Journal of molecular medicine (Berlin, Germany)最新文献

{"title":"ATF4 in proximal tubules modulates kidney function and modifies the metabolome.","authors":"Yuling Chi, Eduardo Mere Del Aguila, Tuo Zhang, Charles D Warren, Helen R Hoxie, Qiuying Chen, Steven S Gross, Jacob B Geri, David M Nanus, Lorraine J Gudas","doi":"10.1007/s00109-025-02559-4","DOIUrl":"10.1007/s00109-025-02559-4","url":null,"abstract":"<p><p>Activating transcription factor 4 (ATF4) is a transcription factor that mediates the response to stress at the cellular, tissue, and organism level. We deleted the gene encoding ATF4 in the proximal tubules of the mouse kidney by using a temporal and cell type-specific approach. We show that ATF4 plays a major role in regulating the transcriptome and proteome, which, in turn, influences the metabolome and kidney functions. Genome-wide transcriptomics and single-plot, solid-phase-enhanced sample preparation (SP3)-proteomics studies reveal that ATF4 deletion changes more than 30% of transcripts and, similarly, corresponding proteins in the proximal tubules. Gene Set Enrichment Analysis indicates major changes in transporters, including amino acid transporters. Metabolomic analyses show that these changes in transporters are associated with altered profiles of amino acids in the blood, kidney, and urine. Stable isotope glutamine tracing in primary tubule cells isolated from kidney cortices confirms that ATF4 regulates glutamine transport and metabolism. We suggest that even in the absence of additional stresses, such as kidney injury, ATF4 in the proximal tubules modulates both retention of specific nutrients and excretion of catabolic products like creatinine to maintain normal kidney function. KEY MESSAGES: Activating transcription factor 4 (ATF4) deletion changed more than 30% of genome-wide transcripts and corresponding proteins in the proximal tubules. One set of the profound changes occurred in amino acid transporters and Slc22 family transporters. Changes in transporters were accompanied by altered profiles of amino acids and wastes in the blood, kidney, and urine. ATF4 in the kidney proximal tubules plays a key role in regulating both the reabsorption of nutrients and the excretion of wastes.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144340795","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TIPE2: a novel regulatory factor for cardiovascular-related diseases.","authors":"Ruomei Li, Zhikun Guo","doi":"10.1007/s00109-025-02564-7","DOIUrl":"https://doi.org/10.1007/s00109-025-02564-7","url":null,"abstract":"<p><p>Tumor necrosis factor-α-inducible protein 8-like 2 (TIPE2) is a novel regulatory factor involved in innate and adaptive immunity that negatively regulates the functions of toll-like receptors and T-cell receptors. Its selective expression within the immune system serves to inhibit inflammatory responses and maintain immune homeostasis. Inflammation and immune cell signaling initiate the innate immune response in the cardiovascular system through intricate acute and chronic adaptation processes, resulting in tissue damage and significantly contributing to the onset and progression of cardiovascular diseases. Consequently, TIPE2 presents a potential target for the diagnosis and treatment of various cardiovascular diseases. This paper reviews the structural characteristics and biological functions of TIPE2, as well as its role in the onset and progression of cardiovascular diseases, providing new strategies for prevention and treatment.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144328434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Selenium and selenoproteins: key regulators of ferroptosis and therapeutic targets in cancer.","authors":"Jaewang Lee, Jong-Lyel Roh","doi":"10.1007/s00109-025-02563-8","DOIUrl":"https://doi.org/10.1007/s00109-025-02563-8","url":null,"abstract":"<p><p>The interplay between selenium (Se) metabolism and ferroptosis presents a compelling area of study in cancer biology. This review synthesizes the current understanding of key pathways implicated in ferroptosis susceptibility, with a focus on the role of selenoproteins, particularly glutathione peroxidase 4 (GPX4), which mitigates lipid peroxidation and prevents ferroptotic cell death through the system Xc^-/GSH axis. Additionally, selenoprotein P contributes to Se transport, playing a crucial role in ferroptosis resistance observed in certain cancers. Targeting Se pathways, especially disrupting GPX4 and selenoprotein P functions, offers promising avenues for cancer therapy. The differential dependence of cancer cells on Se and selenoproteins highlights the potential for selective induction of ferroptosis in malignant cells. Future research should focus on unraveling the mechanistic underpinnings of Se-mediated ferroptosis and exploring combinatorial therapeutic strategies. This review sets the stage for innovative approaches that leverage Se metabolism to enhance cancer treatment efficacy through ferroptosis modulation. KEY MESSAGES: Selenium (Se) and selenoproteins regulate ferroptosis, a lipid peroxidation-driven form of cell death. GPX4, a Se-dependent enzyme, defends cells by neutralizing lipid hydroperoxides. Xc^-/GSH/GPX4 and FSP1-CoQ₁₀ pathways are critical in modulating ferroptosis susceptibility. Selenoprotein P, SEPHS2, and SQOR highlight vulnerabilities in Se-dependent cancer cell survival. Se's role in balancing antioxidant defense and ferroptosis offers therapeutic insights.