Cell Death Discovery最新文献

{"title":"Satb2 and Nr4a2 are required for the differentiation of cortical layer 6b.","authors":"Li Zhao, Yun-Chao Tao, Ling Hu, Xi-Yue Liu, Qiong Zhang, Lei Zhang, Yu-Qiang Ding, Ning-Ning Song","doi":"10.1038/s41420-025-02402-2","DOIUrl":"10.1038/s41420-025-02402-2","url":null,"abstract":"<p><p>Cortical layer 6 is divided into two sublayers, and layer 6b is situated above the white matter with distinct architecture from layer 6a. Layer 6b arises from the subplate and contains the earliest born neurons in the development of cerebral cortex. Although great progress has been made in understanding the cortical morphogenesis, there is a dearth of knowledge regarding the molecular mechanisms governing the development of layer 6b neurons. Here we report that transcription factor special AT-rich binding protein 2 (Satb2) and nuclear receptor subfamily 4 group A member 2 (Nr4a2) are required for the normal differentiation layer 6b neurons. Upon conditional deletion of Satb2 in the cortex (Satb2^Emx1 CKO) or selectively inactivation of Satb2 in layer 6b neurons only (Satb2^Nr4a2CreER CKO), the expressions of layer 6b-specific genes (i.e., Ctgf, Cplx3, Trh and Tnmd) were significantly reduced, whereas that of Nr4a2 was dramatically increased, underscoring that Satb2 is involved in the differentiation of layer 6b neurons in a cell-autonomous manner. On the other hand, when Nr4a2 was deleted in the cortex, the expressions of Trh and Tnmd were upregulated with unchanged expression of Ctgf and Cplx3. Notably, the defective differentiation resulting from the deletion of Satb2 remained in Satb2/Nr4a2 double CKO mice. In summary, our findings indicated that both Satb2 and Nr4a2 are required for the differentiation of layer 6b neurons possibly via different pathways.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"126"},"PeriodicalIF":6.1,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11958660/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751336","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":"Functions and mechanisms of non-histone post-translational modifications in cancer progression.","authors":"Zongyang Li, Tao Zhu, Yushu Wu, Yongbo Yu, Yunjiang Zang, Lebo Yu, Zhilei Zhang","doi":"10.1038/s41420-025-02410-2","DOIUrl":"10.1038/s41420-025-02410-2","url":null,"abstract":"<p><p>Protein post-translational modifications (PTMs) refer to covalent and enzymatic alterations to folded or nascent proteins during or after protein biosynthesis to alter the properties and functions of proteins. PTMs are modified in a variety of types and affect almost all aspects of cell biology. PTMs have been reported to be involved in cancer progression by influencing multiple signaling pathways. The mechanism of action of histone PTMs in cancer has been extensively studied. Notably, evidence is mounting that PTMs of non-histone proteins also play a vital role in cancer progression. In this review, we provide a systematic description of main non-histone PTMs associated with cancer progression, including acetylation, lactylation, methylation, ubiquitination, phosphorylation, and SUMOylation, based on recent studies.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"125"},"PeriodicalIF":6.1,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11958777/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751398","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":"Antitumor activity of gilteritinib, an inhibitor of AXL, in human solid tumors.","authors":"Zuxiong Zhang, Ruxia Hu, Jie Liu, Xiaohan Yang, Youban Xiao, Xi Xu, Xinxin Liu, Wen Zeng, Shuyong Zhang, Liefeng Wang","doi":"10.1038/s41420-025-02417-9","DOIUrl":"10.1038/s41420-025-02417-9","url":null,"abstract":"<p><p>AXL, a receptor tyrosine kinase, has recently emerged as a potential therapeutic target against various types of cancer. Gilteritinib, a FDA-approved small-molecule inhibitor, is used for the treatment of patients with FLT3-mutated acute myeloid leukemia. However, the antitumor activity of gilteritinib in solid tumors remains poorly elucidated. In this study, we explored the antitumor activity of gilteritinib in AXL-expressing esophageal cancer (EC), ovarian cancer (OC), and gastric cancer (GC), along with the underlying molecular mechanisms. Our data demonstrated that gilteritinib significantly inhibited cell proliferation and spheroid formation by triggering apoptosis and cell cycle arrest in AXL-positive EC, OC, and GC cells. Moreover, we found that gilteritinib treatment repressed EC, OC, and GC cell migration and invasion. Mechanistically, RNA-seq analysis revealed that gilteritinib significantly downregulated multiple cancer-related pathways, including those related to apoptosis, the cell cycle, the mTOR pathway, the AMPK pathway, the p53 pathway, the FOXO pathway, the Hippo pathway, and the Wnt pathway. Gilteritinib inhibited a unique set of E2F- and MYC target-associated genes in EC, OC, and GC cells. Intriguingly, interrogation of the EC, OC, and GC cohort demonstrated that these genes were overexpressed and associated with poor prognosis. Gilteritinib also displayed strong antitumor effects on AXL-positive PDX-derived explants (PDXEs) and PDX-derived organoids (PDXOs) ex vivo and PDXs in vivo. Collectively, these findings reveal that gilteritinib represents a potent therapeutic agent for the treatment of AXL-positive solid tumors. Zhang et al. demonstrate superior therapeutic efficacy of Gilteritinib, a FDA-approved small-molecule inhibitor, in the AXL-expressing esophageal cancer, ovarian cancer and gastric cancer cell lines, PDXOs and PDXs models. This work highlights Gilteritinib as a novel and potent therapeutic approach for the treatment of AXL-positive solid tumors.