Allosteric pocket of the dengue virus (serotype 2) NS2B/NS3 protease: In silico ligand screening and molecular dynamics studies of inhibition

The allosteric pocket of the Dengue virus (DENV2) NS2B/NS3 protease, which is proximal to its catalytic triad, represents a promising drug target (Othman et al., 2008). We have explored this binding site through large-scale virtual screening and molecular dynamics simulations followed by calculations of binding free energy. We propose two mechanisms for enzyme inhibition. A ligand may either destabilize electronic density or create steric effects relating to the catalytic triad residues NS3-HIS51, NS3-ASP75, and NS3-SER135. A ligand may also disrupt movement of the C-terminal of NS2B required for inter-conversion between the “open” and “closed” conformations. We found that chalcone and adenosine derivatives had the top potential for drug discovery hits, acting through both inhibitory mechanisms. Studying the molecular mechanisms of these compounds might be helpful in further investigations of the allosteric pocket and its potential for drug discovery.     

Getting it right: modeling of pH, solvent and "nearly" everything else in virtual screening of biological targets

“Getting it right” refers to the careful modeling of all elements in the living system, i.e. biological macromolecules, ligands and water molecules. In addition, careful attention should be paid to the protonation state of ionizable functional groups on the ligands and residues at the active site. Computational technology based on the empirical HINT program is described to: (1) calculate free energy scores for ligand binding; (2) include the implicit and explicit effects of water in and around the ligand binding site; and (3) incorporate the effects of global and local pH in molecular models. This last point argues for the simultaneous consideration of a number of molecular models, each with different protonation profiles. Data from recent studies of protein–ligand systems (trypsin, thrombin, neuraminidase, HIV-1 protease and others) are used to illustrate the concepts in the paper. Also discussed are experimental factors related to accurate free energy predictions with this and other computational technologies.     

Multiple annotation for biodiversity: developing an annotation framework among biology,linguistics and text technology

Language Resources and Evaluation - Biodiversity information is contained in countless digitized and unprocessed scholarly texts. Although automated extraction of these data has been gaining...     

Computational intelligence and visual computing: an emerging technology for software engineering

 The discipline of Software Engineering is abstract and complex with all its endeavors being cast in a knowledge-intensive environment. It is not surprising that there have been a number of important initiatives that have attempted to address a burning need for solid development tools and comprehensive environments supporting an in-depth analysis. The objective of this study is to discuss a role of Computational Intelligence (CI) and visual computing being viewed as a sound methodological and algorithmic environment for knowledge-oriented Software Engineering. The CI itself is regarded as a synergistic consortium of granular computing (including fuzzy sets) promoting abstraction, neurocomputing supporting various learning schemes and evolutionary computing providing important faculties of global optimization. By its very nature, CI embraces a diversity of design paradigms; in particular it promotes a top-down approach (when exploiting fuzzy sets first and afterwards working in the neural network environment) or bottom-up style (where these two technologies are used in a reverse order). Visual computing is inherently associated with CI: it is human-centric where fuzzy sets make visualization activities feasible. Fuzzy sets are treated as a graphic means of accepting information from users. They are regarded as a vehicle used to visualize results in a linguistic manner. Software Engineering and CI are highly compatible: they are knowledge-intensive, human-oriented, and have to deal with various manifestations of the abstract world of software constructs and thought processes. This multifaceted conceptual compatibility is a prerequisite for the development of vital synergistic links that bring the technology of CI into Software Engineering. The symbiosis accrues considerable benefits for both technologies by posing new categories of challenging and highly stimulating problems. The facet of visual computing is essential in handling of software processes and software products. The intent of this study is to provide a general overview of this new development in Software Engineering. In particular, we highlight a number of selected and most visible trends occurring at the junction of CI and Software Engineering. Furthermore we discuss several specific applications of the technology of CI to software cost estimation, analysis of software measures and neural models of software quality. Support from the Natural Sciences and Engineering Research Council of Canada (NSERC) and the Alberta Software Engineering Research Consortium (ASERC) is gratefully acknowledged.     

