基于结构的组蛋白去乙酰化酶抑制剂虚拟筛选

组蛋白去乙酰化酶是抗肿瘤作用的新靶点,基于该酶复合物的三维结构,首先对具有分子多样性的数据库进行了虚拟筛选;然后根据已知HDAC抑制剂的结构特征和筛选的结果,以及与生物大分子互补性,选择合理的构建单元,组建靶向的虚拟组合库;最后进行数据库虚拟筛选,对分子对接的结果进行评分,选择出理论上与HDAC有较好结合能力的化合物,设计了酰胺类、脲类和酰肼类全新结构类型的HDAC抑制剂,初步生物活性评价结果表明,预期有生物活性的化合物显示出一定的HDAC酶抑制活性。     

Prediction of dual agents as an activator of mutant p53 and inhibitor of Hsp90 by docking,molecular dynamic simulation and virtual screening

Heat shock protein90s (Hsp90s) play a crucial role in the development of cancer, and their inhibitors are a main target for tumor suppression. P53 also is a tumor suppressor, but in cancer cells, mutations in the p53 gene lead to the inactivation and accumulation of protein. For instance, the ninth p53 cancer mutation, Y220C, destabilizes the p53 core domain. Small molecules have been assumed to bind to Y220C DNA-binding domain and reactivate cellular mutant p53 functions. In this study, one of the mutant p53 activators is suggested as an Hsp90 inhibitor according to a pyrazole scaffold. To confirm a new ligand as a dual agent, molecular docking and molecular dynamic simulations were performed on both proteins (p53 and Hsp90). Molecular dynamic simulations were also conducted to evaluate the obtained results on the other two pyrazole structures, one known as Hsp90 inhibitor and the other as the reported mutant p53 activator. The findings indicate that the new ligand was stable in the active site of both proteins. Finally, a virtual screening was performed on ZINC database, and a set of new dual agents was proposed according to the new ligand scaffold.     

Identification of potent inhibitors of DNA methyltransferase 1 (DNMT1) through a pharmacophore-based virtual screening approach

DNA methylation is an epigenetic change that results in the addition of a methyl group at the carbon-5 position of cytosine residues. DNA methyltransferase (DNMT) inhibitors can suppress tumour growth and have significant therapeutic value. However, the established inhibitors are limited in their application due to their substantial cytotoxicity. Additionally, the standard drugs for DNMT inhibition are non-selective cytosine analogues with considerable cytotoxic side-effects. In the present study, we have designed a workflow by integrating various ligand-based and structure-based approaches to discover new agents active against DNMT1. We have derived a pharmacophore model with the help of available DNMT1 inhibitors. Utilising this model, we performed the virtual screening of Maybridge chemical library and the identified hits were then subsequently filtered based on the Naïve Bayesian classification model. The molecules that have returned from this classification model were subjected to ensemble based docking. We have selected 10 molecules for the biological assay by inspecting the interactions portrayed by these molecules. Three out of the ten tested compounds have shown DNMT1 inhibitory activity. These compounds were also found to demonstrate potential inhibition of cellular proliferation in human breast cancer MDA-MB-231 cells. In the present study, we have utilized a multi-step virtual screening protocol to identify inhibitors of DNMT1, which offers a starting point to develop more potent DNMT1 inhibitors as anti-cancer agents.     

Discovery of potent inhibitor for matrix metalloproteinase-9 by pharmacophore based modeling and dynamics simulation studies

Matrix metalloproteinase-9 (MMP-9) is an attractive target for anticancer therapy. In the present study ligand based pharmacophore modeling was performed to elucidate the structural elements for a diverse class of MMP-9 inhibitors. The pharmacophore model was validated through Güner-Henry (GH) scoring method. The final pharmacophore model consisted of three hydrogen bond acceptors (HBA), and two ring aromatic regions (RA). This model was utilized to screen the natural compound database to seek novel compounds as MMP-9 inhibitors. The identified hits were validated using molecular docking and molecular dynamics simulation studies. Finally, one compound named Hinokiflavone from Juniperus communis had high binding free energy of −26.54 kJ/mol compared with the known inhibitors of MMP-9. Cytotoxicity for hinokiflavone was evaluated by MTT assay. Inhibition of MMP-9 in the presence of hinokiflavone was detected by gelatin zymography and gelatinolytic inhibition assay. Results revealed that the natural compounds derived based on the developed pharmacophore model would be useful for further design and development of MMP-9 inhibitors.     

