Frontiers in Cell and Developmental Biology最新文献

{"title":"Interleukin-1 receptor-dependent and -independent caspase-1 activity in retinal cells mediated by receptor interacting protein 2.","authors":"Brandon A Coughlin, Barbara Christian, Brett Trombley, Susanne Mohr","doi":"10.3389/fcell.2024.1467799","DOIUrl":"10.3389/fcell.2024.1467799","url":null,"abstract":"<p><strong>Introduction: </strong>Inflammation and cell death play an important role in the pathogenesis of diabetic retinopathy. Previously we observed sustained activation of pro-inflammatory caspase-1 in retinas of diabetic animals and patients. In this study, we aimed to look at mechanisms underlying chronic caspase-1 activation <i>in vitro</i> and <i>in vivo</i>.</p><p><strong>Methods: </strong>Non-diabetic and diabetic wild type and IL-1 receptor (IL-1R1) knockout mice were used for <i>in vivo</i> experiments. Diabetes was induced using STZ (streptozotocin). Human Müller cells were used for <i>in vitro</i> studies. Cells were treated with either 5 mM or 25 mM glucose or interleukin-1beta (IL-1β) in the presence or absence of IL-1 receptor antagonist (IL-1ra) or siRNA against RIP2 (receptor interacting protein-2) for up to 96 h. Outcome measurements to assess Müller cell functions included measurements of caspase-1 activity using a fluorescence peptide substrate, production of IL-1β by Elisa, and cell death using trypan blue exclusion assays.</p><p><strong>Results: </strong>Our <i>in vivo</i> results demonstrate that caspase-1 activation progresses from an IL-1R1 independent mechanism at 10 weeks of diabetes to an IL-1R1 dependent mechanism at 20 weeks indicating that feedback through IL-1R1 is crucial for sustained caspase-1 activity in retinas of mice. A similar hyperglycemia-mediated caspase-1/IL-1β/IL-1R1 feedback signaling was detected <i>in vitro</i> in human Müller cells which was prevented by treatment with IL-1ra. Our data also indicate that hyperglycemia induces caspase-1 activation initially but IL-1β sustains caspase-1 activation via caspase-1/IL-1β/IL-1R1 feedback and we identified RIP2 as mediator for both hyperglycemia- and IL-1β-induced caspase-1 activation. Activation of caspase-1/IL-1β/IL-1R1 feedback signaling caused Müller cell death which was prevented by RIP2 knockdown.</p><p><strong>Discussion: </strong>We conclude that any intervention in caspase-1/IL-1β/IL-1R1 feedback signaling presents novel therapeutic options for the treatment of diabetic retinopathy.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"12 ","pages":"1467799"},"PeriodicalIF":4.6,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11525982/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum: Pyroptosis and gasdermins-Emerging insights and therapeutic opportunities in metabolic dysfunction-associated steatohepatitis.","authors":"Christian Stoess, Aleksandra Leszczynska, Lin Kui, Ariel E Feldstein","doi":"10.3389/fcell.2024.1461581","DOIUrl":"https://doi.org/10.3389/fcell.2024.1461581","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.3389/fcell.2023.1218807.].</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"12 ","pages":"1461581"},"PeriodicalIF":4.6,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11522226/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544718","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extra-cerebral recombination activity of Emx1-Cre and nestin-Cre in the kidney.","authors":"Min Wang, Xiaojuan Liu, Yin Fang, Qintong Li","doi":"10.3389/fcell.2024.1480217","DOIUrl":"10.3389/fcell.2024.1480217","url":null,"abstract":"<p><p>Individuals with neurodevelopmental disorders (NDDs) are frequently diagnosed with comorbidities in other organs, indicating that NDD risk genes may have extra-cerebral functions. The engineered mouse models are pivotal in understanding the functions of candidate NDD genes. Here, we report that Emx1-Cre and nestin-Cre mouse strains, the popular tools to study brain development, also exhibit recombination activity in the kidney. We find that both Emx1-Cre and nestin-Cre can drive recombination in epithelial cells lining proximal and distal convoluted tubules of the nephron. Additionally, nestin-Cre drives recombination in the glomerulus of the nephron. Furthermore, we use Emx1-Cre and nestin-Cre to knock out <i>Larp7</i>, a gene linked to a human NDD called Alazami syndrome. We find that <i>Larp7</i> knockout using nestin-Cre, but not Emx1-Cre, results in elevated blood urea nitrogen. This result suggests a compromised kidney function, reminiscent of recently revealed renal anomalies in Alazami syndrome patients. Many genes have been knocked out using Emx1-Cre and nestin-Cre to study their roles during embryonic neurogenesis. It will be of great interest to reinvestigate whether the renal development and function is affected in these existing mouse models.