Design, synthesis and evaluation of cyclothialidine analogues as DNA gyrase inhibitors

Cyclothialidine, a natural product isolated from Streptomyces .filipinensis NR0484, has been proven to be a potent and selective inhibitor of the bacterial enzyme DNA gyrase. Gyrase inhibition results in cell death, the enzyme being the target of several currently used antibiotics. Cyclothialidine showed poor activity against whole bacterial cells, highlighting scope for improvement regarding cell membrane pemeability in order for the full potential of this new class of antibiotics to be realised, Structurally, cyclothialidine contains a 12-membered lactone ring which is partly integrated into a pentapeptide chain, with a substituted aromatic moiety bordering the lactone, Retrosynthetically it can be traced back to cis-3-hydroxyproline, 3,5-dihydroxy-2,6-dimethylbenzoic acid and four commercially available amino acids; two serine, one cysteine and one alanine. In this work, a model of cyclothialidine was synthesised in order to establish the methodology for more complex compounds. Analogues with hydroxy, dihydroxy and dihydroxymethyl substituted aromatic moieties were then prepared to ensure successful protection methods could be performed and the pharmacophore synthesised. The key aromatic moiety, 2,6-dimethyl-3,5-dihydroxybenzoic acid was produced via two successive Mannich reaction/reduction steps. Acid protection using 4-nitrobenzyl bromide and TBDMS hydroxyl protection followed by bromination of one methyl afforded the desired intermediate. Reaction with a serine/cysteine dipeptide, followed by deprotection and cyclisation under Mitsunobu conditions lead to the 12-membered lactone. An amine substituted aromatic analogue and also replacement of the cysteine sulphur by oxygen were attempted but without success. In an effort to improve cell permeability, a conjugate was synthesised between the pharmacophore and a cholesterol moiety. It was hoped the steroid fragment would serve to increase potency by escorting the molecule through the lipid environment of the cell membrane. The pharmacophore and conjugate were tested against a variety of bacterial strains but the conjugate failed to improve activity.

Computer aided design and manufacture of form-rolls

Cold roll forming of thin-walled sections is a very useful process in the sheet metal industry. However, the conventional method for the design and manufacture of form-rolls, the special tooling used in the cold roll forming process, is a very time consuming and skill demanding exercise. This thesis describes the establishment of a stand-alone minicomputer based CAD/CAM system for assisting the design and manufacture of form-rolls. The work was undertaken in collaboration with a leading manufacturer of thin-walled sections. A package of computer programs have been developed to provide computer aids for every aspect of work in form-roll design and manufacture. The programs have been successfully implemented, as an integrated CAD/CAM software system, on the ICL PERQ minicomputer with graphics facilities. Thus, the developed CAD/CAM system is a single-user workstation, with software facilities to help the user to perform the conventional roll design activities including the design of the finished section, the flower pattern, and the form-rolls. A roll editor program can then be used to modify, if required, the computer generated roll profiles. As far as manufacturing is concerned, a special-purpose roll machining program and postprocessor can be used in conjunction to generate the NC control part-programs for the production of form-rolls by NC turning. Graphics facilities have been incorporated into the CAD/CAM software programs to display drawings interactively on the computer screen throughout all stages of execution of the CAD/CAM software. It has been found that computerisation can shorten the lead time in all activities dealing with the design and manufacture of form-rolls, and small or medium size manufacturing companies can gain benefits from the CAD/CM! technology by developing, according to its own specification, a tailor-made CAD/CAM software system on a low cost minicomputer.

Investigative framework for research into the design of manufacturing processes

This paper is based a major research project run by a team from the Innovation, Design and Operations Management Research Unit at the Aston Business School under SERC funding. International Computers Limited (!CL), the UK's largest indigenous manufacturer of mainframe computer products, was the main industrial collaborator in the research. During the period 1985-89 an integrated production system termed the "Modular Assembly Cascade'' was introduced to the Company's mainframe assembly plant at Ashton-under-Lyne near Manchester. Using a methodology primarily based upon 'participative observation', the researchers developed a model for analysing this manufacturing system design called "DRAMA". Following a critique of the existing literature on Manufacturing Strategy, this paper will describe the basic DRAMA model and its development from an industry specific design methodology to DRAMA II, a generic model for studying organizational decision processes in the design and implementation of production systems. From this, the potential contribution of the DRAMA model to the existing knowledge on the process of manufacturing system design will be apparent.

