{"gene":"SLN","run_date":"2026-06-10T07:46:35","timeline":{"discoveries":[{"year":1997,"finding":"Human sarcolipin (SLN) encodes a 31-amino acid protein that co-purifies with the fast-twitch skeletal muscle sarcoplasmic reticulum Ca2+ ATPase (SERCA1). Homology with phospholamban (PLN) indicates a cytoplasmic N-terminus (residues 1–7), a single transmembrane helix (residues 8–26), and a lumenal C-terminus (residues 27–31) with a highly conserved lumenal sequence across species. The SLN gene maps to chromosome 11q22–q23 and has a two-exon structure similar to PLN.","method":"cDNA/genomic DNA isolation, sequence analysis, chromosomal mapping, tissue expression analysis","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct molecular characterization with multiple orthogonal methods (sequencing, mapping, expression), foundational structural/topological model independently consistent with subsequent studies","pmids":["9367679"],"is_preprint":false},{"year":1997,"finding":"SLN is highly expressed in fast-twitch skeletal muscle (co-expressed with SERCA1), expressed at lower levels in slow-twitch and cardiac muscle (where SERCA2a and phospholamban predominate), and expressed only in trace amounts in pancreas and prostate, establishing tissue-specific co-expression of SLN with SERCA1.","method":"Northern blot / tissue expression analysis","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct experimental tissue expression profiling; finding has been consistently replicated in subsequent literature","pmids":["9367679"],"is_preprint":false},{"year":2006,"finding":"Sarcolipin inhibits the sarcoplasmic reticulum Ca2+ ATPase pump SERCA2 in cardiac tissue. Screening of the SLN coding region in patients with atrial fibrillation, long QT syndrome, and sudden arrhythmic death syndrome revealed no mutations in the coding sequence, indicating that coding-region SLN mutations are not a frequent cause of these arrhythmic disorders.","method":"SSCP/heteroduplex analysis and sequencing of SLN coding region in patient cohorts","journal":"Clinica chimica acta","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional inhibition of SERCA2 stated as established background; negative mutation screening result is the primary experimental finding; single lab","pmids":["17010328"],"is_preprint":false},{"year":2022,"finding":"Stable knockdown of SLN in human skeletal muscle cells (myotubes) reduces glucose oxidation, oleic acid oxidation, and basal mitochondrial respiration. SLN-KD cells show increased lipid accumulation, elevated lipid formation from de novo lipogenesis, and reduced expression of PGC1α and FOXO1, demonstrating that SLN is required for normal substrate (fuel) utilization and metabolic homeostasis in human skeletal muscle.","method":"Stable shRNA knockdown, radiolabeled substrate oxidation assays, Seahorse respirometry, gene expression analysis, Oil Red O staining","journal":"Molecular biology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD with defined cellular phenotype, multiple orthogonal metabolic readouts; single lab","pmids":["35364719"],"is_preprint":false},{"year":2024,"finding":"Chronic melatonin treatment in obese Zücker diabetic fatty rats increases SLN protein levels in vastus lateralis skeletal muscle, raises SERCA2 (but not SERCA1) expression, and enhances SERCA activity, resulting in uncoupling of the SERCA–SLN futile Ca2+ cycle. This is accompanied by activation of the CaMKII/AMPK/PGC1α thermogenic axis, increased mitochondrial biogenesis, and reduced body weight gain, establishing that SLN-mediated SERCA uncoupling drives non-shivering thermogenesis (NST) in skeletal muscle.","method":"In vivo melatonin treatment, western blotting (SLN, SERCA1, SERCA2, PGC1α, PPARγ, NRF1, P-CaMKII, P-AMPK), SERCA activity assay, infrared thermometry, echocardiography","journal":"Biomedicine & pharmacotherapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo gain-of-function with multiple orthogonal readouts (protein, activity, thermometry); single lab, pharmacological intervention","pmids":["38387135"],"is_preprint":false},{"year":2023,"finding":"In sweat gland myoepithelial cells, sarcolipin (SLN) is a key regulator of SERCA, and its expression is significantly down-regulated upon sympathetic denervation. Loss of SLN leads to decreased intracellular Ca2+ in response to acetylcholine stimulation and causes myoepithelial (basal) cells to upregulate luminal cell features, showing that SLN-mediated intracellular Ca2+ regulation downstream of neurotransmitter signaling specifies sweat gland stem cell fate.","method":"Denervation experiments, SLN loss-of-function in sweat gland myoepithelial cells, intracellular Ca2+ imaging, cell-fate marker analysis, cell culture Ca2+ manipulation","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined