Journal of General Physiology最新文献

{"title":"Obscurin deficiency leads to compensated dilated cardiomyopathy and increased arrhythmias.","authors":"Josè Manuel Pioner, Enrico Pierantozzi, Raffaele Coppini, Egidio Maria Rubino, Valentina Biasci, Giulia Vitale, Annunziatina Laurino, Lorenzo Santini, Marina Scardigli, Davide Randazzo, Camilla Olianti, Matteo Serano, Daniela Rossi, Chiara Tesi, Elisabetta Cerbai, Stephan Lange, Carlo Reggiani, Leonardo Sacconi, Corrado Poggesi, Cecilia Ferrantini, Vincenzo Sorrentino","doi":"10.1085/jgp.202413696","DOIUrl":"10.1085/jgp.202413696","url":null,"abstract":"<p><p>Obscurin is a large muscle protein whose multiple functions include providing mechanical strength to the M-band and linking the sarcomere to the sarcoplasmic reticulum. Mutations in obscurin are linked to various forms of muscle diseases. This study compares cardiac function in a murine model of obscurin deletion (KO) with wild-type (WT) in vivo and ex vivo. Echocardiography showed that KO hearts had larger (+20%) end-diastolic and end-systolic volumes, reduced fractional shortening, and impaired ejection fraction, consistent with dilated cardiomyopathy. However, stroke volume and cardiac output were preserved due to increased end-diastolic volume. Morphological analyses revealed reduced sarcoplasmic reticulum volume, with preserved T-tubule network. While myofilament function was preserved in isolated myofibrils and skinned trabeculae, experiments in intact trabeculae revealed that Obscn KO hearts compared with WT displayed (1) reduced active tension at high frequencies and during resting-state contractions, (2) impaired positive inotropic and lusitropic response to β-adrenergic stimulation (isoproterenol 0.1 μM), and (3) faster mechanical restitution, suggesting reduced sarcoplasmic reticulum refractoriness. Intracellular [Ca2+]i measurements showed reduced peak systolic and increased diastolic levels in KO versus WT cardiomyocytes. Western blot experiments revealed lower SERCA and phospholamban (PLB) expression and reduced PLB phosphorylation in KO mice. While action potential parameters and conduction velocity were unchanged, β-adrenergic stimulation induced more frequent spontaneous Ca2+ waves and increased arrhythmia susceptibility in KO compared with WT. Taken together, these findings suggest that obscurin deletion, in adult mice, is linked to compensated dilated cardiomyopathy, altered E-C coupling, impaired response to inotropic agents, and increased propensity to arrhythmias.</p>","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"157 4","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12077377/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144010104","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glycerol storage increases passive stiffness of muscle fibers through effects on titin extensibility.","authors":"Seong-Won Han, Justin Kolb, Gerrie P Farman, Jochen Gohlke, Henk L Granzier","doi":"10.1085/jgp.202413729","DOIUrl":"10.1085/jgp.202413729","url":null,"abstract":"<p><p>To study the physiological and pathological mechanisms of muscle, it is crucial to store muscle samples in ways that preserve their properties. Glycerol is commonly used for storage, as it stabilizes muscle proteins, slows enzymatic activity, and minimizes degradation. However, previous studies validating glycerol storage have not examined its effects on passive properties. In this study, mouse extensor digitorum longus (EDL) muscles were stored in 50% glycerol in relaxing solution with protease inhibitors for various durations, then rehydrated in physiological solutions to assess mechanical properties. Active properties remained unchanged, but passive stress was sensitive to glycerol storage, showing a 56.5 ± 13.6% increase after 4 days, and this effect was permanent. The increase was most pronounced at sarcomere lengths, where titin's PEVK segment extension dominates. Using gelsolin, we determined whether the passive stress increase requires the thin filament, which is known to interact with titin's PEVK region. Both glycerol-stored fibers with and without thin filament extraction exhibited increased passive stress, suggesting that the underlying mechanism is intrinsic to titin. Finally, fibers treated with methylglyoxal, a reactive carbonyl and glycating agent that forms cross-links on lysine residues, showed a significant increase in passive stress in fibers stored in relaxing solution but not in glycerol. Thus, glycerol storage elevates passive stress in a titin-specific manner, likely involving lysine residues in the PEVK. Therefore, glycerol storage should be avoided when assessing passive stiffness. We further showed that, for long-term preservation, storage of rapidly frozen muscle at -80°C is a viable option.