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"12 ","pages":"1480217"},"PeriodicalIF":4.6,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11521858/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142550053","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advances in understanding the regulation of pluripotency fate transition in embryonic stem cells.","authors":"Yong Kang Jia, Yang Yu, Li Guan","doi":"10.3389/fcell.2024.1494398","DOIUrl":"10.3389/fcell.2024.1494398","url":null,"abstract":"<p><p>Embryonic stem cells (ESCs) sourced from the inner cell mass of blastocysts, are akin to this tissue in function but lack the capacity to form all extraembryonic structures. mESCs are transient cell populations that express high levels of transcripts characteristic of 2-cell (2C) embryos and are identified as \"2-cell-like cells\" (2CLCs). Previous studies have shown that 2CLCs can contribute to both embryonic and extraembryonic tissues upon reintroduction into early embryos. Approximately 1% of mESCs dynamically transition from pluripotent mESCs into 2CLCs. Nevertheless, the scarcity of mammalian embryos presents a significant challenge to the molecular characterization of totipotent cells. To date, Previous studies have explored various methods for reprogramming pluripotent cells into totipotent cells. While there is a good understanding of the molecular regulatory network maintaining ES pluripotency, the process by which pluripotent ESCs reprogram into totipotent cells and the associated molecular mechanisms of totipotent regulation remain poorly understood. This review synthesizes recent insights into the regulatory pathways of ESC reprogramming into 2CLC, exploring molecular mechanisms modulated by transcriptional regulators, small molecules, and epigenetic changes. The objective is to construct a theoretical framework for the field of researchers.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"12 ","pages":"1494398"},"PeriodicalIF":4.6,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11521825/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544715","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Revisiting the role of MicroRNAs in the pathogenesis of idiopathic pulmonary fibrosis.","authors":"Zhimin Zhou, Yuhong Xie, Qianru Wei, Xinyue Zhang, Zhihao Xu","doi":"10.3389/fcell.2024.1470875","DOIUrl":"10.3389/fcell.2024.1470875","url":null,"abstract":"<p><p>Idiopathic pulmonary fibrosis (IPF) is a prevalent chronic pulmonary fibrosis disease characterized by alveolar epithelial cell damage, fibroblast proliferation and activation, excessive extracellular matrix deposition, and abnormal epithelial-mesenchymal transition (EMT), resulting in tissue remodeling and irreversible structural distortion. The mortality rate of IPF is very high, with a median survival time of 2-3 years after diagnosis. The exact cause of IPF remains unknown, but increasing evidence supports the central role of epigenetic changes, particularly microRNA (miRNA), in IPF. Approximately 10% of miRNAs in IPF lung tissue exhibit differential expression compared to normal lung tissue. Diverse miRNA phenotypes exert either a pro-fibrotic or anti-fibrotic influence on the progression of IPF. In the context of IPF, epigenetic factors such as DNA methylation and long non-coding RNAs (lncRNAs) regulate differentially expressed miRNAs, which in turn modulate various signaling pathways implicated in this process, including transforming growth factor-β1 (TGF-β1)/Smad, mitogen-activated protein kinase (MAPK), and phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) pathways. Therefore, this review presents the epidemiology of IPF, discusses the multifaceted regulatory roles of miRNAs in IPF, and explores the impact of miRNAs on IPF through various pathways, particularly the TGF-β1/Smad pathway and its constituent structures. Consequently, we investigate the potential for targeting miRNAs as a treatment for IPF, thereby contributing to advancements in IPF research.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"12 ","pages":"1470875"},"PeriodicalIF":4.6,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11521927/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modification of Lhx2 activity for <i>ex vivo</i> amplification of human iPSC-derived hematopoietic stem/progenitor cells.","authors":"Kenji Kitajima, Yuna Takahashi, Hikaru Ando, Minako Shingai, Mako Hamasaki, Miyu Tanikawa, Mai Kanokoda, Marino Nakajima, Yasumasa Nishito, Takahiko Hara","doi":"10.3389/fcell.2024.1482989","DOIUrl":"https://doi.org/10.3389/fcell.2024.1482989","url":null,"abstract":"<p><p>Hematopoietic stem cells (HSCs) obtained from patient-derived human induced pluripotent stem cells (iPSCs) are a promising tool for curing various hematological disorders. We previously demonstrated that enforced expression