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

Viral neutralization by antibody-imposed physical disruption.

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

Reliability analysis of transmission components under elastohydrodynamic lubrication conditions

Lubricants are commonly used to improve the tribological performance of mechanical components in power transmission systems. The localized high pressure generated within the lubricants would induce elastic surface deformation and increase the lubricant viscosity. Lubrication with the consideration of these effects is commonly known as elastohydrodynamic lubrication (EHL). In engineering practice, surfaces are always flawed by roughness, which may significantly influence hydrodynamic flows and the entraining action. A complete separation of the contacting interfaces by the lubricating fluid is preferred to enhance the reliabilities and reduce the lifetime cost. However, nowadays technology allows modern machines to operate in more severe conditions, e.g., under heavier loads at higher temperatures or lubricated by lower-viscosity oils, which may result in a thinner lubricant film than the magnitude of the roughness and thus lead to the coexistence of the hydrodynamic lubricant film and asperity contact. Such a lubrication regime is referred to as mixed EHL and has long been recognized. Generally, the materials in contact are assumed to be homogeneous. Many materials, nevertheless, have a heterogeneous structure at a certain level of observation. From an engineering point of view, heterogeneous materials, such as composites, coated materials and other multi-layered materials, are desirable to enhance particular properties of materials. However, the presence of the undesirable defects formed unintentionally during the material manufacturing process, such as inclusions, voids, dislocations and cracks, would result in stress concentrations and consequently lead to fracture and fatigue of materials. Therefore, it is of great significance to take the heterogeneous effects of contact components into consideration for their reliability analysis. In addition, modern machinery is required to operate under severe loading conditions. Such conditions would lead to the plastic evolution of the materials which plays a significant role in their reliability. Analysis of such plastic evolution would thus provide guidance to improve the design of component structures. A semi-analytical solution is first developed for materials with inhomogeneous inclusions subjected to EHL point contact with the consideration of surface roughness. In this solution, the inclusions are homogenized according to Eshelby’s equivalent inclusion method with unknown eigenstrains to be determined. A surface coating layer is also considered and assumed as an inclusion of finite size located on the surface, and thus the same methodology applies. The disturbed surface deformation due to the presence of surface coating and inclusions is iteratively introduced into the lubricant film thickness upon the realization of convergence. The discrete convolution and fast Fourier transform technology is adopted to improve the computational efficiency. Based on this solution, a three-dimensional model of line-contact EHL with inclusions distributed periodically along the contact length direction has been developed upon the implement of an algorithm based on fast Fourier transform technology. Based on the elastic solution of the subsurface stress field, a closed-form solution of plasto-EHL line and point contact for materials with inhomogeneous inclusions is further presented. The plastic strains are iteratively obtained by a procedure involving a plasticity loop and an incremental loading process, and the disturbed deformation caused by the plastic strains along with that caused by the equivalent eigenstrains is introduced to update the lubricant film thickness. The solution takes into account the mutual interactions among inclusions and their surrounding plastic regions, thus leading to an accurate description of the surface pressure distributions, film thickness profiles, plastic zones and subsurface stress field. The solution is then extended to model materials with cracks and inhomogeneous inclusions under plane-strain condition. The crack is modeled by a distribution of edge dislocations with unknown densities according to the distributed dislocation technique. With an assumption that the crack surfaces are not in contact, free surface traction conditions of cracks are employed to formulate the governing equations. Coupled governing equations with unknown equivalent eigenstrains and dislocation densities are established to describe the stress and strain fields beneath the contact surfaces. Stress intensity factors are obtained based on the solution of the dislocation densities. It can be predicted that these solutions have potential applications for the reliability analysis of mechanical components made from composites or with near-surface defects beneath their surfaces, and would provide guidance for minimizing the potential damage of heterogeneous materials induced by embedded inclusions and cracks under lubricated contact.Doctor of Philosophy (MAE

Plasto-elastohydrodynamic lubrication of heterogeneous materials in impact motion

