Design and synthesis of potential antimicrobial agents

Chorismate mutase is one of the essential enzymes in the shikimate pathway and is key to the survival of the organism Mycobacterium tuberculosis. The x-ray crystal structure of this enzyme from Mycobacterium tuberculosis was manipulated to prepare an initial set of in silico protein models of the active site. Known inhibitors of the enzyme were docked into the active site using the flexible ligand / flexible active site side chains approach implemented in CAChe Worksystem (Fujitsu Ltd). The resulting complexes were refined by molecular dynamics studies in explicit water using Amber 9. This yielded a further set of protein models that were used for additional rounds of ligand docking. A binding hypothesis was established for the enzyme and this was used to screen a database of commercially available drug-like compounds. From these results new potential ligands were designed that fitted appropriately into the active site and matched the functional groups and binding motifs founds therein. Some of these compounds and close analogues were then synthesized and submitted for biological evaluation. As a separate part of this thesis, analogues of very active anti-tuberculosis pyridylcarboxamidrazone were also prepared. This was carried out by the addition and the deletion of the substitutions from the lead compound thereby preparing heteroaryl carboxamidrazone derivatives and related compounds. All these compounds were initially evaluated for biological activity against various gram positive organisms and then sent to the TAACF (USA) for screening against Mycobacterium tuberculosis. Some of the new compounds proved to be at least as potent as the original lead compound but less toxic.

Design and synthesis of novel hydrogels for biological applications

The aims of this project were:1) the synthesis of a range of new polyether-based vinylic monomers and their incorporation into poly(2-hydroxyethyl methacrylate) (poly(HEMA)) based hydrogel networks, of interest to the contact lens industry.2) the synthesis of a range of alkyltartronic acids, and their derivatives. These molecules may ultimately be used to produce functionalised poly(-hydroxy acids) of potential interest in either drug delivery or surgical suture applications. The novel syntheses of a range of both methoxy poly(ethylene glycol) acrylates (MPEGAs) and poly(ethylene glycol) acrylates (PEGAs) are described. Products were obtained in very good yields. These new polyether-based vinylic monomers were copolymerised with 2-hydroxyethyl methacrylate (HEMA) to produce a range of hydrogels. The equilibrium water contents (EWC) and surface properties of these copolymers containing linear polyethers were examined. It was found that the EWC was enhanced by the presence of the hydrophilic polyether chains.Results suggest that the polyether side chains express themselves at the polymer surface, thus dictating the surface properties of the gels. Consequentially, this leads to an advantageous reduction in the surface adhesion of biological species. A synthesis of a range of alkyltartronic acids is also described. The acids prepared were obtained in very good yields using a novel four-stage synthesis. These acids were modified to give potassium monoethyl alkyltartronates. Although no polyesterification is described in this thesis, these modified alkyltartronic acid derivatives are considered to be potentially excellent starting materials for poly (alkyltartronic acid) synthesis via anhydrocarboxylate or anhydrosulphite cyclic monomers.

Design and implementation of graphical user interfaces for complex simulations

The development of increasingly powerful computers, which has enabled the use of windowing software, has also opened the way for the computer study, via simulation, of very complex physical systems. In this study, the main issues related to the implementation of interactive simulations of complex systems are identified and discussed. Most existing simulators are closed in the sense that there is no access to the source code and, even if it were available, adaptation to interaction with other systems would require extensive code re-writing. This work aims to increase the flexibility of such software by developing a set of object-oriented simulation classes, which can be extended, by subclassing, at any level, i.e., at the problem domain, presentation or interaction levels. A strategy, which involves the use of an object-oriented framework, concurrent execution of several simulation modules, use of a networked windowing system and the re-use of existing software written in procedural languages, is proposed. A prototype tool which combines these techniques has been implemented and is presented. It allows the on-line definition of the configuration of the physical system and generates the appropriate graphical user interface. Simulation routines have been developed for the chemical recovery cycle of a paper pulp mill. The application, by creation of new classes, of the prototype to the interactive simulation of this physical system is described. Besides providing visual feedback, the resulting graphical user interface greatly simplifies the interaction with this set of simulation modules. This study shows that considerable benefits can be obtained by application of computer science concepts to the engineering domain, by helping domain experts to tailor interactive tools to suit their needs.

