Immunology最新文献

{"title":"LGR4 Deficiency Aggravates Skin Inflammation and Epidermal Hyperplasia in Imiquimod-Induced Psoriasis.","authors":"Mengfei Xue, Ruijie Yang, Guihong Li, Zhizhan Ni, Yuqing Chao, Kairui Shen, Hua Ren, Bing Du, Juliang Qin, Zhenliang Sun","doi":"10.1111/imm.13873","DOIUrl":"https://doi.org/10.1111/imm.13873","url":null,"abstract":"<p><p>Psoriasis is a chronic inflammatory skin disease characterised by inflammatory cell infiltration, keratinocyte hyperproliferation and increased neovascularization. Despite extensive research, the precise mechanisms underlying psoriasis pathology and treatment strategies remain unclear because of a complex aetiology and disease progression. Hence, in this study, we aimed to identify potential therapeutic targets for psoriasis and explore their effects on disease progression. We observed that G protein-coupled receptor LGR4 attenuates psoriasis progression. Bioinformatics analysis of publicly available clinical data revealed lower LGR4 expression in the skin lesions of patients with psoriasis than in their non-lesioned skin. Both in vitro (HaCaT cell) and in vivo (mouse) models confirmed this phenomenon. The Lgr4-knockout mouse model further confirmed that LGR4 plays a positive role in psoriasis progression. Specifically, Lgr4 knockout promoted the secretion of inflammatory factors, accumulation of local immunocyte infiltration in skin lesions, and keratinocyte proliferation. In conclusion, we demonstrated that LGR4 is critical to limiting psoriasis progression, suggesting that it is a viable target for the clinical management of this skin condition.</p>","PeriodicalId":13508,"journal":{"name":"Immunology","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142675697","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic Regulation of Inflammation: Exploring the Potential Benefits of Itaconate in Autoimmune Disorders.","authors":"Yin Luo, Li-Yan Jiang, Zhe-Zhen Liao, Yuan-Yuan Wang, Ya-Di Wang, Xin-Hua Xiao","doi":"10.1111/imm.13875","DOIUrl":"https://doi.org/10.1111/imm.13875","url":null,"abstract":"<p><p>Itaconic acid and its metabolites have demonstrated significant therapeutic potential in various immune diseases. Originating from the tricarboxylic acid cycle in immune cells, itaconic acid can modulate immune responses, diminish inflammation, and combat oxidative stress. Recent research has uncovered multiple mechanisms through which itaconic acid exerts its effects, including the inhibition of inflammatory cytokine production, activation of anti-inflammatory pathways, and modulation of immune cell function by regulating cellular metabolism. Cellular actions are influenced by the modulation of metabolic pathways, such as inhibiting succinate dehydrogenase (SDH) activity or glycolysis, activation of nuclear-factor-E2-related factor 2 (Nrf2), boosting cellular defences against oxidative stress, and suppression of immune cell inflammation through the NF-κB pathway. This comprehensive review discusses the initiation, progression, and mechanisms of action of itaconic acid and its metabolites, highlighting their modulatory effects on various immune cell types. Additionally, it examines their involvement in immune disease like rheumatoid arthritis, multiple sclerosis, type 1 diabetes mellitus, and autoimmune hepatitis, offering greater understanding for creating new therapies for these ailments.</p>","PeriodicalId":13508,"journal":{"name":"Immunology","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142619370","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RNA technology and nanocarriers empowering in vivo chimeric antigen receptor therapy","authors":"Jingsheng Cai,&nbsp;Shaoyi Chen,&nbsp;Zheng Liu,&nbsp;Haoran Li,&nbsp;Peiyu Wang,&nbsp;Fan Yang,&nbsp;Yun Li,&nbsp;Kezhong Chen,&nbsp;Ming Sun,&nbsp;Mantang Qiu","doi":"10.1111/imm.13861","DOIUrl":"10.1111/imm.13861","url":null,"abstract":"<p>The remarkable success of mRNA-based coronavirus 2019 (COVID-19) vaccines has propelled the advancement of nanomedicine, specifically in the realm of RNA technology and nanomaterial delivery systems. Notably, significant strides have been made in the development of RNA-based in vivo chimeric antigen receptor (CAR) therapy. In comparison to the conventional ex vivo CAR therapy, in vivo CAR therapy offers several benefits including simplified preparation, reduced costs, broad applicability and decreased potential for carcinogenic effects. This review summarises the RNA-based CAR constructs in in vivo CAR therapy, discusses the current applications of in vivo delivery vectors and outlines the immune cells edited with CAR molecules. We aim for the conveyed messages to contribute towards the advancement of in vivo CAR application.