Arc-Length Parameterized NURBS Tool Path Generation and Velocity Profile Planning for Accurate 3-Axis Curve Milling

In modern industrial CNC (Computer Numerical Control) machining processes, the pursuing of higher accuracy and efficiency has always been one of the most important tasks to be discussed and studied. A lot of proposed algorithms are developed in order to optimize the machining performance in either of the above focused domains. Nevertheless, there is forever a trade-off between gaining less machining error and providing higher feed rate. As for machining a free-shaped curve (e.g., Bezier curves, B-splines and NURBS) in a three-dimensional space, a better manner to balance out the aforementioned trade-offs turns out to be even more critical and essential. The conventional iterative function used for tool path generation could cause feed rate fluctuation during the actual machining, and it thus might lead to failure on constraining the error within the machining accuracy requirement. Another potential problem occurs when the machining process comes across into a relatively high curvature segment with the prescribed high feed rate, due to the machine axial acceleration limit, the machine may not be able to maintain the tool tip trajectory within the error tolerance. Therefore, a new approach to NURBS tool path generation for high feed rate machining is proposed. In this work, several criterions are set for checking the viability of the prescribed feed rate and adjusting it according to the actual shape of the objective curve and the capability of the machine. After the offline feed rate viability check and readjustment, a new iterative algorithm based on the arc-length re-parameterized NURBS function would be implemented to calculate the tool path in real-time. By using this proposed method, the feed rate fluctuation is diminished and the overall efficiency of the machining process would have been optimized under the condition of accuracy guaranteed

Power and Fuel Economy Optimization of Unthrottled Spark-Ignition Engines Using Highly Flexible Hydraulic Variable Valve Actuation System

Variety of technologies along with the mechanisms for their implementations have been developed in order to pursue possible improvements in the performance and efficiency of gasoline engines. Yet, most of the commonly used techniques, such as the cam-based variable valve timings (VVT) and variable compression ratio (VCR), are realized by different kinds of complicated mechanisms, providing an extended but still relatively limited adjustability, for attaining improved valve timings and different engine cycles according to the varying working conditions of the engine. The hydraulic variable valve actuation (HVVA) system, however, can provide greater freedoms to the engine valve motions than most of the traditional cam-based valve train systems do. By considering the characteristics of the HVVA system, the strategies of putting its outstanding flexibilities into use for further improving the performances of gasoline engines with respect to power and fuel economy are developed in this research. By utilizing the flexibility offered by the HVVA system, a set of new valve motion strategies is developed for realizing an unthrottled engine load control. In this research, the late exhaust valve closure (LEVC) and early intake valve closure (EIVC) strategies are adopted at the same time for granting the engine an internal exhaust gas recirculation (IEGR) feature and together evolved into a tunable IEGR scheme for fulfilling the partial engine loads without throttling. Alternatively, the realization to the proposed variable Atkinson cycle (VAC), which is realized by late intake valve closures (LIVCs), can also achieve the same goal of unthrottled engine load control for partial load operations. Moreover, an HVVA engine model is proposed and built in GT-suite, which is able to capture the interdependencies of the HVVA system and the engine operations, and is as well carefully calibrated by experimental data acquired from individual bench tests of the HVVA system and the baseline engine. The HVVA engine in this research is a converted from a baseline single-cylinder engine and is able to carry out a variable Otto cycle (VOC) at full engine load operations for achieving higher power performance while realizing a variable Atkinson cycle (VAC) or a tunable IEGR feature at partial engine load operations for gaining better fuel economy without having any further modifications or attaching additional components to the engine. In addition, a set of genetic algorithm (GA)-based optimization schemes is also developed for identifying the proper operating parameters of the HVVA engine when adopting any of the proposed engine operation schemes. A MATLAB-Simulink and GT-Suite coupling simulation structure is proposed for carrying out the GA approaches. Furthermore, these GA optimizers are designed to be capable of maintaining their proper functionality while non-linear constraints are taken into considerations. By running the HVVA engine with the optimized operating parameters identified by the proposed GA optimizations, noticeable improvements on the engine outputs at full load operations and fuel economy at partial load operations are revealed. Benefited from the features of the HVVA system, the tunings of the HVVA engine can be flexibly customized to fulfill any requirements towards different desired engine characteristics. At last, with the corresponding operating parameters be optimized by the proposed GA optimization techniques, all the proposed HVVA valve motion strategies are carried out by an actual prototype HVVA engine and are qualitatively validated by experiments. The experimental results are showing expected outcomes on the improvements to the engine's power and fuel economy performances under corresponding operations. A power improvement of 12.3% is noticed from the experiments by running the HVVA engine in the proposed VOC operation at the exemplary 1000rpm engine speed. In addition, comparing to the throttled operation of the baseline engine, the experiment studies show also the HVVA engine is able to run with leaner air-fuel mixtures to achieve the same desired partial engine load operations by adopting the IEGR scheme or the VAC operation. With an adopted air-fuel ratio (AFR) of 16.1 for the IEGR scheme and 16.3 for the VAC scheme, the engine could realize the same exemplary speed-load operation of 1000rpm/5.2Nm, while the baseline engine with throttling load control requires an AFR of 14.7 to achieve the same partial load operation

