Apoptosis最新文献

{"title":"Involvement of copper in cell death and cancer.","authors":"Jiahao Xie, Yue Su, Wenzhong Shang, Yanfang Wu, Junjia He, Ting Li, Yeyu Shen, Youni Zhang, Xiangmin Tong, Qiong Bian","doi":"10.1007/s10495-024-02059-9","DOIUrl":"https://doi.org/10.1007/s10495-024-02059-9","url":null,"abstract":"<p><p>Copper (cu) is an essential micronutrient required for numerous metabolic processes. It plays a crucial role in cellular respiration by participating in the electron transport chain and facilitating numerous biological reactions. Various diseases, including cancer, demonstrate localized elevation of copper levels and/or alterations in the overall distribution of copper. Modulating local or systemic copper levels as a novel therapeutic approach for treating and ameliorating diseases has emerged as a prominent trend in disease management, particularly in the realm of cancer therapy, which is currently under investigation. The objective of this review is to offer a thorough examination of copper metabolism in both physiological and pathological contexts. Specifically, it delves into how copper ions can effectively target and stimulate tumor cell death via the process known as cuproptosis in cancer patients. Furthermore, this review explores the utilization of three categories of anticancer medications (copper ion carriers, copper complexes, and copper chelating agents) pertaining to copper metabolism within the realm of cancer therapy, elucidating on the distinct mechanisms through which they exert their effects.</p>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142862572","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Necroptosis in obesity: a complex cell death event.","authors":"Zunhai Liu, Simeng Wang, Wentao Wang, Rui Lv, Chao Sun","doi":"10.1007/s10495-024-02055-z","DOIUrl":"https://doi.org/10.1007/s10495-024-02055-z","url":null,"abstract":"<p><p>Obesity is an exceedingly prevalent and frequent health issue in today's society. Fat deposition is accompanied by low-grade inflammation in fat tissue and throughout the body, leading to metabolic disorders that ultimately promote the onset of obesity-related diseases. The development of obesity is accompanied by cell death events such as apoptosis as well as pyroptosis, however, the role of necroptosis in obesity has been widely reported in recent years. Necroptosis, a mode of cell death distinct from apoptosis and necrosis, is associated with developing many inflammatory conditions and their associated diseases. It also exhibits modulation of apoptosis and pyroptosis. It is morphologically similar to necroptosis, characterized by the inhibition of caspase-8, the formation of membrane pores, and the subsequent rupture of the plasma membrane. This paper focuses on the key pathways and molecules of necroptosis, exploring its connections with apoptosis and pyroptosis, and its implications in obesity. This paper posits that the modulation of necroptosis-related targets may represent a novel potential therapeutic avenue for the prevention and treatment of obesity-induced systemic inflammatory responses, and provides a synopsis of potential molecular targets that may prove beneficial in obesity-associated inflammatory diseases.</p>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142862745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EFNA4-enhanced deubiquitination of SLC7A11 inhibits ferroptosis in hepatocellular carcinoma.","authors":"Xingyi Zhong, Zhiqin Zhu, Yangfeng Du, Lingzhi Long, Ziping Xie, Yangfeng Zhang, Huijun Yao, Junhao Lin, Fengsheng Chen","doi":"10.1007/s10495-024-02042-4","DOIUrl":"https://doi.org/10.1007/s10495-024-02042-4","url":null,"abstract":"<p><p>EFNA4, a member of the Ephrin-A ligand family, may influence hepatocellular carcinoma cells through two distinct mechanisms: one reliant on specific Eph receptor binding and the other independent of receptor involvement. However, EFNA4's influence on HCC via non-Eph receptor pathways remains unclear. In this study, we aimed to investigate the role of EFNA4 in a receptor-independent environment. Firstly, we constructed an environment lacking Eph receptors via CRISPR/Cas9 and found that EFNA4 could still partially promote HCC proliferation and metastasis in vivo and in vitro. Further analyses of apoptosis, ROS, and GPX4 expression revealed that overexpression of EFNA4 would inhibit ferroptosis in HCC. Mechanistically, EFNA4 was positively correlated with SLC7A11 and directly interacted with SLC7A11 in HCC via bioinformatics analysis. We demonstrated that the structural domain (a.a. 161-201) of EFNA4 specifically binds to the domain (a.a. 222-501) of SLC7A11, which led to the deubiquitination of SLC7A11. Subsequently, we found that EFNA4 would recruit the deubiquitinase USP9X, resulting in inhibition of SLC7A11 degradation, which ultimately inhibits ferroptosis and enhances the proliferation and metastasis of HCC. In conclusion, we demonstrated that EFNA4 promotes the proliferation and metastasis of HCC independent of Eph receptors by inhibiting ferroptosis and advancing the deubiquitination of SLC7A11 by recruiting the deubiquitinase USP9X. This indicates that EFNA4 could act as a potential prognostic marker and a prospective therapeutic target in patients with HCC.