Discovery and structural characterization of a therapeutic antibody against coxsackievirus A10

9月20日，《科学》子刊《科学•进展》（Science Advances）刊出了我校夏宁邵教授团队发表的题为“Discovery and structural characterization of a therapeutic antibody against coxsackievirus A10”的研究论文。该研究首次发现手足口病重要病原体柯萨奇病毒A组10型（CVA10）不同类型病毒颗粒共有的优势中和表位，揭示了病毒颗粒及其与优势中和抗体复合物的精确三维结构，阐明了中和抗体的功能与作用机制，为新型疫苗和治疗药物的研制提供了重要的理论基础。 该研究首次揭示并描绘了CVA10的病毒颗粒及其优势中和表位的精确特征，发现了具有良好应用潜能的治疗性中和抗体，为新型疫苗和特异性治疗药物的研究提供了关键基础。 我校夏宁邵教授、程通副教授和美国加州大学洛杉矶分校纳米系统研究所Z. Hong Zhou（周正洪）教授、美国加州大学圣地亚哥分校颜晓东博士为该论文的共同通讯作者。我校博士生朱瑞、徐龙发博士后、郑清炳工程师、李少伟教授和美国加州大学洛杉矶分校崔彦祥博士后为该论文共同第一作者。【Abstract】Coxsackievirus A10 (CVA10) recently emerged as a major pathogen of hand, foot, and mouth disease and herpangina in children worldwide, and lack of a vaccine or a cure against CVA10 infections has made therapeutic antibody identification a public health priority. By targeting a local isolate, CVA10-FJ-01, we obtained a potent antibody, 2G8, against all three capsid forms of CVA10. We show that 2G8 exhibited both 100% preventive and 100% therapeutic efficacy against CVA10 infection in mice. Comparisons of the near-atomic cryo–electron microscopy structures of the three forms of CVA10 capsid and their complexes with 2G8 Fab reveal that a single Fab binds a border region across the three capsid proteins (VP1 to VP3) and explain 2G8’s remarkable cross-reactivities against all three capsid forms. The atomic structures of this first neutralizing antibody of CVA10 should inform strategies for designing vaccines and therapeutics against CVA10 infections.This work was supported by grants from the National Science and Technology Major Projects for Major New Drugs Innovation and Development (2018ZX09711003-005-003), the National Science and Technology Major Project of Infectious Diseases (2017ZX10304402-002-003), the National Natural Science Foundation of China (31670933 and 81801646), and the National Institutes of Health (R37-GM33050, GM071940, DE025567, and AI094386). We acknowledge the use of instruments at the Electron Imaging Center for Nanomachines supported by the University of California, Los Angeles and by instrumentation grants from NIH (1S10RR23057 and 1U24GM116792) and NSF (DBI-1338135 and DMR-1548924). 该研究获得了国家自然科学基金、新药创制国家科技重大专项、传染病防治国家科技重大专项和美国国立卫生研究院基金的资助

Atomic structures of enterovirus D68 in complex with two monoclonal antibodies define distinct mechanisms of viral neutralization

