European Journal of Immunology最新文献_第4页

Researcher Reflections—Inspiring Paths in Academia

IF 4.5 3区医学

European Journal of Immunology Pub Date : 2024-12-23 DOI: 10.1002/eji.202451717

Annika Hausmann, Ioana Sandu, Rami Bechara, Liv Eidsmo, Adrian Liston, Shruti Naik, Charlotte L. Scott, Matteo Villa, Eduardo Villablanca, Natalia Muñoz-Wolf

{"title":"Researcher Reflections—Inspiring Paths in Academia","authors":"Annika Hausmann, Ioana Sandu, Rami Bechara, Liv Eidsmo, Adrian Liston, Shruti Naik, Charlotte L. Scott, Matteo Villa, Eduardo Villablanca, Natalia Muñoz-Wolf","doi":"10.1002/eji.202451717","DOIUrl":"https://doi.org/10.1002/eji.202451717","url":null,"abstract":"<div>\u0000 \u0000 The journey of early-career researchers (ECRs) in immunology is marked by many challenges but also exciting prospects. Here we bring a snapshot of the recent ECR workshop organized by the Young European Federation of Immunology Societies (yEFIS) during the 7th European Congress of Immunology (ECI), which took place in Dublin Ireland from September 1 to 4, 2024. This article brings forward the unique experiences and perspectives of eight Principal Investigators (PIs) and the events that shaped their careers in immunology. Navigating challenges, from mastering intricate laboratory techniques, securing tenure, or moving countries, to finding the right balance between family and research life; their stories reveal the diverse paths to independence within academia. This series celebrates scientific accomplishments acknowledging the non-linearity of career paths and the value of passion for discovery, self-confidence, resilience, and perseverance in their academic journeys.\u0000 </div>","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"55 2","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143424298","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}

引用次数: 0

B Cell Receptor Repertoire Analysis of the CD21lo B Cell Compartment in Healthy Individuals, Patients With Sjögren's Disease, and Patients With Radiographic Axial Spondyloarthritis 健康个体、Sjögren病患者和x线轴性脊柱炎患者CD21lo B细胞区室的B细胞受体库分析

IF 4.5 3区医学

European Journal of Immunology Pub Date : 2024-12-20 DOI: 10.1002/eji.202451398

Rick Wilbrink, Linda van der Weele, Anneke J. P. L. Spoorenberg, Niek de Vries, Ilse T. G. Niewold, Gwenny M. Verstappen, Frans G. M. Kroese

{"title":"B Cell Receptor Repertoire Analysis of the CD21lo B Cell Compartment in Healthy Individuals, Patients With Sjögren's Disease, and Patients With Radiographic Axial Spondyloarthritis","authors":"Rick Wilbrink, Linda van der Weele, Anneke J. P. L. Spoorenberg, Niek de Vries, Ilse T. G. Niewold, Gwenny M. Verstappen, Frans G. M. Kroese","doi":"10.1002/eji.202451398","DOIUrl":"10.1002/eji.202451398","url":null,"abstract":"B cells with low or absent expression of CD21 (CD21lo B cells) gained attention due to their expansion in the peripheral blood of patients with immune-mediated, rheumatic diseases. This is not only observed in typical autoimmune diseases like systemic lupus erythematosus and Sjögren's disease (SjD) but also in radiographic axial spondyloarthritis (r-axSpA), which is considered an autoinflammatory disease. To gain more insight into the origins of the heterogeneous CD21lo B-cell population, and its relation to the plasmablast (PB) compartment, we profiled the B-cell-receptor (BCR) repertoire in CD27− and CD27+ fractions of CD21lo B cells and early PBs using next-generation sequencing. Populations were sorted from peripheral blood of healthy individuals, SjD patients, and r-axSpA patients (n = 10 for each group). In healthy individuals and both patient groups, our findings indicate that CD27−CD21lo B cells, which exhibit few mutations in their BCR, may develop into CD27+CD21lo B cells and PBs, both marked by considerably more mutations. Given the known expansion of circulating CD27−CD21lo B cells in SjD and r-axSpA patients and clonal relationships with both CD27+CD21lo B cells and early PBs, these cells might actively contribute to (pathological) immune responses in rheumatic diseases with autoimmune and/or autoinflammatory characteristics.","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"55 2","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/eji.202451398","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142870639","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}