</p>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142799164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microglia programmed cell death in neurodegenerative diseases and CNS injury.","authors":"Ling Cai, Qiuyue Fan, Rui Pang, Chen Chen, Yueman Zhang, Haiyi Xie, Jingyi Huang, Yu Wang, Peiying Li, Dan Huang, Xia Jin, Yuxi Zhou, Yan Li","doi":"10.1007/s10495-024-02041-5","DOIUrl":"https://doi.org/10.1007/s10495-024-02041-5","url":null,"abstract":"<p><p>Programmed cell death (PCD) has emerged as a critical regulatory mechanism in the initiation and progression of various pathological conditions. PCD in microglia, including necroptosis, pyroptosis, apoptosis, ferroptosis, and autophagy, occurs in a variety of central nervous system (CNS) diseases. Dysregulation of microglia can lead to excessive tissue damage or neuronal death in CNS injury. Various injury stimuli trigger aberrant activation of the PCD pathway of microglia, which then further leads to inflammatory cascades that exacerbates CNS pathology in a vicious cycle. Therefore, targeting PCD in microglia is considered an important avenue for the treatment of various neurodegenerative diseases and CNS injury. In this review, we summarize the major and recent findings focusing on the mechanisms of PCD in microglia modulating functions in neurodegenerative diseases and CNS injury and provide a systematic overview of the current inhibitors targeting various PCD pathways, which may provide important therapeutic targets that merit further investigation.</p>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142799172","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial CLPB is a pro-survival factor at the onset of granulocytic differentiation of mouse myeloblastic cells.","authors":"Tomasz Wenta, Guanpeng Wang, Tessa Van Buren, Michal Zolkiewski, Anna Zolkiewska","doi":"10.1007/s10495-024-02053-1","DOIUrl":"https://doi.org/10.1007/s10495-024-02053-1","url":null,"abstract":"<p><p>Loss-of-function mutations in the CLPB gene lead to congenital neutropenia due to impaired neutrophil differentiation. CLPB, a member of the AAA+ family of proteins, resides in the intermembrane space of mitochondria. The mechanism by which a loss of CLPB elicits defects in the differentiation program of neutrophil precursor cells is not understood. Here, we used 32D clone 3 (32Dcl3) cells, an interleukin-3 (IL-3)-dependent mouse myeloblastic cell line model, to investigate the effects of CLPB knockout on myeloblast-to-neutrophil differentiation in vitro. We found that CLPB-deficient 32Dcl3 cells showed a decreased mitochondrial membrane potential and increased levels of insoluble HAX1 aggregates in mitochondria, as compared to control cells. Despite those abnormalities, CLPB loss did not affect cell proliferation rates in the presence of IL-3 but it increased apoptosis after IL-3 withdrawal and simultaneous induction of cell differentiation with granulocytic colony stimulating factor (G-CSF). CLPB-deficient cells that survived the stress associated with IL-3 withdrawal/G-CSF treatment expressed the same levels of differentiation markers as control cells. Moreover, we found that increased apoptosis of CLPB-deficient cells is linked to production of reactive oxygen species (ROS). N-acetylcysteine, exogenous free fatty acids, or exogenous citrate protected CLPB-deficient 32Dcl3 cells from apoptosis at the onset of differentiation. The protective effect of citrate was abolished by inhibition of ATP-citrate lyase (ACLY), an enzyme that converts cytosolic citrate into acetyl-CoA, a substrate for protein acetylation. We propose that citrate supplementation may help mitigate the effects of CLPB loss by facilitating ACLY-dependent ROS detoxification in granulocytic precursor cells.</p>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2024-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142791067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GAS5 long non-coding RNA interacts with microRNA-205 to relieve fibroblast-like synoviocyte inflammation and ferroptosis in osteoarthritis.","authors":"Yanglin Gu, Guangchang Wang, Peng Chen","doi":"10.1007/s10495-024-02051-3","DOIUrl":"https://doi.org/10.1007/s10495-024-02051-3","url":null,"abstract":"<p><p>This study aimed to explore the role of the growth arrest-specific five gene (GAS5) long non-coding RNA (lncRNA) in fibroblast-like synoviocytes (FLSs) during the development of osteoarthritis (OA). A total of 25 OA synovial tissues and nine healthy control tissues were collected, and their GAS5 expression was