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"124"},"PeriodicalIF":6.1,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11954984/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742355","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":"Metabolic reprogram and T cell differentiation in inflammation: current evidence and future perspectives.","authors":"Yuxin Shi, Hao Zhang, Changhong Miao","doi":"10.1038/s41420-025-02403-1","DOIUrl":"10.1038/s41420-025-02403-1","url":null,"abstract":"<p><p>T cell metabolism and differentiation significantly shape the initiation, progression, and resolution of inflammatory responses. Upon activation, T cells undergo extensive metabolic shifts to meet distinct functional demands across various inflammatory stages. These metabolic alterations are not only critical for defining different T cell subsets, but also for sustaining their activity in inflammatory environments. Key signaling pathways-including mTOR, HIF-1α, and AMPK regulate these metabolic adaptions, linking cellular energy states with T cell fate decisions. Insights into the metabolic regulation of T cells offer potential therapeutic strategies to manipulate T cell function, with implications for treating autoimmune diseases, chronic inflammation, and cancer by targeting specific metabolic pathways.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"123"},"PeriodicalIF":6.1,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11953409/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742357","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":"FASN promotes lipid metabolism and progression in colorectal cancer via the SP1/PLA2G4B axis.","authors":"Xin Liu, Jiachun Lu, Xiangyu Ni, Yuxin He, Jiayu Wang, Zilin Deng, Guangbo Zhang, Tongguo Shi, Weichang Chen","doi":"10.1038/s41420-025-02409-9","DOIUrl":"10.1038/s41420-025-02409-9","url":null,"abstract":"<p><p>Abnormal metabolic reprogramming is essential for tumorigenesis, metastasis, and the regulation of immune responses. Fatty acid synthase (FASN), a key enzyme in lipid metabolism, plays a crucial role in these processes. However, the relationship between FASN-mediated lipid reprogramming and the immune response in colorectal cancer (CRC) remains unclear. The present study demonstrated that FASN expression is elevated in CRC tissues and is significantly associated with poor prognosis. Functional experiments revealed that FASN promotes proliferation, migration, invasion, and phosphatidylcholine (PC) production in CRC cells. Additionally, in vivo experiments revealed that FASN knockdown significantly inhibits tumor growth and the spread of CRC cells to the lungs. Mechanistically, FASN, which is upregulated in CRC tissues, drives cancer cell proliferation, metastasis, and PC metabolism through the SP1/PLA2G4B axis, subsequently suppressing the antitumor response of natural killer (NK) cells in a PC-dependent manner. These findings provide new insights into lipid metabolism and the immunobiology of CRC, suggesting potential targets for the treatment and prevention of CRC. Schematic diagram showing the mechanism by which FASN promotes cancer cell proliferation, metastasis, and PC metabolism in CRC via the SP1/PLA2G4B axis, subsequently suppressing the antitumor response of NK cells in a PC-dependent manner. FFA free fatty acid, LPA lysophosphatidic acid, PA phosphatidate, DAG diglyceride, PC phosphatidylcholine, LPC lysophosphatidylcholine, CE cholesterol ester, TAG triacylglycerol.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"122"},"PeriodicalIF":6.1,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11950308/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143728917","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":"Proinflammatory cytokines sensitise mesenchymal stromal cells to apoptosis.","authors":"Natalie L Payne, Swee Heng Milon Pang, Andrew J Freeman, Dilara C Ozkocak, Justin W Limar, Georgia Wallis, Di Zheng, Senora Mendonca, Lorraine A O'Reilly, Daniel H D Gray, Ivan K H Poon, Tracy S P Heng","doi":"10.1038/s41420-025-02412-0","DOIUrl":"10.1038/s41420-025-02412-0","url":null,"abstract":"<p><p>Mesenchymal stromal cells (MSCs) exert broad therapeutic effects across a range of inflammatory diseases. Their mechanism of action has largely been attributed to paracrine