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144319186","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of HOMER2 frameshift extension variant on auditory function and development.","authors":"Eunjung Han, Ju Ang Kim, Saemi Park, Jin Hee Han, Min Young Kim, Yehree Kim, Ngoc-Trinh Tran, Bong Jik Kim, June Choi, Byung Yoon Choi","doi":"10.1007/s00109-025-02556-7","DOIUrl":"https://doi.org/10.1007/s00109-025-02556-7","url":null,"abstract":"<p><p>The HOMER2 gene, crucial for synaptic signaling and calcium homeostasis in the auditory system, is linked to sensorineural hearing loss (SNHL), with its variants contributing to severe SNHL in older adults, often necessitating cochlear implants in their 60 s or 70 s. In this study, we identified a novel frameshift extension variant, c.1033delC (p.Arg345Glufs*64; p.R345Efs*64), which introduces a significantly longer protein extension than previously reported extension variants, in a patient in their sixties presenting with progressive profound SNHL. To investigate the pathogenic potential of this variant, we employed molecular modeling and zebrafish models, comparing wild-type HOMER2, a hypothetical p.R345* variant involving alteration of the most C-terminal 10 amino acids, and the patient-derived p.R345Efs*64 variant. AlphaFold2 predicts that the p.R345Efs*64 variant causes significant structural changes in the HOMER2 EVH1 domain, disrupting interactions with Cdc42 and contributing to SNHL. Zebrafish models show that this variant, which combines truncation and extension features, impairs neuromast hair cell function and exacerbates auditory phenotypes, while also increasing cardiac anomalies. In comparison, the p.R345* variant showed an obvious milder impact. Our findings suggest that the pathogenic effect of the p.R345Efs*64 variant is more driven by the extension beyond the stop codon. Here we report that a novel frameshift extension variant of HOMER2, which arises as a causative gene in elderly patients with profound SNHL, highlighting the need for genetic diagnosis in this population. Our findings reveal a solid pathogenic gain-of-function effect related to the long extension to the C-terminal of HOMER2, and a possible link to cardiac anomalies.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144295618","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Specialized pro-resolving mediators: key regulators in placental function and pregnancy complications.","authors":"Luisa G Sousa, Georgina Correia-da-Silva, Natércia Teixeira, Bruno Miguel Fonseca","doi":"10.1007/s00109-025-02561-w","DOIUrl":"https://doi.org/10.1007/s00109-025-02561-w","url":null,"abstract":"<p><p>Specialized pro-resolving mediators (SPMs) are bioactive lipids derived from essential fatty acids that play a key role in resolving inflammation and modulating immune responses, thereby maintaining tissue homeostasis in various physiological contexts, including pregnancy. In healthy pregnancies, inflammation is a biological response necessary for vascular remodeling, embryo implantation as well as delivery and an increase in SPMs such as lipoxin A4 (LXA4) and resolvin D1 (RvD1) supports homeostasis and facilitates inflammation resolution. However, pregnancy complications such as spontaneous abortion, fetal growth restriction (FGR), and preeclampsia are often associated with disrupted SPM levels and receptor activity. In spontaneous abortion, altered SPM levels are linked to impaired endometrial receptivity, defective trophoblast invasion, poor epithelial-to-mesenchymal transition, and enhanced inflammation. Similarly, FGR is associated with reduced LXA4 levels, which contribute to placental vascular dysfunction and impaired trophoblast migration. Preeclampsia is characterized by dysregulated SPM levels and a pro-inflammatory environment, indicating insufficient resolutive activity. Therapeutic approaches to enhance SPM levels, such as aspirin-triggered lipoxins and omega-3 fatty acid supplementation, have demonstrated potential benefits. However, inconsistent clinical outcomes highlight the need for personalized treatment strategies. This review explores the role of SPMs in pregnancy, focusing on their molecular mechanisms and the development