The analysis of plastic evolution and material inhomogeneity is required for an accurate description of lubrication under impact loading. This work develops a semi-analytical model for heterogeneous materials in impact motion under plasto-elastohydrodynamic lubrication (PEHL) with limited inlet oil. A plasticity loop is proposed to obtain the accumulative plastic strain iteratively based on the analysis of the stress state. The inhomogeneous inclusion within the materials is homogenized with unknown eigenstrains according to the equivalent inclusion method. The surface displacements induced by the plastic strains and eigenstrains are introduced into the gap between the contact bodies to update the lubrication film thickness until the convergence is achieved. The consideration of plastic strains and eigenstrains makes the model more realistic for PEHL under impact loading. The responses including the pressure, film thickness, starvation parameter, residual deformation, temperature, and subsurface elastoplastic fields during the impact–rebound process are discussed. After the model validation against the reference data, the effects of material inhomogeneity and strain hardening on the lubrication response, as well as the typical features of elastic perfectly-plastic materials, are investigated to provide guidance for material reliability analysis.Nanyang Technological UniversityNational Research Foundation (NRF)This research work was conducted in the SMRT-NTU Smart Urban Rail Corporate Laboratory with funding support from the National Research Foundation, Singapore, SMRT, Singapore and Nanyang Technological University, Singapore. QD also acknowledges the support from National Natural Science Foundation of China (Grant No. 51905051)

Modelling of non-Newtonian starved thermal-elastohydrodynamic lubrication of heterogeneous materials in impact motion

This study presents a numerical model for the thermal-elastohydrodynamic lubrication of heterogeneous materials in impact motion, in which a rigid ball bounces on a starved non-Newtonian oil-covered plane surface of an elastic semi-infinite heterogeneous solid with inhomogeneous inclusions. The impact–rebound process and the microscopic response of the subsurface inhomogeneous inclusions are investigated. The inclusions are homogenized according to Eshelby’s equivalent inclusion method. The Elrod algorithm is adopted to determine the lubrication starvation based on the solutions of pressure and film thickness, while the lubricant velocity and shear rate of the non-Newtonian lubricant are derived by using the separation flow method. The dynamic response of the cases subjected to constant impact mass, momentum, and energy is discussed to reveal the influence of the initial drop height on the impact–rebound process. The results imply that the inclusion disturbs the subsurface stress field and affects the dynamic response of the contact system when the surface pressure is high. The impact energy is the decisive factor for the stress peak, maximum hydrodynamic force, and restitution coefficient, while the dynamic response during the early approaching process is controlled by the drop height.Nanyang Technological UniversityNational Research Foundation (NRF)Published versionThis research work was conducted in the SMRT-NTU Smart Urban Rail Corporate Laboratory with funding support from the National Research Foundation (NRF), Singapore, SMRT, Singapore and Nanyang Technological University, Singapore. Q.B. also acknowledges the support from National Natural Science Foundation of China, China (Grant No. 51905051)

A model of mixed lubrication based on non-normalized discretization and its application for multilayered materials

This study presents a generalized model of mixed elastohydrodynamic lubrication, in which the dimensional Reynolds equation is discretized according to a modified differential scheme based on the full analysis of the pressure balance within the lubrication region. The model is capable of a wide range of lubrication regimes from fully hydrodynamic down to boundary lubrication, and both the steady-state and the time-dependent conditions can be considered. A simplified computational procedure is proposed for elliptical contacts without the ellipticity parameters specified. The evolution of lubrication behavior at startup and shutdown conditions is investigated and the transient effect of surface waviness is discussed. The model application is then extended to contacts of multilayered materials, and the effects of the layer stiffness and the fabrication methods on the stress fields and lubrication performance are analyzed. The conclusions may potentially provide some insightful information for the design and analysis of functional materials and their engineering structures

Coefficient Problems for a Class of Univalent Functions

In this paper, a new subclass has been defined as Ω of the univalent function in D={z∈C:|z|1}. The central goal of this paper is to determine estimates for logarithmic coefficients, inverse logarithmic coefficients, some cases of the Hankel determinant and Zalcman functionals Jn,m of inverse functions

Numerical analysis of transient elastohydrodynamic lubrication during startup and shutdown processes

In this study, a numerical model is developed for the analysis of elastohydrodynamic lubrication (EHL) at transient conditions during startup and shutdown processes. The time-dependent solutions are derived from an iterative algorithm with surface roughness involved, and the initial value is specified as the solution of the dry contact for the startup or steady-state solution of the lubrication contact at the starting velocity for the shutdown. The technique of discrete convolution and fast Fourier transform (DC-FFT) is employed to improve the computational efficiency. Solutions for smooth surfaces are compared with those obtained numerically and experimentally, and good consistency can be found. Profiles of pressure and film thickness and contours of subsurface stresses are analyzed to reveal the effects of acceleration/deceleration on the lubrication evolution. An isotropic roughness is then taken into account for the analysis. It is concluded that the coupling effects of the lubricant cavitation and oriented roughness would result in complex profiles of pressure and film thickness due to their disturbances to the lubrication film. A machined rough surface is presented to demonstrate the generality of the model. The analysis may potentially provide guidance to estimate the behavior of mechanical elements