bioRxiv : the preprint server for biology最新文献

{"title":"Altered Purinergic Signaling and CD8+ T Cell Dysregulation in STAT3 GOF Syndrome.","authors":"Jose S Campos Duran, Samir Sayed, Megan C Dalalo, Andrea A Mauracher, Montana S Knight, Peyton E Conrey, Aaron B Schultz, Ceire A Hay, Robert B Lindell, Christian A Howard, Eric D Abrams, Erica G Schmitt, Martin A Thelin, Sarah Bluestein, Christine M Seroogy, Tamara C Pozos, Akaluck Thatayatikom, Ingrid Lundgren, Amelie Gauthier, Scott W Canna, Helen C Su, Michael D Keller, Ottavia M Delmonte, Lisa R Forbes Satter, Steven M Holland, Jenna R E Bergerson, Jennifer W Leiding, Neil Romberg, Alexandra F Freeman, Alejandro V Villarino, Mark S Anderson, Megan A Cooper, Tiphanie P Vogel, Sarah E Henrickson","doi":"10.1101/2024.12.12.626682","DOIUrl":"10.1101/2024.12.12.626682","url":null,"abstract":"<p><p>Signal transduction downstream of activating stimuli controls CD8+ T cell biology, however these external inputs can become uncoupled from transcriptional regulation in Primary Immune Regulatory Disorders (PIRDs). Gain-of-function (GOF) variants in STAT3 amplify cytokine signaling and cause a severe PIRD characterized by early onset autoimmunity, lymphoproliferation, recurrent infections, and immune dysregulation. In both primary human and mouse models of STAT3 GOF, CD8+ T cells have been implicated as pathogenic drivers of autoimmunity. The molecular mechanisms by which STAT3 GOF variants drive this pathology remain unclear. We found that naive CD8+ T cells have an increased capacity for IFN-g and TNF-a secretion. Given this dysregulation of CD8+ T cell function, we evaluated changes in immunoregulatory pathways and found evidence of dysregulated purinergic signaling via high dimensional immune profiling, single-cell RNA sequencing, and functional assessment. Specifically, while expression of CD39, which transforms ATP to AMP, was increased on CD8+ T cells from patients with STAT3 GOF, downstream purinergic family members, CD73 and the adenosine receptor, A2AR, were downregulated, impairing the potential to produce or sense inhibitory adenosine. Patients with STAT3 GOF can be clinically treated with JAK inhibitors, and this partially normalized naive CD8+ T cell dysregulation, including aberrant cytokine production. The extent of normalization scaled with normalization of CD73 and A2AR. This suggests that a dysregulated purinergic signaling axis plays an important role in CD8+ T cell dysregulation in STAT3 GOF, which may have implications for other inflammatory disorders with amplified STAT signaling.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11661228/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142879070","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enzymatic epimerization of monoterpene indole alkaloids in Kratom.","authors":"Allwin McDonald, Yoko Nakamura, Carsten Schotte, Kin Lau, Ryan Alam, Adriana A Lopes, C Robin Buell, Sarah O'Connor","doi":"10.1101/2024.12.13.628308","DOIUrl":"10.1101/2024.12.13.628308","url":null,"abstract":"<p><p>Monoterpene indole alkaloids (MIAs) are a large, structurally diverse class of bioactive natural products. These compounds are biosynthetically derived from a stereoselective Pictet-Spengler condensation that generates a tetrahydro-β-carboline scaffold characterized by a 3 <i>S</i> stereocenter. However, a subset of MIAs contain a non-canonical 3 <i>R</i> stereocenter. Herein, we report the basis for 3 <i>R</i> -MIA biosynthesis in <i>Mitragyna speciosa</i> (Kratom). We discover the presence of the iminium species, 20 <i>S</i> -3-dehydrocorynantheidine, which led us to hypothesize that isomerization of 3 <i>S</i> to 3 <i>R</i> occurs by oxidation and stereoselective reduction downstream of the initial Pictet-Spengler condensation. Isotopologue feeding experiments implicated young leaves and stems as the sites for pathway biosynthesis, facilitating the identification of an oxidase/reductase pair that catalyzes this epimerization. This enzyme pair has broad substrate specificity, suggesting that the oxidase and reductase may be responsible for the formation of many 3 <i>R</i> -MIAs and downstream spirooxindole alkaloids in Kratom. These enzymes allow biocatalytic access to a range of previously inaccessible pharmacologically active compounds.