Computer aided design and manufacture for three dimensional milling

Advances in both computer technology and the necessary mathematical models capable of capturing the geometry of arbitarily shaped objects has led to the development in this thesis of a surface generation package called 'IBSCURF' aimed at providing a more economically viable solution to free-form surface manufacture. A suit of computer programs written in FORTRAN 77 has been developed to provide computer aids for every aspect of work in designing and machining free-form surfaces. A vector-valued parametric method was used for shape description and a lofting technique employed for the construction of the surface. The development of the package 'IBSCURF' consists of two phases. The first deals with CAD. The design process commences in defining the cross-sections which are represented by uniform B-spline curves as approximations to give polygons. The order of the curve and the position and number of the polygon vertices can be used as parameters for the modification to achieve the required curves. When the definitions of the sectional curves is complete, the surface is interpolated over them by cubic cardinal splines. To use the CAD function of the package to design a mould for a plastic handle, a mathematical model was developed. To facilitate the integration of design and machining using the mathematical representation of the surface, the second phase of the package is concerned with CAM which enables the generation of tool offset positions for ball-nosed cutters and a general post-processor has been developed which automatically generates NC tape programs for any CNC milling machine. The two phases of these programs have been successfully implemented, as a CAD/CAM package for free-form surfaces on the VAX 11/750 super-minicomputer with graphics facilities for displaying drawings interactively on the terminal screen. The development of this package has been beneficial in all aspects of design and machining of free form surfaces.

Aspects of the design and operation of production control systems in manufacturing industry

Computerised production control developments have concentrated on Manufacturing Resources Planning (MRP II) systems. The literature suggests however, that despite the massive investment in hardware, software and management education, successful implementation of such systems in manufacturing industries has proved difficult. This thesis reviews the development of production planning and control systems, in particular, investigates the causes of failures in implementing MRP/MRP II systems in industrial environments and argues that the centralised and top-down planning structure, as well as the routine operational methodology of such systems, is inherently prone to failure. The thesis reviews the control benefits of cellular manufacturing systems but concludes that in more dynamic manufacturing environments, techniques such as Kanban are inappropriate. The basic shortcomings of MRP II systems are highlighted and a new enhanced operational methodology based on distributed planning and control principles is introduced. Distributed Manufacturing Resources Planning (DMRP), was developed as a capacity sensitive production planning and control solution for cellular manufacturing environments. The system utilises cell based, independently operated MRP II systems, integrated into a plant-wide control system through a Local Area Network. The potential benefits of adopting the system in industrial environments is discussed and the results of computer simulation experiments to compare the performance of the DMRP system against the conventional MRP II systems presented. DMRP methodology is shown to offer significant potential advantages which include ease of implementation, cost effectiveness, capacity sensitivity, shorter manufacturing lead times, lower working in progress levels and improved customer service.

An advanced real-time predictive maintenance framework for large scale machine systems

This thesis introduces and develops a novel real-time predictive maintenance system to estimate the machine system parameters using the motion current signature. Recently, motion current signature analysis has been addressed as an alternative to the use of sensors for monitoring internal faults of a motor. A maintenance system based upon the analysis of motion current signature avoids the need for the implementation and maintenance of expensive motion sensing technology. By developing nonlinear dynamical analysis for motion current signature, the research described in this thesis implements a novel real-time predictive maintenance system for current and future manufacturing machine systems. A crucial concept underpinning this project is that the motion current signature contains infor­mation relating to the machine system parameters and that this information can be extracted using nonlinear mapping techniques, such as neural networks. Towards this end, a proof of con­cept procedure is performed, which substantiates this concept. A simulation model, TuneLearn, is developed to simulate the large amount of training data required by the neural network ap­proach. Statistical validation and verification of the model is performed to ascertain confidence in the simulated motion current signature. Validation experiment concludes that, although, the simulation model generates a good macro-dynamical mapping of the motion current signature, it fails to accurately map the micro-dynamical structure due to the lack of knowledge regarding performance of higher order and nonlinear factors, such as backlash and compliance. Failure of the simulation model to determine the micro-dynamical structure suggests the pres­ence of nonlinearity in the motion current signature. This motivated us to perform surrogate data testing for nonlinearity in the motion current signature. Results confirm the presence of nonlinearity in the motion current signature, thereby, motivating the use of nonlinear tech­niques for further analysis. Outcomes of the experiment show that nonlinear noise reduction combined with the linear reverse algorithm offers precise machine system parameter estimation using the motion current signature for the implementation of the real-time predictive maintenance system. Finally, a linear reverse algorithm, BJEST, is developed and applied to the motion current signature to estimate the machine system parameters.