引用次数: 0

Characterization of Human CD8αβ Interaction With Classical and Unconventional MHC Molecules 人CD8αβ与经典和非常规MHC分子相互作用的表征

IF 4.5 3区医学

European Journal of Immunology Pub Date : 2024-12-20 DOI: 10.1002/eji.202451230

Ben de Wet, Robert Alan Simmons, Richard J. Suckling, Rita Szoke-Kovacs, Salah Mansour, Marco Lepore, David K. Cole, Jakub Jaworski, Alexandra L. Chapman, Milos Aleksic

{"title":"Characterization of Human CD8αβ Interaction With Classical and Unconventional MHC Molecules","authors":"Ben de Wet, Robert Alan Simmons, Richard J. Suckling, Rita Szoke-Kovacs, Salah Mansour, Marco Lepore, David K. Cole, Jakub Jaworski, Alexandra L. Chapman, Milos Aleksic","doi":"10.1002/eji.202451230","DOIUrl":"10.1002/eji.202451230","url":null,"abstract":"The CD8 co-receptor exists as both an αα homodimer, expressed on subsets of specialized lymphoid cells, and as an αβ heterodimer, which is the canonical co-receptor on cytotoxic T-cells, tuning TCR thymic selection and antigen-reactivity in the periphery. However, the biophysical parameters governing human CD8αβ interactions with classical MHC class I (MHCI) and unconventional MHC-like molecules have not been determined. Using hetero-dimerized Fc-fusions to generate soluble human CD8αβ, we demonstrate similar weak binding affinity to multiple different MHCI alleles compared with CD8αα. We observed that both forms of CD8 bound to certain alleles with stronger affinity than others and found that the affinity of thymically selected TCRs was inversely associated with the affinity of the CD8 co-receptor for the different alleles. We further demonstrated the binding of CD8αα and CD8αβ to the unconventional MHC-like molecule, MHCI-related protein 1, with a similar affinity as for classical MHCI, but no interaction was observed for the other unconventional MHC-like molecules, CD1a, b, c, or d. In summary, this is the first characterization of human CD8αβ binding to MHCI and MHC-like molecules that revealed an intriguing relationship between CD8 binding affinity for different MHCI alleles and the selection of TCRs in the thymus.","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"55 1","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739670/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142862655","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}

引用次数: 0

Half-Life Extension of the IgG-Degrading Enzyme (IdeS) Using Fc-Fusion Technology 利用fc融合技术延长igg降解酶（IdeS）半衰期。

IF 4.5 3区医学

European Journal of Immunology Pub Date : 2024-12-20 DOI: 10.1002/eji.202451264

Victoria Daventure, Melissa Bou-Jaoudeh, Emna Hannachi, Alejandra Reyes-Ruiz, Amélia Trecco, Sandrine Delignat, Sébastien Lacroix-Desmazes, Claire Deligne