基于3D虚拟现实技术的弹药检测虚拟训练系统设计

目前提出的弹药检测虚拟训练系统接收检测信号接收率较低,检测虚拟训练成功率较低。基于3D虚拟现实技术设计一种新的弹药检测虚拟训练系统,硬件由主控操作机、检测总线接口以及资源测试器组成,软件部分在3D虚拟现实技术下构建虚拟空间,在开放式软件结构构建的基础上进行检测指标划分,对用户界面的文件进行整改,按照弹药检测的指标数据提升整改的方向正确性,选用自检公式对检测的信息进行系统自检,依据检测到的问题的发生形式判断下一次问题发生的触发机制,由此避免下一次问题的产生,从而实现软件流程。实验结果表明,基于3D虚拟现实技术的弹药检测虚拟训练系统能有效提高信号接收率,增强虚拟训练接收成功率,具有较强的应用性。     

基于国产平台的虚拟化操作系统架构研究及其实现

高性能计算操作系统面临独特的需求与挑战,这些需求与挑战涵盖并发与高效、系统弹性与容错、异构性、I/O和访存带宽、低噪等诸多方面。传统宏内核操作系统并不能完全满足HPC领域的独特需求,因而需要为HPC定制操作系统。提出虚拟化操作系统架构,该架构主要包含两部分：（1）虚拟机监视器与轻量级内核相结合的虚拟化操作系统架构;（2）支持分时复用虚拟机与空间分割虚拟机相结合的虚拟机监视器架构。在国产平台上设计并实现了一个简单的系统原型Hypervk,说明了上述架构的可行性。初步的实验结果表明,系统具有较好的效率、低噪特性与可行性,在一定程度上可以满足HPC操作系统独特的需求。     

基于虚拟机部署策略的云平台容错即服务方法

针对如何充分利用云基础架构层资源,满足上层云应用系统租户对应用系统容错的需求多样性和高可靠性要求的问题,提出一种面向租户和云服务提供商的、基于虚拟机部署策略的云平台容错即服务方法。该方法根据租户的特定容错需求适配适合的容错方法及容错级别,据此计算并最优化云服务提供商的收益和资源使用量,在此基础上对提供容错服务的虚拟机进行优化部署,充分利用底层虚拟机资源为租户的云应用系统提供更为可靠的容错服务。实验结果表明,所提方法能够在保障云服务提供商收益的基础上,为多租户云应用系统实现更灵活且可靠性更高的容错服务。     

A comparison of ligand based virtual screening methods and application to corticotropin releasing factor 1 receptor

Ligand based virtual screening approaches were applied to the CRF1 receptor. We compared ECFP6 fingerprints, FTrees, Topomers, Cresset FieldScreen, ROCS OpenEye shape Tanimoto, OpenEye combo-score and OpenEye electrostatics. The 3D methods OpenEye Shape Tanimoto, combo-score and Topomers performed the best at separating actives from inactives in retrospective experiments. By virtue of their higher enrichment the same methods identified more active scaffolds. However, amongst a given number of active compounds the Cresset and OpenEye electrostatic methods contained more scaffolds and returned ranked compounds with greater diversity. A selection of the methods were employed to recommend compounds for screening in a prospective experiment. New CRF1 actives antagonists were found. The new actives contained different underlying chemical architecture to the query molecules, results indicative of successful scaffold-hopping.     

Effects of technical and social design on virtual community identification: a comparison approach

We investigated how virtual community (VC) design, both technical and social decisions adopted by VC management teams, might affect the development of members’ identification with the VC. Adopting a comparison approach developed in studying formal organisational identification, we develop the research model explaining the effects of VC design on VC identification. A survey study involving 412 members from seven VCs revealed that identified VC design factors (community presentation and community empowerment) have significant impacts on identification by making the perceived VC identities attractive. We concluded with a discussion of the key managerial and research implications of our findings.     

一类动态联盟组织的结构及运行保障

结合具体对象提出了在不断变化的一类动态联盟运行结构中保持系统受控性能连续性和一致性的一种解决方案;根据离散事件动态系统监控理论的构造性方法,提出了规范化的联盟构建和重组的操作方法及对应的计算机描述;提出动态联盟运行可靠性保障的概念和组成,把技术和人文两个方面紧密联系起来,为动态联盟的组建、重组和运行提供了一种有效的方法.     