</p>","PeriodicalId":13508,"journal":{"name":"Immunology","volume":"173 4","pages":"634-653"},"PeriodicalIF":4.9,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imm.13861","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142345954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multiomic-based immune response profiling in migraine, vestibular migraine and Meniere's disease","authors":"Pablo Cruz-Granados,&nbsp;Lidia Frejo,&nbsp;Patricia Perez-Carpena,&nbsp;Juan Carlos Amor-Dorado,&nbsp;Emilio Dominguez-Duran,&nbsp;Maria Jose Fernandez-Nava,&nbsp;Angel Batuecas-Caletrio,&nbsp;Elisheba Haro-Hernandez,&nbsp;Marta Martinez-Martinez,&nbsp;Jose A. Lopez-Escamez","doi":"10.1111/imm.13863","DOIUrl":"10.1111/imm.13863","url":null,"abstract":"<p>Migraine (MI) is the most common neurological disease, affecting with 20% of the world population. A subset of 25% of MI patients showcase concurrent vestibular symptoms, which may classify as vestibular migraine (VM). Meniere's disease (MD) is a complex inner ear disorder defined by episodes of vertigo associated with tinnitus and sensorineural hearing loss with a significant autoimmune/autoinflammatory contribution, which symptoms overlap with VM. Blood samples from 18 patients with MI (5), VM (5) and MD (8) and 6 controls were collected and compared in a case–control study. Droplet-isolated nuclei from mononuclear cells used to generate scRNAseq and scATACseq data sets from MI, VM and MD. MI and VM have no differences in their immune transcriptome; therefore, they were considered as a single cluster for further analyses. Natural Killer (NK) cells transcriptomic data support a polarisation triggered by Type 1 innate immune cells via the release of interleukin (IL)-12, IL-15 and IL-18. According to the monocyte scRNAseq data, there were two MD clusters, one inactive and one driven by monocytes. The unique pathways of the MI + VM cluster were cellular responses to metal ions, whereas MD monocyte-driven cluster pathways showed responses to biotic stimuli. MI and MD have different immune responses. These findings support that MI and VM have a Type 1 immune lymphoid cell response, and that there are two clusters of MD patients, one inactive and one Monocyte-driven.</p>","PeriodicalId":13508,"journal":{"name":"Immunology","volume":"173 4","pages":"768-779"},"PeriodicalIF":4.9,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imm.13863","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142261864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aspergillus fumigatus-derived gliotoxin impacts innate immune cell activation through modulating lipid mediator production in macrophages","authors":"Kerstin Günther,&nbsp;Vivien Nischang,&nbsp;Zoltan Cseresnyés,&nbsp;Thomas Krüger,&nbsp;Dalia Sheta,&nbsp;Zahraa Abboud,&nbsp;Thorsten Heinekamp,&nbsp;Markus Werner,&nbsp;Olaf Kniemeyer,&nbsp;Andreas Beilhack,&nbsp;Marc Thilo Figge,&nbsp;Axel A. Brakhage,&nbsp;Oliver Werz,&nbsp;Paul M. Jordan","doi":"10.1111/imm.13857","DOIUrl":"10.1111/imm.13857","url":null,"abstract":"<p>Gliotoxin (GT), a secondary metabolite and virulence factor of the fungal pathogen <i>Aspergillus fumigatus</i>, suppresses innate immunity and supports the suppression of host immune responses. Recently, we revealed that GT blocks the formation of the chemotactic lipid mediator leukotriene (LT)B₄ in activated human neutrophils and monocytes, and in rodents <i>in vivo,</i> by directly inhibiting LTA₄ hydrolase. Here, we elucidated the impact of GT on LTB₄ biosynthesis and the entire lipid mediator networks in human M1- and M2-like monocyte-derived macrophages (MDMs) and in human tissue-resident alveolar macrophages. In activated M1-MDMs with high capacities to generate LTs, the formation of LTB₄ was effectively suppressed by GT, connected to attenuated macrophage phagocytic activity as well as human neutrophil movement and migration. In resting macrophages, especially in M1-MDMs, GT elicited strong formation of prostaglandins, while bacterial exotoxins from <i>Staphylococcus aureus</i> evoked a broad spectrum of lipid mediator biosynthesis in both MDM phenotypes. We conclude that GT impairs functions of activated innate immune cells through selective suppression of LTB₄ biosynthesis, while GT may also prime the immune system by provoking prostaglandin formation in macrophages.</p>","PeriodicalId":13508,"journal":{"name":"Immunology","volume":"173 4","pages":"748-767"},"PeriodicalIF":4.9,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imm.13857","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142261863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Featured Cover","authors":"","doi":"10.1111/imm.13862","DOIUrl":"https://doi.org/10.1111/imm.13862","url":null,"abstract":"<p>Cover illustration: The cover image is based on the article <i>Erythropoietin induces tumour progression and CD39 expression on immune cells in a preclinical model of triple-negative breast cancer</i> by Stéphanie Bessoles et al., https://doi.org/10.1111/imm.13832.