{"title":"Half-Life Extension of the IgG-Degrading Enzyme (IdeS) Using Fc-Fusion Technology","authors":"Victoria Daventure, Melissa Bou-Jaoudeh, Emna Hannachi, Alejandra Reyes-Ruiz, Amélia Trecco, Sandrine Delignat, Sébastien Lacroix-Desmazes, Claire Deligne","doi":"10.1002/eji.202451264","DOIUrl":"10.1002/eji.202451264","url":null,"abstract":"Imlifidase (IdeS) is a bacterial protease that hydrolyzes human IgG in their hinge region, decreasing their half-life and abrogating their Fc-mediated properties. It is now successfully used in therapy to prevent graft rejection during kidney transplants and is being clinically evaluated in several IgG-mediated autoimmune diseases. IdeS short half-life however limits its clinical use, particularly in the case of chronic diseases that would request repeated administrations. Here, we developed IdeS-Fc fusion proteins as a divalent homodimer (IdeS-Fcdiv) or a monovalent heterodimer (IdeS-Fcmonov), in order to extend the IgG-depleting action of IdeS over time. Both IdeS-Fc efficiently separated monoclonal and polyclonal human IgG into F(ab')2 and Fc fragments, although with slower kinetics than their native counterpart. IdeS-Fcmonov exhibited a seven-fold half-life extension in vivo as compared with IdeS, and a significantly better residual cleavage of human IgG at later time points after injection. Our results provide proof of concept for the use of an IdeS with extended IgG-hydrolyzing functions in vivo that could rapidly translate to the clinic.","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"55 2","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/eji.202451264","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142862698","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}

引用次数: 0

The Efficiency of Brain-Derived Neurotrophic Factor Secretion by mRNA-Electroporated Regulatory T Cells Is Highly Impacted by Their Activation Status mRNA导入的调节性T细胞分泌脑源性神经营养因子的效率受其活化状态的影响很大。

IF 4.5 3区医学

European Journal of Immunology Pub Date : 2024-12-19 DOI: 10.1002/eji.202451005

Jasper Van den Bos, Ibo Janssens, Morgane Vermeulen, Amber Dams, Hans De Reu, Stefanie Peeters, Carole Faghel, Yousra El Ouaamari, Inez Wens, Nathalie Cools

{"title":"The Efficiency of Brain-Derived Neurotrophic Factor Secretion by mRNA-Electroporated Regulatory T Cells Is Highly Impacted by Their Activation Status","authors":"Jasper Van den Bos, Ibo Janssens, Morgane Vermeulen, Amber Dams, Hans De Reu, Stefanie Peeters, Carole Faghel, Yousra El Ouaamari, Inez Wens, Nathalie Cools","doi":"10.1002/eji.202451005","DOIUrl":"10.1002/eji.202451005","url":null,"abstract":"Genetic engineering of regulatory T cells (Tregs) presents a promising avenue for advancing immunotherapeutic strategies, particularly in autoimmune diseases and transplantation. This study explores the modification of Tregs via mRNA electroporation, investigating the influence of T-cell activation status on transfection efficiency, phenotype, and functionality. For this CD45RA+ Tregs were isolated, expanded, and modified to overexpress brain-derived neurotrophic factor (BDNF). Kinetics of BDNF expression and secretion were explored. Treg activation state was assessed by checking the expression of activation markers CD69, CD71, and CD137. Our findings show that only activated Tregs secrete BDNF post-genetic engineering, even though both activated and resting Tregs express BDNF intracellularly. Notably, the mTOR pathway and CD137 are implicated in the regulation of protein secretion in activated Tregs, indicating a complex interplay of signalling pathways. This study contributes to understanding the mechanisms governing protein expression and secretion in engineered Tregs, offering insights for optimizing cell-based therapies and advancing immune regulation strategies.","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"55 2","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/eji.202451005","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142862699","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}

引用次数: 0

BAFF Blockade Attenuates B Cell MALT Formation in Conditional Nlrc5-Deficient Mice With Helicobacter felis Infection BAFF阻断可减少感染幽门螺杆菌的nlrc5缺陷小鼠B细胞MALT的形成。

IF 4.5 3区医学

European Journal of Immunology Pub Date : 2024-12-17 DOI: 10.1002/eji.202451355

Dongmei Tong, Yuqi He, Shambel Araya Haile, Zoe Lee, Lena H. M. Le, Jack Emery, Georgie Wray-McCann, Michelle Chonwerawong, Dana J. Philpott, Paul J. Hertzog, Pascal Schneider, Richard L. Ferrero, Le Ying

