Viral neutralization by antibody-imposed physical disruption

中和抗体是机体抵御病毒入侵的一类免疫球蛋白，也是疫苗发挥作用的主要效应分子。目前已知的中和抗体作用机制，主要包括阻断病毒-细胞相互作用和介导免疫调理作用。最近我校夏宁邵教授团队研究结果揭示了一种由抗体诱导病毒原位崩解的中和新机制。该研究首次揭示了抗体的直接物理碰撞中和机制，并提出诱导这类中和抗体的方法，有助于病毒保护性抗体和疫苗设计，适用于多种病原体，而不仅限于戊型肝炎病毒。分子疫苗学和分子诊断学国家重点实验室夏宁邵教授、李少伟教授和顾颖副教授为该论文的共同通讯作者，郑清炳博士、硕士生蒋婕、博士生何茂洲和郑子峥副教授为共同第一作者。In adaptive immunity, organisms produce neutralizing antibodies (nAbs) to eliminate invading pathogens. Here, we explored whether viral neutralization could be attained through the physical disruption of a virus upon nAb binding. We report the neutralization mechanism of a potent nAb 8C11 against the hepatitis E virus (HEV), a nonenveloped positive-sense single-stranded RNA virus associated with abundant acute hepatitis. The 8C11 binding flanks the protrusion spike of the HEV viruslike particles (VLPs) and leads to tremendous physical collision between the antibody and the capsid, dissociating the VLPs into homodimer species within 2 h. Cryo-electron microscopy reconstruction of the dissociation intermediates at an earlier (15-min) stage revealed smeared protrusion spikes and a loss of icosahedral symmetry with the capsid core remaining unchanged. This structural disruption leads to the presence of only a few native HEV virions in the ultracentrifugation pellet and exposes the viral genome. Conceptually, we propose a strategy to raise collision-inducing nAbs against single spike moieties that feature in the context of the entire pathogen at positions where the neighboring space cannot afford to accommodate an antibody. This rationale may facilitate unique vaccine development and antimicrobial antibody design.This research was supported by grants from the Natural Science Foundation of Fujian Province (Grant 2017J07005), the National Science and Technology Major Project of Infectious Diseases (Grant 2018ZX10101001-002), and the National Natural Science Foundation of China (Grants 81871247, 81991490, and 81571996).国家自然科学基金重大项目、海峡联合项目和面上项目、福建省自然科学杰出青年基金、国家传染病科技重大专项等资助了该项研究

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

Design and implement of printing control system oriented printed electronics

印制电子技术作为一种新兴的信息电子技术，正受到愈来愈多人的广泛关注。而一套专门的喷印控制系统是印制电子技术得以实现的基础。本文针对目前喷印控制系统中存在的诸多问题，设计并实现了一套面向印制电子的喷印控制系统。该系统采用运动控制与喷头控制分离的控制策略，并基于模块化的设计思想，设计了包括命令解析、运动控制、喷头控制在内的七个模块。测试结果表明，该系统实现了对喷头温度、电压、驱动脉冲等的精确控制，满足印制电子技术对喷印控制系统的各项性能指标，并且能够根据用户的个性化需求喷印出各种结构的图形，从而为印制电子技术的发展和工业应用提供了一条可行之路

Study of Forming Experiment of Inkjet-printed Grids for Solar Cell

采用喷墨打印技术印制太阳电池栅线具有诸多优点.在硅片上喷墨打印栅线的过程中,聚合成型的纳米银液滴之间的距离、硅片温度及栅线的重复喷印次数对栅线形貌起着决定性作用.通过改变喷印栅线控制参数的分组实验,在3D显微镜下观测栅线形貌,从而发现控制参数对栅线形貌特征的影响关系。实验结果表明,选择恰当的喷印控制参数可以制备出形貌良好的细栅线

Hierarchical artificial bee colony optimizer for multilevel threshold image segmentation

