Mechanisms of Ageing and Development最新文献

{"title":"Association of Cytomegalovirus Serostatus with ELOVL2 Methylation: Implications for Lipid Metabolism, Inflammation, DNA Damage, and Repair Capacity in the MARK-AGE Study Population.","authors":"Robertina Giacconi, Chiara Pirazzini, Maria Giulia Bacalini, Paolo Garagnani, Miriam Capri, Claudio Franceschi, Carlo Fortunato, Gretta Veronica Badillo Pazmay, Alexander Bürkle, María Moreno Villanueva, Maurizio Cardelli, Francesco Piacenza, Monia Cecati, Laura Cianfruglia, Martijn E T Dollé, Eugène Jansen, Tilman Grune, Efstathios S Gonos, Birgit Weinberger, Ewa Sikora, Michele Zampieri, Paola Caiafa, Fabio Ciccarone, Anna Reale, Florence Debacq-Chainiaux, Wolfgang Stuetz, Mikko Hurme, P Eline Slagboom, Jürgen Bernhardt, Fabiola Olivieri, Marco Malavolta","doi":"10.1016/j.mad.2025.112043","DOIUrl":"https://doi.org/10.1016/j.mad.2025.112043","url":null,"abstract":"<p><p>Cytomegalovirus (CMV) infection has been linked to accelerated biological aging, potentially increasing the risk of cardiovascular disease. DNA methylation of the gene Elongation Of Very Long Chain Fatty Acids-Like 2 (ELOVL2) is a molecular biomarker for aging, and its gene product is involved in polyunsaturated fatty acid synthesis, which impacts immune and inflammatory responses. This study, conducted in the MARK-AGE population, aimed to investigate the relationship between CMV infection and ELOVL2 methylation in adults aged 35-75, as well as the influence of CMV IgG levels on lipid metabolism, inflammation, DNA damage, and DNA repair. Our data revealed a higher prevalence of ischemic heart disease, atrial fibrillation, hypertension, and diabetes in CMV-positive individuals. CMV IgG levels were positively associated with ELOVL2 methylation at specific CpG sites and with increased expression of DNA methyltransferase-1 (DNMT1). CMV IgG was linked to lipid imbalances, such as increased BMI, VLDL-cholesterol, triglycerides, and HDL1-cholesterol. Additionally, ELOVL2 methylation was associated with systemic inflammation markers, lipid parameters and altered T-cell subsets. A negative correlation was observed between CMV IgG levels and both baseline DNA integrity and repair capacity. These results suggest that CMV infection might promote cardiovascular disease through ELOVL2 hypermethylation, lipid dysregulation, inflammation, and DNA damage.</p>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":" ","pages":"112043"},"PeriodicalIF":5.3,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537227","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Heart of the matter: Mitochondrial dynamics and genome alterations in cardiac aging","authors":"Claudie Gabillard-Lefort ,&nbsp;Théophile Thibault ,&nbsp;Guy Lenaers ,&nbsp;Rudolf J. Wiesner ,&nbsp;Jeanne Mialet-Perez ,&nbsp;Olivier R. Baris","doi":"10.1016/j.mad.2025.112044","DOIUrl":"10.1016/j.mad.2025.112044","url":null,"abstract":"<div><div>Cardiac pathological aging is a serious health issue, with cardiovascular diseases still being a leading cause of deaths worldwide. Therefore, there is an urgent need to identify culprit factors involved in this process. In the last decades, mitochondria, which are crucial for cardiac function, have emerged as major contributors. Mitochondria are organelles involved in a plethora of metabolic pathways and cell processes ranging from ATP production to calcium homeostasis or regulation of apoptotic pathways. This review provides a general overview of the pathomechanisms involving mitochondria during cardiac aging, with a focus on the role of mitochondrial dynamics and mitochondrial DNA (mtDNA). These mechanisms involve imbalanced mitochondrial fusion and fission, loss of mtDNA integrity leading to tissue mosaic of mitochondrial deficiency, as well as mtDNA release in the cytoplasm, promoting inflammation via the NLRP3, cGAS/STING and TLR9 pathways. Potential links between mtDNA, mitochondrial damage and the accumulation of senescent cells in the heart are also discussed. A better understanding of how these factors impact on heart function and accelerate its pathological aging should lead to the development of new therapies to promote healthy aging and restore age-induced cardiac dysfunction.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"224 ","pages":"Article 112044"},"PeriodicalIF":5.3,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143512363","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The relationship between physical activity and telomere length in women: A systematic review","authors":"Jeni Page ,&nbsp;Catherine Stephens ,&nbsp;Melissa Richard ,&nbsp;Elizabeth Lyons ,&nbsp;Elizabeth Baumler ,&nbsp;M. Terese Verklan ,&nbsp;Elizabeth Lorenzo","doi":"10.1016/j.mad.2025.112042","DOIUrl":"10.1016/j.mad.2025.112042","url":null,"abstract":"<div><div>Telomere length (TL) is a biomarker of cellular aging with variations observed by sex, age, race, and ethnicity. Prior studies have suggested that physical activity (PA) may positively impact TL by potentially