Aging Cell最新文献

{"title":"Macrophage Subpopulation Promotes Skeletal Muscle Regeneration Through HGF/MET Signaling-Mediated Skeletal Muscle Stem Cell Proliferation.","authors":"Hiroyuki Koike, Miho Sugimura, Rie Ouchi, Yuki Yoshimoto, Ichiro Manabe, Yumiko Oishi","doi":"10.1111/acel.70042","DOIUrl":"https://doi.org/10.1111/acel.70042","url":null,"abstract":"<p><p>Macrophages are key regulators of skeletal muscle regeneration, yet the specific macrophage subpopulations responsible for this process and their cell-cell interactions remain insufficiently understood, as does the mechanism underlying age-related impairment of skeletal muscle regeneration. We utilized single-cell RNA sequencing to identify transcriptionally distinct macrophage subpopulations within skeletal muscle from young (8-week-old) and aged (24-month-old) mice. Among them, the Mac_1 subpopulation interacted with muscle satellite cells (MuSCs) and promoted their proliferation through HGF/c-Met signaling that suppressed Cdkn1b expression. This interaction was critical for efficient muscle regeneration in vivo and in a 3D-muscle organoid model. The age-related decline in muscle regeneration was associated with reduced HGF expression in Mac_1 macrophages. Administration of exogenous HGF to aged mice and macrophage-depleted young mice partially rescued the impaired muscle regeneration. This study elucidates a mechanism of skeletal muscle regeneration that offers insight into potential strategies for preventing and treating skeletal muscle diseases, including sarcopenia.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70042"},"PeriodicalIF":8.0,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143707864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BRD4/MAP2K7/PGF Signaling Axis Promotes Senescence and Extracellular Matrix Metabolism of Nucleus Pulposus Cells in Intervertebral Disk Degeneration.","authors":"Guangzhi Zhang, Lei Li, Zhili Yang, Zhenyu Cao, Xuchang Hu, Yonggang Wang, Xuewen Kang","doi":"10.1111/acel.70034","DOIUrl":"https://doi.org/10.1111/acel.70034","url":null,"abstract":"<p><p>Intervertebral disk degeneration (IDD) is a common age-related degenerative disease of the spine that imposes a substantial economic burden on both families and society. Despite substantial advances in understanding the mechanisms underlying IDD, effective therapeutic interventions for its treatment and prevention remain elusive. Our previous study identified a positive correlation between IDD severity and bromodomain-containing protein 4 (BRD4) expression. However, the multifaceted role of BRD4 in IDD is still not fully understood. This study explored the abnormal elevation of BRD4 expression in nucleus pulposus (NP) tissues from patients with IDD and in an age-related rat model of IDD. We found that BRD4 levels were positively correlated with NP senescence and extracellular matrix (ECM) degradation and inversely correlated with ECM anabolism. These relationships were further confirmed through assays measuring senescence-associated β-galactosidase activity, the expression of senescence markers P21 and P16, senescence-associated secretory phenotype indicators (IL-6, IL-8, MMP3, and MMP13), as well as ECM metabolism markers such as collagen II and aggrecan. Mechanistically, aberrant BRD4 expression was found to upregulate MAP2K7, which in turn enhances PGF expression, promoting NP cell senescence and ECM metabolism. These findings highlight the crucial role of the BRD4/MAP2K7/PGF signaling axis in cellular senescence and ECM regulation, suggesting that BRD4 represents a promising therapeutic target for IDD.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70034"},"PeriodicalIF":8.0,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699170","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Drug-Based Lifespan Extension in Mice Strongly Affects Lipids Across Six Organs.","authors":"Sara Greenfield, Nathaniel C Stevens, Lauren Bishop, Zachary Rabow, Daniela C Soto, Abdali Omar Abdullah, Richard A Miller, Oliver Fiehn","doi":"10.1111/acel.14465","DOIUrl":"https://doi.org/10.1111/acel.14465","url":null,"abstract":"<p><p>Caloric restriction is associated with slow aging in model organisms. Additionally, some drugs have also been shown to slow aging in rodents. To better understand metabolic mechanisms that are involved in increased lifespan, we analyzed metabolomic differences in six organs of 12-month-old mice using five interventions leading to extended longevity, specifically caloric restriction, 17-α estradiol, and caloric restriction mimetics rapamycin, canagliflozin, and acarbose. These interventions generally have a stronger effect in males than in females. Using Jonckheere's trend test to associate increased average lifespans with metabolic changes for each sex, we found sexual dimorphism in metabolism of plasma, liver, gastrocnemius muscle, kidney, and inguinal fat. Plasma showed the strongest trend of differentially expressed compounds, highlighting potential benefits of plasma in tracking healthy aging. Using chemical set enrichment analysis, we found that the majority of these affected compounds were