Aging Cell最新文献

{"title":"Fkbp5 gene deletion: Circadian rhythm profile and brain proteomics in aged mice.","authors":"Niat T Gebru, Jennifer Guergues, Laura A Verdina, Jessica Wohlfahrt, Shuai Wang, Debra S Armendariz, Marsilla Gray, David Beaulieu-Abdelahad, Stanley M Stevens, Danielle Gulick, Laura J Blair","doi":"10.1111/acel.14314","DOIUrl":"10.1111/acel.14314","url":null,"abstract":"<p><p>FKBP51, also known as FK506-binding protein 51, is a molecular chaperone and scaffolding protein with significant roles in regulating hormone signaling and responding to stress. Genetic variants in FKBP5, which encodes FKBP51, have been implicated in a growing number of neuropsychiatric disorders, which has spurred efforts to target FKBP51 therapeutically. However, the molecular mechanisms and sub-anatomical regions influenced by FKBP51 in these disorders are not fully understood. In this study, we aimed to examine the impact of Fkbp5 ablation using circadian phenotyping and molecular analyses. Our findings revealed that the lack of FKBP51 did not significantly alter circadian rhythms, as detected by wheel-running activity, but did offer protection against stress-mediated disruptions in rhythmicity in a sex-dependent manner. Protein changes in Fkbp5 KO mice, as measured by histology and proteomics, revealed alterations in a brain region- and sex-dependent manner. Notably, regardless of sex, aged Fkbp5 KOs showed elevated MYCBP2, FBXO45, and SPRYD3 levels, which are associated with neuronal-cell adhesion and synaptic integrity. Additionally, pathways such as serotonin receptor signaling and S100 family signaling were differentially regulated in Fkbp5 KO mice. Weighted protein correlation network analysis identified protein networks linked with synaptic transmission and neuroinflammation. The information generated by this work can be used to better understand the molecular changes in the brain during aging and in the absence of Fkbp5, which has implications for the continued development of FKBP51-focused therapeutics for stress-related disorders.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":null,"pages":null},"PeriodicalIF":8.0,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142118474","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":"Unacylated Ghrelin Protects Against Age-Related Loss of Muscle Mass and Contractile Dysfunction in Skeletal Muscle.","authors":"Hyunyoung Kim, Rojina Ranjit, Dennis R Claflin, Constantin Georgescu, Jonathan D Wren, Susan V Brooks, Benjamin F Miller, Bumsoo Ahn","doi":"10.1111/acel.14323","DOIUrl":"https://doi.org/10.1111/acel.14323","url":null,"abstract":"<p><p>Sarcopenia, the progressive loss of muscle mass and function, universally affects older adults and is closely associated with frailty and reduced quality of life. Despite the inevitable consequences of sarcopenia and its relevance to healthspan, no pharmacological therapies are currently available. Ghrelin is a gut-released hormone that increases appetite and body weight through acylation. Acylated ghrelin activates its receptor, growth hormone secretagogue receptor 1a (GHSR1a), in the brain by binding to it. Studies have demonstrated that acyl and unacylated ghrelin (UnAG) both have protective effects against acute pathological conditions independent of receptor activation. Here, we investigated the long-term effects of UnAG in age-associated muscle atrophy and contractile dysfunction in mice. Four-month-old and 18-month-old mice were subjected to either UnAG or control treatment for 10 months. UnAG did not affect food consumption or body weight. Gastrocnemius and quadriceps muscle weights were reduced by 20%-30% with age, which was partially protected against by UnAG. Specific force, force per cross-sectional area, measured in isolated extensor digitorum longus muscle was diminished by 30% in old mice; however, UnAG prevented the loss of specific force. UnAG also protected from decreases in mitochondrial respiration and increases in hydrogen peroxide generation of skeletal muscle of old mice. Results of bulk mRNA-seq analysis and our contractile function data show that UnAG reversed neuromuscular junction impairment that occurs with age. Collectively, our data revealed the direct role of UnAG in mitigating sarcopenia in mice, independent of food consumption or body weight, implicating UnAG treatment as a potential therapy against sarcopenia.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":null,"pages":null},"PeriodicalIF":8.0,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142118476","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":"Modeling aging and retinal degeneration with mitochondrial DNA mutation burden.","authors":"John Sturgis, Rupesh Singh, Quinn R Caron, Ivy S Samuels, Thomas Micheal Shiju, Aditi Mukkara, Paul Freedman, Vera L Bonilha","doi":"10.1111/acel.14282","DOIUrl":"10.1111/acel.14282","url":null,"abstract":"<p><p>Somatic mitochondrial DNA (mtDNA) mutation accumulation has been observed in individuals with retinal degenerative disorders. To study the effects of aging and mtDNA mutation accumulation in the retina, a polymerase gamma (POLG) exonuclease-deficient model, the Polg^D257A mutator mice (D257A), was