compared. To confirm GAS5 expression in vitro, interleukin (IL)-1β was used to mimic a cellular OA model based on isolated FLSs. Quantitative polymerase chain reaction revealed higher expression levels of GAS5 in OA samples than in non-OA samples. In vitro, the stimulation of FLSs by IL-1β induced high GAS5 expression. The IL-1β-exposed cells exhibited impaired growth, viability, and antioxidant capacity, as well as increased cell death, production of cellular and lipid ROS, and inflammatory cytokine levels. The expression levels of ferroptosis-related proteins in FLSs were also altered in IL-1β-exposed cells. GAS5 was observed to directly target and inhibit micro-RNA 205, partially reversing the effect of GAS5 silencing on cell proliferation, cell death, oxidative stress, inflammation, and FLS ferroptosis. FLS ferroptosis is recognized to be involved in OA development, and the downregulation of the GAS5 lncRNA exhibits protective effects by suppressing ferroptosis and sponging miR-205 in FLSs in OA, thereby providing a novel strategy for the treatment of OA. The GAS5-miR-205 axis can regulate inflammation and oxidative stress in the FLSs of patients with OA.</p>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2024-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142791064","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HIG-2 promotes glioma stemness and radioresistance mediated by IGFBP2-rich microparticles in hypoxia.","authors":"Ying Yang, Ting Sun, Xuefei Xue, Huiling Tan, Yanyan Li, Wei Yang","doi":"10.1007/s10495-024-02045-1","DOIUrl":"https://doi.org/10.1007/s10495-024-02045-1","url":null,"abstract":"<p><p>Hypoxia can weaken the efficacy of radiotherapy and decrease tumor immunogenicity leading to immune escape. Thus, a thorough understanding of the key signaling pathways regulated by hypoxia is vitally important to enhance the radiosensitivity and improve immunosuppressive microenvironment of glioma. In this study, we verified the crucial role of hypoxia-inducible gene 2 (HIG-2) in lipid droplet (LD) accumulation and demonstrated that HIG-2 binding to frizzled class receptor 10 (FZD10) activated Wnt/β-catenin signaling pathway and increased its downstream insulin-like growth factor binding protein 2 (IGFBP2) level in microparticles (MPs) derived from glioma stem cells (GSCs), leading to decreased radiosensitivity and immunogenicity of MPs-receiving cells via the cross-talk between GSCs and non-stem glioma cells (GCs). These findings suggest that HIG-2 may be a promising target in glioma radiotherapy and/or immunotherapy.</p>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142779131","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Probiotic DNA regulates intestinal Th2 polarization by inducing epithelial cells to produce PD-L1.","authors":"Shuo Song, Hanqing Zhang, Le Liu, Minyao Li, Xiangyu Wang, Haotao Zeng, Miao Zhao, Pixin Ran, Qing Shu, Pingchang Yang","doi":"10.1007/s10495-024-02043-3","DOIUrl":"https://doi.org/10.1007/s10495-024-02043-3","url":null,"abstract":"<p><p>Th2 polarization is a characteristic feature of many immune diseases; its pathogenesis is still being elucidated. Probiotics have immune regulatory effects. This study is aimed at testing the impact of Lactobacillus rhamnosus (LR) DNA on regulating Th2 polarization and elucidating its underlying mechanism. In this study, ovalbumin plus alum protocol was used to establish the Th2 polarization status in the mouse intestine. Mice received LR-DNA gavage daily for five days. The expression of programmed cell death ligand-1 (PD-L1) in intestinal epithelial cells was assessed using RT-qPCR, enzyme-linked immunosorbent assay, and immunohistochemistry. The results showed that the expression of PD-L1 was detected in mouse intestinal epithelial cells, which was up regulated by LR-DNA gavage daily for 5 days. The expression of PD-L1 was also detected in T84 cells, which could be increased by exposing them to LR-DNA in culture. RNA sequencing results showed that the gene activities of Kdm5a, foxo1 and Pdl1 could be upregulated by LR-DNA in mouse intestinal epithelial cells. The epithelial cell-derived PD-L1 induced the activated Th2 cell apoptosis by interacting with programmed cell death protein-1 (PD-1). Administration of LR-DNA, but not live probiotics, alleviated experimental Th2 polarization in a food allergy mouse model. In conclusion, LR-DNA induces intestinal epithelial cells to produce PD-L1, which induces the activated Th2 cell apoptosis. Administration of LR-DNA mitigated experimental Th2 polarization in the intestine.