of the LIM-homeobox transcription factor Lhx2, which is essential for mouse embryonic hematopoiesis, leads to generation of engraftable and expandable hematopoietic stem cells (HSCs) from mouse iPSCs. However, it remained unknown whether Lhx2 can induce HSCs from human iPSCs. Here, we investigated the effect of Lhx2 overexpression on hematopoietic differentiation of human iPSCs. Unexpectedly, Lhx2 severely inhibited proliferation of human iPSC-derived hematopoietic cells. Thus, Lhx2 exhibited differential effects on mouse and human hematopoietic cells. Further studies implied that the inhibitory effect of Lhx2 on human iPSC-derived hematopoietic cells was due to insufficient transcriptional activation ability. Therefore, we modified Lhx2 to strengthen its activity as a transcriptional activator. This modified Lhx2 could induce <i>ex vivo</i> amplification of human iPSC-derived hematopoietic stem/progenitor cells (HSPCs). We believe that these findings will facilitate the development of a method to efficiently produce HSCs from human iPSCs.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"12 ","pages":"1482989"},"PeriodicalIF":4.6,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11518812/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tensions on the actin cytoskeleton and apical cell junctions in the <i>C. elegans</i> spermatheca are influenced by spermathecal anatomy, ovulation state and activation of myosin.","authors":"Fereshteh Sadeghian, Noa W F Grooms, Samuel H Chung, Erin J Cram","doi":"10.3389/fcell.2024.1490803","DOIUrl":"10.3389/fcell.2024.1490803","url":null,"abstract":"<p><strong>Introduction: </strong>Cells generate mechanical forces mainly through myosin motor activity on the actin cytoskeleton. In <i>C. elegans</i>, actomyosin stress fibers drive contractility of the smooth muscle-like cells of the spermatheca, a distensible, tube-shaped tissue in the hermaphrodite reproductive system and the site of oocyte fertilization. Stretching of the spermathecal cells by oocyte entry triggers activation of the small GTPase Rho. In this study, we asked how forces are distributed <i>in vivo</i>, and explored how spermathecal tissue responds to alterations in myosin activity.</p><p><strong>Methods: </strong>In animals expressing GFP labeled actin or apical membrane complexes, we severed these structures using femtosecond laser ablation and quantified retractions. RNA interference was used to deplete key contractility regulators.</p><p><strong>Results: </strong>We show that the basal actomyosin fibers are under tension in the occupied spermatheca. Reducing actomyosin contractility by depletion of the phospholipase C-ε/PLC-1 or non-muscle myosin II/NMY-1, leads to distended spermathecae occupied by one or more embryos, but does not alter tension on the basal actomyosin fibers. However, activating myosin through depletion of the Rho GAP SPV-1 increases tension on the actomyosin fibers, consistent with earlier studies showing Rho drives spermathecal contractility. On the inner surface of the spermathecal tube, tension on the apical junctions is decreased by depletion of PLC-1 and NMY-1. Surprisingly, when basal contractility is increased through SPV-1 depletion, the tension on apical junctions also decreases, with the most significant effect on the junctions aligned in perpendicular to the axis of the spermatheca.</p><p><strong>Discussion: </strong>Our results suggest that much of the tension on the basal actin fibers in the occupied spermatheca is due to the presence of the embryo. Additionally, increased tension on the outer basal surface may compress the apical side, leading to lower tensions apically. The three dimensional shape of the spermatheca plays a role in force distribution and contractility during ovulation.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"12 ","pages":"1490803"},"PeriodicalIF":4.6,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11518831/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544725","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum: A role for TRPC3 in mammalian testis development.","authors":"Zhenhua Ming, Stefan Bagheri-Fam, Emily R Frost, Janelle M Ryan, Brittany Vining, Vincent R Harley","doi":"10.3389/fcell.2024.1484634","DOIUrl":"https://doi.org/10.3389/fcell.2024.1484634","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.3389/fcell.2024.1337714.].