic follow-up on the cytotoxic mechanism","pmids":["23994057"],"is_preprint":false}],"current_model":"Nestin (NES) is a type VI intermediate filament protein that cannot self-assemble but co-assembles with other intermediate filament proteins (vimentin, peripherin, neurofilament proteins); a short neuronal isoform (Nes-S) expressed in DRG neurons exerts a cytoprotective function required for sensory and motor neuron survival, while a further truncated isoform (Nes-SΔ₁₀₇₋₂₅₄) is assembly-deficient and cytotoxic."},"narrative":{"mechanistic_narrative":"Nestin (NES) is a type VI intermediate filament protein that cannot self-assemble but instead co-assembles into filaments with partner intermediate filament proteins; a short neuronal isoform, Nes-S, identified in rat dorsal root ganglia (DRG) neurons co-assembles with vimentin in vimentin-positive cells and with peripherin and neurofilament proteins in neuronal cells and primary DRG neurons [PMID:23319587]. Nes-S serves a cytoprotective role: its knockdown impairs survival of cultured DRG neurons while its exogenous expression enhances neuronal cell viability [PMID:23319587]. Beyond these isoform-specific co-assembly and survival functions, no further mechanistic detail on Nes-S has been characterized in the available corpus.","teleology":[{"year":2013,"claim":"Establishing how a short nestin isoform behaves in the cytoskeleton answered whether Nes-S contributes to filament networks and to neuronal survival, defining a cytoprotective role for the isoform.","evidence":"Transfection into IF-free SW13 and N2a cells with co-assembly and immunofluorescence assays, plus siRNA knockdown with cell viability readout in primary DRG neurons","pmids":["23319587"],"confidence":"Medium","gaps":["Molecular mechanism by which Nes-S promotes neuronal survival is undefined","Whether co-assembly with partner filaments is required for the cytoprotective effect is not resolved","Findings are in rat/rodent cell systems without in vivo confirmation"]},{"year":2013,"claim":"Characterizing a rod-domain-truncated isoform addressed whether structural integrity of nestin determines its protective versus toxic behavior, showing assembly competence separates cytoprotection from cytotoxicity.","evidence":"Transfection into SW13 and N2a cells, co-assembly assays, and caspase-3 activation assay in HEK293T cells","pmids":["23994057"],"confidence":"Low","gaps":["Single lab, single paper with limited mechanistic follow-up on the cytotoxic mechanism","Pathway linking aggregation to caspase-3 activation is unknown","Physiological relevance of the truncated isoform in neurons is unestablished"]},{"year":null,"claim":"The molecular pathway connecting Nes-S co-assembly to neuronal survival, and the determinants of the cytotoxic truncated isoform, remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No identified downstream effectors of Nes-S cytoprotection","No structural model of nestin co-assembly with partner filaments","No in vivo validation of isoform-specific functions"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0]}],"pathway":[],"complexes":[],"partners":["VIM","PRPH"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P48681","full_name":"Nestin","aliases":[],"length_aa":1621,"mass_kda":177.4,"function":"Required for brain and eye development. Promotes the disassembly of phosphorylated vimentin intermediate filaments (IF) during mitosis and may play a role in the trafficking and distribution of IF proteins and other cellular factors to daughter cells during progenitor cell division. Required for survival, renewal and mitogen-stimulated proliferation of neural progenitor cells (By similarity)","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/P48681/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NES","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"IPO7","stoichiometry":0.2},{"gene":"VIM","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/NES","total_profiled":1310},"omim":[{"mim_id":"621283","title":"COILED-COIL DOMAIN-CONTAINING PROTEIN 85C; CCDC85C","url":"https://www.omim.org/entry/621283"},{"mim_id":"621223","title":"ALLOGRAFT INFLAMMATORY FACTOR 1-LIKE PROTEIN; AIF1L","url":"https://www.omim.org/entry/621223"},{"mim_id":"620696","title":"RBPJ-INTERACTING