{"title":"BAFF Blockade Attenuates B Cell MALT Formation in Conditional Nlrc5-Deficient Mice With Helicobacter felis Infection","authors":"Dongmei Tong, Yuqi He, Shambel Araya Haile, Zoe Lee, Lena H. M. Le, Jack Emery, Georgie Wray-McCann, Michelle Chonwerawong, Dana J. Philpott, Paul J. Hertzog, Pascal Schneider, Richard L. Ferrero, Le Ying","doi":"10.1002/eji.202451355","DOIUrl":"10.1002/eji.202451355","url":null,"abstract":"<div>\u0000 \u0000 Helicobacter infection is a key cause of gastric B cell mucosa–associated lymphoid tissue (MALT) lymphoma. This study examined the role of B cell–activating factor (BAFF), a major driver of B cell proliferation and many B cell disorders, in this malignancy using a model in which conditional knockout mice for NOD-like receptor family CARD domain-containing 5 (Nlrc5) are infected with Helicobacter felis. Gastric BAFF production was significantly increased in H. felis–infected Nlrc5mø-KO mice compared to wild-type. Blocking BAFF signalling, before or after the onset of Helicobacter-induced gastritis, significantly reduced MALT development, with fewer gastric B cell follicles and reduced gland hyperplasia. BAFF blockade also reshaped the immune cell landscape in the stomach, resulting in fewer CD4+ T cells, Tregs, macrophages and dendritic cells. Using a cell culture model, we identified the protein-coding BAFF transcripts that are upregulated in NLRC5-deficient macrophages stimulated with either H. felis or the NLRC5 agonist, lipopolysaccharide. Among the upregulated variants, TNFSF13B (BAFF)-206 acts as a transcription factor and is reported to enhance BAFF production in autoimmune diseases and cancer. Altogether, these findings implicate the NLRC5–BAFF signalling axis in Helicobacter-induced B cell MALT lymphoma, highlighting BAFF inhibition as a potential therapeutic approach.\u0000 </div>","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"55 2","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142833398","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}

引用次数: 0

Distinct Tissue-Dependent Composition and Gene Expression of Human Fetal Innate Lymphoid Cells 人胎儿先天淋巴样细胞的不同组织依赖性组成和基因表达。

IF 4.5 3区医学

European Journal of Immunology Pub Date : 2024-12-15 DOI: 10.1002/eji.202451150

Inga E. Rødahl, Martin A. Ivarsson, Liyen Loh, Jeff E. Mold, Magnus Westgren, Danielle Friberg, Jenny Mjösberg, Niklas K. Björkström, Nicole Marquardt, Douglas F. Nixon, Jakob Michaëlsson

引用次数: 0

TOX Does Not Drive Sepsis-Induced T-Cell Exhaustion 毒素不会导致败血症诱导的 T 细胞耗竭

IF 4.5 3区医学

European Journal of Immunology Pub Date : 2024-12-15 DOI: 10.1002/eji.202451395

Yingyu Qin, Yilin Qian, Shengqiu Liu, Rong Chen

{"title":"TOX Does Not Drive Sepsis-Induced T-Cell Exhaustion","authors":"Yingyu Qin, Yilin Qian, Shengqiu Liu, Rong Chen","doi":"10.1002/eji.202451395","DOIUrl":"10.1002/eji.202451395","url":null,"abstract":"<div>\u0000 \u0000 The immune system undergoes profound dysregulation in sepsis, characterized by hyperinflammation in the acute phase followed by long-lasting immunosuppression. T-cell exhaustion has been proposed as one facet of sepsis-related immunosuppression, which is characterized by impaired effector function and continuous expression of PD1. However, the current analysis of T-cell exhaustion in the post-sepsis is inadequate. Our current study has identified a progressive increase in the frequency of CD44+CD11a+ memory T cells during the post-sepsis phase, accompanied by the upregulation of exhaustion markers (PD-1, Lag3, and Tim3) and functional impairments in these cells. TOX is traditionally recognized as a key regulator driving CD8+ T-cell exhaustion in cancer and chronic infection. However, we demonstrate that TOX does not play a critical role in T-cell exhaustion during chronic sepsis but rather is involved in T-cell effector function. Both knockout and “knockdown” of TOX failed to alleviate sepsis-induced T-cell exhaustion. Instead, deletion of TOX impaired the effector function of T cells in chronic sepsis, contradicting its impact on short-term TCR engagement. Our study provides a novel insight into sepsis-induced T-cell exhaustion, highlighting the distinct characteristics of T-cell exhaustion programmed by sepsis.\u0000 </div>","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"55 2","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142826999","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}