elongating telomeres and slowing cellular aging. However, research examining the optimal type and intensity of PA needed to elicit these changes specific to women remains limited. This systematic review aimed to investigate variations in TL in response to PA among women, exploring how these effects differ by age, race, or ethnicity. Following PRISMA guidelines, searches across five databases identified 17 relevant studies published from 2008 to 2022. A narrative synthesis of study findings indicated PA did not have a significant relationship with TL in women. However, a possible positive relationship was noted between specific types of PA and TL, specific to combined aerobic and strength-training PA and high intensity interval training interventions. The impact of PA on TL appeared to be age-dependent as well, showing significant positive relationships between PA and TL in early and later adulthood but not in middle adulthood. Findings related to race or ethnicity were inconclusive due to limited analyses from the included studies. The studies varied greatly by PA type, intensity, duration, and frequency, which, along with the reliance on self-reported PA measures in the observational studies, impacted the ability to draw firm conclusions. This review underscores the necessity for future research in large cohort studies using objectively measured PA interventions to further clarify the complex associations between PA and TL in women.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"224 ","pages":"Article 112042"},"PeriodicalIF":5.3,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143472653","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vascular participation in bone healing: Implications related to advancing age and morbidity","authors":"Rhonda D. Prisby","doi":"10.1016/j.mad.2025.112041","DOIUrl":"10.1016/j.mad.2025.112041","url":null,"abstract":"<div><div>Fracture non-union and the related morbidities represent a global health concern. While many factors are necessary for proper bone healing following fracture, the vascular system is requisite. Important considerations include vascular morphology in bone and marrow and the regulation of tissue blood flow. This review discusses the types of fracture management and associated bone repair (i.e., intramembranous vs. endochondral), the phases of bone healing, and the role of the bone vascular network. Finally, fracture healing is considered in the context of advanced age and morbidity.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"224 ","pages":"Article 112041"},"PeriodicalIF":5.3,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143429479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aging: A struggle for beneficial to overcome negative factors made by muscle and bone","authors":"Steven S. Welc ,&nbsp;Marco Brotto ,&nbsp;Kenneth E. White ,&nbsp;Lynda F. Bonewald","doi":"10.1016/j.mad.2025.112039","DOIUrl":"10.1016/j.mad.2025.112039","url":null,"abstract":"<div><div>Musculoskeletal health is strongly influenced by regulatory interactions of bone and muscle. Recent discoveries have identified a number of key mechanisms through which soluble factors released during exercise by bone exert positive effects on muscle and by muscle on bone. Although exercise can delay the negative effects of aging, these beneficial effects are diminished with aging. The limited response of aged muscle and bone tissue to exercise are accompanied by a failure in bone and muscle communication. Here, we propose that exercise induced beneficial factors must battle changes in circulating endocrine and inflammatory factors that occur with aging. Furthermore, sedentary behavior results in the release of negative factors impacting the ability of bone and muscle to respond to physical activity especially with aging. In this review we report on exercise responsive factors and evidence of modification occurring with aging.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"224 ","pages":"Article 112039"},"PeriodicalIF":5.3,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143422506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The EZH2/MCM Complex/hTERT axis facilitates hepatocellular carcinoma progression by inhibiting cellular senescence","authors":"Ziyi Shen ,&nbsp;Yuanhui Wang ,&nbsp;Jie Gao ,&nbsp;Wei Gu ,&nbsp;Ziyi Ren ,&nbsp;Luanqi Xu ,&nbsp;Rui Qian ,&nbsp;Qinyi Miao ,&nbsp;Xiaomeng Hu ,&nbsp;Yan Wu ,&nbsp;Wei Liu ,&nbsp;Yi Cai ,&nbsp;Chunpeng (Craig) Wan ,&nbsp;Yansong Zhu ,&nbsp;Lei Sun ,&nbsp;Tingdong Yan","doi":"10.1016/j.mad.2025.112040","DOIUrl":"10.1016/j.mad.2025.112040","url":null,"abstract":"<div><div>The complex pathogenesis of hepatocellular carcinoma (HCC) limits the effectiveness of current therapies. Through RNA sequencing of cancerous and adjacent non-cancerous tissues from six HCC patients, we identified a significant upregulation of MCM2–7 genes, which encode proteins that form the MCM complex, a DNA helicase involved in DNA replication and cell cycle progression. We focused on MCM2, MCM3, and MCM7, and observed that knockdown of these proteins inhibited HCC cell proliferation. Further analysis revealed a critical regulatory axis involving EZH2, the MCM complex, and hTERT. EZH2 was found to be highly correlated with MCM complex gene expression and directly bound to the MCM gene promoters, regulating their expression. This EZH2/MCM complex/hTERT axis may play a key role in suppressing cellular senescence, thereby promoting HCC progression. Knocking down MCM complex genes reduced hTERT expression, inducing HCC cell senescence and enhancing the therapeutic efficacy of sorafenib. These findings suggest that the EZH2/MCM complex/hTERT axis could serve as a novel therapeutic target for HCC.