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11661350/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142879400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PEX1^G843D remains functional in peroxisome biogenesis but is rapidly degraded by the proteasome.","authors":"Connor J Sheedy, Soham P Chowdhury, Bashir A Ali, Julia Miyamoto, Eric Z Pang, Julien Bacal, Katherine U Tavasoli, Chris D Richardson, Brooke M Gardner","doi":"10.1101/2024.12.10.627778","DOIUrl":"10.1101/2024.12.10.627778","url":null,"abstract":"<p><p>The PEX1/PEX6 AAA-ATPase is required for the biogenesis and maintenance of peroxisomes. Mutations in <i>HsPEX1</i> and <i>HsPEX6</i> disrupt peroxisomal matrix protein import and are the leading cause of Peroxisome Biogenesis Disorders (PBDs). The most common disease-causing mutation in PEX1 is the <i>Hs</i>PEX1^G843D allele, which results in a reduction of peroxisomal protein import. Here we demonstrate that <i>in vitro</i> the homologous yeast mutant, <i>Sc</i>Pex1^G700D, reduces the stability of Pex1's active D2 ATPase domain and impairs assembly with Pex6, but can still form an active AAA-ATPase motor. <i>In vivo</i>, <i>Sc</i>Pex1^G700D exhibits only a slight defect in peroxisome import. We generated model human <i>Hs</i>PEX1^G843D cell lines and show that PEX1^G843D is rapidly degraded by the proteasome, but that induced overexpression of PEX1^G843D can restore peroxisome import. Additionally, we found that the G843D mutation reduces PEX1's affinity for PEX6, and that impaired assembly is sufficient to induce degradation of PEX1^WT. Lastly, we found that fusing a deubiquitinase to PEX1^G843D significantly hinders its degradation in mammalian cells. Altogether, our findings suggest a novel regulatory mechanism for PEX1/PEX6 hexamer assembly and highlight the potential of protein stabilization as a therapeutic strategy for PBDs arising from the G843D mutation and other PEX1 hypomorphs.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11661142/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142879506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A small molecule enhances arrestin-3 binding to the β₂-adrenergic receptor.","authors":"Han Kurt, Ali Akyol, Cagdas Devrim Son, Chen Zheng, Irene Gado, Massimiliano Meli, Erica Elisa Ferrandi, Ivan Bassanini, Francesca Vasile, Vsevolod V Gurevich, Aylin Nebol, Esra Cagavi, Giulia Morra, Ozge Sensoy","doi":"10.1101/2024.12.12.628161","DOIUrl":"10.1101/2024.12.12.628161","url":null,"abstract":"<p><p>G protein-coupled receptor (GPCR) signaling is terminated by arrestin binding to a phosphorylated receptor. Binding propensity has been shown to be modulated by stabilizing the pre-activated state of arrestin through point mutations or C-tail truncation. Here, we hypothesize that pre-activated rotated states can be stabilized by small molecules, and this can promote binding to phosphorylation-deficient receptors, which underly a variety of human disorders. We performed virtual screening on druggable pockets identified on pre-activated conformations in Molecular Dynamics trajectories of arrestin-3, and found a compound targeting an activation switch, the back loop at the inter-domain interface. According to our model, consistent with available biochemical and structural data, the compound destabilized the ionic lock between the finger and the back loop, and enabled transition of the `gate loop` towards the pre-activated state, which stabilizes pre-activated inter-domain rotation. The predicted binding pocket is consistent with saturation-transfer difference NMR data indicating close contact between the piperazine moiety of the compound and C/finger loops. The compound increases in-cell arrestin-3 binding to phosphorylation-deficient and wild-type β₂-adrenergic receptor, but not to muscarinic M2 receptor, as verified by FRET and NanoBiT. This study demonstrates that the back loop can be targeted to modulate interaction of arrestin with phosphorylation-deficient GPCRs in a receptor-specific manner.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11661165/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142879430","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A click chemistry-based biorthogonal approach for the detection and identification of protein lysine malonylation for osteoarthritis research.","authors":"Anupama Binoy, Pandurangan Nanjan, Kavya Chellamuthu, Huanhuan Liu, Shouan Zhu","doi":"10.1101/2024.12.12.628274","DOIUrl":"10.1101/2024.12.12.628274","url":null,"abstract":"<p><p>Lysine malonylation is a post-translational modification where a malonyl group, characterized by a negatively charged carboxylate, is covalently attached to the Ɛ-amino side chain of lysine, influencing protein structure and function. Our laboratory identified Mak upregulation in cartilage under aging and obesity, contributing to osteoarthritis (OA). Current antibody-based detection methods face limitations in identifying Mak targets. Here, we introduce an alkyne-functionalized probe, MA-diyne, which metabolically incorporates into proteins, enabling copper(I) ion-catalyzed click reactions to conjugate labeled proteins with azide-based fluorescent dyes or affinity purification tags. In-gel fluorescence confirms MA-diyne incorporation into proteins across various cell types and species, including mouse