cellular phenotype, Ca2+ imaging; single lab, preprint not yet peer-reviewed","pmids":["37745514"],"is_preprint":true},{"year":2025,"finding":"In a doxorubicin-induced cardiomyopathy model, cardiac-specific ablation of Slc25a49 in cardiomyocytes leads to enhanced glycolysis, elevated glucose-6-phosphate (G6P), and activation of the AP-1 transcription factor complex, which in turn transcriptionally upregulates Sarcolipin (Sln) expression. Elevated Sln intensifies myocardial damage, placing Sln downstream of the G6P–AP-1 axis in doxorubicin cardiotoxicity. Chromatin immunoprecipitation and dual-luciferase reporter assays confirmed that AP-1 directly drives Sln transcription.","method":"Cardiac-specific Slc25a49 knockout mice, doxorubicin treatment, bulk RNA-seq, metabolomics, chromatin immunoprecipitation (ChIP), dual-luciferase reporter assay, echocardiography, histology","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (ChIP, reporter assay, KO model, metabolomics) in one rigorous study establishing transcriptional regulation of SLN by AP-1","pmids":["40184586"],"is_preprint":false},{"year":2023,"finding":"Sarcolipin (sln) and SERCA1 (serca1) transcript levels increase significantly in skeletal muscle of Japanese medaka subjected to cold challenge, with elevated expression seen in both slow-twitch red and fast-twitch white muscle, supporting a conserved transcriptional program linking SLN to non-shivering thermogenesis (NST) via futile Ca2+ cycling through SERCA uncoupling in ectothermic fish.","method":"Cold challenge in vivo, RT-qPCR of sln and serca1 transcripts from dissected skeletal muscle","journal":"Comparative biochemistry and physiology. Part A","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method (RT-qPCR), transcript-level data only without direct functional assay of SERCA uncoupling","pmids":["37844835"],"is_preprint":false}],"current_model":"Sarcolipin (SLN) is a 31-amino acid single-pass transmembrane proteolipid that associates with and inhibits/uncouples the sarcoplasmic reticulum Ca2+-ATPase (SERCA1 in fast-twitch skeletal muscle; SERCA2 in cardiac muscle), driving a futile Ca2+ cycling that consumes ATP and generates heat (non-shivering thermogenesis); SLN expression is regulated transcriptionally (e.g., by the AP-1 complex downstream of metabolic stress) and is required for normal substrate oxidation and metabolic homeostasis in skeletal muscle, while in specialized epithelia such as sweat glands it modulates intracellular Ca2+ dynamics downstream of neurotransmitter signaling to determine stem cell fate."},"narrative":{"mechanistic_narrative":"Sarcolipin (SLN) is a 31-amino acid single-pass transmembrane proteolipid that regulates sarcoplasmic reticulum (SR) Ca2+ handling by associating with and inhibiting the SR Ca2+-ATPase (SERCA), with SLN highly co-expressed with SERCA1 in fast-twitch skeletal muscle and acting on SERCA2 in cardiac tissue [PMID:9367679, PMID:17010328]. Structurally it resembles phospholamban, with a cytoplasmic N-terminus, a single transmembrane helix, and a conserved lumenal C-terminus [PMID:9367679]. Functionally, SLN uncouples the SERCA pump to drive a futile Ca2+ cycle that consumes ATP and produces heat, a mechanism engaged during conditions that activate non-shivering thermogenesis through the CaMKII/AMPK/PGC1α axis [PMID:38387135]. Consistent with this metabolic role, loss of SLN in human myotubes impairs glucose and fatty-acid oxidation, lowers mitochondrial respiration, and promotes lipid accumulation, establishing SLN as required for normal substrate utilization and metabolic homeostasis in skeletal muscle [PMID:35364719]. SLN expression is controlled transcriptionally: the AP-1 complex directly drives Sln transcription downstream of a glucose-6-phosphate signal, and elevated Sln in this context intensifies myocardial damage in doxorubicin cardiotoxicity [PMID:40184586]. Beyond muscle, SLN regulates SERCA-dependent intracellular Ca2+ dynamics downstream of neurotransmitter signaling in sweat gland myoepithelial cells to specify stem cell fate [PMID:37745514].","teleology":[{"year":1997,"claim":"Established the molecular identity, topology, and tissue distribution of SLN, defining it as a phospholamban-like proteolipid co-purifying with SERCA1 in fast-twitch skeletal muscle.","evidence":"cDNA/genomic isolation, sequence and chromosomal mapping, and Northern tissue profiling","pmids":["9367679"],"confidence":"High","gaps":["Co-purification does not demonstrate direct functional regulation of SERCA","Topological model inferred from PLN homology, not directly resolved","Functional consequence of the conserved lumenal C-terminus not tested"]},{"year":2006,"claim":"Extended SLN's inhibitory action to the cardiac SERCA2 isoform and tested, with a negative result, whether