11月5日，《自然》子刊《自然•微生物学》（Nature Microbiology）在线刊出了我校夏宁邵教授团队发表的题为“Atomic Structures of Enterovirus D68 in Complex with Two Monoclonal Antibodies Define Distinct Mechanisms of Viral Neutralization”的研究论文。这是夏宁邵教授团队在《自然•通讯》（Nature Communications，2017）、《科学•进展》（Science Advances，2018）上发表手足口病重要病原体CVA6、CVA10研究论文之后的又一项关于肠道病毒的重要研究成果。该研究通过解析肠道病毒D组68型（EV-D68）不同类型病毒颗粒及其免疫复合物的高分辨率结构，系统阐明了EV-D68病毒的生活周期及各时期的病毒中和机制，进一步完善了小RNA病毒的吸附入胞及感染机制理论，为EV-D68新型疫苗、抗病毒治疗药物的研发提供重要的理论指导。该研究依托电镜技术平台，解析了EV-D68病毒生活周期中的三种代表性颗粒成熟颗粒、脱衣壳中间态和前体病毒衣壳的近原子分辨率结构，阐明了三种病毒颗粒间的结构差异，以及成熟颗粒转变为脱衣壳中间态的分子机制。夏宁邵教授、李少伟教授、程通副教授和美国国立卫生研究院（NIH）高级研究员Barney Graham博士为该论文的共同通讯作者。郑清炳工程师、博士生朱瑞、博士后徐龙发、博士生何茂洲和美国加州大学圣地亚哥分校颜晓东博士为该论文共同第一作者。【Abstract】Enterovirus D68 (EV-D68) undergoes structural transformation between mature, cell-entry intermediate (A-particle) and empty forms throughout its life cycle. Structural information for the various forms and antibody-bound capsids will facilitate the development of effective vaccines and therapeutics against EV-D68 infection, which causes childhood respiratory and paralytic diseases worldwide. Here, we report the structures of three EV-D68 capsid states representing the virus at major phases. We further describe two original monoclonal antibodies (15C5 and 11G1) with distinct structurally defined mechanisms for virus neutralization. 15C5 and 11G1 engage the capsid loci at icosahedral three-fold and five-fold axes, respectively. To block viral attachment, 15C5 binds three forms of capsids, and triggers mature virions to transform into A-particles, mimicking engagement by the functional receptor ICAM-5, whereas 11G1 exclusively recognizes the A-particle. Our data provide a structural and molecular explanation for the transition of picornavirus capsid conformations and demonstrate distinct mechanisms for antibody-mediated neutralization.This work was supported by a grant from the National Science and Technology Major Projects for Major New Drugs Innovation and Development (no. 2018ZX09711003-005-003), the National Science and Technology Major Project of Infectious Diseases (no. 2017ZX10304402-002-003), the National Natural Science Foundation of China (no. 81401669 and 81801646) and the Natural Science Foundation of Fujian Province (no. 2015J05073). This work was supported in part by funding by the National Institutes of Health (grants R37-GM33050, GM071940, DE025567 and AI094386). We acknowledge the use of instruments at the Electron Imaging Center for Nanomachines supported by UCLA and by instrumentation grants from the NIH (1S10RR23057 and 1U24GM116792) and NSF (DBI-1338135 and DMR-1548924). 该研究获得了国家自然科学基金、新药创制国家科技重大专项、传染病防治国家科技重大专项和美国国立卫生研究院基金的资助

Identification of antibodies with non-overlapping neutralization sites that target coxsackievirus A16

手足口病（Hand, Foot and Mouth Disease，HFMD）是一种由人肠道病毒引起的全球性传染病，主要发生于5岁以下的婴幼儿。2月5日，我校夏宁邵教授团队在《细胞》子刊《细胞•宿主与微生物》（Cell Host & Microbe）上在线发表题为“Identification of antibodies with non-overlapping neutralization sites that target coxsackievirus A16”的研究论文。该研究首次揭示了手足口病主要病原体柯萨奇病毒A组16型（CVA16）三种衣壳颗粒形式与三种不同类型的治疗性中和抗体的全面相互作用细节和非重叠的中和表位结构信息，阐明了CVA16成熟颗粒是疫苗候选主要保护性免疫原的理论基础，建立了可指导疫苗研制的免疫原特异检测方法，为CVA16疫苗及抗病毒药物研究提供关键基础。我校夏宁邵教授、李少伟教授、程通副教授和美国加州大学洛杉矶分校纳米系统研究所Z. Hong Zhou（周正洪）教授为该论文的共同通讯作者。我校博士生何茂洲、徐龙发博士后、郑清炳高级工程师、博士生朱瑞和尹志超为该论文共同第一作者。【Abstract】Hand, foot, and mouth disease is a common childhood illness primarily caused by coxsackievirus A16 (CVA16), for which there are no current vaccines or treatments. We identify three CVA16-specific neutralizing monoclonal antibodies (nAbs) with therapeutic potential: 18A7, 14B10, and NA9D7. We present atomic structures of these nAbs bound to all three viral particle forms—the mature virion, A-particle, and empty particle—and show that each Fab can simultaneously occupy the mature virion. Additionally, 14B10 or NA9D7 provide 100% protection against lethal CVA16 infection in a neonatal mouse model. 18A7 binds to a non-conserved epitope present in all three particles, whereas 14B10 and NA9D7 recognize broad protective epitopes but only bind the mature virion. NA9D7 targets an immunodominant site, which may overlap the receptor-binding site. These findings indicate that CVA16 vaccines should be based on mature virions and that these antibodies could be used to discriminate optimal virion-based immunogens.This work was supported by grants from the Major Program of National Natural Science Foundation of China ( 81991490 ), the National Science and Technology Major Projects for Major New Drugs Innovation and Development ( 2018ZX09711003-005-003 ), the National Science and Technology Major Project of Infectious Diseases ( 2017ZX10304402-002-003 ), the National Natural Science Foundation of China ( 31670933 and 81801646 ), the China Postdoctoral Science Foundation ( 2018M640599 and 2019T120557 ), the Principal Foundation of Xiamen University ( 20720190117 ), and the National Institutes of Health ( R37-GM33050 , GM071940 , DE025567 , and AI094386 ). 该研究获得了国家自然科学基金、新药创制国家科技重大专项、传染病防治国家科技重大专项和美国国立卫生研究院基金的资助