</p>","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"157 4","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12063555/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144046092","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sensory neuron sodium channels as pain targets; from cocaine to Journavx (VX-548, suzetrigine).","authors":"John N Wood, Nieng Yan, Jian Huang, Jing Zhao, Armen Akopian, James J Cox, C Geoffrey Woods, Mohammed A Nassar","doi":"10.1085/jgp.202513778","DOIUrl":"https://doi.org/10.1085/jgp.202513778","url":null,"abstract":"<p><p>Voltage-gated sodium channels underpin electrical signaling in sensory neurons. Their activity is an essential element in the vast majority of pain conditions, making them significant drug targets. Sensory neuron sodium channels play roles not only in afferent signaling but also in a range of efferent regulatory mechanisms. Side effects through actions on other cell types and efferent signaling are thus important issues to address during analgesic drug development. As an example, the human genetic evidence for NaV1.7 as an ideal pain target contrasts with the side effects of NaV1.7 antagonists. In this review, we describe the history and progress toward the development of useful analgesic drugs and the renewed focus on NaV1.8 as a key target in pain treatment. NaV1.8 antagonists alone or in combination with other analgesics are likely to provide new opportunities for pain relief for the vast number of people (about 33% of the population) impacted by chronic pain, particularly present in aging populations.</p>","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"157 4","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12036950/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144006433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential state-dependent Nav1.8 inhibition by suzetrigine, LTGO-33, and A-887826.","authors":"Sooyeon Jo, Akie Fujita, Tomás Osorno, Robert G Stewart, Patric M Vaelli, Bruce P Bean","doi":"10.1085/jgp.202413719","DOIUrl":"10.1085/jgp.202413719","url":null,"abstract":"<p><p>Nav1.8 sodium channels are expressed in pain-sensing neurons, and some Nav1.8 inhibitors significantly reduce pain in clinical trials. Several Nav1.8 inhibitors have an unusual state dependence whereby inhibition is relieved by depolarization. We compared the state-dependent action of several Nav1.8 channel inhibitors to test whether inhibition is relieved during action potential (AP) firing under physiological conditions to produce \"reverse use dependence.\" A-887826 inhibition was substantially relieved by AP waveforms applied at 20 Hz at 37°C. In contrast, there was no relief during AP trains with suzetrigine (VX-548) or LTGO-33, even though inhibition could be effectively removed by long, strong depolarizations. These differences were explained by differences in the voltage dependence and kinetics with which the compounds dissociate from depolarized channels and rebind to resting state channels. Suzetrigine required the strongest depolarizations for relief (midpoint +33 mV) and relief was slow (tau >300 ms at +20 mV), so almost no relief occurred during an AP waveform. Relief from A-887826 required weaker depolarizations (midpoint +13 mV) and was much faster, so some relief occurred during each AP waveform and accumulated during 20-Hz trains. LTGO-33 required the weakest depolarizations for relief (midpoint -11 mV) and relief was even faster than for A-887826, but reinhibition between AP waveforms was far faster than for A-887826, so that relief did not accumulate during AP trains at 20 Hz. The results show that, unlike A-887826, there is no use-dependent relief of inhibition by suzetrigine or LTGO-33 with physiological voltage waveforms at physiological temperatures, but each for different reasons.</p>","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"157 4","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11938940/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143712189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prediction and biological significance of small changes in binding of leiomodin to tropomyosin.","authors":"Eduardo Sánchez Díaz, Brayan Osegueda, Svetlana Minakhina, Nickolas Starks, Stefanie Novak, Dmitri Tolkatchev, Carol C Gregorio, Alla S Kostyukova, Garry E Smith","doi":"10.1085/jgp.202413641","DOIUrl":"https://doi.org/10.1085/jgp.202413641","url":null,"abstract":"<p><p>In cardiac muscle, regulation of actin polymerization at the thin filament pointed end is controlled by two structurally similar but functionally antagonistic proteins, leiomodin-2 and tropomodulin-1. Both proteins contain tropomyosin-binding site 1, which is essential for their recruitment to the pointed end. Using circular dichroism, we determined changes in melting temperatures (ΔTm) for complexes of tropomyosin and leiomodin-2 fragments containing several hypomorphic mutations, which moderately affect binding to tropomyosin. We ran molecular dynamics simulations for the complexes and calculated standard Gibbs free energies of binding, which we found to strongly correlate with the ΔTm. We found that the E34Q mutation in leiomodin-2 resulted in a decrease in the melting temperature of the complex of tropomyosin and leiomodin-2 fragments, indicating a decrease in the affinity of leiomodin-2 for tropomyosin. Although modest, this change in in vitro affinity made leiomodin-2 a weaker competitor for tropomyosin than tropomodulin-1 in cardiomyocytes. This mutation significantly reduced the ability of leiomodin-2 to displace tropomodulin-1 at thin filament pointed ends and affected the ability of leiomodin-2 to elongate thin filaments. Our results highlight the essential role of the tropomyosin-binding site in the dynamic equilibrium between tropomodulin-1 and leiomodin-2 at the pointed end of thin filaments. Our data also suggest the potential use of the correlation between ΔTm and the modeled standard Gibbs free energies of binding to predict changes in the stability of complexes between tropomyosin and leiomodin or tropomodulin isoforms.