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"224 ","pages":"Article 112040"},"PeriodicalIF":5.3,"publicationDate":"2025-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143388112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oral frailty indicators and cardio- and cerebrovascular diseases in older age: A systematic review","authors":"Vittorio Dibello ,&nbsp;Frank Lobbezoo ,&nbsp;Francesco Panza ,&nbsp;Madia Lozupone ,&nbsp;Alberto Pilotto ,&nbsp;Vitalba Vitale ,&nbsp;Carlo Custodero ,&nbsp;Antonio Dibello ,&nbsp;Vincenzo Vertucci ,&nbsp;Antonio Daniele ,&nbsp;Daniele Manfredini ,&nbsp;Vincenzo Solfrizzi","doi":"10.1016/j.mad.2024.112010","DOIUrl":"10.1016/j.mad.2024.112010","url":null,"abstract":"<div><div>Oral health indicators may contribute to the oral frailty phenotype, an age-related gradual loss of oral function together with a decline in cognitive and physical functions. The present systematic review synthetized current knowledge on the associations of oral frailty indicators and major cardio- and cerebrovascular diseases in older age, including coronary heart disease (CHD), arteriosclerosis, arrhythmias, hypertension, cardiovascular diseases not otherwise specified (NOS), and stroke. The study is registered on PROSPERO-(CRD42023397932). From database inception to March 31, 2024, six different electronic databases were consulted assessing the eligibility of 50,005 records against the inclusion criteria and 20 studies on 226,025 older adults were included. Five different indicators of oral frailty (number of teeth, periodontal disease, general oral health, dry mouth, and bite force) were related to cardio- and cerebrovascular diseases. The number of teeth was associated with all the outcomes except hypertension, followed by periodontal disease associated with CHD, arteriosclerosis, hypertension, and stroke. General oral health and dry mouth were associated with CHD/arrhythmias and CHD/stroke, respectively. Finally, bite force was associated only with cardiovascular diseases NOS. The present findings could help to assess the contribution of each oral frailty indicator to the development of cardio- and cerebrovascular diseases in older age.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"223 ","pages":"Article 112010"},"PeriodicalIF":5.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142770414","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The impact of sleep and exercise on brain atrophy in mild cognitive impairment","authors":"Maamoon Mian ,&nbsp;Jihane Tahiri ,&nbsp;Saadeddine Habbal ,&nbsp;Fatima Aftan ,&nbsp;P. Hemachandra Reddy","doi":"10.1016/j.mad.2024.112023","DOIUrl":"10.1016/j.mad.2024.112023","url":null,"abstract":"<div><div>Chronic sleep deprivation and lack of physical exercise may have detrimental effects on overall health, particularly in terms of brain health, with significant implications for cognitive function and well-being. This review explores the impact of chronic sleep deprivation and physical exercise on brain atrophy in mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Drawing insights from 40 selected studies, the review synthesizes evidence on these lifestyle factors' correlations with neurodegenerative changes. Chronic sleep deprivation disrupts circadian rhythms and neurochemical pathways, potentially accelerating brain atrophy, while physical exercise preserves brain structure by enhancing vascular health, reducing inflammation, and supporting synaptic plasticity, particularly in regions like the hippocampus. Results highlight distinct patterns of brain atrophy in AD and MCI, underscoring the potential for targeted interventions to mitigate cognitive decline. Understanding the relationship between sleep disruption and brain health provides insights into strategies for possibly delaying neurodegenerative diseases like MCI, which represents a milder form of Alzheimer's, and AD. The findings underscore the potential utility of integrating sleep therapy and physical exercise interventions in clinical practice for early detection of mild cognitive impairment and potentially delaying disease progression. This integrated approach has been found to promote healthy aging, reduce atrophy rates, and enhance cognitive resilience across aging populations.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"223 ","pages":"Article 112023"},"PeriodicalIF":5.