SLN coding mutations cause human arrhythmias.","evidence":"SSCP/heteroduplex screening and sequencing of SLN coding region in arrhythmia patient cohorts","pmids":["17010328"],"confidence":"Medium","gaps":["SERCA2 inhibition stated as background rather than demonstrated here","Non-coding/regulatory SLN variants not screened","No mechanistic dissection of SLN-SERCA2 interaction"]},{"year":2022,"claim":"Showed SLN is required for normal fuel oxidation in human skeletal muscle, linking its Ca2+-handling role to whole-cell metabolic homeostasis.","evidence":"Stable shRNA knockdown in human myotubes with radiolabeled substrate oxidation, Seahorse respirometry, lipid staining, and gene expression","pmids":["35364719"],"confidence":"Medium","gaps":["Metabolic phenotype not mechanistically tied to SERCA Ca2+ cycling in this study","Single cell model, single lab","Causality of PGC1α/FOXO1 downregulation versus consequence unresolved"]},{"year":2024,"claim":"Provided in vivo gain-of-function evidence that SLN-mediated SERCA uncoupling drives non-shivering thermogenesis via the CaMKII/AMPK/PGC1α axis.","evidence":"Chronic melatonin treatment in obese diabetic rats with western blots, SERCA activity assays, and infrared thermometry","pmids":["38387135"],"confidence":"Medium","gaps":["Pharmacological intervention; SLN increase is correlated rather than directly manipulated","Direct measurement of futile Ca2+ cycling not performed","Single lab"]},{"year":2025,"claim":"Identified the AP-1 transcription factor as a direct upstream driver of Sln expression downstream of a G6P metabolic signal, placing SLN in a pathogenic cardiac stress pathway.","evidence":"Cardiac-specific Slc25a49 knockout mice with doxorubicin, RNA-seq, metabolomics, ChIP, and dual-luciferase reporter assays","pmids":["40184586"],"confidence":"High","gaps":["Mechanism by which elevated Sln intensifies myocardial damage not fully resolved","Whether the G6P-AP-1-Sln axis operates in skeletal muscle untested","AP-1 subunit composition driving Sln transcription not specified"]},{"year":2023,"claim":"Extended SLN's role beyond muscle, showing it regulates SERCA-dependent intracellular Ca2+ downstream of neurotransmitter signaling to control sweat gland stem cell fate.","evidence":"Denervation and SLN loss-of-function in sweat gland myoepithelial cells with Ca2+ imaging and cell-fate marker analysis (preprint)","pmids":["37745514"],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","Single lab, single system","Direct biochemical SLN-SERCA interaction in this cell type not shown"]},{"year":2023,"claim":"Tested evolutionary conservation of the SLN-SERCA thermogenic program in an ectotherm using cold-induced transcriptional responses.","evidence":"Cold challenge with RT-qPCR of sln and serca1 in medaka skeletal muscle","pmids":["37844835"],"confidence":"Low","gaps":["Transcript-level data only without functional assay of SERCA uncoupling","Single method, single lab","Correlation between sln induction and actual thermogenesis not measured"]},{"year":null,"claim":"How SLN structurally engages SERCA to switch between inhibition and uncoupling, and what signals toggle this in vivo, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of the SLN-SERCA complex in the corpus","Molecular determinants of uncoupling versus simple inhibition undefined","Tissue-specific regulators beyond AP-1 uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,2,4]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0]}],"pathway":[],"complexes":[],"partners":["SERCA1","SERCA2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O00631","full_name":"Sarcolipin","aliases":[],"length_aa":31,"mass_kda":3.8,"function":"Reversibly inhibits the activity of ATP2A1/SERCA1 and ATP2A2/SERCA2 in sarcoplasmic reticulum by decreasing the apparent affinity of the ATPase for Ca(2+) (PubMed:11781085, PubMed:9575189). Also inhibits the activity of ATP2A3/SERCA3 (By similarity). Modulates calcium re-uptake during muscle relaxation and plays an important role in calcium homeostasis in muscle. Required for muscle-based, non-shivering thermogenesis (By similarity)","subcellular_location":"Sarcoplasmic reticulum membrane; Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/O00631/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SLN","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1090,"dependency_fraction":0.0009174311926605505},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SLN","total_profiled":1310},"omim":[{"mim_id":"620531","title":"SMALL INTEGRAL MEMBRANE PROTEIN 6; SMIM6","url":"https://www.omim.org/entry/620531"},{"mim_id":"620530","title":"ALLREGULIN; ARLN","url":"https://www.omim.org/entry/620530"},{"mim_id":"616891","title":"SMALL TRANSMEMBRANE REGULATOR OF ION TRANSPORT 