Glass frit bonding: an universal technology for wafer level encapsulation and packaging

This paper reports on glass frit wafer bonding, which is a universally usable technology for wafer level encapsulation and packaging. After explaining the principle and the process flow of glass frit bonding, experimental results are shown. Glass frit bonding technology enables bonding of surface materials commonly used in MEMS technology. It allows hermetic sealing and a high process yield. Metal lead throughs at the bond interface are possible, because of the planarizing glass interlayer. Examples of surface micromachined sensors demonstrate the potential of glass–frit bonding.     

Speech technology for automatic teller machines: an investigation of user attitude and performance

Despite the success and widespread use of Automatic Teller Machines (ATMs), a significant proportion of bank customers can not or will not use them, or experience difficulties in their interactions. Speech technology has been suggested as a means by which non-users might be encouraged to use ATMs, while simultaneously improving usability for all. The potential advantages of speech interfaces include hands-free and eyes-free use for physically- and visuallyimpaired users, and improved ease and speed of use through increased ‘naturalness’ of the interaction. This study investigated user attitudes to the concepts of a speech-based ATM, via large-scale survey and a series of focus groups. Objective performance was also considered in user trials with a prototype speech-driven ATM. The idea of using speech for ATM transactions led to a number of concerns. Privacy (the concern over one's personal financial details being overheard) and security (the fear of potential attackers hearing the user withdraw cash) were the major reasons given. The user trials confirmed that possible solutions, such as the adoption of a hood over the ATM or the use of a telephone handset as the speech input/output device, were ineffective. Groups of impaired users, particularly visually-impaired subjects, were more positive about the concept of speech, citing various difficulties with current visual-manual interactions. Most non-users, however, would not be encouraged to use ATMs with the addition of speech. The paper discusses these and other issues relating to the likely success of using speech for ATM applications.     

Factors affecting e-training adoption: an examination of perceived cost,computer self-efficacy and the technology acceptance model

The objective of this paper is to highlight the role that perceived cost, computer self-efficacy and the technology acceptance model (TAM) constructs have in e-training adoption in the Nigerian civil service. With the use of the SmartPLS 2.0 M3 software, a framework that included perceived cost, computer self-efficacy and TAM constructs (perceived usefulness (PU) and perceived ease of use (PEOU)) was tested on 450 heads of departments. Scales on perceived cost, computer self-efficacy, PU and PEOU developed by previous studies were modified accordingly and used. This paper found perceived cost to have a significant effect on e-training adoption. Computer self-efficacy was statistically insignificant through PEOU. In addition, PEOU had an indirect effect through PU. Therefore, only PU of the TAM constructs indicated strong predictive strength in e-training adoption. This paper showed that with e-training adoption, facilities such as computers can be put in place, which can improve the outlook of the civil service. In addition, the cost that is usually associated with traditional training can be reduced, increasing the opportunity to invest in other aspects of the civil service which can help in adding to the overall performance. Relationships were examined in this paper, which were shown to be favourable to e-training adoption in the Nigerian civil service.     

Ergonomics and human factors: the paradigms for science,engineering, design,technology and management of human-compatible systems

This paper provides a theoretical perspective on human factors and ergonomics (HFE), defined as a unique and independent discipline that focuses on the nature of human-artefact interactions, viewed from the unified perspective of the science, engineering, design, technology and management of human-compatible systems. Such systems include a variety of natural and artificial products, processes and living environments. The distinguishing features of the contemporary HFE discipline and profession are discussed and a concept of ergonomics literacy is proposed. An axiomatic approach to ergonomics design and a universal measure of system-human incompatibility are also introduced. It is concluded that the main focus of the HFE discipline in the 21st century will be the design and management of systems that satisfy human compatibility requirements.     