lipids, particularly in male tissues, in addition to significant differences in trends for amino acids, which were particularly apparent in the kidney. We also found strong metabolomic effects in adipose tissues. Inguinal fat exhibited surprising increases in neutral lipids with polyunsaturated side chains in male mice. In female mice, gonadal fat showed trends proportional to lifespan extension effect across multiple lipid classes, particularly phospholipids. Interestingly, for most tissues, we found similar changes induced by lifespan-extending interventions to metabolomic differences between untreated 12-month-old mice and 4-month-old mice. This finding implies that lifespan-extending treatments tend to reverse metabolic phenotypes to a biologically younger stage.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e14465"},"PeriodicalIF":8.0,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699172","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deciphering Novel Communication Patterns in T Regulatory Cells From Very Old Adults.","authors":"Tegan McTaggart, Jing Xuan Lim, Katie J Smith, Bronagh Heaney, David McDonald, Gillian Hulme, Rafiqul Hussain, Jonathan Coxhead, Derek A Mann, Avan A Sayer, Antoneta Granic, Shoba Amarnath","doi":"10.1111/acel.70044","DOIUrl":"https://doi.org/10.1111/acel.70044","url":null,"abstract":"<p><p>Regulatory T cells (Tregs) are important in maintaining tolerance and are key players in immunity. In aging, increased Treg function along with low-grade inflammation has been reported. This dichotomy of enhanced Treg function along with inflammation highlights the importance of understanding Treg biology and communication patterns in the very old. In this proof-of-concept study, we demonstrate that aged Tregs (85 years) do not significantly communicate with CD4⁺ and CD8⁺ T effectors when compared with healthy < 66-year-olds. Of note was the enhanced communication of aged Tregs with CD3⁺CD8⁺CD56⁺CD161^- NK-like T-cell populations, which are important in antitumor and chronic viral diseases in older individuals. We found that in turn this population of killer-like T cells showed diminished cytotoxic characteristics, and killer receptor expression. Taken together, our proof-of-concept study delineates the biology of Tregs and identifies previously undefined communication patterns in the very old.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70044"},"PeriodicalIF":8.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143655569","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanistic Insights Into 5'-tiRNA-His-GTG Mediated Activation of the JNK Pathway in Skin Photoaging.","authors":"Lihao Liu, Zhuohong Xu, Xiaoxi Dai, Xuyue Zhou, Lihao Chen, Chao Luan, Dan Huang, Hongying Chen, Jiaan Zhang, Yu Hu, Kun Chen","doi":"10.1111/acel.70049","DOIUrl":"https://doi.org/10.1111/acel.70049","url":null,"abstract":"<p><p>UV exposure leads to skin damage, thus inducing skin aging. The aims of this study were to explore the differences in tRNA-derived small RNAs (tsRNAs) expression in the Human dermal fibroblasts (HDF cells) photoaging cell model and to explore the biological functions of tsRNA in skin photoaging. In this study, we found that in both photoaging cell models and the skin of photoaging mice, the 5'-tiRNA-His-GTG expression levels were significantly elevated. In HDF cells, overexpression of 5'-tiRNA-His-GTG induces cellular senescence. Inhibition of 5'-tiRNA-His-GTG attenuates UVB-induced cellular senescence in the photoaging cell model. Intradermal injection of Adeno-associated virus 9-5'-tiRNA-His-GTG -Inhibition ameliorates UVB-induced skin photoaging in nude mice. We confirmed that 5'-tiRNA-His-GTG targeted nuclear pore proteins 98, which further activated the JNK signaling pathway and induced cell senescence. Targeting 5'-tiRNA-His-GTG may provide a novel therapeutic option for ameliorating skin photoaging.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70049"},"PeriodicalIF":8.0,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143646607","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Xanthine Derivative With Novel Heat Shock Protein 90-Alpha Inhibitory and Senolytic Properties.","authors":"Sandra Atlante, Luca Cis, Davide Pirolli, Michela Gottardi Zamperla, Veronica Barbi, Antonello Mai, Clemens Zwergel, Serena Marcozzi, Maria Elisa Giuliani, Giorgia Bigossi, Giovanni Lai, Fiorenza Orlando, Robertina Giacconi, Fabrizia Lattanzio, Giulia Matacchione, Chiara Giordani, Massimo Bracci, Fabiola Olivieri, Federico Boschi, Paola Tabarelli De Fatis, Giovanni Battista Ivaldi, Marco Malavolta, Antonella Farsetti, Maria Cristina De Rosa, Carlo Gaetano","doi":"10.1111/acel.70047","DOIUrl":"https://doi.org/10.1111/acel.70047","url":null,"abstract":"<p><p>The accumulation of senescent cells contributes to aging and related diseases; therefore, discovering safe senolytic agents-compounds that selectively eliminate senescent cells-is a critical priority. Heat shock protein 90 (HSP90) inhibitors (HSP90i), traditionally investigated for cancer treatment, have shown potential as senolytic agents. However, inhibitors face