signalling, orchestrated by an array of factors produced by MSCs that are collectively termed the \"secretome\". Strategies to enhance the release of these soluble factors by pre-exposure to inflammatory cytokines, a concept known as \"licensing\", is thought to provide a means of enhancing MSC efficacy. Yet, recent evidence shows that intravenously infused MSCs entrapped within the lungs undergo apoptosis, and their subsequent clearance by host phagocytes is essential for their therapeutic efficacy. We therefore sought to clarify the mechanisms governing regulated cell death in MSCs and how exposure to inflammatory cytokines impacts this process. Our results show that MSCs are relatively resistant to cell death induced via the extrinsic pathway of apoptosis, as well as stimuli that induce necroptosis, a form of regulated inflammatory cell death. Instead, efficient killing of MSCs required triggering of the mitochondrial pathway of apoptosis, via inhibition of the pro-survival proteins MCL-1 and BCL-XL. Apoptotic bodies were readily released by MSCs during cell disassembly, a process that was inhibited in vitro and in vivo when the apoptotic effectors BAK and BAX were genetically deleted. Licensing of MSCs by pre-exposure to the inflammatory cytokines TNF and IFN-γ increased the sensitivity of MSCs to intrinsic apoptosis in vitro and accelerated their in vivo clearance by host cells within the lungs after intravenous infusion. Taken together, our study demonstrates that inflammatory \"licensing\" of MSCs facilitates cell death by increasing their sensitivity to triggers of the intrinsic pathway of apoptosis and accelerating the kinetics of apoptotic cell disassembly.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"121"},"PeriodicalIF":6.1,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11950399/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143728927","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":"BH3 mimetics augment cytotoxic T cell killing of acute myeloid leukemia via mitochondrial apoptotic mechanism.","authors":"Kapil Saxena, Shao-Hsi Hung, Esther Ryu, Shailbala Singh, Qi Zhang Tatarata, Zhihong Zeng, Zhe Wang, Marina Y Konopleva, Cassian Yee","doi":"10.1038/s41420-025-02375-2","DOIUrl":"10.1038/s41420-025-02375-2","url":null,"abstract":"<p><p>Adoptive cell therapy (ACT) can address an unmet clinical need for patients with relapsed/refractory acute myeloid leukemia (AML), but its effect is often modest in the setting of high tumor burden. In this study, we postulated that strategies to lower the AML apoptotic threshold will augment T cell killing of AML cells. BH3 mimetics, such as venetoclax, are a clinically approved class of compounds that predispose cells to intrinsic apoptosis by inhibiting anti-apoptotic mitochondrial proteins. We explored the anti-leukemic efficacy of BH3 mimetics combined with WT1-specific CD8+ T cells on AML cell lines and primary samples from patients with a diverse array of disease characteristics to evaluate if lowering the cellular apoptotic threshold via inhibition of anti-apoptotic mitochondrial proteins can increase leukemic cell sensitivity to T cell therapy. We found that the combination approach of BH3 mimetic and CD8+ T cells led to significantly increased killing of established AML lines as well as of adverse-risk primary AML leukemic blast cells. In contrast to the hypothesis that enhanced killing would be due to combined activation of the intrinsic and extrinsic apoptotic pathways, our data suggests that CTL-mediated killing of AML cells was accomplished primarily through activation of the intrinsic/mitochondrial apoptotic pathway. This highly effective combinatorial activity due to convergence on the mitochondrial apoptotic pathway was conserved across multiple AML cell lines and primary samples, suggesting that mitochondrial priming may represent a novel mechanism of optimizing adoptive cell therapy for AML patients.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"120"},"PeriodicalIF":6.1,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11947210/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143718095","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":"Comprehensive analysis of cellular metrics: From proliferation to mitochondrial membrane potential and cell death in a single sample.","authors":"Sirina Sabirova, Gulnaz Sharapova, Aida Budyukova, Marina Gomzikova, Anna Brichkina, Nick A Barlev, Albert Rizvanov, Nikita Markov, Hans-Uwe Simon","doi":"10.1038/s41420-025-02391-2","DOIUrl":"10.1038/s41420-025-02391-2","url":null,"abstract":"<p><p>Changes in cell number during in vitro experiments and pharmacological screenings primarily depend on two factors: cell death and proliferation. The dynamics of these processes determine whether cell populations expand and accumulate or, conversely, decrease over time. Understanding the biological mechanisms governing these changes is crucial for deciphering the mode of action of any pharmacological or genetic treatment in fundamental research