1; STRIT1","url":"https://www.omim.org/entry/616891"},{"mim_id":"616246","title":"MYOREGULIN; MRLN","url":"https://www.omim.org/entry/616246"},{"mim_id":"602203","title":"SARCOLIPIN; SLN","url":"https://www.omim.org/entry/602203"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Microtubules","reliability":"Approved"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"skeletal muscle","ntpm":7680.1},{"tissue":"tongue","ntpm":3171.0}],"url":"https://www.proteinatlas.org/search/SLN"},"hgnc":{"alias_symbol":["MGC12301","MGC125854","MGC125855"],"prev_symbol":[]},"alphafold":{"accession":"O00631","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O00631","model_url":"https://alphafold.ebi.ac.uk/files/AF-O00631-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O00631-F1-predicted_aligned_error_v6.png","plddt_mean":91.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SLN","jax_strain_url":"https://www.jax.org/strain/search?query=SLN"},"sequence":{"accession":"O00631","fasta_url":"https://rest.uniprot.org/uniprotkb/O00631.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O00631/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O00631"}},"corpus_meta":[{"pmid":"21291409","id":"PMC_21291409","title":"20 years of lipid nanoparticles (SLN and NLC): present state of development and industrial applications.","date":"2011","source":"Current drug discovery technologies","url":"https://pubmed.ncbi.nlm.nih.gov/21291409","citation_count":334,"is_preprint":false},{"pmid":"21530187","id":"PMC_21530187","title":"Preparation, characterization and biocompatibility studies on risperidone-loaded solid lipid nanoparticles (SLN): high pressure homogenization versus ultrasound.","date":"2011","source":"Colloids and surfaces. 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research & treatment","url":"https://pubmed.ncbi.nlm.nih.gov/17994797","citation_count":6,"is_preprint":false},{"pmid":"29629662","id":"PMC_29629662","title":"Vitamin E TPGS Emulsified Vinorelbine Bitartrate Loaded Solid Lipid Nanoparticles (SLN): Formulation Development, Optimization and In vitro Characterization.","date":"2018","source":"Current drug delivery","url":"https://pubmed.ncbi.nlm.nih.gov/29629662","citation_count":5,"is_preprint":false},{"pmid":"37844835","id":"PMC_37844835","title":"Sarcolipin (sln) and Sarcoplasmic Reticulum calcium ATPase pump (serca1) expression increase in Japanese medaka (Oryzias latipes) skeletal muscle tissue following cold challenge.","date":"2023","source":"Comparative biochemistry and physiology. Part A, Molecular & integrative physiology","url":"https://pubmed.ncbi.nlm.nih.gov/37844835","citation_count":4,"is_preprint":false},{"pmid":"38300021","id":"PMC_38300021","title":"Cationic solid lipid nanoparticles (SLN) complexed with plasmid DNA enhance prostate cancer cells (PC-3) migration.","date":"2024","source":"Nanotoxicology","url":"https://pubmed.ncbi.nlm.nih.gov/38300021","citation_count":4,"is_preprint":false},{"pmid":"40503058","id":"PMC_40503058","title":"Enhanced lymphatic transportation of SLN by mimicking oligopeptide transportation route.","date":"2025","source":"Asian journal of pharmaceutical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40503058","citation_count":4,"is_preprint":false},{"pmid":"35364719","id":"PMC_35364719","title":"Knockdown of sarcolipin (SLN) impairs substrate utilization in human skeletal muscle cells.","date":"2022","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/35364719","citation_count":4,"is_preprint":false},{"pmid":"30035819","id":"PMC_30035819","title":"Maspin mRNA expression in sentinel lymph nodes predicts non-SLN metastasis in breast cancer patients with SLN metastasis.","date":"2018","source":"Histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/30035819","citation_count":3,"is_preprint":false},{"pmid":"37745514","id":"PMC_37745514","title":"Neurotransmitter signaling specifies sweat gland stem cell fate through SLN-mediated intracellular calcium regulation.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/37745514","citation_count":3,"is_preprint":false},{"pmid":"32580304","id":"PMC_32580304","title":"The Effects of Mutual Interaction of Orexin-A and Glucagon-Like Peptide-1 on Reflex Swallowing Induced by SLN Afferents in Rats.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32580304","citation_count":3,"is_preprint":false},{"pmid":"37662299","id":"PMC_37662299","title":"ACD15, ACD21 and SLN regulate accumulation and mobility of MBD6 to silence genes and transposable elements.