</p>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142779159","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Machine learning-based analysis of programmed cell death types and key genes in intervertebral disc degeneration.","authors":"Yigang Lv, Jiawei Du, Haoning Xiong, Lei Feng, Di Zhang, Hengxing Zhou, Shiqing Feng","doi":"10.1007/s10495-024-02047-z","DOIUrl":"https://doi.org/10.1007/s10495-024-02047-z","url":null,"abstract":"<p><p>Intervertebral disc degeneration (IVDD) is intricately associated with various forms of programmed cell death (PCD). Identifying key PCD types and associated genes is essential for understanding the molecular mechanisms underlying IVDD and discovering potential therapeutic targets. This study aimed to elucidate core PCD types, related genes, and potential drug interactions in IVDD using comprehensive bioinformatic and experimental approaches. Using datasets GSE167199, GSE176205, GSE34095, GSE56081, and GSE70362, relevant gene expression and clinical data were analyzed. Differential expression gene (DEG) analysis identified upregulated genes linked to 15 PCD types. Gene Set Variation Analysis (GSVA) was employed to pinpoint key PCD types contributing to disc degeneration. Core genes were identified through machine learning techniques, while immune infiltration and single-cell analysis helped identify apoptosis-related cell types. Molecular docking, along with in vivo and in vitro experiments using a murine IVDD model, validated potential drug interactions. The results identified apoptosis, autophagy, ferroptosis, and necroptosis as key PCD types in IVDD. A gene module associated with apoptosis showed a strong correlation with the severity of disc degeneration, revealing 34 central genes in the gene network. Drug screening identified Glibenclamide as effectively interacting with PDCD6 and UBE2K. Subsequent in vitro and in vivo experiments demonstrated that Glibenclamide reduced apoptosis and delayed disc degeneration progression. This study provides a comprehensive bioinformatics analysis of PCD in IVDD, identifying four primary PCD types contributing to the disease's progression. The findings offer novel insights into the molecular pathology of disc degeneration and suggest promising therapeutic strategies for future treatment development.</p>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142779143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Melatonin ameliorates inflammation and improves outcomes of ischemia/reperfusion injury in patients undergoing coronary artery bypass grafting surgery: a randomized placebo-controlled study.","authors":"Eman Ahmed Casper, Lamia El Wakeel, Nagwa A Sabri, Ramy Khorshid, Mohamed A Gamal, Sarah F Fahmy","doi":"10.1007/s10495-024-02040-6","DOIUrl":"https://doi.org/10.1007/s10495-024-02040-6","url":null,"abstract":"<p><p>To investigate the protective role of high dose melatonin concerning myocardial I/R injury and inflammation in patients undergoing on-pump coronary artery bypass grafting (CABG) surgery by evaluating IR/inflammatory biomarkers and clinical outcomes. This was a prospective; randomized; single-blinded placebo-controlled study conducted at cardio-thoracic surgery department of the Academy of the Cardiovascular and Thoracic Surgery, Ain Shams University. Eligible patients were randomly allocated to; melatonin-treated group (MTG) or placebo-treated group (PTG). The MTG (n = 17) received 60 mg/day melatonin capsules daily starting 5 days before surgery in addition to the standard of care. PTG (n = 17) received placebo also 5 days before surgery plus standard of care. The levels of nuclear factor kappa beta (NF-κb) (primary outcome), tumor necrosis factor (TNF-α), cardiac troponins I, and IL-6 levels were all assessed for both groups at five time points: baseline before melatonin or placebo administration (T0), before cross-clamp application(T1), 5 min after cross-clamp removal(T2), 6 h after cross-clamp removal(T3) and 24 h after cross-clamp removal(T4). Blood pressure was assessed at baseline, pre-operative and 24-hours post-operative. The Quality of recovery-40 score (QOR-40) was assessed for both groups on day 4 after surgery. TNF-α levels decreased in the MTG at T1(p = 0.034) versus PTG. At T2(p = 0.005), and T3(p = 0.04), TNF-α significantly increased in PTG versus MTG. Troponins significantly increased in PTG at T3 (p = 0.04) versus MTG. NF-κB levels declined at T1 (p = 0.013) and T2 (p = 0.0001) in MTG compared to PTG. IL-6 significantly increased in PTG versus MTG at T3 (p = 0.04). The QOR-40 score significantly decreased in MTG versus PTG. MTG had statistically significant decrease in DBP compared to the placebo group (p = 0.024). MTG had a statistically significant shorter intubation time than did the placebo group (p = 0.03). Melatonin 60 mg was well-tolerated without any reported side effects. Our findings suggested that melatonin could ameliorate myocardial I/R injury after on-pump CABG and that this outcome was essentially correlated to its antiapoptotic and anti-inflammatory effects. Trial registration: ClinicalTrials.gov registration number NCT05552586, 9/2022.</p>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142779150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}