INTAMAP: the design and implementation of an interoperable automated interpolation web service

INTAMAP is a Web Processing Service for the automatic spatial interpolation of measured point data. Requirements were (i) using open standards for spatial data such as developed in the context of the Open Geospatial Consortium (OGC), (ii) using a suitable environment for statistical modelling and computation, and (iii) producing an integrated, open source solution. The system couples an open-source Web Processing Service (developed by 52°North), accepting data in the form of standardised XML documents (conforming to the OGC Observations and Measurements standard) with a computing back-end realised in the R statistical environment. The probability distribution of interpolation errors is encoded with UncertML, a markup language designed to encode uncertain data. Automatic interpolation needs to be useful for a wide range of applications and the algorithms have been designed to cope with anisotropy, extreme values, and data with known error distributions. Besides a fully automatic mode, the system can be used with different levels of user control over the interpolation process.

Toward an atomistic understanding of the immune synapse:large-scale molecular dynamics simulation of a membrane-embedded TCR-pMHC-CD4 complex

T-cell activation requires interaction of T-cell receptors (TCR) with peptide epitopes bound by major histocompatibility complex (MHC) proteins. This interaction occurs at a special cell-cell junction known as the immune or immunological synapse. Fluorescence microscopy has shown that the interplay among one agonist peptide-MHC (pMHC), one TCR and one CD4 provides the minimum complexity needed to trigger transient calcium signalling. We describe a computational approach to the study of the immune synapse. Using molecular dynamics simulation, we report here on a study of the smallest viable model, a TCR-pMHC-CD4 complex in a membrane environment. The computed structural and thermodynamic properties are in fair agreement with experiment. A number of biomolecules participate in the formation of the immunological synapse. Multi-scale molecular dynamics simulations may be the best opportunity we have to reach a full understanding of this remarkable supra-macromolecular event at a cell-cell junction.

Handbook of research on user interface design and evaluation for mobile technology

In recent years, mobile technology has been one of the major growth areas in computing. Designing the user interface for mobile applications, however, is a very complex undertaking which is made even more challenging by the rapid technological developments in mobile hardware. Mobile human-computer interaction, unlike desktop-based interaction, must be cognizant of a variety of complex contextual factors affecting both users and technology. The Handbook of Research on User Interface Design and Evaluation provides students, researchers, educators, and practitioners with a compendium of research on the key issues surrounding the design and evaluation of mobile user interfaces, such as the physical environment and social context in which a mobile device is being used and the impact of multitasking behavior typically exhibited by mobile-device users. Compiling the expertise of over 150 leading experts from 26 countries, this exemplary reference tool will make an indispensable addition to every library collection.

Design and validity of a miniaturized open-field aberrometer

PURPOSE: To validate a new miniaturised, open-field wavefront device which has been developed with the capacity to be attached to an ophthalmic surgical microscope or slit-lamp. SETTING: Solihull Hospital and Aston University, Birmingham, UK DESIGN: Comparative non-interventional study. METHODS: The dynamic range of the Aston Aberrometer was assessed using a calibrated model eye. The validity of the Aston Aberrometer was compared to a conventional desk mounted Shack-Hartmann aberrometer (Topcon KR1W) by measuring the refractive error and higher order aberrations of 75 dilated eyes with both instruments in random order. The Aston Aberrometer measurements were repeated five times to assess intra-session repeatability. Data was converted to vector form for analysis. RESULTS: The Aston Aberrometer had a large dynamic range of at least +21.0 D to -25.0 D. It gave similar measurements to a conventional aberrometer for mean spherical equivalent (mean difference ± 95% confidence interval: 0.02 ± 0.49D; correlation: r=0.995, p<0.001), astigmatic components (J0: 0.02 ± 0.15D; r=0.977, p<0.001; J45: 0.03 ± 0.28; r=0.666, p<0.001) and higher order aberrations RMS (0.02 ± 0.20D; r=0.620, p<0.001). Intraclass correlation coefficient assessments of intra-sessional repeatability for the Aston Aberrometer were excellent (spherical equivalent =1.000, p<0.001; astigmatic components J0 =0.998, p<0.001, J45=0.980, p<0.01; higher order aberrations RMS =0.961, p<0.001). CONCLUSIONS: The Aston Aberrometer gives valid and repeatable measures of refractive error and higher order aberrations over a large range. As it is able to measure continuously, it can provide direct feedback to surgeons during intraocular lens implantations and corneal surgery as to the optical status of the visual system.