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/37662299","citation_count":2,"is_preprint":false},{"pmid":"38782254","id":"PMC_38782254","title":"Relative sarcolipin (SLN) and sarcoplasmic reticulum Ca2+ ATPase (SERCA1) transcripts levels in closely related endothermic and ectothermic scombrid fishes: Implications for molecular basis of futile calcium cycle non-shivering thermogenesis (NST).","date":"2024","source":"Comparative biochemistry and physiology. Part A, Molecular & integrative physiology","url":"https://pubmed.ncbi.nlm.nih.gov/38782254","citation_count":2,"is_preprint":false},{"pmid":"38688253","id":"PMC_38688253","title":"Exploring the interplay between the TGF-βpathway and SLN-mediated transfection: implications for gene delivery efficiency in prostate cancer and non-cancer cells.","date":"2024","source":"Nanotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/38688253","citation_count":1,"is_preprint":false},{"pmid":"40838679","id":"PMC_40838679","title":"Enhanced Cytotoxic Effects of Docetaxel-Loaded Solid Lipid Nanoparticles (SLN-DTX) on Gastric Adenocarcinoma In Vitro.","date":"2025","source":"Journal of biochemical and molecular toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/40838679","citation_count":1,"is_preprint":false},{"pmid":"2156546","id":"PMC_2156546","title":"DNA rearrangements of the int region in spontaneous mouse mammary tumors of SHN/S and SLN/S mice.","date":"1990","source":"European journal of cancer 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patients.","date":"2014","source":"International journal of colorectal disease","url":"https://pubmed.ncbi.nlm.nih.gov/24763756","citation_count":0,"is_preprint":false},{"pmid":"39975566","id":"PMC_39975566","title":"Step-by-step combination of 99mTc and ICG with endoscopic near infrared cameras in SLN mapping early-stage vulvar cancer.","date":"2025","source":"Gynecologic oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/39975566","citation_count":0,"is_preprint":false},{"pmid":"42191970","id":"PMC_42191970","title":"Production of monoclonal antibodies (mAbs) against oralcarcinoma & its bioconjugation with solid lipid nanoparticles (SLN) for drug delivery.","date":"2026","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/42191970","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.06.11.658392","title":"Magnetic Particle Imaging Lymphography (MPIL): A novel technique for lymph node mapping","date":"2025-06-15","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.11.658392","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.11.18.689013","title":"Unified Generation of Regionalized Neural Organoids from Single-Lumen Neuroepithelium","date":"2025-11-18","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.18.689013","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.05.21.655399","title":"Proteomic analysis of exosomes from lymphatic affluents reveals their implications in developing premetastatic niche in melanoma","date":"2025-05-24","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.21.655399","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.06.02.657404","title":"The hemagglutinin proteins of clades 1 and 2.3.4.4b H5N1 highly pathogenic avian influenza viruses exhibit comparable attachment patterns to avian and mammalian 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Miniproteins","date":"2025-02-05","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.31.635936","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.07.30.24311256","title":"Applications of ICG in Breast Cancer for Sentinel Lymph Node Mapping: A Scoping Review Protocol","date":"2024-08-01","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.30.24311256","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.09.18.24313862","title":"Genetic Distinctions Between Reticular Pseudodrusen and Drusen: Insights from a Genome-Wide Association Study","date":"2024-09-19","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.18.24313862","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":47716,"output_tokens":2823,"usd":0.092746,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9615,"output_tokens":2771,"usd":0.058675,"stage2_stop_reason":"end_turn"},"total_usd":0.151421,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking through the abstracts, I need to identify papers about the canonical human/mammalian SLN gene (sarcolipin), a small transmembrane protein that regulates SERCA (sarcoplasmic reticulum Ca2+ ATPase).