of targeted supplementation strategies to optimize their protective effects in managing high-risk pregnancies. KEY MESSAGES: Physiological pregnancies involve a gradual increase in SPM levels. LXA4 and RvD1 may have a context-dependent role in placentation by negatively regulating endometrial decidualization, trophoblast EMT and invasion, which contributes to spontaneous abortion, while positively regulating endothelial function, trophoblast survival and M2-macrophage polarization, which supports pregnancy. SPMs are essential to preserve endothelial integrity and support trophoblast proliferation, and appear downregulated in FGR. Preeclampsia is correlated with dysregulated SPM levels and a reduced LXA4/TNFα ratio, which suggests insufficient anti-inflammatory action. Therapeutic strategies that enhance SPMs production such as aspirin and DHA supplementation show considerable promise, particularly in preventing complications in high-risk pregnancies.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144251921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MicroRNA-100-5p in exosomes from human placental mesenchymal stem cells: a key modulator of anti-psoriatic effects through mTOR/S6 K1 pathway.","authors":"Yu-Chen Huang, Chao-Yuan Chang, Chun-Jen Huang","doi":"10.1007/s00109-025-02560-x","DOIUrl":"https://doi.org/10.1007/s00109-025-02560-x","url":null,"abstract":"<p><p>Exosomes from mesenchymal stem cells (MSCs) demonstrate therapeutic potential against psoriasis, primarily due to their anti-inflammatory properties. However, the specific components within the exosomal cargo, particularly microRNAs, that mediate this activity remain unclear. This study investigated the role of a specific microRNA in mediating the therapeutic effects of exosomes from human placenta MSCs (MSC-exosomes) in an imiquimod (IMQ)-induced psoriasis murine model, with a focus on the underlying mechanisms, particularly the downstream pathways of the specific microRNA. Our small RNA sequencing analysis identified microRNA (miR)-100-5p as a potential target. Adult male Balb/c mice were then randomly assigned to the IMQ, IMQ plus MSC-exosomes (IMQ + Exo), IMQ plus MSC-exosomes treated with a specific miR-100-5p inhibitor (IMQ + Exoi), or IMQ plus agomiR-100-5p group (IMQ + AgomiR) (n = 6 per group). Control groups were also included. Mice were sacrificed, and psoriasis severity was assessed the day after 6 consecutive days of daily IMQ exposure, followed by 7 consecutive days of daily treatment. The IMQ + Exo group exhibited significantly lower epidermal thickness, levels of inflammatory cytokines and psoriasis-related cytokines (interleukin [IL]-12, IL-17, and IL-23), and expression of mammalian target of rapamycin (mTOR)/S6 kinase 1 (S6K1) (the predicted downstream target of miR-100-5p), compared to the IMQ group (all p < 0.05). Notably, inhibition of miR-100-5p nullified these therapeutic effects of MSC-exosomes. This study provides evidence that miR-100-5p plays a crucial role in mediating the therapeutic effects of MSC-exosomes in an IMQ-induced murine psoriasis model, potentially by modulating the mTOR/S6K1 pathway. KEY MESSAGES: • Exosomes from human placental mesenchymal stem sells demonstrate therapeutic potential against psoriasis. • MicroRNA-100-5p plays a crucial role in mediating the therapeutic effects of mesenchymal stem cells exosomes in an imiquimod-induced murine psoriasis  model, potentially by modulating the mammalian target of rapamycin/S6 kinase 1 pathway.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144251918","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Serum proteins and faecal microbiota as potential biomarkers in newly diagnosed, treatment-naïve inflammatory bowel disease and irritable bowel syndrome patients.","authors":"Mario Matijašić, Anja Barešić, Hana Čipčić Paljetak, Mihaela Perić, Marina Panek, Ana Kunović, Dina Ljubas Kelečić, Darija Vranešić Bender, Katja Grubelić Ravić, Dunja Rogić, Margareta Antolic, Ivana Horvat, Ivana Kraljević, Marko Banić, Željko Krznarić, Donatella Verbanac","doi":"10.1007/s00109-025-02558-5","DOIUrl":"https://doi.org/10.1007/s00109-025-02558-5","url":null,"abstract":"<p><p>Molecular biomarkers are valuable tools to predict the disease and determine its course. Several markers have been associated with inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS); however, none is sufficiently reliable to enable accurate diagnosis. We characterized a broad panel of serum proteins to assess disease-specific biomarker profiles and associate these findings with faecal microbiota composition in newly diagnosed IBD and IBS patients and healthy individuals. The study cohort consisted of 49 newly diagnosed treatment-naïve adult patients (13 Crohn's disease (CD), 13 ulcerative colitis (UC), and 23 IBS) and 12 healthy individuals. Inflammatory