引用次数: 0

KIRA6 is an Effective and Versatile Mast Cell Inhibitor of IgE-mediated Activation KIRA6 是一种有效的多用途肥大细胞抑制剂，能抑制 IgE 介导的活化。

IF 4.5 3区医学

European Journal of Immunology Pub Date : 2024-12-15 DOI: 10.1002/eji.202451348

Veronika Wunderle, Thomas Wilhelm, Shatha Boukeileh, Jonas Goßen, Michael A. Margreiter, Roman Sakurov, Sandro Capellmann, Maike Schwoerer, Nabil Ahmed, Gina Bronneberg, Michel Arock, Christian Martin, Thomas Schubert, Francesca Levi-Schaffer, Giulia Rossetti, Boaz Tirosh, Michael Huber

{"title":"KIRA6 is an Effective and Versatile Mast Cell Inhibitor of IgE-mediated Activation","authors":"Veronika Wunderle, Thomas Wilhelm, Shatha Boukeileh, Jonas Goßen, Michael A. Margreiter, Roman Sakurov, Sandro Capellmann, Maike Schwoerer, Nabil Ahmed, Gina Bronneberg, Michel Arock, Christian Martin, Thomas Schubert, Francesca Levi-Schaffer, Giulia Rossetti, Boaz Tirosh, Michael Huber","doi":"10.1002/eji.202451348","DOIUrl":"10.1002/eji.202451348","url":null,"abstract":"Mast cell (MC)-driven allergic diseases are constantly expanding and require the development of novel pharmacological MC stabilizers. Allergen/antigen (Ag)-triggered activation via crosslinking of the high-affinity receptor for IgE (FcεRI) is fundamentally regulated by SRC family kinases, for example, LYN and FYN, exhibiting positive and negative functions. We report that KIRA6, an inhibitor for the endoplasmic reticulum stress sensor IRE1α, suppresses IgE-mediated MC activation by inhibiting both LYN and FYN. KIRA6 attenuates Ag-stimulated early signaling and effector functions such as degranulation and proinflammatory cytokine production/secretion in murine bone marrow-derived MCs. Moreover, Ag-triggered bronchoconstriction in an ex vivo model and IgE-mediated stimulation of human MCs were repressed by KIRA6. The interaction of KIRA6 with three MC-relevant tyrosine kinases, LYN, FYN, and KIT, and the potential of KIRA6 structure as a pharmacophore for the development of respective single-, dual-, or triple-specificity inhibitors, was evaluated by homology modeling and molecular dynamics simulations. We found that KIRA6 particularly strongly binds the inactive state of LYN, FYN, and KIT with comparable affinities. In conclusion, our data suggest that the chemical structure of KIRA6 as a pharmacophore can be further developed to obtain an effective MC stabilizer.","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"55 2","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/eji.202451348","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142826994","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}

引用次数: 0

Human Genetic GLUT1 Deficiency Results in Impaired T Cellular IFN-γ Production 人类遗传性GLUT1缺乏导致T细胞IFN-γ产生受损。

IF 4.5 3区医学

European Journal of Immunology Pub Date : 2024-12-13 DOI: 10.1002/eji.202451066

Renske de Jong, Anandhi Rajendiran, Judit Turyne Hriczko, Sudheendra Hebbar Subramanyam, Alina Rein, Martin Häusler, Thorsten Orlikowsky, Norbert Wagner, Daniel Erny, Kim Ohl, Klaus Tenbrock

引用次数: 0