Emerging structures and dynamic mechanisms ofγ-secretase for Alzheimer’s disease

γ-Secretase,called“the proteasome of the membrane,”is a membrane-embedded protease complex that cleaves 150+peptide substrates with central roles in biology and medicine,including amyloid precursor protein and the Notch family of cell-surface receptors.Mutations inγ-secretase and amyloid precursor protein lead to early-onset familial Alzheimer’s disease.γ-Secretase has thus served as a critical drug target for treating familial Alzheimer’s disease and the more common late-onset Alzheimer’s disease as well.However,critical gaps remain in understanding the mechanisms of processive proteolysis of substrates,the effects of familial Alzheimer’s disease mutations,and allosteric modulation of substrate cleavage byγ-secretase.In this review,we focus on recent studies of structural dynamic mechanisms ofγ-secretase.Different mechanisms,including the“Fit-Stay-Trim,”“Sliding-Unwinding,”and“Tilting-Unwinding,”have been proposed for substrate proteolysis of amyloid precursor protein byγ-secretase based on all-atom molecular dynamics simulations.While an incorrect registry of the Notch1 substrate was identified in the cryo-electron microscopy structure of Notch1-boundγ-secretase,molecular dynamics simulations on a resolved model of Notch1-boundγ-secretase that was reconstructed using the amyloid precursor protein-boundγ-secretase as a template successfully capturedγ-secretase activation for proper cleavages of both wildtype and mutant Notch,being consistent with biochemical experimental findings.The approach could be potentially applied to decipher the processing mechanisms of various substrates byγ-secretase.In addition,controversy over the effects of familial Alzheimer’s disease mutations,particularly the issue of whether they stabilize or destabilizeγ-secretase-substrate complexes,is discussed.Finally,an outlook is provided for future studies ofγ-secretase,including pathways of substrate binding and product release,effects of modulators on familial Alzheimer’s disease mutations of theγ-secretase-substrate complexes.Comprehensive understanding of the functional mechanisms ofγ-secretase will greatly facilitate the rational design of effective drug molecules for treating familial Alzheimer’s disease and perhaps Alzheimer’s disease in general.

REQUIREMENTS AND DESIGN METHOD FOR MATCHING AIRCRAFT GUNS WITH THEIR SUPPORTING STRUCTURE

In aircraft structural dynamic design the matching of guns with their supporting structure is one of the most important tasks on which hinges the success or failure of the structural design. The design curves for matching guns with their supporting structure can be obtained from response calculations of the plate-spring system supporting the gun on the ground,the model structure tested on the ground and the actual structure.A set of matching curves is given for engineering application.Then,the matching design can be accomplished by means of impact load spectrograms so as to perform an optimal structural design and to make further improvements on dynamic design program.

3D Digital Design of Cranes' Structures Based on Hybrid Software Architecture

3D digital design for cranes’ structures based on hybrid software architecture of Client/Server and Browser/Server is introduced in this paper. Based on Pro/ENGINEER platform,3D parametric model family is built to allow generation of feasible configurations of cranes’ structures in Client/Server framework. Taking use of Visual C++,the second exploiting software kit provided by Pro/ENGINEER and ANSYS GUI/APDL modeling patterns,an integration method of 3D CAD and CAE is achieved,which includes regeneration of 3D parametric model,synchronous updating and analysis of FEA model. As in Browser/Server framework,the 3D CAD models of parts,components and the whole structure could also be displayed in the customer’s browser in VRML format.

Structural Design and Analysis of Small Flapping Wing Aircraft Based on the Crank Slider Mechanism

In this project,the miniaturization of the aircraft was realized under the premise of strong maneuverability,high concealability,and driving a certain load,and the flight mode and structural characteristics of birds were imitated.A small bionic flapping wing aircraft was built.The flapping of the wing was realized by the crank slider mechanism,and the sizes of each part were calculated according to the bionics formula.The wingspan was 360.37 mm,the body width was 22 mm,the body length was 300 mm,the wing area was 0.05 m^(2),the flapping amplitude was 71°.ADAMS software was used to simulate the dynamics of the designed aircraft,and the variation of flapping amplitude and angular velocity during the movement of the aircraft was obtained,which verified the feasibility of the mechanism.The prototype aircraft was made for flight test,and the designed bionic flapping wing aircraft achieved the expected effect.It provides a theoretical basis and data support for the design and manufacture of small flapping wing aircraft.