Information technology, operational, and management competencies for supply chain agility: Findings from case studies

Given the growing emphasis on the need for supply chain agility to sustain competitive advantage, this study explores the impact of the relationship between supply chain competence and supply chain agility on firm performance. Although the influence of supply chain agility on firm performance has been acknowledged, this study further articulates the relationship from the perspective of inter-organizational collaboration. We develop a conceptual model based on the resource-based view and employ a multi-case study method in this exploratory research. Our findings highlight the importance of distinguishing the difference between supply chain agility and supply chain competence and their impact on firm performance. This study contributes to the growing body of conceptual and empirical literature on supply chain agility and adds to the understanding of the complexity of supply chain competence.     

Attuning speech-enabled interfaces to user and context for inclusive design: technology, methodology and practice

This paper presents a methodology to apply speech technology for compensating sensory, motor, cognitive and affective usage difficulties. It distinguishes (1) an analysis of accessibility and technological issues for the identification of context-dependent user needs and corresponding opportunities to include speech in multimodal user interfaces, and (2) an iterative generate-and-test process to refine the interface prototype and its design rationale. Best practices show that such inclusion of speech technology, although still imperfect in itself, can enhance both the functional and affective information and communication technology-experiences of specific user groups, such as persons with reading difficulties, hearing-impaired, intellectually disabled, children and older adults.

RUR53: an unmanned ground vehicle for navigation,recognition, and manipulation

ABSTRACT

This paper proposes RUR53: an Unmanned Ground Vehicle able to navigate through, identify, and reach areas of interest. There, it can recognize, localize, and manipulate work tools to perform both indoor and outdoor complex tasks. Indeed, a wide range of sensors composes the robot and enables it to perceive vast workspaces, reach distant targets, and face the uncertainties of the real world. Precise object detection is also guaranteed, essential to manipulate objects of different shapes and materials. Moreover, a customized 3-finger gripper makes the gripping mode suitable for any lightweight object. Two modalities are proposed: autonomous and teleoperated, letting both unskilled and skilled human operators easily adapt the system to complete personalized tasks. The paper exhaustively describes RUR53 architecture and demonstrates its good performance while executing both indoor and outdoor navigation and manipulation tasks. A specific case study is described where the proposed modular architecture allows to easily switch to a semi-teleoperated mode: the 2017 Mohamed Bin Zayed International Robotics Challenge, where our team ranked third in the Grand Challenge in collaboration with the Czech Technical University in Prague, the University of Pennsylvania, and the University of Lincoln (UK).     

Microsystems for controlled genetic perturbation of live Drosophila embryos: RNA interference, development robustness and drug screening

A combination of genetic regulation and microenvironmental perturbation might prove especially useful for identifying the fundamental mechanisms responsible for development biology and critical bio-chemical networks. This could transform our understanding of genomics, proteomics, and drug discovery and lead to personalized drugs and molecular diagnostics for improved healthcare. With the complete sequencing of the Drosophila melanogaster, there has been a growing interest in correlating its genetics to human disease. The Drosophila embryo is an excellent whole-animal model, and is ideal for high throughput analysis. This review highlights research on the recent development of miniature tools to study critical cellular processes in Drosophila embryogenesis. First, we discuss the use of micro-injectors to conduct chip-level RNA interference experiments on self-assembled Drosophila embryos in order to determine how genes contribute to the growth and function of a developing organism. Second, we review recent progress on perturbing the microenvironment as a complementary approach to perturbing the genetic components of the development network. We designed a bio-compatible microfluidic device that automatically positions live embryos within a fluid-filled imaging channel and exposes embryos to constant or biphasic temperature or different drug concentrations. We have demonstrated that a thermal gradient applied across live Drosophila embryos results in asynchronous cellularization. Additionally, preliminary drug screening experiments were carried out on live Drosophila embryos in both 96-well plates and microfluidic channels. Time-lapse differential interference contrast microscopic images were taken to show the effects of colchicine (399.40 Da) and cytochalasin D (507.62 Da) on cellularization.     