</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"12 ","pages":"1484634"},"PeriodicalIF":4.6,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11519811/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544717","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cellular and transcriptomic changes by the supplementation of aged rat serum in human pluripotent stem cell-derived myogenic progenitors.","authors":"Sin-Ruow Tey, Ryan S Anderson, Clara H Yu, Samantha Robertson, Heidi Kletzien, Nadine P Connor, Kaori Tanaka, Yasuyuki Ohkawa, Masatoshi Suzuki","doi":"10.3389/fcell.2024.1481491","DOIUrl":"10.3389/fcell.2024.1481491","url":null,"abstract":"<p><strong>Introduction: </strong>The changing composition of non-cell autonomous circulating factors in blood as humans age is believed to play a role in muscle mass and strength loss. The mechanisms through which these circulating factors act in age-related skeletal muscle changes is not fully understood. In this study, we used human myogenic progenitors derived from human pluripotent stem cells to study non-cell autonomous roles of circulating factors during the process of myogenic differentiation.</p><p><strong>Methods: </strong>Myogenic progenitors from human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) were supplemented with serum samples from aged or young Fischer 344 × Brown Norway F1-hybrid rats. The effect of aged or young serum supplementation on myogenic progenitor proliferation, myotube formation capacity, differentiation, and early transcriptomic profiles were analyzed.</p><p><strong>Results: </strong>We found that aged rat serum supplementation significantly reduced cell proliferation and increased cell death in both ESC- and iPSC-derived myogenic progenitors. Next, we found that the supplementation of aged rat serum inhibited myotube formation and maturation during terminal differentiation from progenitors to skeletal myocytes when compared to the cells treated with young adult rat serum. Lastly, we identified that gene expression profiles were affected following serum supplementation in culture.</p><p><strong>Discussion: </strong>Together, aged serum supplementation caused cellular and transcriptomic changes in human myogenic progenitors. The current data from our <i>in vitro</i> model possibly simulate non-cell autonomous contributions of blood composition to age-related processes in human skeletal muscle.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"12 ","pages":"1481491"},"PeriodicalIF":4.6,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11518775/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544716","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrating clinical and genomic landscape analysis of perineural invasion identify ACTA1 as an oncogene for oral squamous cell carcinoma.","authors":"Sheng Chen, Tongchao Zhao, Yuxian Song, Xiaofeng Huang, Yanhong Ni, Liang Ding, Yong Fu, Qingang Hu, Yi Wang","doi":"10.3389/fcell.2024.1458879","DOIUrl":"https://doi.org/10.3389/fcell.2024.1458879","url":null,"abstract":"<p><strong>Background: </strong>Perineural invasion (PNI) has been shown to be a key pathological feature of several types of cancer, including oral squamous epithelial carcinoma (OSCC). However, the overall clinical and genomic landscape of PNI⁺ OSCC are still unclear, and the molecular mechanism of PNI remains to be further investigated.</p><p><strong>Methods: </strong>279 OSCC samples were extracted from the TCGA database and grouped according to PNI. The clinicopathological information, prognostic and survival analyses were performed. The Cibersort algorithm and ESTIMATE algorithm was used to estimate the impacts on proportion of immune cells, immune score and stromal score by PNI. Immunotherapy prediction analysis was also performed. 167 differentially expressed genes were screened for functional enrichment analysis. Actin α1 (ACTA1) protein, which was significantly upregulated in the PNI⁺ group, was selected for validation in our OSCC patient's cohort (n = 70). We next analyzed the ratio and absolute number of key immunocytes in peripheral blood of OSCC patients according to Actin α1 expression by flow cytometry.</p><p><strong>Results: </strong>PNI was more likely to occur in patients with advanced tumors and worse prognosis. Immunomodulation analyses showed that T cells follicular helper and cells were significantly lower, but M2 macrophages and total stromal score was significantly higher in PNI⁺ OSCC. Immunotherapy prediction analyses showed that PNI⁺ OSCC may be more sensitive to CTLA4 inhibitor treatment. 167 differentially expressed genes were identified and enriched in muscle structure and cell movement-related pathway. Among them, Actin α1 (ACTA1) was significantly upregulated in PNI⁺ advanced OSCC with worse clinical outcome whose had relatively low ratio of CD3⁺CD8⁺ circulating cytotoxic T cells.</p><p><strong>Conclusion: </strong>PNI⁺ OSCC patients with upregulated of Actin α1 could benefit from cytotoxic T cell-mediated immunotherapy.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"12 ","pages":"1458879"},"PeriodicalIF":4.6,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11519412/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544720","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}