</p>","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"157 4","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12020486/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144046096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Loss of intracellular FGF14 (iFGF14) increases excitability of mature hippocampal pyramidal neurons.","authors":"Joseph L Ransdell, Yarimar Carrasquillo, Marie K Bosch, Rebecca L Mellor, David M Ornitz, Jeanne M Nerbonne","doi":"10.1085/jgp.202413597","DOIUrl":"https://doi.org/10.1085/jgp.202413597","url":null,"abstract":"<p><p>Mutations in FGF14, which encodes intracellular fibroblast growth factor 14 (iFGF14), have been linked to spinocerebellar ataxia type 27 (SCA27), a multisystem disorder associated with deficits in motor coordination and cognitive function. Mice lacking iFGF14 (Fgf14-/-) display similar phenotypes, and we have previously shown that the deficits in motor coordination reflect reduced excitability of cerebellar Purkinje neurons, owing to a hyperpolarizing shift in the voltage-dependence of voltage-gated Na+ (Nav) current steady-state inactivation. Here, we present the results of experiments designed to test the hypothesis that loss of iFGF14 also attenuates the intrinsic excitability of mature hippocampal pyramidal neurons. Current-clamp recordings from CA1 pyramidal neurons in acute in vitro slices, however, revealed that evoked repetitive firing rates were higher in Fgf14-/- than in wild type (WT) cells. Also, in contrast with Purkinje neurons, voltage-clamp recordings demonstrated that the loss of iFGF14 did not affect the voltage dependence of steady-state inactivation of the Nav currents in CA1 pyramidal neurons. In addition, in contrast with results reported for neonatal (rat) hippocampal pyramidal neurons in dissociated cell culture, immunohistochemical experiments revealed that loss of iFGF14 does not disrupt the localization or alter the normalized distribution of α-Nav1.6 or α-ankyrin G labeling along the axon initial segments (AIS) of mature hippocampal CA1 neurons in situ. However, the integrated intensities of α-Nav1.6 labeling were significantly higher along the AIS of Fgf14-/-, compared with WT, adult hippocampal CA1 pyramidal neurons, consistent with the marked increase in the excitability of CA1 neurons with the loss of iFGF14.</p>","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"157 4","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12051480/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144006488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanisms underlying the distinct K+ dependencies of periodic paralysis.","authors":"Brent D Foy, Chris Dupont, Phillip V Walker, Kirsten Denman, Kathrin L Engisch, Mark M Rich","doi":"10.1085/jgp.202413610","DOIUrl":"10.1085/jgp.202413610","url":null,"abstract":"<p><p>Patients with periodic paralysis have attacks of weakness precipitated by depolarization of muscle. Each form of periodic paralysis is associated with unique changes in serum K+ during attacks of weakness. In hypokalemic periodic paralysis (hypoKPP), the mutation-induced gating pore current causes weakness associated with low serum K+. In hyperkalemic periodic paralysis (hyperKPP), mutations increase a non-inactivating Na+ current (Na persistent or NaP), which causes weakness associated with elevation of extracellular K+. In Andersen-Tawil syndrome, mutations causing loss of Kir channel function cause weakness associated with either low or high K+. We developed a computer model to address two questions: (1) What mechanisms are responsible for the distinct K+ dependencies of muscle depolarization-induced weakness in the three forms of periodic paralysis? (2) Why does extracellular K+ become elevated during attacks of weakness in hyperKPP, reduced in hypoKPP, and both elevated and reduced in Andersen-Tawil syndrome? We experimentally tested the model assumptions about resting potential in normal K+ solution in hyperKPP and hypoKPP. Recreating the distinct K+ dependence of all three forms of periodic paralysis required including the K+ and voltage dependence of current through Kir channels, the extracellular K+ and intracellular Na+ dependence of the Na/K ATPase activity, and the distinct voltage dependencies of the gating pore current and NaP. A key factor determining whether muscle would depolarize was the direction of small net K+ and net Na+ fluxes, which altered ion concentrations over hours. Our findings may aid in development of novel therapy for diseases with dysregulation of muscle excitability.