AND TUBULIN-ASSOCIATED PROTEIN 1; RITA1","url":"https://www.omim.org/entry/620696"},{"mim_id":"620169","title":"ATOS HOMOLOG B; ATOSB","url":"https://www.omim.org/entry/620169"},{"mim_id":"620168","title":"ATOS HOMOLOG A; ATOSA","url":"https://www.omim.org/entry/620168"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Intermediate filaments","reliability":"Enhanced"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"heart muscle","ntpm":151.3}],"url":"https://www.proteinatlas.org/search/NES"},"hgnc":{"alias_symbol":["FLJ21841"],"prev_symbol":[]},"alphafold":{"accession":"P48681","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P48681","model_url":"https://alphafold.ebi.ac.uk/files/AF-P48681-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P48681-F1-predicted_aligned_error_v6.png","plddt_mean":48.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NES","jax_strain_url":"https://www.jax.org/strain/search?query=NES"},"sequence":{"accession":"P48681","fasta_url":"https://rest.uniprot.org/uniprotkb/P48681.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P48681/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P48681"}},"corpus_meta":[{"pmid":"10075936","id":"PMC_10075936","title":"A leucine-rich nuclear export signal in the p53 tetramerization domain: regulation of subcellular localization and p53 activity by NES 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bioanalytical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/34622320","citation_count":3,"is_preprint":false},{"pmid":"37164541","id":"PMC_37164541","title":"Human LUHMES and NES cells as models for studying primary cilia in neurons.","date":"2023","source":"Methods in cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/37164541","citation_count":2,"is_preprint":false},{"pmid":"40089503","id":"PMC_40089503","title":"Phosphate-dependent nuclear export via a non-classical NES class recognized by exportin Msn5.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/40089503","citation_count":2,"is_preprint":false},{"pmid":"37598897","id":"PMC_37598897","title":"Experience-dependent Tip60 nucleocytoplasmic transport is regulated by its NLS/NES sequences for neuroplasticity gene control.","date":"2023","source":"Molecular and cellular neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/37598897","citation_count":2,"is_preprint":false},{"pmid":"40598613","id":"PMC_40598613","title":"The CRM1-dependent NES257-266 motif in the matrix protein: another factor influencing Newcastle disease virus propagation and virulence.","date":"2025","source":"Veterinary research","url":"https://pubmed.ncbi.nlm.nih.gov/40598613","citation_count":1,"is_preprint":false},{"pmid":"36533634","id":"PMC_36533634","title":"TERT silencing alters the expression of ARG1, GLUL, VIM, NES genes and hsa-miR-29b-3p in the T98G cell line.","date":"2022","source":"Nucleosides, nucleotides & nucleic acids","url":"https://pubmed.ncbi.nlm.nih.gov/36533634","citation_count":1,"is_preprint":false},{"pmid":"41060775","id":"PMC_41060775","title":"Application of Gas-Phase Electrophoresis (nES GEMMA Instrumentation) in Molecular Weight Determination.","date":"2025","source":"Journal of mass spectrometry : JMS","url":"https://pubmed.ncbi.nlm.nih.gov/41060775","citation_count":1,"is_preprint":false},{"pmid":"27225342","id":"PMC_27225342","title":"NES-REBS: A novel nuclear export signal prediction method using regular expressions and biochemical properties.","date":"2016","source":"Journal of bioinformatics and computational biology","url":"https://pubmed.ncbi.nlm.nih.gov/27225342","citation_count":1,"is_preprint":false},{"pmid":"34543886","id":"PMC_34543886","title":"nES-DMA with Charge-reduction based on Soft X-ray Radiation: Analysis of a Recombinant Monoclonal Antibody.","date":"2021","source":"Journal of chromatography. B, Analytical technologies in the biomedical and life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34543886","citation_count":1,"is_preprint":false},{"pmid":"40620418","id":"PMC_40620418","title":"Strong Immune Privileges of MSC and Other Nes-GFP+ Progenitors in Bone Marrow of Transgenic Mice.","date":"2025","source":"Immune network","url":"https://pubmed.ncbi.nlm.nih.gov/40620418","citation_count":1,"is_preprint":false},{"pmid":"12020830","id":"PMC_12020830","title":"The