chondrocytes, adipocytes, Hek293T cells, and <i>C. elegans</i>. Pull-down experiments identified known Mak proteins such as GAPDH and Aldolase. The extent of MA-diyne modification was higher in Sirtuin 5-deficient cells suggesting these modified proteins are Sirtuin 5 substrates. Pulse-chase experiments confirmed the dynamic nature of protein malonylation. Quantitative proteomics identified 1136 proteins corresponding to 8903 peptides with 429 proteins showing 1-fold increase in labeled group. Sirtuin 5 regulated 374 of these proteins. Pull down of newly identified proteins such as β-actin and Stat3 was also done. This study highlights MA-diyne as a powerful chemical tool to investigate the molecular targets and functions of lysine malonylation in OA conditions.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11661220/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142879440","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cell surface crowding is a tunable biophysical barrier to cell-cell fusion.","authors":"Daniel S W Lee, Liya F Oster, Sungmin Son, Daniel A Fletcher","doi":"10.1101/2024.12.12.628283","DOIUrl":"10.1101/2024.12.12.628283","url":null,"abstract":"<p><p>Cell-cell fusion is fundamental to developmental processes such as muscle formation, as well as to viral infections that cause pathological syncytia. An essential step in fusion is close membrane apposition, but cell membranes are crowded with proteins, glycoproteins, and glycolipids, all of which must be cleared before a fusion pore can be nucleated. Here, we find that cell surface crowding drastically reduces fusogenicity in multiple systems, independent of the method for driving fusion. We estimate that cell surface crowding presents an energetic barrier to membrane apposition on the scale of <math><mrow><mo>∼</mo> <mn>100</mn> <msub><mi>k</mi> <mi>B</mi></msub> <mi>T</mi></mrow> </math> , greater than that of bare membrane fusion. We show that increasing cell surface crowding reduces fusion efficiency of PEG-mediated and fusogen-mediated cell-cell fusion, as well as synthetic membranes under force. Interestingly, we find that differentiating myoblasts naturally decrease cell surface crowding prior to fusion. Cell surface crowding presents an underappreciated biophysical barrier that may be tuned developmentally and could be targeted externally to control tissue-specific cell-cell fusion.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11661186/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142879452","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Data-driven synapse classification reveals a logic of glutamate receptor composition.","authors":"Kristina D Micheva, Anish K Simhal, Jenna Schardt, Stephen J Smith, Richard J Weinberg, Scott F Owen","doi":"10.1101/2024.12.11.628056","DOIUrl":"10.1101/2024.12.11.628056","url":null,"abstract":"<p><p>The rich diversity of synapses facilitates the capacity of neural circuits to transmit, process and store information. Here, we used multiplex super-resolution proteometric imaging through array tomography to define features of single synapses in the adult mouse neocortex. We find that glutamatergic synapses cluster into subclasses that parallel the distinct biochemical and functional categories of receptor subunits: GluA1/4, GluA2/3 and GluN1/GluN2B. Two of these subclasses align with physiological expectations based on synaptic plasticity: large AMPAR-rich synapses may represent potentiated synapses, whereas small NMDAR-rich synapses suggest \"silent\" synapses. The NMDA receptor content of large synapses correlates with spine neck diameter, and thus the potential for coupling to the parent dendrite. Conjugate array tomography's rigorous registration of immunofluorescence with electron microscopy provides validation for future super-resolution imaging studies in other systems. No barriers prevent generalization of this approach to other species, laying a foundation for future studies of human disorders and therapeutics.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11661198/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142878884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of DNA methylation in PBMCs and donor-matched iPSCs shows methylation is reset during stem cell reprogramming.","authors":"Xylena Reed, Cory A Weller, Sara Saez-Atienzar, Alexandra Beilina, Sultana Solaiman, Makayla Portley, Mary Kaileh, Roshni Roy, Jinhui Ding, A Zenobia Moore, D Thad Whitaker, Bryan J Traynor, J Raphael Gibbs, Sonja W Scholz, Mark R Cookson","doi":"10.1101/2024.12.13.627515","DOIUrl":"10.1101/2024.12.13.627515","url":null,"abstract":"<p><p>DNA methylation is an important epigenetic mechanism that helps define and maintain cellular functions. It is influenced by many factors, including environmental exposures, genotype, cell