Data-Driven Structural Design Optimization for Petal-Shaped Auxetics Using Isogeometric Analysis

Focusing on the structural optimization of auxetic materials using data-driven methods,a back-propagation neural network(BPNN)based design framework is developed for petal-shaped auxetics using isogeometric analysis.Adopting a NURBSbased parametric modelling scheme with a small number of design variables,the highly nonlinear relation between the input geometry variables and the effective material properties is obtained using BPNN-based fitting method,and demonstrated in this work to give high accuracy and efficiency.Such BPNN-based fitting functions also enable an easy analytical sensitivity analysis,in contrast to the generally complex procedures of typical shape and size sensitivity approaches.

In-Plane and Out-of-Plane Mechanical Properties of Zero Poisson’s Ratio Cellular Structures for Morphing Application

Intelligent structures like zero Poisson’s ratio(ZPR)cellular structures have been widely applied to the engineering fields such as morphing wings in recent decades,owing to their outstanding characteristics including light weight and low effective modulus. In-plane and out-of-plane mechanical properties of ZPR cellular structures are investigated in this paper. A theoretical method for calculating in-plane tensile modulus,in-plane shear modulus and out-of-plane bending modulus of ZPR cellular structures is proposed,and the impacts of the unit cell geometrical configurations on in-plane tensile modulus,in-plane shear modulus and out-of-plane bending modulus are studied systematically based on finite element(FE)simulation. Experimental tests validate the feasibility and effectiveness of the theoretical and FE analysis. And the results show that the in-plane and out-of-plane mechanical properties of ZPR cellular structures can be manipulated by designing cell geometrical parameters.

Insights into the structural biology of G-protein coupled receptors impacts drug design for central nervous system neurodegenerative processes

In the last few years, there have been important new insights into the structural biology of G-protein coupled receptors. It is now known that allosteric binding sites are involved in the affinity and selec- tivity of ligands for G-protein coupled receptors, and that signaling by these receptors involves both G-protein dependent and independent pathways. The present review outlines the physiological and pharmacological implications of this perspective for the design of new drugs to treat disorders of the central nervous system. Specifically, new possibilities are explored in relation to allosteric and or- thosteric binding sites on dopamine receptors for the treatment of Parkinson＇s disease, and on muscarinic receptors for Alzheimer＇s disease. Future research can seek to identify ligands that can bind to more than one site on the same receptor, or simultaneously bind to two receptors and form a dimer. For example, the design of bivalent drugs that can reach homo/hetero-dimers of D2 dopa- mine receptor holds promise as a relevant therapeutic strategy for Parkinson＇s disease. Regarding the treatment of Alzheimer＇s disease, the design of dualsteric ligands for mono-oligomeric mus- carinic receptors could increase therapeutic effectiveness by generating potent compounds that could activate more than one signaling pathway.

Effects of Team Structure on Innovation Performance： An Empirical Study

Teamwork is gaining increasing attention in a broader management research. In addition to previous research on the relationship between team structure and innovation performance, this study draws from an interesting experience-based theory advanced by Kelley and Littman （2005）, which examines teams from design thinking perspective, and tests its contributions and effects on team＇s innovation performance. According to Kelley and Littman any team should include the following team roles： The anthropologist, the experimenter, the cross-pollinator, the hurdler, the collaborator, the director, the experience architect, the set designer, the storyteller, and the caregiver. We develop theoretical logics to explain how team structure that includes these key team roles and competences lead to a better innovation performance, and propose pertinent hypotheses. Experimental-empirical research and quantitative analysis were used in the study. The study conducted multiple experiments on three samples： a group of foreign entrepreneurship students, a group of technical students, and an additional group of randomly selected individuals, aged between 20 and 58, with diverse backgrounds. A special approach was implemented and a new instrument was developed to evaluate individuals in teams. While the results show that team that possess the major competences proposed by Kelley and Littman are more innovative, preliminary results also show that not all team roles are equally important. Moreover, team roles should be allocated equally among members for better collaboration, member satisfaction, and quick response, and within one team, one prevailing personality is optimal in terms of innovativeness. We discuss the implications of our findings for future research and managerial practice.