and pre-clinical trials. In this context, we introduce a robust and efficient flow cytometry-based methodology that enables comprehensive analysis of key cellular parameters that indicate changes in cell numbers. This approach encompasses the assessment of cell count along with critical maintenance parameters including proliferation, cell cycle dynamics, apoptosis, cell permeability, and mitochondrial depolarization. These parameters are intricately linked, offering a detailed view of the cellular state. The described methodology is versatile and adaptable for analyzing various cell types, whether at steady state or in response to treatments. To develop this workflow, we integrated and optimised multiple flow cytometry-based stainings such as annexin V, propidium iodide, bromodeoxyuridine, CellTrace Violet, and JC-1 into a unified protocol. This article offers a detailed, step-by-step guide to the entire method, covering aspects such as timing, sample preparation techniques, and the reagents used. Additionally, it includes examples of the data that can be obtained with this technique and illustrates its multiparametric visualization. Collectively, this methodology facilitates the rapid acquisition of up to eight different parameters from a single sample in one experiment.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"119"},"PeriodicalIF":6.1,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11933298/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699673","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":"New insights into T cell metabolism in liver cancer: from mechanism to therapy.","authors":"Jie Xiao, Ting Liu, Fanxin Zeng, Jinhua Zhang","doi":"10.1038/s41420-025-02397-w","DOIUrl":"10.1038/s41420-025-02397-w","url":null,"abstract":"<p><p>Liver cancer is the sixth most common cancer worldwide and the third most common cause of cancer mortality. The development and progression of liver cancer and metastases is a multifaceted process involving numerous metabolic pathways. T cells have a protective role in the defense against cancer, and manipulating metabolic pathways in T cells can alter their antitumor activity. Furthermore, Liver cancer and T cell nutrition competition lead to T cell dysfunction through various molecular mechanisms. Some nanomaterials and drugs can improve T cell metabolism and promote the anti-liver cancer function of T cells. This review discusses the current literature regarding metabolic changes in liver cancer, the role of T cells in liver cancer, T cell metabolism in liver cancer, and targeted T cell metabolism therapy for liver cancer. The promise and challenges of studying target T cell metabolism for treating liver cancer are also addressed. Targeting T cell metabolism is a promising approach for treating liver cancer.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"118"},"PeriodicalIF":6.1,"publicationDate":"2025-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11930970/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143691320","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":"The natural alkaloid nitidine chloride targets RNA polymerase I to inhibit ribosome biogenesis and repress cancer cell growth.","authors":"Igor Voukeng, Jing Chen, Denis L J Lafontaine","doi":"10.1038/s41420-025-02396-x","DOIUrl":"10.1038/s41420-025-02396-x","url":null,"abstract":"<p><p>Nature is an abundant and largely untapped source of potent bioactive molecules. Ribosome biogenesis modulators have proven effective in suppressing cancer cell growth and are currently being evaluated in clinical trials for anticancer therapies. In this study, we characterized the alkaloid nitidine chloride (NC), produced by the endemic Cameroonian plant Fagara (and other plants). We demonstrate that NC kills cancer cells regardless of their p53 status and inhibits tumor growth in vitro. Furthermore, NC profoundly suppresses global protein synthesis. Treatment of human cells with NC causes severe nucleolar disruption and inhibits pre-rRNA synthesis by destabilizing key factors required for recruitment of RNA polymerase I to ribosomal DNA promoters. In vitro, NC intercalates into DNA and inhibits topoisomerases I and II. Consistently, NC treatment activates a DNA damage response. We propose that the torsional stress on rDNA caused by topoisomerase inhibition leads to loss of RNA polymerase I function and to shutdown of ribosome biogenesis. Although NC has long been suspected of possessing anticancer properties, here we provide a molecular explanation for its mechanism of action. In budding yeast cells, interestingly, NC inhibits cell growth, impairs ribosome biogenesis, and disrupts nucleolar structure. This suggests that its mode of action is at least partially evolutionarily conserved.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"116"},"PeriodicalIF":6.1,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11929923/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143691322","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}