and metabolism-related serum proteins were assessed using PEA multiplex panels, while gut microbiota composition was determined by 16 s rRNA gene amplicon sequencing. Serum proteins AXIN1, TNFSF14, RNASE3, EN-RAGE, OSM, ST1A1, CA13 and NADK were identified as markers with the most promising specificity/sensitivity and predictivity between healthy and disease groups, while IL-17A and TNFRSF9 enabled differentiation between IBD and IBS patients. Increased abundance of Enterobacteriaceae was associated with protein markers significantly elevated in IBD/IBS. In contrast, depletion of beneficial taxa like Ruminococcaceae and Verucomicrobiaceae (i.e. Akkermansia muciniphila) was associated with decrease of a set of markers in diseased groups. Differences in the abundance of Turicibacteriaceae were more predictive to discern CD from UC than any of the serum proteins investigated. By using a broad panel of inflammation and metabolism-related proteins, we determined serum markers with significantly different levels in treatment-naïve IBD and IBS patients compared to healthy individuals, as well as between IBD and IBS. KEY MESSAGES : Significant changes in the levels of several serum proteins and abundances of faecal bacterial taxa between study groups were found. Increased levels of AXIN1, TNFSF14, RNASE3, EN-RAGE, OSM, ST1A1, CA13 and NADK characterize both IBD and IBS, while IL-17A and TNFRSF9 differentiate IBD from IBS. Increase of Enterobacteriaceae and depletion of beneficial taxa Ruminococcaceae and Verucomicrobiaceae (i.e. Akkermansia muciniphila) was found in IBD and IBS. Differences in Turicibacteriaceae were more predictive to discern CD from UC than any of the serum proteins investigated.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144251920","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to: MiR‑30c‑1‑3p targets matrix metalloproteinase 9 involved in the rupture of abdominal aortic aneurysms.","authors":"Lin Yang,&nbsp;Hong-Gang Sui,&nbsp;Meng-Meng Wang,&nbsp;Jia-Yin Li,&nbsp;Xiao-Feng He,&nbsp;Jing-Yuan Li,&nbsp;Xiao-Zeng Wang","doi":"10.1007/s00109-022-02267-3","DOIUrl":"https://doi.org/10.1007/s00109-022-02267-3","url":null,"abstract":"","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":" ","pages":"1801"},"PeriodicalIF":4.7,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9691476/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40657552","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to: LncRNA GATA3‑AS1 promoted invasion and migration in human endometrial carcinoma by regulating the miR‑361/ARRB2 axis.","authors":"Yu-Xi Liu,&nbsp;Shuo Yuan,&nbsp;Xiao-Jing Liu,&nbsp;Yan-Xi Huang,&nbsp;Pin Qiu,&nbsp;Jie Gao,&nbsp;Gao-Pi Deng","doi":"10.1007/s00109-022-02259-3","DOIUrl":"https://doi.org/10.1007/s00109-022-02259-3","url":null,"abstract":"","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":" ","pages":"1671"},"PeriodicalIF":4.7,"publicationDate":"2022-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40559182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Histone modification in podocyte injury of diabetic nephropathy.","authors":"Simeng Wang,&nbsp;Xinyu Zhang,&nbsp;Qinglian Wang,&nbsp;Rong Wang","doi":"10.1007/s00109-022-02247-7","DOIUrl":"https://doi.org/10.1007/s00109-022-02247-7","url":null,"abstract":"<p><p>Diabetic nephropathy (DN), an important complication of diabetic microvascular disease, is one of the leading causes of end-stage renal disease (ESRD), which brings heavy burdens to the whole society. Podocytes are terminally differentiated glomerular cells, which act as a pivotal component of glomerular filtration barrier. When podocytes are injured, glomerular filtration barrier is damaged, and proteinuria would occur. Dysfunction of podocytes contributes to DN. And degrees of podocyte injury influence prognosis of DN. Growing evidences have shown that epigenetics does a lot in the evolvement of podocyte injury. Epigenetics includes DNA methylation, histone modification, and non-coding RNA. Among them, histone modification plays an indelible role. Histone modification includes histone methylation, histone acetylation, and other modifications such as histone phosphorylation, histone ubiquitination, histone ADP-ribosylation, histone crotonylation, and histone β-hydroxybutyrylation. It can affect chromatin structure and regulate gene transcription to exert its function. This review is to summarize documents about pathogenesis of podocyte injury, most importantly, histone modification of podocyte injury in DN recently to provide new ideas for further molecular research, diagnosis, and treatment.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":" ","pages":"1373-1386"},"PeriodicalIF":4.7,"publicationDate":"2022-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33447512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}