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":13508,"journal":{"name":"Immunology","volume":"173 2","pages":"i"},"PeriodicalIF":4.9,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imm.13862","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142174227","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inherent metabolic preferences differentially regulate the sensitivity of Th1 and Th2 cells to ribosome‐inhibiting antibiotics","authors":"Neha Jawla, Raunak Kar, Veena S. Patil, G. Aneeshkumar Arimbasseri","doi":"10.1111/imm.13860","DOIUrl":"https://doi.org/10.1111/imm.13860","url":null,"abstract":"Mitochondrial translation is essential to maintain mitochondrial function and energy production. Mutations in genes associated with mitochondrial translation cause several developmental disorders, and immune dysfunction is observed in many such patients. Besides genetic mutations, several antibiotics targeting bacterial ribosomes are well‐established to inhibit mitochondrial translation. However, the effect of such antibiotics on different immune cells is not fully understood. Here, we addressed the differential effect of mitochondrial translation inhibition on different subsets of helper T cells (Th) of mice and humans. Inhibition of mitochondrial translation reduced the levels of mitochondrially encoded electron transport chain subunits without affecting their nuclear‐encoded counterparts. As a result, mitochondrial oxygen consumption reduced dramatically, but mitochondrial mass was unaffected. Most importantly, we show that inhibition of mitochondrial translation induced apoptosis, specifically in Th2 cells. This increase in apoptosis was associated with higher expression of Bim and Puma, two activators of the intrinsic pathway of apoptosis. We propose that this difference in the sensitivity of Th1 and Th2 cells to mitochondrial translation inhibition reflects the intrinsic metabolic demands of these subtypes. Though Th1 and Th2 cells exhibit similar levels of oxidative phosphorylation, Th1 cells exhibit higher levels of aerobic glycolysis than Th2 cells. Moreover, Th1 cells are more sensitive to the inhibition of glycolysis, while higher concentrations of glycolysis inhibitor 2‐deoxyglucose are required to induce cell death in the Th2 lineage. These observations reveal that selection of metabolic pathways for substrate utilization during differentiation of Th1 and Th2 lineages is a fundamental process conserved across species.","PeriodicalId":13508,"journal":{"name":"Immunology","volume":"20 1","pages":""},"PeriodicalIF":6.4,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142214522","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of psoriasis-associated immune marker G3BP2 through single-cell RNA sequencing and meta analysis","authors":"Shuangshuang Gao,&nbsp;Huayu Fan,&nbsp;Ting Wang,&nbsp;Jinguang Chen","doi":"10.1111/imm.13851","DOIUrl":"10.1111/imm.13851","url":null,"abstract":"<p>Psoriasis is a chronic skin disease with an increasing prevalence each year. However, the mechanisms underlying its onset and progression remain unclear, and effective therapeutic targets are lacking. Therefore, we employs an innovative approach by combining single-cell RNA sequencing (scRNA-seq) with meta-analysis. This not only elucidates the potential mechanisms of psoriasis at the cellular level but also identifies immunoregulatory marker genes that play a statistically significant role in driving psoriasis progression through comprehensive analysis of multiple datasets. Skin tissue samples from 12 psoriasis patients underwent scRNA-seq, followed by quality control, filtering, PCA dimensionality reduction, and tSNE clustering analysis to identify T cell subtypes and differentially expressed genes (DEGs) in psoriatic skin tissue. Next, three psoriasis datasets were standardised and merged to identify differentially expressed genes (DEGs). Subsequently, weighted gene co-expression network analysis (WGCNA) was applied for clustering analysis of gene co-expression network modules and to assess the correlation between these modules and DEGs. Least absolute shrinkage and selection operator (LASSO) regression and receiver operating characteristic (ROC) curve analyses were conducted to select disease-specific genes and evaluate their diagnostic value. Single-cell data revealed nine cell types in psoriatic skin tissue, with seven T cell subtypes identified. Intersection analysis identified ADAM8 and G3BP2 as key genes. Through the integration of scRNA-seq and Meta analysis, we identified the immunoregulatory marker gene G3BP2, which is associated with the onset and progression of psoriasis and holds clinical significance. G3BP2 is speculated to promote the development of psoriasis by increasing the proportion of CD8+ T cells.