type, sex, and aging. Since age is the primary risk factor for developing neurodegenerative diseases, it is important to determine if aging-related DNA methylation is retained when cells are reprogrammed to an induced Pluripotent Stem Cell (iPSC) state. Here, we selected peripheral blood mononuclear cells (PBMCs; n = 99) from a cohort of diverse and healthy individuals enrolled in the Genetic and Epigenetic Signatures of Translational Aging Laboratory Testing (GESTALT) study to convert to iPSCs. After reprogramming we evaluated the resulting iPSCs for DNA methylation signatures to determine if they reflect the confounding factors of age and environmental factors. We used genome-wide DNA methylation arrays in both cell types to show that the epigenetic clock is largely reset to an early methylation age after conversion of PBMCs to iPSCs. We further examined the epigenetic age of each cell type using an Epigenome-wide Association Study (EWAS). Finally, we identified a set of methylation Quantitative Trait Loci (methQTL) in each cell type. Our results show that age-related DNA methylation is largely reset in iPSCs, and each cell type has a unique set of methylation sites that are genetically influenced.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11661179/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142879483","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>E. coli</i> transcription factors regulate promoter activity by a universal, homeostatic mechanism.","authors":"Vinuselvi Parisutham, Sunil Guharajan, Melina Lian, Hannah Rogers, Shannon Joyce, Mariana Noto Guillen, Robert C Brewster","doi":"10.1101/2024.12.09.627516","DOIUrl":"10.1101/2024.12.09.627516","url":null,"abstract":"<p><p>Transcription factors (TFs) may activate or repress gene expression through an interplay of different mechanisms, including RNA polymerase (RNAP) recruitment, exclusion, and initiation. TFs often have drastically different regulatory behaviors depending on promoter context and interacting cofactors. However, the detailed mechanisms by which each TF affects transcription and produce promoter-dependent regulation is unclear. Here, we discover that a simple model explains the regulatory effects of <i>E. coli</i> TFs in a range of contexts. Specifically, we measure the relationship between basal promoter activity and its regulation by diverse TFs and find that the contextual changes in TF function are determined entirely by the basal strength of the regulated promoter: TFs exert lower fold-change on stronger promoters under a precise inverse scaling. Remarkably, this scaling relationship holds for both activators and repressors, indicating a universal mechanism of gene regulation. Our data, which spans between 100-fold activation to 1000-fold repression, is consistent with a model of regulation driven by stabilization of RNAP at the promoter for every TF. Crucially, this indicates that TFs naturally act to maintain homeostatic expression levels across genetic or environmental perturbations, ensuring robust expression of regulated genes.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11661191/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142879416","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-read Transcriptomics of Caviid Gammaherpesvirus 1: Compiling a Comprehensive RNA Atlas.","authors":"Gábor Torma, Ákos Dörmő, Ádám Fülöp, Dóra Tombácz, Máté Mizik, Amanda M Pretory, See-Chi Lee, Zsolt Toth, Zsolt Boldogkői","doi":"10.1101/2024.12.11.627975","DOIUrl":"10.1101/2024.12.11.627975","url":null,"abstract":"<p><p>Caviid gammaherpesvirus 1 (CaGHV-1), formerly known as the guinea pig herpes-like virus, is an oncogenic gammaherpesvirus with a sequenced genome but an as-yet uncharacterized transcriptome. Using nanopore long-read RNA sequencing, we annotated the CaGHV-1 genome and constructed a detailed transcriptomic atlas. Our findings reveal diverse viral mRNAs and non-coding RNAs, along with mapped promoter elements for each viral gene. We demonstrated that the CaGHV-1 RTA lytic cycle transcription factor activates its own promoter, similar to KSHV, and that the CaGHV-1 ORF50 promoter responds to RTA proteins from other gammaherpesviruses, highlighting the evolutionary conservation of RTA-mediated transcriptional mechanisms. Additionally, our analysis uncovered extensive transcriptional overlap within the viral genome, suggesting a role in regulating global gene expression. Given its tumorigenic properties, broad host range, and non-human pathogenicity, this work establishes CaGHV-1 as a promising small animal model for investigating human gammaherpesvirus pathogenesis.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11661164/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142879487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}