</p>","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"157 3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11792889/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143191162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Marfan syndrome cardiomyocytes show excess of titin isoform N2BA and extended sarcomeric M-band.","authors":"Dalma Kellermayer, Cristina M Șulea, Hedvig Tordai, Kálmán Benke, Miklós Pólos, Bence Ágg, Roland Stengl, Máté Csonka, Tamás Radovits, Béla Merkely, Zoltán Szabolcs, Miklós Kellermayer, Balázs Kiss","doi":"10.1085/jgp.202413690","DOIUrl":"10.1085/jgp.202413690","url":null,"abstract":"<p><p>Marfan syndrome (MFS) is an autosomal dominant disease caused by mutations in the gene (FBN1) of fibrillin-1, a major determinant of the extracellular matrix (ECM). Functional impairment in the cardiac left ventricle (LV) of these patients is usually a consequence of aortic valve disease. However, LV passive stiffness may also be affected by chronic changes in mechanical load and ECM dysfunction. Passive stiffness is determined by the giant sarcomeric protein titin that has two main cardiac splice isoforms: the shorter and stiffer N2B and the longer and more compliant N2BA. Their ratio is thought to reflect myocardial response to pathologies. Whether this ratio and titin's sarcomeric layout is altered in MFS is currently unknown. Here, we studied LV samples from MFS patients carrying FBN1 mutation, collected during aortic root replacement surgery. We found that the N2BA:N2B titin ratio was elevated, indicating a shift toward the more compliant isoform. However, there were no alterations in the total titin content compared with healthy humans based on literature data. Additionally, while the gross sarcomeric structure was unaltered, the M-band was more extended in the MFS sarcomere. We propose that the elevated N2BA:N2B titin ratio reflects a general adaptation mechanism to the increased volume overload resulting from the valvular disease and the direct ECM disturbances so as to reduce myocardial passive stiffness and maintain diastolic function in MFS.</p>","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"157 3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11893164/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143588307","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel Ca2+ wave mechanisms in cardiac myocytes revealed by multiscale Ca2+ release model.","authors":"Morris Vysma, James S Welsh, Derek R Laver","doi":"10.1085/jgp.202413543","DOIUrl":"10.1085/jgp.202413543","url":null,"abstract":"<p><p>Integrating cellular sarcoplasmic reticulum (SR) Ca2+ release with the known Ca2+ activation properties of RyR2s remains challenging. The sharp increase in SR Ca2+ permeability above a threshold SR luminal [Ca2+] is not reflected in RyR2 kinetics from single-channel studies. Additionally, the current paradigm that global Ca2+ release (Ca2+ waves) arises from interacting local events (Ca2+ sparks) faces a key issue that these events rarely activate neighboring sites. We present a multiscale model that reproduces Ca2+ sparks and waves in skinned ventricular myocytes using experimentally validated RyR2 kinetics. The model spans spatial domains from 10-8 to 10-4 m and timescales from 10-6 to 10 s. Ca2+ release sites are distributed in cubic voxels (0.25-µm sides) informed by super-resolution micrographs. We use parallel computing to calculate Ca2+ transport, diffusion, and buffering. Substantial increases in SR Ca2+ release occur, and Ca2+ waves initiate when Ca2+ sparks become prolonged above a threshold SR [Ca2+]. These prolonged events (Ca2+ embers) are much more likely than Ca2+ sparks to activate release from neighboring sites and accumulate increases in cytoplasmic [Ca2+] along with an associated fall in Ca2+ buffering power. This primes the cytoplasm for Ca2+-induced Ca2+ release (CICR) that produces Ca2+ waves. Thus, Ca2+ ember formation and CICR are both essential for initiation and propagation of Ca2+ waves. Cell architecture, along with the differential effects of RyR2 opening and closing rates, collectively determines the SR [Ca2+] threshold for Ca2+ embers, waves, and the phenomenon of store overload-induced Ca2+ release.</p>","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"157 3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11893170/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143568862","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"How the Blind Watchmaker messed around with potassium channels.","authors":"Lawrence Salkoff","doi":"10.1085/jgp.202513783","DOIUrl":"10.1085/jgp.202513783","url":null,"abstract":"<p><p>Studies of potassium channel evolution from the Jegla group contribute valuable insights into the evolution of complexity in electrical signaling and the conservation and repurposing of key molecular components throughout evolutionary history.</p>","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"157 3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11922088/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143665386","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}