used. POLG is an enzyme responsible for regulating mtDNA replication and repair. Retinas of young and older mice with this mutation were analyzed in vivo and ex vivo to provide new insights into the contribution of age-related mitochondrial (mt) dysfunction due to mtDNA damage. Optical coherence tomography (OCT) image analysis revealed a decrease in retinal and photoreceptor thickness starting at 6 months of age in mice with the D257A mutation compared to wild-type (WT) mice. Electroretinography (ERG) testing showed a significant decrease in all recorded responses at 6 months of age. Sections labeled with markers of different types of retinal cells, including cones, rods, and bipolar cells, exhibited decreased labeling starting at 6 months. However, electron microscopy analysis revealed differences in retinal pigment epithelium (RPE) mt morphology beginning at 3 months. Interestingly, there was no increase in oxidative stress and parkin-mediated mitophagy in the ages analyzed in the retina or RPE of D257A mice. Additionally, D257A RPE exhibited an accelerated rate of autofluorescence cytoplasmic granule formation and accumulation. Mt markers displayed different abundance in protein lysates obtained from retina and RPE samples. These findings suggest that the accumulation of mtDNA mutations leads to impaired mt function and accelerated aging, resulting in retinal degeneration.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":null,"pages":null},"PeriodicalIF":8.0,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142102448","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":"Periodic protein-restricted diets extend the lifespan of high-fat diet-induced Drosophila melanogaster males.","authors":"Ruohua Wang, Qiushuang Zhu, He Huang, Mengxia Yang, Xinyue Wang, Yuanjie Dong, Yuqiao Li, Yue Guan, Lei Zhong, Yucun Niu","doi":"10.1111/acel.14327","DOIUrl":"https://doi.org/10.1111/acel.14327","url":null,"abstract":"<p><p>Research has shown that sustained protein restriction can improve the effects of a high-fat diet on health and extend lifespan. However, long-term adherence to a protein-restricted diet is challenging. Therefore, we used a fly model to investigate whether periodic protein restriction (PPR) could also mitigate the potential adverse effects of a high-fat diet and extend healthy lifespan. Our study results showed that PPR reduced body weight, lipid levels, and oxidative stress induced by a high-fat diet in flies and significantly extended the healthy lifespan of male flies. Lipid metabolism and transcriptome results revealed that the common differences between the PPR group and the control group and high-fat group showed a significant decrease in palmitic acid in the PPR group; the enriched common differential pathways Toll and Imd were significantly inhibited in the PPR group. Further analysis indicated a significant positive correlation between palmitic acid levels and gene expression in the Toll and Imd pathways. This suggests that PPR effectively improves fruit fly lipid metabolism, reduces palmitic acid levels, and thereby suppresses the Toll and Imd pathways to extend the healthy lifespan of flies. Our study provides a theoretical basis for the long-term effects of PPR on health and offers a new dietary adjustment option for maintaining health in the long term.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":null,"pages":null},"PeriodicalIF":8.0,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142102449","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":"Premature cognitive decline in a mouse model of tuberous sclerosis.","authors":"J Krummeich, L Nardi, C Caliendo, D Aschauer, V Engelhardt, A Arlt, J Maier, F Bicker, M D Kwiatkowski, K Rolski, K Vincze, R Schneider, S Rumpel, S Gerber, M J Schmeisser, S Schweiger","doi":"10.1111/acel.14318","DOIUrl":"https://doi.org/10.1111/acel.14318","url":null,"abstract":"<p><p>Little is known about the influence of (impaired) neurodevelopment on cognitive aging. We here used a mouse model for tuberous sclerosis (TS) carrying a heterozygous deletion of the Tsc2 gene. Loss of Tsc2 function leads to mTOR hyperactivity in mice and patients. In a longitudinal behavioral analysis, we found premature decline of hippocampus-based cognitive functions together with a significant reduction of immediate early gene (IEG) expression. While we did not detect any morphological changes of hippocampal projections and synaptic contacts, molecular markers of neurodegeneration were increased and the mTOR signaling cascade was downregulated in hippocampal synaptosomes. Injection of IGF2, a molecule that induces mTOR signaling, could fully rescue cognitive impairment and IEG expression in aging Tsc2^+/- animals. This data suggests that TS is an exhausting disease that causes erosion of the mTOR pathway over time and IGF2 is a promising avenue for treating age-related degeneration in mTORopathies.