基于虚拟仪器技术的蓄电池监测系统的设计与实现

介绍了一个基于虚拟仪器技术、实用的阀控铅酸蓄电池组监测系统,该系统可对分散在不同地点的设备实行统一的检测、参数记录和报表打印等日常管理工作。给出了系统的硬件组成及软件模块功能,并在此基础上,讨论了深入利用NI的DataSocket技术,组建基于Web的测控网络,通过Web服务器完成相关的测试功能,充分实现信息共享。     

Local variable access behavior of a hardware-translation based Java virtual machine

Hardware bytecode translation is a technique to improve the performance of the Java virtual machine (JVM), especially on the portable devices for which the overhead of dynamic compilation is significant. However, since the translation is done on a single bytecode basis, a naive implementation of the JVM generates frequent memory accesses for local variables which can be not only a performance bottleneck but also an obstacle for instruction folding. A solution to this problem is to add a small register file to the data path of the microprocessor which is dedicated for storing local variables. However, the effectiveness of such a local variable register file depends on the size and the local variable access behavior of the applications.In this paper, we analyze the local variable access behavior of various Java applications. In particular, we will investigate the fraction of local variable accesses that are covered by the register file of a varying size, which determines the chip area overhead and the operation speed. We also evaluate the effectiveness of the sliding register window for parameter passing in context of JVM and on-the-fly optimization of local variable to register file mapping.With two types of exceptions, a 16-entry register file achieves coverages of up to 98%. The first type of exception is represented by the SAXON XSLT processor for which the effect of cold miss is significant. Adding the sliding window feature to the register file for parameter passing turns 6.2-13.3% of total accesses from miss to hit to the register file for the SAXON with XSLTMark. The second type of exception is represented by the FFT, which accesses more than 16 local variables for most of method invocations. In this case, on-the-fly profiling is effective. The hit ratio of a 16-entry register file for the FFT is increased from 44% to 83% by an array of 8-bit counters.     

基于LabVIEW的多功能虚拟频谱分析仪的设计

针对传统频谱分析仪器价格昂贵、维护成本高、操作复杂等问题,根据虚似仪器的设计理论,介绍了一种基于USB2.0总线的多功能虚拟频谱分析仪的设计过程,该设计采用ADI公司的AD9288BST-40芯片实现信号的采集功能,主控卡的FPGA芯片将采集的信号传送至上位机,然后在上位机实现多功能频谱分析仪的功能开发。最后通过功能测试结果验证了设计的可行性和准确性。     

基于LabVIEW和FPGA的多通道虚拟逻辑分析仪的设计

基于模块化虚拟仪器技术,阐述了一种以FPGA为硬件基础,以LabVIEW为软件核心的多通道虚拟逻辑分析仪的设计理念及实施方案。重点论述硬件电路设计和软件数据分析处理方法。最后给出虚拟逻辑分析仪的实测结果。     

基于Kinect的拳击虚拟训练系统

沙袋击打训练是拳击训练的有效手段,应用体感交互技术和虚拟现实,设计并实现了虚拟的沙袋击打仿真系统。该系统主要包含虚拟场景搭建、体感交互和训练信息系统。拳击场景建立了拳台、沙袋、拳击手套和背景模型,并通过Direct 3D接口加载到虚拟系统中。交互系统通过Kinect体感传感器追踪并获取训练者骨骼关节点坐标,从中提取肘、腕关节建立空间向量并计算击打速度和击打力,控制虚拟拳头击打虚拟沙袋,通过体感交互的方式虚拟真实训练过程,并在信息系统中记录训练信息。实验和测试表明,此系统能够实现模拟训练的功能,为拳击游戏与教学提供了新的手段。     

基于VIIS-EM平台的虚拟数字集成电路测试仪的设计

基于模块化虚拟仪器的设计思想,设计出一种以VIIS-EM平台为核心,以LabVIEW为工具进行图形化编程的虚拟数字集成电路测试仪,并论述了其实现方案。重点分析了硬件电路的搭建思路和软件的控制流程,最后给出虚拟数字集成电路测试仪的测试结果。     

Docking and ADMET prediction of few GSK-3 inhibitors divulges 6-bromoindirubin-3-oxime as a potential inhibitor