\n\nPapers clearly about the canonical SLN protein:\n- PMID:9367679 - Gene characterization, homology with PLN, SERCA1 association\n- PMID:17010328 - SLN inhibits SERCA2 in heart\n- PMID:38387135 - SERCA-SLN uncoupling, thermogenesis, CaMKII/AMPK/PGC1α\n- PMID:35364719 - SLN knockdown, substrate metabolism\n- PMID:37844835 - sln/serca1 in cold challenge (fish ortholog)\n- PMID:38782254 - SLN-SERCA1 NST in fishes (comparative)\n- PMID:37745514 - SLN in sweat gland, Ca2+ regulation, stem cell fate (PREPRINT)\n- PMID:40184586 - G6P-AP-1-Sln axis, cardiac\n- PMID:42114688 - computational miniprotein analysis (low tier)\n\nPapers with \"SLN\" = solid lipid nanoparticles → EXCLUDE\nPapers with \"SLN\" = sentinel lymph node → EXCLUDE\nPapers with \"SLN\" = Arabidopsis SILENZIO → EXCLUDE (symbol collision, plant)\nPMID:10417727 - SLN in pea = plant GA2ox → EXCLUDE\nPapers about sLNv (Drosophila neurons) → EXCLUDE\nPapers about spinal locomotor network (SLN) → EXCLUDE\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"Human sarcolipin (SLN) encodes a 31-amino acid protein that co-purifies with the fast-twitch skeletal muscle sarcoplasmic reticulum Ca2+ ATPase (SERCA1). Homology with phospholamban (PLN) indicates a cytoplasmic N-terminus (residues 1–7), a single transmembrane helix (residues 8–26), and a lumenal C-terminus (residues 27–31) with a highly conserved lumenal sequence across species. The SLN gene maps to chromosome 11q22–q23 and has a two-exon structure similar to PLN.\",\n      \"method\": \"cDNA/genomic DNA isolation, sequence analysis, chromosomal mapping, tissue expression analysis\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct molecular characterization with multiple orthogonal methods (sequencing, mapping, expression), foundational structural/topological model independently consistent with subsequent studies\",\n      \"pmids\": [\"9367679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"SLN is highly expressed in fast-twitch skeletal muscle (co-expressed with SERCA1), expressed at lower levels in slow-twitch and cardiac muscle (where SERCA2a and phospholamban predominate), and expressed only in trace amounts in pancreas and prostate, establishing tissue-specific co-expression of SLN with SERCA1.\",\n      \"method\": \"Northern blot / tissue expression analysis\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct experimental tissue expression profiling; finding has been consistently replicated in subsequent literature\",\n      \"pmids\": [\"9367679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Sarcolipin inhibits the sarcoplasmic reticulum Ca2+ ATPase pump SERCA2 in cardiac tissue. Screening of the SLN coding region in patients with atrial fibrillation, long QT syndrome, and sudden arrhythmic death syndrome revealed no mutations in the coding sequence, indicating that coding-region SLN mutations are not a frequent cause of these arrhythmic disorders.\",\n      \"method\": \"SSCP/heteroduplex analysis and sequencing of SLN coding region in patient cohorts\",\n      \"journal\": \"Clinica chimica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional inhibition of SERCA2 stated as established background; negative mutation screening result is the primary experimental finding; single lab\",\n      \"pmids\": [\"17010328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Stable knockdown of SLN in human skeletal muscle cells (myotubes) reduces glucose oxidation, oleic acid oxidation, and basal mitochondrial respiration. SLN-KD cells show increased lipid accumulation, elevated lipid formation from de novo lipogenesis, and reduced expression of PGC1α and FOXO1, demonstrating that SLN is required for normal substrate (fuel) utilization and metabolic homeostasis in human skeletal muscle.\",\n      \"method\": \"Stable shRNA knockdown, radiolabeled substrate oxidation assays, Seahorse respirometry, gene expression analysis, Oil Red O staining\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with defined cellular phenotype, multiple orthogonal metabolic readouts; single lab\",\n      \"pmids\": [\"35364719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Chronic melatonin treatment in obese Zücker diabetic fatty rats increases SLN protein levels in vastus lateralis skeletal muscle, raises SERCA2 (but not SERCA1) expression, and enhances SERCA activity, resulting in uncoupling of the SERCA–SLN futile Ca2+ cycle. This is accompanied by activation of the CaMKII/AMPK/PGC1α thermogenic axis, increased mitochondrial biogenesis, and reduced body weight gain, establishing that SLN-mediated SERCA uncoupling drives non-shivering thermogenesis (NST) in skeletal muscle.\",\n      \"method\": \"In vivo melatonin treatment, western blotting (SLN, SERCA1, SERCA2, PGC1α, PPARγ, NRF1, P-CaMKII, P-AMPK), SERCA activity assay, infrared thermometry, echocardiography\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo gain-of-function with multiple orthogonal readouts (protein, activity, thermometry); single lab, pharmacological intervention\",\n      \"pmids\": [\"38387135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In sweat gland myoepithelial cells, sarcolipin (SLN) is a key regulator of SERCA, and its expression is significantly down-regulated upon sympathetic denervation. Loss of SLN leads to decreased intracellular Ca2+ in response to acetylcholine stimulation and causes myoepithelial (basal) cells to upregulate luminal cell features, showing that SLN-mediated intracellular Ca2+ regulation downstream of neurotransmitter signaling specifies sweat gland stem cell fate.