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":null,"pages":null},"PeriodicalIF":8.0,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142078556","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":"Pathogenic TDP-43 accelerates the generation of toxic exon1 HTT in Huntington's disease knock-in mice.","authors":"Dazhang Bai, Fuyu Deng, Qingqing Jia, Kaili Ou, Xiang Wang, Junqi Hou, Longhong Zhu, Mingwei Guo, Su Yang, Guohui Jiang, Shihua Li, Xiao-Jiang Li, Peng Yin","doi":"10.1111/acel.14325","DOIUrl":"https://doi.org/10.1111/acel.14325","url":null,"abstract":"<p><p>Huntington's disease (HD) is caused by a CAG repeat expansion in exon1 of the HTT gene that encodes a polyglutamine tract in huntingtin protein. The formation of HTT exon1 fragments with an expanded polyglutamine repeat has been implicated as a key step in the pathogenesis of HD. It was reported that the CAG repeat length-dependent aberrant splicing of exon1 HTT results in a short polyadenylated mRNA that is translated into an exon1 HTT protein. Under normal conditions, TDP-43 is predominantly found in the nucleus, where it regulates gene expression. However, in various pathological conditions, TDP-43 is mislocalized in the cytoplasm. By investigating HD knock-in mice, we explore whether the pathogenic TDP-43 in the cytoplasm contributes to HD pathogenesis, through expressing the cytoplasmic TDP-43 without nuclear localization signal. We found that the cytoplasmic TDP-43 is increased in the HD mouse brain and that its mislocalization could deteriorate the motor and gait behavior. Importantly, the cytoplasmic TDP-43, via its binding to the intron1 sequence (GU/UG)n of the mouse Htt pre-mRNA, promotes the transport of exon1-intron1 Htt onto ribosome, resulting in the aberrant generation of exon1 Htt. Our findings suggest that cytoplasmic TDP-43 contributes to HD pathogenesis via its binding to and transport of nuclear un-spliced mRNA to the ribosome for the generation of a toxic protein product.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":null,"pages":null},"PeriodicalIF":8.0,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142054228","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":"Mitochondrial heterogeneity and crosstalk in aging: Time for a paradigm shift?","authors":"Antentor O Hinton, Zer Vue, Estevão Scudese, Kit Neikirk, Annet Kirabo, Monty Montano","doi":"10.1111/acel.14296","DOIUrl":"https://doi.org/10.1111/acel.14296","url":null,"abstract":"<p><p>The hallmarks of aging have been influential in guiding the biology of aging research, with more recent and growing recognition of the interdependence of these hallmarks on age-related health outcomes. However, a current challenge is personalizing aging trajectories to promote healthy aging, given the diversity of genotypes and lived experience. We suggest that incorporating heterogeneity-including intrinsic (e.g., genetic and structural) and extrinsic (e.g., environmental and exposome) factors and their interdependence of hallmarks-may move the dial. This editorial perspective will focus on one hallmark, namely mitochondrial dysfunction, to exemplify how consideration of heterogeneity and interdependence or crosstalk may reveal new perspectives and opportunities for personalizing aging research. To this end, we highlight heterogeneity within mitochondria as a model.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":null,"pages":null},"PeriodicalIF":8.0,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142071504","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":"Chronic β3-AR stimulation activates distinct thermogenic mechanisms in brown and white adipose tissue and improves systemic metabolism in aged mice.","authors":"Duraipandy Natarajan, Bhuvana Plakkot, Kritika Tiwari, Shoba Ekambaram, Weidong Wang, Michael Rudolph, Mahmoud A Mohammad, Shaji K Chacko, Madhan Subramanian, Stefano Tarantini, Andriy Yabluchanskiy, Zoltan Ungvari, Anna Csiszar, Priya Balasubramanian","doi":"10.1111/acel.14321","DOIUrl":"https://doi.org/10.1111/acel.14321","url":null,"abstract":"<p><p>Adipose thermogenesis has been actively investigated as a therapeutic target for improving metabolic dysfunction in obesity. However, its applicability to middle-aged and older populations, which bear the highest obesity prevalence in the United States (approximately 40%), remains uncertain due to age-related decline in thermogenic responses. In this study, we investigated the effects of chronic thermogenic stimulation using the β3-adrenergic (AR) agonist CL316,243 (CL) on systemic metabolism and adipose function in aged (18-month-old) C57BL/6JN mice. Sustained β3-AR treatment resulted in reduced fat mass, increased energy expenditure, increased fatty acid oxidation and mitochondrial activity in adipose depots, improved glucose homeostasis, and a favorable adipokine profile. At the cellular level, CL treatment increased uncoupling protein 1 (UCP1)-dependent thermogenesis in brown adipose tissue (BAT). However, in white adipose tissue (WAT) depots, CL treatment increased glycerol and lipid de novo lipogenesis (DNL) and turnover suggesting the activation of the futile substrate cycle of lipolysis and reesterification in a UCP1-independent manner. Increased lipid turnover was also associated with the simultaneous upregulation of proteins involved in glycerol metabolism, fatty acid oxidation, and reesterification in WAT. Further, a dose-dependent impact of CL treatment on inflammation was observed, particularly in subcutaneous WAT, suggesting a potential mismatch between fatty acid supply and oxidation. These findings indicate that chronic β3-AR stimulation activates distinct cellular mechanisms that increase energy expenditure in BAT and WAT to improve systemic metabolism in aged mice. Considering that people lose BAT with aging, activation of futile lipid cycling in WAT presents a novel strategy for improving age-related metabolic dysfunction.