This paper presents a novel optimization algorithm, namely hierarchical artificial bee colony optimization (HABC) for multilevel threshold image segmentation, which employs a pool of optimal foraging strategies to extends the classical artificial bee colony framework to a cooperative and hierarchical fashion. In the proposed hierarchical model, the higher-level species incorporates the enhanced information change mechanism based on crossover operator to enhance the global search ability between species. In the bottom level, with the divide- and-conquer approach, each subpopulation runs the original ABC method in parallel for part-dimensional optimum, which can be aggregated into a complete solution for the upper level. The experimental results on a set of benchmarks demonstrated the effectiveness of the proposed algorithm. Furthermore, we applied the HABC algorithm to the multilevel image segmentation problem. Experimental results of the new algorithm on a variety of images demonstrated the performance superiority of the proposed algorithm

Artificial Bee Colony Algorithm Based on K-Means Clustering for Droplet Property Optimization

The major challenge in printable electronics fabrication is to effectively and accurately control a drop-on-demand (DoD) inkjet printhead for high printing quality. In this paper, a prediction model based on Lumped Element Modeling (LEM) is proposed to search the parameters of driving waveform for obtaining the desired droplet properties. Although the evolution algorithms are helpful to solve this problem, the classical evolution algorithms may get trapped into local optimal due to the inefficiency of local search. To overcome it, we present an improved artificial bee colony algorithm based on K-means clustering (KCABC), which enhances the population diversity by dynamically clustering and increases the convergence rates by the modification of information communication in the employed bees’ phase. Combined with KCABC, the prediction model is applied to optimize the droplet volume and velocity of nano-silver ink for high printing quality. Experimental results demonstrate the proposed prediction model with KCABC plays a good performance in terms of efficiency and accuracy of searching the appropriate combination of waveform parameters for printable electronics fabrication

Modeling and optimizing industrial inkjet printhead for printable electronics fabrication

The most significant issues in printable electronics fabrication are the printing quality and efficiency delivered by drop-on-demand (DOD) industrial inkjet printhead. Aiming to characterize the nonlinear behaviors of piezoelectric inkjet printhead, the dynamic lumped element model (DLEM) is proposed to cast the original LEM into a time-varying and nonlinear fashion. At the same time , the PSO-based optimization for paramenters is incorporated in DLEM. Due to new characteristics, DLEM can accurately simulate the inkjet-printed nanosilver droplet formation process and effectively predicate optimal combinations of high-frequency driving waveform with high printing quality. From extensive experimental studies, the effectiveness and efficiency of the proposed DLEM is validated

Multispecies Coevolution Particle Swarm Optimization Based on Previous Search History

A hybrid coevolution particle swarm optimization algorithm with dynamic multispecies strategy based on k-means clustering and nonrevisit strategy based on Binary Space Partitioning fitness tree (called MCPSO-PSH) is proposed. Previous search history memorized into the Binary Space Partitioning fitness tree can effectively restrain the individuals' revisit phenomenon. The whole population is partitioned into several subspecies and cooperative coevolution is realized by an information communication mechanism between subspecies, which can enhance the global search ability of particles and avoid premature convergence to local optimum. To demonstrate the power of the method, comparisons between the proposed algorithm and state-of-the-art algorithms are grouped into two categories: 10 basic benchmark functions (10-dimensional and 30-dimensional), 10 CEC2005 benchmark functions (30-dimensional), and a real-world problem (multilevel image segmentation problems). Experimental results show that MCPSO-PSH displays a competitive performance compared to the other swarm-based or evolutionary algorithms in terms of solution accuracy and statistical tests

Multi-species particle swamis optimization based on orthogonal learning and its application for optimal design of a butterfly-shaped patch antenna

A new multi-species particle swarm optimization with a two-level hierarchical topology and the orthogonal learning strategy (OMSPSO) is proposed, which enhances the global search ability of particles and increases their convergence rates. The numerical results on 10 benchmark functions demonstrated the effectiveness of our proposed algorithm. Then, the proposed algorithm is presented to design a butterfly-shaped microstrip patch antenna. Combined with the HFSS solver, a butterfly-shaped patch antenna with a bandwidth of about 40.1% is designed by using the proposed OMSPSO. The return loss of the butterfly-shaped antenna is greater than 10 dB between 4.15 and 6.36 GHz. The antenna can serve simultaneously for the high-speed wireless computer networks (5.15-5.35 GHz) and the RFID systems (5.8 GHz)