Study on The Relationship between The Structural Design and Shell Fabric of Men＇s Trousers Based on Skin Stretch

In general,for the majority of men,the amount of exercise is relatively large,so the dress requirements for the men＇ s trousers gradually have new requirements.It pays more attention to comfort and personality.The theoretical basis of the clothing loose amount and structural design are both the shape change cased by skin stretch of human body under various movement conditions,the human body has different postures,which will generate different skin stretch data.The combination of static body type and dynamic movements of human body determines clothing structure design,different body movements,different degree of movements and changes in skin stretch all have a direct impact on the form of clothing attached to the human body.

The Importance of Design Spectra and Site Class for the Design of High-Rise Buildings

On November 26,2019 a strong earthquake of magnitude M6.4 occurred close to the City of Durrës,Albania(15.6 km WSW(west southwest)of Mamurras and 22 km SSW(south southwest)of Durrës),causing fatalities and considerable damages in many buildings.In this article we present and analyze,by means of observational data and numerical simulation,the behavior under this earthquake of an 8-floor RC(reinforcement concrete)building,by using design spectra referring to KTP-N.2-89 and Eurocode 8.The main purpose of the authors is to better understand and evaluate the seismic performance of high-rise buildings under the design spectra with a period of soil oscillation close to the fundamental period of the structure.

某S形人行景观桥的方案优化与深化设计

对某S形人行景观桥进行方案优化与深化设计的过程,包括主梁结构体系、菱形斜交网架、桥墩造型三个方面的优化。此三者都是基于三维参数化设计。设计的最终目标,是在尽量还原方案造型的基础上,使得景观桥梁的主梁、网架、桥墩各部分比例和谐,达到形态与受力的统一。

S-CO_(2)循环用电机设计

文章介绍了S-CO_(2)发电的基本概念和应用前景,对比国外各研究机构同类型电机的基本结构,完成电机结构设计、电磁设计与校核、转子腔与蜗壳腔的密封方案设计和电机出线的密封方案设计。为高速S-CO_(2)循环电机结构、电磁设计研究提供参考。

Design of aircraft structures against threat of bird strikes

In this paper, a method to design bird-strike-resistant aircraft structures is presented and illustrated through examples. The focus is on bird strike experiments and simulations. The explicit finite element software PAM-CRASH is employed to conduct bird strike simulations, and a coupled Smooth Particles Hydrodynamic（SPH） and Finite Element（FE） method is used to simulate the interaction between a bird and a target structure. The SPH method is explained, and an SPH bird model is established. Constitutive models for various structural materials, such as aluminum alloys, composite materials, honeycomb, and foam materials that are used in aircraft structures,are presented, and model parameters are identified by conducting various material tests. Good agreements between simulation results and experimental data suggest that the numerical model is capable of predicting the dynamic responses of various aircraft structures under a bird strike,and numerical simulation can be used as a tool to design bird-strike-resistant aircraft structures.