Flexibility in large scale projects

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Supply chain integration:challenges and solutions

Since its introduction by management consultants in the early 1980s, supply chain management (SCM) has been primarily concerned with the integration of processes and activities both within and between organisations. The concept of supply chain integration (SCI) is based on documented evidence that suggests that much of the waste throughout businesses is a consequence of fragmented supply chain configurations. However, there is also evidence to suggest that the achievement of higher levels of intra- and inter-firm integration presents an array of managerial challenges. The need for innovation in all aspects of SCM is widely recognised. Given the pivotal role of the integration paradigm within SCM, any meaningful innovation in this area must focus heavily on this issue. This chapter outlines some of the challenges by exploring the evolving SCM business context. It goes on to relate SCM theory to the widely cited Porter value chain concept. The core of the chapter provides a detailed description of SCI based on a wide variety of literature. It does so with particular reference to the challenges inherent in implementing an integrated business paradigm with a view to identifying a range of possible innovative solutions. The adoption of more integrated supply chain structures raises questions regarding the nature of both internal and external customer/supplier relationships. The effective management of such relationships is, therefore, given particular focus.

A computational model of intonation for yorùbá text-to-speech synthesis:design and analysis

In this paper we present the design and analysis of an intonation model for text-to-speech (TTS) synthesis applications using a combination of Relational Tree (RT) and Fuzzy Logic (FL) technologies. The model is demonstrated using the Standard Yorùbá (SY) language. In the proposed intonation model, phonological information extracted from text is converted into an RT. RT is a sophisticated data structure that represents the peaks and valleys as well as the spatial structure of a waveform symbolically in the form of trees. An initial approximation to the RT, called Skeletal Tree (ST), is first generated algorithmically. The exact numerical values of the peaks and valleys on the ST is then computed using FL. Quantitative analysis of the result gives RMSE of 0.56 and 0.71 for peak and valley respectively. Mean Opinion Scores (MOS) of 9.5 and 6.8, on a scale of 1 - -10, was obtained for intelligibility and naturalness respectively.

Using a systems approach in logistics design and planning

The international economic and business environment continues to develop at a rapid rate. Increasing interactions between economies, particularly between Europe and Asia, has raised many important issues regarding transport infrastructure, logistics and broader supply chain management. The potential exists to further stimulate trade provided that these issues are addressed in a logical and systematic manner. However, if this potential is to be realised in practice there is a need to re-evaluate current supply chain configurations. A mismatch currently exists between the technological capability and the supply chain or logistical reality. This mismatch has sharpened the focus on the need for robust approaches to supply chain re-engineering. Traditional approaches to business re-engineering have been based on manufacturing systems engineering and business process management. A recognition that all companies exist as part of bigger supply chains has fundamentally changed the focus of re-engineering. Inefficiencies anywhere in a supply chain result in the chain as a whole being unable to reach its true competitive potential. This reality, combined with the potentially radical impact on business and supply chain architectures of the technologies associated with electronic business, requires organisations to adopt innovative approaches to supply chain analysis and re-design. This paper introduces a systems approach to supply chain re-engineering which is aimed at addressing the challenges which the evolving business environment brings with it. The approach, which is based on work with a variety of both conventional and electronic supply chains, comprises underpinning principles, a methodology and guidelines on good working practice, as well as a suite of tools and techniques. The adoption of approaches such as that outlined in this paper helps to ensure that robust supply chains are designed and implemented in practice. This facilitates an integrated approach, with involvement of all key stakeholders throughout the design process.