An effective HIV-1 integrase inhibitor screening platform: Rationality validation of drug screening,conformational mobility and molecular recognition analysis for PFV integrase complex with viral DNA

As an important target for the development of novel anti-AIDS drugs, HIV-1 integrase (IN) has been widely concerned. However, the lack of a complete accurate crystal structure of HIV-1 IN greatly blocks the discovery of novel inhibitors. In this work, an effective HIV-1 IN inhibitor screening platform, namely PFV IN, was filtered from all species of INs. Next, the 40.8% similarity with HIV-1 IN, as well as the high efficiency of virtual screening and the good agreement between calculated binding free energies and experimental ones all proved PFV IN is a promising screening platform for HIV-1 IN inhibitors. Then, the molecular recognition mechanism of PFV IN by its substrate viral DNA and six naphthyridine derivatives (NRDs) inhibitors was investigated through molecular docking, molecular dynamics simulations and water-mediated interactions analyses. The functional partition of NRDs IN inhibitors could be divided into hydrophobic and hydrophilic ones, and the Mg²⁺ ions, water molecules and conserved DDE motif residues all interacted with the hydrophilic partition, while the bases in viral DNA and residues like Tyr212, Pro214 interacted with the hydrophobic one. Finally, the free energy landscape (FEL) and cluster analyses were performed to explore the molecular motion of PFV IN-DNA system. It is found that the association with NRDs inhibitors would obviously decrease the motion amplitude of PFV IN-DNA, which may be one of the most potential mechanisms of IN inhibitors. This work will provide a theoretical basis for the inhibitor design based on the structure of HIV-1 IN.     

Surface plasmon resonance imaging (SPRi) as an alternative technique for rapid and quantitative screening of small molecules, useful in drug discovery

Surface plasmon resonance imaging (SPRi) is a label free technology for biomolecular interaction, which gives access to binding kinetic parameters from real time acquisition. It offers the possibility to test in a single run a large number of interactions, allowing rapid identification of the most suitable compounds toward a given biological entity. Until now, this technique has proven to be relevant for interaction between relatively large molecules (protein, antibodies, DNA) but has not been challenged yet for the screening of small molecules that can be of interested in the field of drug discovery. As a proof a principle, we have used SPRi to screen for interaction of several small molecules, referred to as G4-ligands on G-quadruplex DNA. This technology allowed to easy discrimination of the binding properties of four G4-ligands on quadruplex DNA models.     

Integrating database technology, rule-based systems and temporal reasoning for effective information systems: the TEMPORA paradigm

Abstract. Recent years have witnessed a growing realization that the development of large data-intensive, transaction-oriented information systems is becoming increasingly more difficult as user requirements become broader and more sophisticated. Contemporary approaches have been criticized for producing systems which are difficult to maintain and which provide little assistance in organizational developments. This paper introduces the TEMPORA paradigm, which is currently under development and which advocates a closer alignment between organizational policy and information system functionality. This viewpoint impacts on a number of critical issues related to the development process of information systems most notably in the nature of conceptual models, the discipline adopted for the development, the type of support provided by CASE tools and the run-time environment. The paper introduces the philosophy and architecture of the TEMPORA paradigm and describes the conceptual models, tools and run-time environment which render such an approach a feasible undertaking.     

Science, technology and society in East Asia: Frameworks for the challenges of the next century

Science and technology development is increasingly driven by the requirements of a globalising world economy. Information and communication technologies both support this globalisation process, and provide opportunities to participate in it. However, the process of development is not uniform. Within nation states and within regions there is considerable inequity in the scale and pace of development. Successful science and technology policies require an understanding of location within a global production network and of local capabilities. This paper explores the prospects for such policies in the context of North East Asia.