formulation, toxicity, and cost challenges. To overcome these limitations, we employed a virtual screening approach combining structure-based prefiltering with a ligand-based pharmacophore model to identify novel, potentially safe HSP90 alpha isoform inhibitors exhibiting senolytic properties. This strategy identified 14 candidate molecules evaluated for senolytic activity in primary human fetal pulmonary fibroblasts. Four compounds exhibited significant HSP90i and senolytic activity, including two novel compounds, namely K4 and K5. The latter, 1-benzyl-3-(2-methylphenyl)-3,7-dihydro-1H-purine-2,6-dione, structurally related to the xanthinic family, emerged as a promising, well-tolerated senolytic agent. K5 demonstrated senolytic activity across various cellular senescence models, including human fibroblasts, mesenchymal stem cells, and breast cancer cells. It was also effective in vivo, extending lifespan in Drosophila and reducing senescence markers in geriatric mice. Additionally, the xanthinic nature of K5 implicates a multimodal action, now including the inhibition of HSP90α, that might enhance its efficacy and selectivity towards senescent cells, Senolytic index SI > 1320 for IMR90 cells, and SI > 770 for WI38 cells, underscoring its therapeutic potential. These findings advance senolytic therapy research, opening new avenues for safer interventions to combat age-related inflammaging and diseases, including cancer, and possibly extend a healthy lifespan.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70047"},"PeriodicalIF":8.0,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143646606","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Compressive Forces Induce Epigenetic Activation of Aged Human Dermal Fibroblasts Through ERK Signaling Pathway.","authors":"Hui Liu, Luezhen Yuan, Lucrezia Baldi, Trinadha Rao Sornapudi, G V Shivashankar","doi":"10.1111/acel.70035","DOIUrl":"https://doi.org/10.1111/acel.70035","url":null,"abstract":"<p><p>Age-related changes in human dermal fibroblasts (HDFs) contribute to impaired wound healing and skin aging. While these changes result in altered mechanotransduction, the epigenetic basis of rejuvenating aging cells remains a significant challenge. This study investigates the effects of compressive forces on nuclear mechanotransduction and epigenetic rejuvenation in aged HDFs. Using a compressive force application model, the activation of HDFs through alpha-smooth muscle actin (ɑ-SMA) is demonstrated. Sustained compressive forces induce significant epigenetic modifications, including chromatin remodeling and altered histone methylation patterns. These epigenetic changes correlate with enhanced cellular migration and rejuvenation. Small-scale drug screening identifies the extracellular signal-regulated kinase (ERK) signaling pathway as a key mediator of compression-induced epigenetic activation. Furthermore, implanting aged cell spheroids into an aged skin model and subjecting the tissue to compressive forces resulted in increased collagen I protein levels. Collectively, these findings demonstrate that applying compressive force to aged fibroblasts activates global epigenetic changes through the ERK signaling pathway, ultimately rejuvenating cellular functions with potential applications for wound healing and skin tissue regeneration.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70035"},"PeriodicalIF":8.0,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143622856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exercise-Induced Cardiac Lymphatic Remodeling Mitigates Inflammation in the Aging Heart.","authors":"Kangsan Roh, Haobo Li, Rebecca Nicole Freeman, Luca Zazzeron, Ahlim Lee, Charles Zhou, Siman Shen, Peng Xia, Justin Ralph Baldovino Guerra, Cedric Sheffield, Timothy P Padera, Yirong Zhou, Sekeun Kim, Aaron Aguirre, Nicolas Houstis, Jason D Roh, Fumito Ichinose, Rajeev Malhotra, Anthony Rosenzweig, James Rhee","doi":"10.1111/acel.70043","DOIUrl":"10.1111/acel.70043","url":null,"abstract":"<p><p>The lymphatic vasculature plays essential roles in fluid balance, immunity, and lipid transport. Chronic, low-grade inflammation in peripheral tissues develops when lymphatic structure or function is impaired, as observed during aging. While aging has been associated with a broad range of heart pathophysiology, its effect on cardiac lymphatic vasculature has not been characterized. Here, we analyzed cardiac lymphatics in aged 20-month-old mice versus young 2-month-old mice. Aged hearts showed reduced lymphatic vascular density, more dilated vessels, and increased inflammation and fibrosis in peri-lymphatic zones. As exercise has shown benefits in several different models of age-related heart disease, we further investigated the effects of aerobic training on cardiac lymphatics. Eight weeks of voluntary wheel running attenuated age-associated adverse remodeling of the cardiac lymphatics, including reversing their dilation, increasing lymph vessel density and branching, and reducing perilymphatic inflammation and fibrosis. Intravital lymphangiography demonstrated improved cardiac lymphatic flow after exercise training. Our findings illustrate that aging leads to cardiac lymphatic dysfunction, and that exercise can improve lymphatic health in aged animals.