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142895687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Senolytics rejuvenate aging cardiomyopathy in human cardiac organoids","authors":"Mariangela Scalise ,&nbsp;Eleonora Cianflone ,&nbsp;Claudia Quercia ,&nbsp;Loredana Pagano ,&nbsp;Antonio Chiefalo ,&nbsp;Antonio Stincelli ,&nbsp;Annalaura Torella ,&nbsp;Barbara Puccio ,&nbsp;Gianluca Santamaria ,&nbsp;Hiram P. Guzzi ,&nbsp;Pierangelo Veltri ,&nbsp;Antonella De Angelis ,&nbsp;Konrad Urbanek ,&nbsp;Georgina M. Ellison-Hughes ,&nbsp;Daniele Torella ,&nbsp;Fabiola Marino","doi":"10.1016/j.mad.2024.112007","DOIUrl":"10.1016/j.mad.2024.112007","url":null,"abstract":"<div><h3>Background</h3><div>Human cardiac organoids closely replicate the architecture and function of the human heart, offering a potential accurate platform for studying cellular and molecular features of aging cardiomyopathy. Senolytics have shown potential in addressing age-related pathologies but their potential to reverse aging-related human cardiomyopathy remains largely unexplored.</div></div><div><h3>Methods</h3><div>We employed human iPSC-derived cardiac organoids (hCOs/hCardioids) to model doxorubicin(DOXO)-induced cardiomyopathy in an aged context. hCardioids were treated with DOXO and subsequently with a combination of two senolytics: dasatinib (D) and quercetin (Q).</div></div><div><h3>Results</h3><div>DOXO-treated hCardioids exhibited significantly increased oxidative stress, DNA damage (pH2AX), cellular senescence (p16^INK4A) and decreased cell proliferation associated with a senescence-associated secretory phenotype (SASP). DOXO-treated hCardioids were considerably deprived of cardiac progenitors and displayed reduced cardiomyocyte proliferation as well as contractility. These distinctive aging-associated characteristics were confirmed by global RNA-sequencing analysis. Treatment with D+Q reversed these effects, reducing oxidative stress and senescence markers, alleviating SASP, and restoring hCardioids viability and function. Additionally, senolytics replenished cardiac progenitors and reversed the cardiomyocyte proliferation deficit.</div></div><div><h3>Conclusions</h3><div>Doxorubicin triggers an age-associated phenotype in hCardioids reliably modelling the main cellular and molecular features of aging cardiomyopathy. Senescence is a key mechanism of the aged-hCOs phenotype as senolytics rejuvenated aged-hCardioids restoring their structure and function while reverting the age-associated regenerative deficit.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"223 ","pages":"Article 112007"},"PeriodicalIF":5.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142770417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell analysis of human peripheral blood reveals high immune response activity in successful ageing individuals","authors":"Yu Wang ,&nbsp;Yuxing Zhang ,&nbsp;Ge Gong ,&nbsp;Quanzhong Liu ,&nbsp;Liangyu Li ,&nbsp;Mingjiong Zhang ,&nbsp;Shuping Shen ,&nbsp;Ran Wang ,&nbsp;Jianqing Wu ,&nbsp;Wei Xu","doi":"10.1016/j.mad.2024.112011","DOIUrl":"10.1016/j.mad.2024.112011","url":null,"abstract":"<div><div>Beneficial remodeling of the immune system in successful ageing individuals (centenarians and supercentenarians) is critical for healthy ageing. However, mechanisms for dynamic regulation of immunity during ageing remain unclear. We use single-cell RNA sequencing (scRNA-seq) as an analytical strategy to study the dynamic regulation of immunity during aging and its molecular mechanisms at the single-cell level. We performed an integrative analysis of 87,215 peripheral blood mononuclear cells, from seven supercentenarians, three centenarians, and four elderly controls, generated by single-cell transcriptomics complemented with fluorescence-activated cell sorting. Animals experiments were also conducted to validate the makers of healthy aging found by our bioinformatic analysis and further explore the dynamic of immune changes during aging process. We found that CD8⁺ effector memory T cells and terminally differentiated B cells were enriched in the longevity group (centenarians and supercentenarians), whereas naïve T cells and Tregs were enriched in elderly controls. CD56^dim NK cells in the longevity group activated Fc-γ receptor signaling. The higher antigen-presenting ability of CD14⁺ monocytes in the longevity group and the CellChat analysis indicated that CD14⁺ monocytes might assist active T and B cells. Here, we revealed the adaptive immune remodeling geromarkers of immunosenescence in centenarians and supercentenarians, which could be considered as biomarkers of healthy aging, and might help sustain immune responses and achieve exceptional longevity.</div></div>","PeriodicalId":18340,"journal":{"name":"Mechanisms of Ageing and Development","volume":"223 ","pages":"Article 112011"},"PeriodicalIF":5.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142770420","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}