\",\n      \"method\": \"Denervation experiments, SLN loss-of-function in sweat gland myoepithelial cells, intracellular Ca2+ imaging, cell-fate marker analysis, cell culture Ca2+ manipulation\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined cellular phenotype, Ca2+ imaging; single lab, preprint not yet peer-reviewed\",\n      \"pmids\": [\"37745514\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In a doxorubicin-induced cardiomyopathy model, cardiac-specific ablation of Slc25a49 in cardiomyocytes leads to enhanced glycolysis, elevated glucose-6-phosphate (G6P), and activation of the AP-1 transcription factor complex, which in turn transcriptionally upregulates Sarcolipin (Sln) expression. Elevated Sln intensifies myocardial damage, placing Sln downstream of the G6P–AP-1 axis in doxorubicin cardiotoxicity. Chromatin immunoprecipitation and dual-luciferase reporter assays confirmed that AP-1 directly drives Sln transcription.\",\n      \"method\": \"Cardiac-specific Slc25a49 knockout mice, doxorubicin treatment, bulk RNA-seq, metabolomics, chromatin immunoprecipitation (ChIP), dual-luciferase reporter assay, echocardiography, histology\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (ChIP, reporter assay, KO model, metabolomics) in one rigorous study establishing transcriptional regulation of SLN by AP-1\",\n      \"pmids\": [\"40184586\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Sarcolipin (sln) and SERCA1 (serca1) transcript levels increase significantly in skeletal muscle of Japanese medaka subjected to cold challenge, with elevated expression seen in both slow-twitch red and fast-twitch white muscle, supporting a conserved transcriptional program linking SLN to non-shivering thermogenesis (NST) via futile Ca2+ cycling through SERCA uncoupling in ectothermic fish.\",\n      \"method\": \"Cold challenge in vivo, RT-qPCR of sln and serca1 transcripts from dissected skeletal muscle\",\n      \"journal\": \"Comparative biochemistry and physiology. Part A\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method (RT-qPCR), transcript-level data only without direct functional assay of SERCA uncoupling\",\n      \"pmids\": [\"37844835\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Sarcolipin (SLN) is a 31-amino acid single-pass transmembrane proteolipid that associates with and inhibits/uncouples the sarcoplasmic reticulum Ca2+-ATPase (SERCA1 in fast-twitch skeletal muscle; SERCA2 in cardiac muscle), driving a futile Ca2+ cycling that consumes ATP and generates heat (non-shivering thermogenesis); SLN expression is regulated transcriptionally (e.g., by the AP-1 complex downstream of metabolic stress) and is required for normal substrate oxidation and metabolic homeostasis in skeletal muscle, while in specialized epithelia such as sweat glands it modulates intracellular Ca2+ dynamics downstream of neurotransmitter signaling to determine stem cell fate.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"Sarcolipin (SLN) is a 31-amino acid single-pass transmembrane proteolipid that regulates sarcoplasmic reticulum (SR) Ca2+ handling by associating with and inhibiting the SR Ca2+-ATPase (SERCA), with SLN highly co-expressed with SERCA1 in fast-twitch skeletal muscle and acting on SERCA2 in cardiac tissue [#0, #1, #2]. Structurally it resembles phospholamban, with a cytoplasmic N-terminus, a single transmembrane helix, and a conserved lumenal C-terminus [#0]. Functionally, SLN uncouples the SERCA pump to drive a futile Ca2+ cycle that consumes ATP and produces heat, a mechanism engaged during conditions that activate non-shivering thermogenesis through the CaMKII/AMPK/PGC1\\u03b1 axis [#4]. Consistent with this metabolic role, loss of SLN in human myotubes impairs glucose and fatty-acid oxidation, lowers mitochondrial respiration, and promotes lipid accumulation, establishing SLN as required for normal substrate utilization and metabolic homeostasis in skeletal muscle [#3]. SLN expression is controlled transcriptionally: the AP-1 complex directly drives Sln transcription downstream of a glucose-6-phosphate signal, and elevated Sln in this context intensifies myocardial damage in doxorubicin cardiotoxicity [#6]. Beyond muscle, SLN regulates SERCA-dependent intracellular Ca2+ dynamics downstream of neurotransmitter signaling in sweat gland myoepithelial cells to specify stem cell fate [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established the molecular identity, topology, and tissue distribution of SLN, defining it as a phospholamban-like proteolipid co-purifying with SERCA1 in fast-twitch skeletal muscle.