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70043"},"PeriodicalIF":8.0,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143622857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Mitochondria-Targeted Peptide Therapeutic Elamipretide Improves Cardiac and Skeletal Muscle Function During Aging Without Detectable Changes in Tissue Epigenetic or Transcriptomic Age.","authors":"Wayne Mitchell, Gavin Pharaoh, Alexander Tyshkovskiy, Matthew Campbell, David J Marcinek, Vadim N Gladyshev","doi":"10.1111/acel.70026","DOIUrl":"10.1111/acel.70026","url":null,"abstract":"<p><p>Aging-related decreases in cardiac and skeletal muscle function are strongly associated with various comorbidities. Elamipretide (ELAM), a novel mitochondria-targeted peptide, has demonstrated broad therapeutic efficacy in ameliorating disease conditions associated with mitochondrial dysfunction across both clinical and pre-clinical models. Herein, we investigated the impact of 8-week ELAM treatment on pre- and post-measures of C57BL/6J mice frailty, skeletal muscle, and cardiac muscle function, coupled with post-treatment assessments of biological age and affected molecular pathways. We found that health status, as measured by frailty index, cardiac strain, diastolic function, and skeletal muscle force, is significantly diminished with age, with skeletal muscle force changing in a sex-dependent manner. Conversely, ELAM mitigated frailty accumulation and was able to partially reverse these declines, as evidenced by treatment-induced increases in cardiac strain and muscle fatigue resistance. Despite these improvements, we did not detect statistically significant changes in gene expression or DNA methylation profiles indicative of molecular reorganization or reduced biological age in most ELAM-treated groups. However, pathway analyses revealed that ELAM treatment showed pro-longevity shifts in gene expression, such as upregulation of genes involved in fatty acid metabolism, mitochondrial translation, and oxidative phosphorylation, and downregulation of inflammation. Together, these results indicate that ELAM treatment is effective at mitigating signs of sarcopenia and cardiac dysfunction in an aging mouse model, but that these functional improvements occur independently of detectable changes in epigenetic and transcriptomic age. Thus, some age-related changes in function may be uncoupled from changes in molecular biological age.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70026"},"PeriodicalIF":8.0,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143622860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cellular Senescence Is a Central Driver of Cognitive Disparities in Aging.","authors":"Matthew P Baier, Rojina Ranjit, Daniel B Owen, Jenna L Wilson, Megan A Stiles, Anthony M Masingale, Zachary Thomas, Anne Bredegaard, David M Sherry, Sreemathi Logan","doi":"10.1111/acel.70041","DOIUrl":"10.1111/acel.70041","url":null,"abstract":"<p><p>Cognitive function in aging is heterogeneous: while some older individuals develop significant impairments and dementia, others remain resilient and retain cognitive function throughout their lifespan. The molecular mechanisms that underlie these divergent cognitive trajectories, however, remain largely unresolved. Here, we utilized a high-resolution home-cage-based cognitive testing paradigm to delineate mechanisms that contribute to age-related cognitive heterogeneity. We cognitively stratified aged C57Bl/6N male mice by cognitive performance into intact (resilient) or impaired subgroups based on young performance benchmarks. Cognitively impaired males exhibited marked reactive gliosis in the hippocampus, characterized by microglial activation, increased astrocyte arborization, and elevated transcriptional expression of reactivity markers. These changes were accompanied by increased markers of cellular senescence and the associated senescence-associated secretory phenotype (SASP) in impaired animals, including p16^INK4a, SASP factors (e.g., Il-6, Il-1b, Mmp3), and SA-β-gal staining in the hippocampus. Notably, clearance of senescent cells using senolytic agents dasatinib and quercetin ameliorated the heterogeneity in cognitive performance observed with age and attenuated impairment-associated gliosis, senescence markers, and mitochondrial dysfunction. Aged female mice could not be stratified into subgroups yet showed increased neuroinflammation with age that was not resolved with senolytics. Collectively, our findings implicate cellular senescence as a central driver of sex-specific neuroinflammation that drives divergent cognitive trajectories in aging. Thus, we demonstrate that senolytic treatment is an effective therapeutic strategy to mitigate cognitive impairment by reducing neuroinflammation and associated metabolic disturbances.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70041"},"PeriodicalIF":8.0,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143612862","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}