Dual-Stage Hybrid Learning Particle Swarm Optimization Algorithm for Global Optimization Problems

Particle swarm optimization (PSO) is a type of swarm intelligence algorithm that is frequently used to resolve specific global optimization problems due to its rapid convergence and ease of operation. However, PSO still has certain deficiencies, such as a poor trade-off between exploration and exploitation and premature convergence. Hence, this paper proposes a dual-stage hybrid learning particle swarm optimization (DHLPSO). In the algorithm, the iterative process is partitioned into two stages. The learning strategy used at each stage emphasizes exploration and exploitation, respectively. In the first stage, to increase population variety, a Manhattan distance based learning strategy is proposed. In this strategy, each particle chooses the furthest Manhattan distance particle and a better particle for learning. In the second stage, an excellent example learning strategy is adopted to perform local optimization operations on the population, in which each particle learns from the global optimal particle and a better particle. Utilizing the Gaussian mutation strategy, the algorithm’s searchability in particular multimodal functions is significantly enhanced. On benchmark functions from CEC 2013, DHLPSO is evaluated alongside other PSO variants already in existence. The comparison results clearly demonstrate that, compared to other cutting-edge PSO variations, DHLPSO implements highly competitive performance in handling global optimization problems

TMK1-mediated auxin signalling regulates differential growth of the apical hook

The plant hormone auxin has crucial roles in almost all aspects of plant growth and development. Concentrations of auxin vary across different tissues, mediating distinct developmental outcomes and contributing to the functional diversity of auxin. However, the mechanisms that underlie these activities are poorly understood. Here we identify an auxin signalling mechanism, which acts in parallel to the canonical auxin pathway based on the transport inhibitor response1 (TIR1) and other auxin receptor F-box (AFB) family proteins (TIR1/AFB receptors)1,2, that translates levels of cellular auxin to mediate differential growth during apical-hook development. This signalling mechanism operates at the concave side of the apical hook, and involves auxin-mediated C-terminal cleavage of transmembrane kinase 1 (TMK1). The cytosolic and nucleus-translocated C terminus of TMK1 specifically interacts with and phosphorylates two non-canonical transcriptional repressors of the auxin or indole-3-acetic acid (Aux/IAA) family (IAA32 and IAA34), thereby regulating ARF transcription factors. In contrast to the degradation of Aux/IAA transcriptional repressors in the canonical pathway, the newly identified mechanism stabilizes the non-canonical IAA32 and IAA34 transcriptional repressors to regulate gene expression and ultimately inhibit growth. The auxin–TMK1 signalling pathway originates at the cell surface, is triggered by high levels of auxin and shares a partially overlapping set of transcription factors with the TIR1/AFB signalling pathway. This allows distinct interpretations of different concentrations of cellular auxin, and thus enables this versatile signalling molecule to mediate complex developmental outcomes

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

Screening Acute HIV Infections among Chinese Men Who Have Sex with Men from Voluntary Counseling & Testing Centers