Atomic structures of Coxsackievirus A6 and its complex with a neutralizing antibody

手足口病是一种由人肠道病毒引起的全球性传染病，主要发生于5岁以下的婴幼儿，严重危害公众健康。根据获得的手足口病流行病学和病原学调查数据，目前认为CVA6与EV71和CVA16一样应作为优先的手足口病疫苗预防对象，亟需研制有效的预防和治疗方法。然而令人遗憾的是，目前对于CVA6的基础病毒学特别是结构生物学知识均缺乏足够了解，严重制约了相关研究的有效开展。 夏宁邵教授团队研究首次揭示了手足口病重要病原体柯萨奇病毒A组6型（CVA6）的病毒颗粒及其与中和抗体复合物的精确三维结构，为新型疫苗和治疗药物的研制提供了重要的理论基础。这项研究发现并精确描绘了CVA6的病毒颗粒及其与优势中和抗体的结构特征，首次完成了对CVA6的高精度“成像”，为新型疫苗和治疗药物研制提供了关键基础。 该研究工作在厦门大学分子疫苗学和分子诊断学国家重点实验室、国家传染病诊断试剂与疫苗工程技术研究中心科研平台完成。夏宁邵教授、颜晓东博士、程通副教授为该研究论文的共同通讯作者。颜晓东博士来自美国加州大学圣地亚哥分校，同时受聘为我校双聘教授。共同第一作者为徐龙发博士生、郑清炳工程师和李少伟教授。【Abstract】Coxsackievirus A6 (CVA6) has recently emerged as a major cause of hand, foot and mouth disease in children worldwide but no vaccine is available against CVA6 infections. Here, we demonstrate the isolation of two forms of stable CVA6 particles-procapsid and A-particle-with excellent biochemical stability and natural antigenicity to serve as vaccine candidates. Despite the presence (in A-particle) or absence (in procapsid) of capsid-RNA interactions, the two CVA6 particles have essentially identical atomic capsid structures resembling the uncoating intermediates of other enteroviruses. Our near-atomic resolution structure of CVA6 A-particle complexed with a neutralizing antibody maps an immune-dominant neutralizing epitope to the surface loops of VP1. The structure-guided cell-based inhibition studies further demonstrate that these loops could serve as excellent targets for designing anti-CVA6 vaccines.This work was supported by a grant from the National Natural Science Foundation of China (No. 31670933 and 81401669), the National Science and Technology Major Projects for Major New Drugs Innovation and Development (No. 2017ZX09101005-005-003), the National Science and Technology Major Project of Infectious Diseases (No. 2017ZX10304402-002-003) and the Natural Science Foundation of Fujian Province (No. 2015J05073). This work was also supported in part by funding to T.S.B. from the National Institutes of Health (Grant R37-GM33050). 研究工作也得到了国际病毒结构生物学权威专家美国加州大学洛杉矶分校周正洪教授的大力支持和帮助，获得了国家自然科学基金、新药创制国家科技重大专项、传染病防治国家科技重大专项和福建省自然科学基金的资助

基于遗传算法的RV减速器零件公差优化设计

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RV减速器国产化批量制造关键问题探讨

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基于提高RV减速器装配成品率，结合其装配尺寸链设计零件公差，运用CATIA对RV减速器进行三维建模。运用三维公差分析软件3DCS给零件添加相关尺寸公差和几何公差，设定测量参数偏心距和齿侧间隙，模拟实际静态装配过程建立3DCS公差仿真模型，对零件公差进行优化和敏感性分析。优化后回差为0.25′～1′，满足回差要求，摆线轮与针齿之间间隙≥0.001 mm，且敏感性分析结果对RV减速器的零件公差设计有一定参考价值

高精密RV减速器传动效率测试与分析

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为了研究扶梯驱动链系统的动力学特性及链轮磨损和链条磨损对链传动性能的影响,以链传动运动学理论和多体动力学理论为基础,采用RecurDyn软件建立扶梯驱动链系统的仿真模型,设置空载和负载两种工况,添加磨损故障条件进行仿真分析,得出正常状态和磨损状态链传动特性的变化规律;分析结果表明,磨损后动载荷显著增大。该方法可为扶梯驱动链系统磨损机理研究及故障诊断提供一定参考