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":null,"pages":null},"PeriodicalIF":8.0,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142034573","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":"Age-related increase of CD38 directs osteoclastogenic potential of monocytic myeloid-derived suppressor cells through mitochondrial dysfunction in male mice.","authors":"Ramkumar Thiyagarajan, Lixia Zhang, Omar D Glover, Kyu Hwan Kwack, Sara Ahmed, Emma Murray, Nanda Kumar Yellapu, Jonathan Bard, Kenneth L Seldeen, Spencer R Rosario, Bruce R Troen, Keith L Kirkwood","doi":"10.1111/acel.14298","DOIUrl":"https://doi.org/10.1111/acel.14298","url":null,"abstract":"<p><p>An aged immune system undergoes substantial changes where myelopoiesis dominates within the bone marrow. Monocytic-MDSCs (M-MDSCs) have been found to play an important role in osteoclastogenesis and bone resorption. In this study, we sought to provide a more comprehensive understanding of the osteoclastogenic potential of bone marrow M-MDSCs during normal aging through transcriptomic and metabolic changes. Using young mature and aged mice, detailed immunophenotypic analyses of myeloid cells revealed that the M-MDSCs were not increased in bone marrow, however M-MDSCS were significantly expanded in peripheral tissues. Although aged mice exhibited a similar number of M-MDSCs in bone marrow, these M-MDSCs had significantly higher osteoclastogenic potential and greater demineralization activity. Intriguingly, osteoclast progenitors from aged bone marrow M-MDSCs exhibited greater mitochondrial respiration rate and glucose metabolism. Further, transcriptomic analyses revealed the upregulation of mitochondrial oxidative phosphorylation and glucose metabolism genes. Interestingly, there was 8-fold increase in Cd38 mRNA gene expression, consistent with the Mouse Aging Cell Atlas transcriptomic database, and confirmed by qRT-PCR. CD38 regulates NAD⁺ availability, and 78c, a small molecule inhibitor of CD38, reduced the mitochondrial oxygen consumption rate and glucose metabolism and inhibited the osteoclastogenic potential of aged mice bone marrow-derived M-MDSCs. These results indicate that the age-related increase in Cd38 expression in M-MDSCs bias the transcriptome of M-MDSCs towards osteoclastogenesis. This enhanced understanding of the mechanistic underpinnings of M-MDSCs and their osteoclastogenesis during aging could lead to new therapeutic approaches for age-related bone loss and promote healthy aging.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":null,"pages":null},"PeriodicalIF":8.0,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142045982","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":"Single-cell transcriptomic atlas of taste papilla aging.","authors":"Wenwen Ren, Weihao Li, Xudong Cha, Shenglei Wang, Boyu Cai, Tianyu Wang, Fengzhen Li, Tengfei Li, Yingqi Xie, Zengyi Xu, Zhe Wang, Huanhai Liu, Yiqun Yu","doi":"10.1111/acel.14308","DOIUrl":"https://doi.org/10.1111/acel.14308","url":null,"abstract":"<p><p>Taste perception is one of the important senses in mammals. Taste dysfunction causes significant inconvenience in daily life, leading to subhealth and even life-threatening condition. Aging is a major cause to taste dysfunction, while the underlying feature related to gustatory aging is still not known. Using single-cell RNA Sequencing, differentially expressed genes between aged and young taste papillae are identified, including upregulated mt-Nd4l and Xist, as well as downregulated Hsp90ab1 and Tmem59. In the Tmem59^-/- circumvallate papillae (CVP), taste mature cell generation is impaired by reduction in the numbers of PLCβ2⁺ and Car4⁺ cells, as well as decreases in expression levels of taste transduction genes. Tmem59^-/- mice showed deficits in sensitivities to tastants. Through screening by GenAge and DisGeNET databases, aging-dependent genes and oral disease-associated genes are identified in taste papillae. In the CVP, aging promotes intercellular communication reciprocally between (cycling) basal cell and mature taste cell by upregulated Crlf1/Lifr and Adam15/Itga5 signaling. By transcriptional network analysis, ribosome proteins, Anxa1, Prdx5, and Hmgb1/2 are identified as transcriptional hubs in the aged taste papillae. Chronological aging-associated transcriptional changes throughout taste cell maturation are revealed. Aged taste papillae contain more Muc5b⁺ cells that are not localized in gustatory gland. Collectively, this study shows molecular and cellular features associated with taste papilla aging.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":null,"pages":null},"PeriodicalIF":8.0,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142015686","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}