Recent studies have shown the public health importance of identifying acute HIV infection (AHI) in the men who have sex with men (MSM) of China, which has a much higher risk of HIV transmission. However, cost-utility analyses to guide policy around AHI screening are lacking.An open prospective cohort was recruited among MSM living in Liaoning Province, Northeast China. Blood samples and epidemiological information were collected every 10 weeks. Third-generation ELISA and rapid test were used for HIV antibody screening, western blot assay (WB) served for assay validation. Antibody negative specimens were tested with 24 mini-pool nucleic acid amplification testing (NAAT). Specimens with positive ELISA but negative or indeterminate WB results were tested with NAAT individually without mixing. A cost-utility analysis of NAAT screening was assessed. Among the 5,344 follow-up visits of 1,765 MSM in 22 months, HIV antibody tests detected 114 HIV chronic infections, 24 seroconverters and 21 antibody indeterminate cases. 29 acute HIV infections were detected with NAAT from 21 antibody indeterminate and 1,606 antibody negative cases. The HIV-1 prevalence and incidence density were 6.6% (95% CI: 5.5–7.9) and 7.1 (95% CI: 5.4–9.2)/100 person-years, respectively. With pooled NAAT and individual NAAT strategy, the cost of an HIV transmission averted was $1,480. The addition of NAAT after HIV antibody tests had a cost-utility ratio of$3,366 per gained quality-adjusted life year (QALY). The input-output ratio of NAAT was about 1∶16.9.The HIV infections among MSM continue to rise at alarming rates. Despite the rising cost, adding pooled NAAT to the HIV antibody screening significantly increases the identification of acute HIV infections in MSM. Early treatment and target-oriented publicity and education programs can be strengthened to decrease the risk of HIV transmission and to save medical resources in the long run

Virus-Free and Live-Cell Visualizing SARS-CoV-2 Cell Entry for Studies of Neutralizing Antibodies and Compound Inhibitors

新型冠状病毒SARS-CoV-2在全球蔓延，给全球公共卫生带来严重威胁。快速研制疫苗、抗体和治疗药物成为科学界面临的重大挑战。由于SARS-CoV-2的高度传染性，采用病毒感染模型进行中和抗体及小分子抑制剂的药效评估需要在高等级生物安全实验室中进行，且常需要数天时间才能完成检测，限制了抗体和药物筛选的效率。发展快速、可视、不依赖于活病毒的新冠病毒入胞检测探针和细胞模型，对于加速新冠病毒抗体和药物的研究有重要意义。夏宁邵教授团队通过CHO真核表达系统高效表达制备出C端融合抗酸荧光蛋白Gamillus的重组新冠病毒spike蛋白STG。STG经SEC分子筛和冷冻电镜确认呈现与天然病毒刺突高度相似的三聚体结构，且与ACE2有很高的亲和力（18.2nM）。STG具备良好的细胞相容性和荧光性质，研究者进一步开发了可定量测定感染恢复期血清、疫苗免疫血清中和抗体（入胞阻断抗体）水平的CSBT检测方法。除了抗体检测评估方面的应用外，该研究发展的探针和模型还可用于筛选分析抑制新冠病毒入胞及胞内转运的小分子化合物。 我校博士后张雅丽，博士生王邵娟、巫洋涛，博士后侯汪衡、袁伦志和深圳市第三人民医院沈晨光博士为共同第一作者。厦门大学夏宁邵教授、袁权教授、程通教授为该论文共同通讯作者。The ongoing corona virus disease 2019 (COVID-19) pandemic, caused by SARS-CoV-2 infection, has resulted in hundreds of thousands of deaths. Cellular entry of SARS-CoV-2, which is mediated by the viral spike protein and ACE2 receptor, is an essential target for the development of vaccines, therapeutic antibodies, and drugs. Using a mammalian cell expression system,a genetically engineered sensor of fluorescent protein (Gamillus)-fused SARS-CoV-2 spike trimer (STG) to probe the viral entry process is developed.In ACE2-expressing cells, it is found that the STG probe has excellent performance in the live-cell visualization of receptor binding, cellular uptake, and intracellular trafficking of SARS-CoV-2 under virus-free conditions. The new system allows quantitative analyses of the inhibition potentials and detailed influence of COVID-19-convalescent human plasmas, neutralizing antibodies and compounds, providing a versatile tool for high-throughput screening and phenotypic characterization of SARS-CoV-2 entry inhibitors. This approach may also be adapted to develop a viral entry visualization system for other viruses.This study was supported by National Natural Science Foundation of China (81993149041 for N.X.; 81902057 for Y.Z.; 81871316 and U1905205 for Q.Y.), the National Science and Technology Major Project of Infectious Diseases (No. 2017ZX10304402‐002‐003 for T.C. and No. 2017ZX10202203‐009 for Q.Y.), the National Science and Technology Major Projects for Major New Drugs Innovation and Development (No. 2018ZX09711003‐005‐003 for T.C.), the Science and Technology Major Project of Fujian (2020YZ014001), the Science and Technology Major Project of Xiamen (3502Z2020YJ01), and the Guangdong Basic and Applied Basic Research Foundation (2020A1515010368 for C.S.). 该研究得到了国家自然科学基金、传染病防治国家科技重大专项、福建省应急科技攻关项目和厦门应急科技攻关项目的支持