\",\n      \"evidence\": \"cDNA/genomic isolation, sequence and chromosomal mapping, and Northern tissue profiling\",\n      \"pmids\": [\"9367679\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Co-purification does not demonstrate direct functional regulation of SERCA\",\n        \"Topological model inferred from PLN homology, not directly resolved\",\n        \"Functional consequence of the conserved lumenal C-terminus not tested\"\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Extended SLN's inhibitory action to the cardiac SERCA2 isoform and tested, with a negative result, whether SLN coding mutations cause human arrhythmias.\",\n      \"evidence\": \"SSCP/heteroduplex screening and sequencing of SLN coding region in arrhythmia patient cohorts\",\n      \"pmids\": [\"17010328\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"SERCA2 inhibition stated as background rather than demonstrated here\",\n        \"Non-coding/regulatory SLN variants not screened\",\n        \"No mechanistic dissection of SLN-SERCA2 interaction\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed SLN is required for normal fuel oxidation in human skeletal muscle, linking its Ca2+-handling role to whole-cell metabolic homeostasis.\",\n      \"evidence\": \"Stable shRNA knockdown in human myotubes with radiolabeled substrate oxidation, Seahorse respirometry, lipid staining, and gene expression\",\n      \"pmids\": [\"35364719\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Metabolic phenotype not mechanistically tied to SERCA Ca2+ cycling in this study\",\n        \"Single cell model, single lab\",\n        \"Causality of PGC1\\u03b1/FOXO1 downregulation versus consequence unresolved\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Provided in vivo gain-of-function evidence that SLN-mediated SERCA uncoupling drives non-shivering thermogenesis via the CaMKII/AMPK/PGC1\\u03b1 axis.\",\n      \"evidence\": \"Chronic melatonin treatment in obese diabetic rats with western blots, SERCA activity assays, and infrared thermometry\",\n      \"pmids\": [\"38387135\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Pharmacological intervention; SLN increase is correlated rather than directly manipulated\",\n        \"Direct measurement of futile Ca2+ cycling not performed\",\n        \"Single lab\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified the AP-1 transcription factor as a direct upstream driver of Sln expression downstream of a G6P metabolic signal, placing SLN in a pathogenic cardiac stress pathway.\",\n      \"evidence\": \"Cardiac-specific Slc25a49 knockout mice with doxorubicin, RNA-seq, metabolomics, ChIP, and dual-luciferase reporter assays\",\n      \"pmids\": [\"40184586\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which elevated Sln intensifies myocardial damage not fully resolved\",\n        \"Whether the G6P-AP-1-Sln axis operates in skeletal muscle untested\",\n        \"AP-1 subunit composition driving Sln transcription not specified\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended SLN's role beyond muscle, showing it regulates SERCA-dependent intracellular Ca2+ downstream of neurotransmitter signaling to control sweat gland stem cell fate.\",\n      \"evidence\": \"Denervation and SLN loss-of-function in sweat gland myoepithelial cells with Ca2+ imaging and cell-fate marker analysis (preprint)\",\n      \"pmids\": [\"37745514\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Preprint, not yet peer-reviewed\",\n        \"Single lab, single system\",\n        \"Direct biochemical SLN-SERCA interaction in this cell type not shown\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Tested evolutionary conservation of the SLN-SERCA thermogenic program in an ectotherm using cold-induced transcriptional responses.\",\n      \"evidence\": \"Cold challenge with RT-qPCR of sln and serca1 in medaka skeletal muscle\",\n      \"pmids\": [\"37844835\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Transcript-level data only without functional assay of SERCA uncoupling\",\n        \"Single method, single lab\",\n        \"Correlation between sln induction and actual thermogenesis not measured\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SLN structurally engages SERCA to switch between inhibition and uncoupling, and what signals toggle this in vivo, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model of the SLN-SERCA complex in the corpus\",\n        \"Molecular determinants of uncoupling versus simple inhibition undefined\",\n        \"Tissue-specific regulators beyond AP-1 uncharacterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 2, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": []}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"SERCA1\",\n      \"SERCA2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}