</p>","PeriodicalId":13508,"journal":{"name":"Immunology","volume":"173 4","pages":"730-747"},"PeriodicalIF":4.9,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142261865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CCR5-mediated homing of regulatory T cells and monocytic-myeloid derived suppressor cells to dysfunctional endothelium contributes to early atherosclerosis","authors":"Shamima Akhtar,&nbsp;Komal Sagar,&nbsp;Ambuj Roy,&nbsp;Milind P. Hote,&nbsp;Sudheer Arava,&nbsp;Alpana Sharma","doi":"10.1111/imm.13859","DOIUrl":"10.1111/imm.13859","url":null,"abstract":"<p>A disbalance between immune regulatory cells and inflammatory cells is known to drive atherosclerosis. However, the exact mechanism is not clear. Here, we investigated the homing of immune regulatory cells, mainly, regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) subsets in asymptomatic coronary artery disease (CAD) risk factor-exposed young individuals (dyslipidemia [DLP] group) and stable CAD patients (CAD group). Compared with healthy controls (HCs), Tregs frequency was reduced in both DLP and CAD groups but expressed high levels of CCR5 in both groups. The frequency of monocytic-myeloid-derived suppressor cells (M-MDSCs) was increased while polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) were decreased in CAD patients only. Interestingly, although unchanged in frequency, M-MDSCs of the DLP group expressed high levels of CCR5. Serum levels of chemokines (CCL5, CX3CL1, CCL26) and inflammatory cytokines (IL-6, IL-1β, IFN-γ, TNF-α) were higher in the DLP group. Stimulation with inflammatory cytokines augmented CCR5 expression in Tregs and M-MDSCs isolated from HCs. Activated endothelial cells showed elevated levels of CX3CL1 and CCL5 in vitro. Blocking CCR5 with D-Ala-peptide T-amide (DAPTA) increased Treg and M-MDSC frequency in C57Bl6 mice fed a high-fat diet. In accelerated atherosclerosis model, DAPTA treatment led to the formation of smooth muscle-rich plaque with less macrophages. Thus, we show that CCR5-CCL5 axis is instrumental in recruiting Tregs and M-MDSCs to dysfunctional endothelium in the asymptomatic phase of atherosclerosis contributing to atherosclerosis progression. Drugs targeting CCR5 in asymptomatic and CAD risk-factor/s-exposed individuals might be a novel therapeutic regime to diminish atherogenesis.</p>","PeriodicalId":13508,"journal":{"name":"Immunology","volume":"173 4","pages":"712-729"},"PeriodicalIF":4.9,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142214523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Contributions of each of the BAFF receptors to the lymphocyte profiles in C57BL/6 mice","authors":"William Stohl,&nbsp;Ying Wu,&nbsp;Malka Stohl","doi":"10.1111/imm.13856","DOIUrl":"10.1111/imm.13856","url":null,"abstract":"<p>BAFF, a vital B cell survival and differentiation factor, has three receptors: B-cell maturation antigen (BCMA), transmembrane activator and CAML interactor (TACI) and BR3. Although B cells are greatly reduced in B6.<i>Baff</i>^−/− (which harbour no BAFF) and B6.<i>Br3</i>^−/− mice (which harbour supra-normal levels of BAFF), the distributions of B cell subsets and relationships between Foxp3⁺ and CD4⁺ cells in these mice differ. Using a large panel of B6 congenic knockout and/or transgenic mice, we demonstrate that (1) supra-normal levels of BAFF per se do not explain the phenotypic differences between B6.<i>Baff</i>^−/− and B6.<i>Br3</i>^−/− mice; (2) B cells are expanded in B6.<i>Taci</i>^−/− mice, with preferential expansion of follicular (FO) B cells at the expense of CD19⁺CD21^−/loCD23^−/lo B cells but without the preferential expansion of Foxp3⁺ cells observed in B6 mice bearing a <i>Baff</i> transgene; (3) despite no expansion in total B cells, percentages of FO B cells and marginal zone B cells are higher and percentages of CD19⁺CD21^−/loCD23^−/lo B cells are lower in young B6.<i>Bcma</i>^−/− mice, consistent with the inability of B6.<i>Br3</i>^−/−<i>.Taci</i>^−/− mice to recapitulate the B cell profile of B6.<i>Baff</i>^−/− mice; and (4) percentages of Foxp3⁺ cells in B6.<i>Br3</i>^−/−<i>.Taci</i>^−/− mice are intermediate between those in B6.<i>Br3</i>^−/− and B6.<i>Taci</i>^−/− mice despite the B cell profile of B6.<i>Br3</i>^−/−<i>.Taci</i>^−/− mice strongly resembling that of B6.<i>Br3</i>^−/− mice. Collectively, our findings point to a non-redundant role for each of the BAFF receptors in determining the ultimate lymphocyte profile of the host. This may have clinically relevant ramifications in that the degree that a candidate therapeutic agent blocks engagement of any given individual BAFF receptor may affect its clinical utility.</p>","PeriodicalId":13508,"journal":{"name":"Immunology","volume":"173 4","pages":"689-711"},"PeriodicalIF":4.9,"publicationDate":"2024-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imm.13856","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142107021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}