nuclear export signal (NES) found in the amino-terminal region of carp MEK1 and MKK6 is lacking in carp MKK4.","date":"2002","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/12020830","citation_count":1,"is_preprint":false},{"pmid":"17168825","id":"PMC_17168825","title":"Antiviral properties of combination peptides of HIV-1 Rev NLS and NES.","date":"2006","source":"Protein and peptide letters","url":"https://pubmed.ncbi.nlm.nih.gov/17168825","citation_count":1,"is_preprint":false},{"pmid":"3387458","id":"PMC_3387458","title":"Pharmacological nature of newer imidazoli(di)nes on rat anococcygeus muscle.","date":"1988","source":"Pharmacological research communications","url":"https://pubmed.ncbi.nlm.nih.gov/3387458","citation_count":1,"is_preprint":false},{"pmid":"41010493","id":"PMC_41010493","title":"Immunomodulatory Effects of Lactobacillus brevis NES-428 in a Hyperthyroidism Mouse Model: Potential Applications for Graves' Disease.","date":"2025","source":"Nutrients","url":"https://pubmed.ncbi.nlm.nih.gov/41010493","citation_count":0,"is_preprint":false},{"pmid":"41322519","id":"PMC_41322519","title":"Gas-Phase Electrophoresis (nES GEMMA Instrumentation) of SARS-CoV-2-Based Virus-like Particles.","date":"2025","source":"ACS omega","url":"https://pubmed.ncbi.nlm.nih.gov/41322519","citation_count":0,"is_preprint":false},{"pmid":"39211127","id":"PMC_39211127","title":"Phosphate-dependent nuclear export via a novel NES class recognized by exportin Msn5.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/39211127","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.07.25337538","title":"Automated Seizure Classification Using Multimodal Large Language Models","date":"2025-10-09","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.07.25337538","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":35805,"output_tokens":1126,"usd":0.062152,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7113,"output_tokens":1233,"usd":0.033195,"stage2_stop_reason":"end_turn"},"total_usd":0.095347,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking through the abstracts, I need to identify papers about the canonical NES (Nestin) gene - the human intermediate filament protein Nestin encoded by the NES gene (also known as FLJ21841).\n\nMost papers in this corpus are about nuclear export signals (NES acronym collision), nanoelectrospray instruments (nES GEMMA), nerolidol synthase (NES enzyme), non-epileptic seizures (NES), or other unrelated topics. I need to focus only on papers about the Nestin protein.\n\nPapers about Nestin (NES gene):\n- PMID:23319587 - Nes-S isoform in DRG neurons\n- PMID:23994057 - Nes-SΔ₁₀₇₋₂₅₄ isoform in DRG\n- PMID:16847871 - Nes-Cre1 transgenic line (tool paper, not mechanistic about Nestin itself)\n- PMID:38356373 - iPSC-derived cells, NES+ TM cells (mostly expression)\n- PMID:35053384 - NES-mScarlet reporter line (tool paper)\n- PMID:36533634 - TERT silencing affects NES expression (expression correlation)\n- PMID:39273022 - NES expression in melanoma (expression/IHC)\n- PMID:40620418 - Nes-GFP+ progenitors immune privilege (no direct Nestin mechanism)\n- PMID:37164541 - NES cells as cilia models (tool/cell model paper)\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"A novel short nestin isoform, Nes-S, was identified in rat dorsal root ganglia (DRG) neurons. Nes-S cannot form filaments by itself in cytoplasmic intermediate filament-free SW13 cells, but co-assembles into filaments with vimentin in vimentin+ SW13 cells, and co-assembles with peripherin and neurofilament proteins in N2a cells and in primary DRG neurons. Knockdown of endogenous Nes-S impairs survival of DRG neurons in primary culture, and exogenous Nes-S enhances viability in N2a cells, establishing a cytoprotective function for this isoform.\",\n      \"method\": \"Transfection into SW13 (IF-free) and N2a cells, co-assembly assays, immunofluorescence, siRNA knockdown with cell viability readout\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD/KO with defined cellular phenotype and co-assembly assays across multiple cell systems in a single lab\",\n      \"pmids\": [\"23319587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A second nestin isoform, Nes-SΔ₁₀₇₋₂₅₄, was identified in rat DRG neurons. Unlike Nes-S, this rod domain-truncated isoform is assembly-compromised, forms aggregates, and does not exert cytoprotective effects. Expression of EGFP-Nes-SΔ₁₀₇₋₂₅₄ in HEK293T cells elevated caspase-3 activation, indicating cytotoxicity.