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.

Multi-criteria logistics distribution network design using SAS/OR

This paper explores the use of the optimization procedures in SAS/OR software with application to the contemporary logistics distribution network design using an integrated multiple criteria decision making approach. Unlike the traditional optimization techniques, the proposed approach, combining analytic hierarchy process (AHP) and goal programming (GP), considers both quantitative and qualitative factors. In the integrated approach, AHP is used to determine the relative importance weightings or priorities of alternative warehouses with respect to both deliverer oriented and customer oriented criteria. Then, a GP model incorporating the constraints of system, resource, and AHP priority is formulated to select the best set of warehouses without exceeding the limited available resources. To facilitate the use of integrated multiple criteria decision making approach by SAS users, an ORMCDM code was implemented in the SAS programming language. The SAS macro developed in this paper selects the chosen variables from a SAS data file and constructs sets of linear programming models based on the selected GP model. An example is given to illustrate how one could use the code to design the logistics distribution network.

State-of-the-art in integrated vehicle health management

Integrated vehicle health management (IVHM) is a collection of data relevant to the present and future performance of a vehicle system and its transformation into information can be used to support operational decisions. This design and operation concept embraces an integration of sensors, communication technologies, and artificial intelligence to provide vehicle-wide abilities to diagnose problems and recommend solutions. This article aims to report the state-of-the-art of IVHM research by presenting a systematic review of the literature. The literature from different sources is collated and analysed, and the major emerging themes are presented. On this basis, the article describes the IVHM concept and its evolution, discusses configurations and existing applications along with main drivers, potential benefits and barriers to adoption, summarizes design guidelines and available methods, and identifies future research challenges.

Integrated strategic supply chain positioning for SME's:an empirical study

Purpose – The purpose of this paper is to report on an investigation into the selection and evaluation of a suitable strategic positioning methodology for SMEs in Singapore. Design/methodology/approach – The research methodology is based on critical review of the literature to identify the potentially most suitable strategic positioning methodology, evaluation and testing of the methodology within the context of SME's in Singapore, and analysis to determine the strengths and weaknesses of the methodology and opportunities for further research. Findings – This paper illustrates a leading integrated strategic positioning decision making process, which has been found to be potentially suitable for SMEs in Singapore, and the process is then applied and evaluated in two industrial case studies. Results in the form of strengths, weaknesses and opportunities are evaluated and discussed in detail, and further research to improve the process has been identified. Practical implications – A practical and integrated strategic supply chain positioning methodology for SMEs to define their own competitive space, among other companies in the manufacturing supply chain, so as to maximize business competitiveness. Originality/value – This paper contributes to the knowledge of the strategic positioning decision process as well as identifies further research to adapt the process for SMEs in Singapore.

Strategic positioning:an integrated decision process for manufacturers

Purpose – This paper describes research that has sought to create a formal and rational process that guides manufacturers through the strategic positioning decision. Design/methodology/approach – The methodology is based on a series of case studies to develop and test the decision process. Findings – A decision process that leads the practitioner through an analytical process to decide which manufacturing activities they should carryout themselves. Practical implications – Strategic positioning is concerned with choosing those production related activities that an organisations should carry out internally, and those that should be external and under the ownership and control of suppliers, partners, distributors and customers. Originality/value – This concept extends traditional decision paradigms, such as those associated with “make versus buy” and “outsourcing”, by looking at the interactions between manufacturing operations and the wider supply chain networks associated with the organisation.

An integrated assessment model for cross-country pipelines

The cross-country petroleum pipelines are environmentally sensitive because they traverse through varied terrain covering crop fields, forests, rivers, populated areas, desert, hills and offshore. Any malfunction of these pipelines may cause devastating effect on the environment. Hence, the pipeline operators plan and design pipelines projects with sufficient consideration of environment and social aspects along with the technological alternatives. Traditionally, in project appraisal, optimum technical alternative is selected using financial analysis. Impact assessments (IA) are then carried out to justify the selection and subsequent statutory approval. However, the IAs often suggest alternative sites and/or alternate technology and implementation methodology, resulting in revision of entire technical and financial analysis. This study addresses the above issues by developing an integrated framework for project feasibility analysis with the application of analytic hierarchy process (AHP), a multiple attribute decision-making technique. The model considers technical analysis (TA), socioeconomic IA (SEIA) and environmental IA (EIA) in an integrated framework to select the best project from a few alternative feasible projects. Subsequent financial analysis then justifies the selection. The entire methodology has been explained here through a case application on cross-country petroleum pipeline project in India.