GSK-3 is a member of cellular kinases with diversified functions such as cellular differentiation, metabolic signaling, neuronal functions and apoptosis. It has been validated as an important therapeutic target in Alzheimer’s disease and type 2 diabetes. Few molecules targeting GSK-3 are currently in clinical trials. In this study, we have compared certain docking and computational ADME (Absorption, Distribution, Metabolism, Excretion) parameters of a few GSK-3 targeted ligands (Indirubin, Hymenialdisine, Meridianins, 6-bromoindirubin-3-oxime) against two control molecules (Tideglusib and LY-2090314) to derive and analyze the basic drug-like properties of the test compounds. Docking between the GSK-3 and various ligands was done using AutoDock while ADME parameters were derived from ADMET server PreADMET and admetSAR. Various docked images were retrieved from docking, indicating the docking sites in the target protein. Out of four compounds tested, 6-bromoindirubin-3-oxime (6-BIO) was found as the best docking and ADME parameters, followed by Hymenialdisine (HMD). The LigPlot interaction results show two residues Leu (188) and Thr (138) to be common at the interaction site. The LD₅₀ of 6-BIO is better than one of the control ligands while very similar to the other. Some of the parameters were very similar to the control ligands, thus, making it a suitable candidate among the test ligands. From this in-silico study, we concluded that 6-BIO is a potent drug candidate which could be further tested in vitro and in vivo to establish a drug molecule. Since, 6-BIO is a chemically modified form of the basic molecule Indirubin, we can hypothesize that certain other modified indirubins could be tested as GSK-3 targeted ligands.     

Evaluation of virtual environment as a form of interactive resuscitation exam

There is scientific evidence confirming the effectiveness of e-learning within resuscitation, however, there is not enough research on modern examination techniques within the scope. The aim of the pilot research is to compare the exam results in the field of Advanced Life Support in a traditional (paper) and interactive (computer) form as well as to evaluate satisfaction of the participants. A survey was conducted which meant to evaluate satisfaction of exam participants. Statistical analysis of the collected data was conducted at a significance level of α?=?0.05 using STATISTICS v. 12. Final results of the traditional exam (67.5%?±?15.8%) differed significantly (p?<?0.001) from the results of the interactive exam (53.3%?±?13.7%). However, comparing the number of students who did not pass the exam (passing point at 51%), no significant differences (p?=?0.13) were observed between the two types exams. The feedback accuracy as well as the presence of well-prepared interactive questions could influence the evaluation of satisfaction of taking part in the electronic test. Significant differences between the results of a traditional test and the one supported by Computer Based Learning system showed the possibility of achieving a more detailed competence verification in the field of resuscitation thanks to interactive solutions.     

Effects of 2D wedge design as a wayfinding facilitator in a 3D virtual environment

The purpose of this study is to investigate users' wayfinding task performance and subjective preference in a three‐dimensional (3D) virtual environment. The research variables are interaction mode (touch sensitive vs body movement modes), viewing perspective [first‐person perspective (1PP) versus third‐person perspective (3PP)], and gender (man versus woman). Three difficult levels of tasks were conducted, i.e., A, A‐P, and A‐A types. The experiment is 2 × 2 × 2 between‐subject design. Participants needed to complete three wayfinding tasks and fill out subjective preference questionnaires regarding task fluency, satisfaction, system usability scale, and NASA Task Load Index (NASA‐TLX). Fifty‐six participants (28 men and 28 women) were invited using convenient sampling method. The results are as follows: (1) Participants adopting touch‐sensitive mode performed better than body movement mode. (2) Participants using touch‐sensitive mode could have better task fluency and higher SUS score, and with less effort and frustration. (3) Participants adopting 3PP had better wayfinding task performance than first‐person perspective. They also had higher system usability scale score and spent less effort for having wider viewing perspective. (4) The gender variable only showed significant effect in A‐P type of wayfinding task. Men performed better than women. It is concluded that adopting touch‐sensitive interaction and 3PP designs can better facilitate users' wayfinding tasks.     

Examining virtual reality as a platform for developing mental models of industrial systems

Industrial systems can be complex and not intuitive to perceive. Therefore, students in technology and engineering programs can benefit from developing mental models of industrial systems during their journey in college. However, more often than not, these students do not have access to industrial facilities; thus, developing mental models for systems is a challenge. This paper examines the merit of an Immersive Virtual Reality (IVR) framework application in creating proper mental models for industrial systems in technology and engineering students. Two IVR applications were developed. One IVR application afforded interaction with components of a prefabricated industrial cooling water system (CWVR). In the other application, students designed and built industrial systems with IVR (system designer VR [SDVR]). SDVR facilitated constructive-generative engagement. A group of 33 students was divided into two; one group (the Design, experimental group) was tasked with building a system with SDVR and interacting with the cooling water system in CWVR. The other group was tasked with directly interacting with the CWVR without building a system with SDVR (the Interaction, comparison group). Students' mental models of the cooling water system in CWVR were evaluated following completing the interaction experience with CWVR. The results demonstrate that the causal model notion of the mental model of the cooling water system was significantly higher in the Design, experimental group. The results suggest that designing a rich IVR application that facilitates constructive-generative engagements may carry merit in informing student mental models of complex technical concepts.