\",\n      \"method\": \"Transfection into SW13 and N2a cells, co-assembly assays, caspase-3 activation assay\",\n      \"journal\": \"Neuroscience letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single paper, limited mechanistic follow-up on the cytotoxic mechanism\",\n      \"pmids\": [\"23994057\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Nestin (NES) is a type VI intermediate filament protein that cannot self-assemble but co-assembles with other intermediate filament proteins (vimentin, peripherin, neurofilament proteins); a short neuronal isoform (Nes-S) expressed in DRG neurons exerts a cytoprotective function required for sensory and motor neuron survival, while a further truncated isoform (Nes-SΔ₁₀₇₋₂₅₄) is assembly-deficient and cytotoxic.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"Nestin (NES) is a type VI intermediate filament protein that cannot self-assemble but instead co-assembles into filaments with partner intermediate filament proteins; a short neuronal isoform, Nes-S, identified in rat dorsal root ganglia (DRG) neurons co-assembles with vimentin in vimentin-positive cells and with peripherin and neurofilament proteins in neuronal cells and primary DRG neurons [#0]. Nes-S serves a cytoprotective role: its knockdown impairs survival of cultured DRG neurons while its exogenous expression enhances neuronal cell viability [#0]. Beyond these isoform-specific co-assembly and survival functions, no further mechanistic detail on Nes-S has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Establishing how a short nestin isoform behaves in the cytoskeleton answered whether Nes-S contributes to filament networks and to neuronal survival, defining a cytoprotective role for the isoform.\",\n      \"evidence\": \"Transfection into IF-free SW13 and N2a cells with co-assembly and immunofluorescence assays, plus siRNA knockdown with cell viability readout in primary DRG neurons\",\n      \"pmids\": [\n        \"23319587\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Molecular mechanism by which Nes-S promotes neuronal survival is undefined\",\n        \"Whether co-assembly with partner filaments is required for the cytoprotective effect is not resolved\",\n        \"Findings are in rat/rodent cell systems without in vivo confirmation\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Characterizing a rod-domain-truncated isoform addressed whether structural integrity of nestin determines its protective versus toxic behavior, showing assembly competence separates cytoprotection from cytotoxicity.\",\n      \"evidence\": \"Transfection into SW13 and N2a cells, co-assembly assays, and caspase-3 activation assay in HEK293T cells\",\n      \"pmids\": [\n        \"23994057\"\n      ],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single lab, single paper with limited mechanistic follow-up on the cytotoxic mechanism\",\n        \"Pathway linking aggregation to caspase-3 activation is unknown\",\n        \"Physiological relevance of the truncated isoform in neurons is unestablished\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular pathway connecting Nes-S co-assembly to neuronal survival, and the determinants of the cytotoxic truncated isoform, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No identified downstream effectors of Nes-S cytoprotection\",\n        \"No structural model of nestin co-assembly with partner filaments\",\n        \"No in vivo validation of isoform-specific functions\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\n        \"term_id\": \"GO:0005198\",\n        \"supporting_discovery_ids\": [\n          0\n        ]\n      }\n    ],\n    \"localization\": [\n      {\n        \"term_id\": \"GO:0005856\",\n        \"supporting_discovery_ids\": [\n          0\n        ]\n      }\n    ],\n    \"pathway\": [],\n    \"complexes\": [],\n    \"partners\": [\n      \"VIM\",\n      \"PRPH\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":2,"faith_total":2,"faith_pct":100.0}}