Design concepts of an aircraft wing： composite and morphing airfoil with auxetic structures

This paper is categorized into two parts. （1） A frame work to design the aircraft wing structure and （2） analysis ofa morphing airfoil with auxetic structure. The developed design frame work in the first part is used to arrive at the sizes of the various components of an aircraft wing structure. The strength based design is adopted, where the design loads are extracted from the aerodynamic loads. The aerodynamic loads acting on a wing structure are converted to equivalent distributed loads, which are further converted point loads to arrive at the shear forces, bending and twisting moments along the wing span. Based on the estimated shear forces, bending and twisting moments, the strength based design is employed to estimate the sizes of various sections of a composite wing structure. A three dimensional numerical model of the composite wing structure has been developed and analyzed for the extreme load conditions. Glass fiber reinforced plastic material is used in the numerical analysis. The estimated natural frequencies are observed to be in the acceptable limits. Furthermore, the discussed design principles in the first part are extended to the design of a morphing airfoil with auxetic structure. The advantages of the morphing airfoil with auxetic structure are （i） larger displacement with limited straining of the components and （ii） unique deformation characteristics, which produce a theoretical in-plane Poisson＇s ratio of -1. Aluminum Alloy AL6061-T651 is considered in the design of all the structural elements. The compliance characteristics of the airfoil are investigated through a numerical model. The numerical results are observed to be in close agreement with the experimental results in the literature.

基于三层B/S结构的水电站中长期优化调度系统

介绍了一种运用Internet技术和数据库技术,采用数据库、服务器、浏览器3层B/S结构模式的水电站中长期优化调度系统。论述了该系统的开发目标、结构功能、关键技术和标准化设计,提出了本系统设计中遇到的关键问题及其解决途径和方法。采用Web Service技术和ASP.NET开发工具,开发出了先进、实用、可靠、界面友好和移植性强的应用软件,并在多个水电站运行,应用情况令人满意。

基于B/S 3层体系结构的软件设计方法研究

运用B/S 3层体系结构开发出符合企业要求的新一代管理系统,成为当前迫切解决的问题。阐明了B/S 3层结构在开发应用程序时的优越性。首先说明使用B/S结构开发软件系统的意义,然后论述基于B/S 3层结构通用的软件设计方法,每1层实现的功能,并阐述其优点。

基于JMF类B/S结构的网络视频会议技术

针对Web网络协同产品设计过程网络会议的需求,分析流媒体传输与控制技术、JMF媒体框架技术,研究RTP/RTCP流媒体传输与控制协议和JMF RTP编程机制,建立类B/S结构的系统框架和基于时间戳的RTCP流媒体同步机制,开发基于JMF类B/S结构的网络视频会议系统,实现总体设计、客户浏览器设计以及与PDM系统的集成。

基于多层C/S结构的医院信息系统的设计

医疗信息系统(HIS)突破了过去“以财务为核心”的旧的管理模式,开始转向“以病人为中心”的新的管理模式,全面支持医院的医疗和管理业务,并以面向医院管理诊断的理念进行HIS的开发。系统结构从2层C/S结构转向了3层,甚至是多层。这种结构不仅可解决多网络、多结构的分布式处理,同时还可以最大限度地保证系统数据的准确性和安全性。提出的多层C/S结构将更适合作为HIS的总体结构,并能提高系统的可维护性和可重用性。用面向对象的分析与设计方法对系统进行对象设计,将大大提高系统的设计效率和系统功能的有效性。在基于角色的访问控制技术的基础上,提出了一种相对独立于应用系统的用户功能项和用户权限控制系统的设计思想,能对系统用户、系统功能项、用户权限等系统资源进行统一管理。

基于三层B/S结构的梯级水电厂中长期优化调度

介绍了一种运用Internet技术和数据库技术,采用数据库、服务器、浏览器三层结构的梯级水电厂中长期优化调度系统,论述了该系统设计与开发的目标、配置环境、系统结构和功能、关键技术和标准化设计。采用Web Service技术和ASP.NET开发工具,开发出了先进、实用、可靠和界面友好的应用软件,并在多个梯级水电厂运行,效果良好。

基于动态S-N曲线的飞机结构日历寿命分析

为科学地确定飞机结构的日历寿命 ,文章认为飞机结构的损伤历程是地面停放环境和空中疲劳载荷协同作用的结果 ,并提出了以动态的S -N曲线为基础 。