Design and development of logistics workflow systems for demand management with RFID

This paper discusses demand and supply chain management and examines how artificial intelligence techniques and RFID technology can enhance the responsiveness of the logistics workflow. This proposed system is expected to have a significant impact on the performance of logistics networks by virtue of its capabilities to adapt unexpected supply and demand changes in the volatile marketplace with the unique feature of responsiveness with the advanced technology, Radio Frequency Identification (RFID). Recent studies have found that RFID and artificial intelligence techniques drive the development of total solution in logistics industry. Apart from tracking the movement of the goods, RFID is able to play an important role to reflect the inventory level of various distribution areas. In today’s globalized industrial environment, the physical logistics operations and the associated flow of information are the essential elements for companies to realize an efficient logistics workflow scenario. Basically, a flexible logistics workflow, which is characterized by its fast responsiveness in dealing with customer requirements through the integration of various value chain activities, is fundamental to leverage business performance of enterprises. The significance of this research is the demonstration of the synergy of using a combination of advanced technologies to form an integrated system that helps achieve lean and agile logistics workflow.

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.

A dynamic feature information model for integrated manufacturing planning and optimization

This paper presents a new, dynamic feature representation method for high value parts consisting of complex and intersecting features. The method first extracts features from the CAD model of a complex part. Then the dynamic status of each feature is established between various operations to be carried out during the whole manufacturing process. Each manufacturing and verification operation can be planned and optimized using the real conditions of a feature, thus enhancing accuracy, traceability and process control. The dynamic feature representation is complementary to the design models used as underlining basis in current CAD/CAM and decision support systems. © 2012 CIRP.

Integrated Dimensional Variation Management in the Digital Factory

This paper describes how dimensional variation management could be integrated throughout design, manufacture and verification, to improve quality while reducing cycle times and manufacturing cost in the Digital Factory environment. Initially variation analysis is used to optimize tolerances during product and tooling design and also results in the creation of a simplified representation of product key characteristics. This simplified representation can then be used to carry out measurability analysis and process simulation. The link established between the variation analysis model and measurement processes can subsequently be used throughout the production process to automatically update the variation analysis model in real time with measurement data. This ‘live’ simulation of variation during manufacture will allow early detection of quality issues and facilitate autonomous measurement assisted processes such as predictive shimming. A study is described showing how these principles can be demonstrated using commercially available software combined with a number of prototype applications operating as discrete modules. The commercially available modules include Catia/Delmia for product and process design, 3DCS for variation analysis and Spatial Analyzer for measurement simulation. Prototype modules are used to carry out measurability analysis and instrument selection. Realizing the full potential of Metrology in the Digital Factory will require that these modules are integrated and software architecture to facilitate this is described. Crucially this integration must facilitate the use of realtime metrology data describing the emerging assembly to update the digital model.

Integrated optimisation of surface roughness and tool performance when face milling 416 SS

Tool life is an important factor to be considered during the optimisation of a machining process since cutting parameters can be adjusted to optimise tool changing, reducing cost and time of production. Also the performance of a tool is directly linked to the generated surface roughness and this is important in cases where there are strict surface quality requirements. The prediction of tool life and the resulting surface roughness in milling operations has attracted considerable research efforts. The research reported herein is focused on defining the influence of milling cutting parameters such as cutting speed, feed rate and axial depth of cut, on three major tool performance parameters namely, tool life, material removal and surface roughness. The research is seeking to define methods that will allow the selection of optimal parameters for best tool performance when face milling 416 stainless steel bars. For this study the Taguchi method was applied in a special design of an orthogonal array that allows studying the entire parameter space with only a number of experiments representing savings in cost and time of experiments. The findings were that the cutting speed has the most influence on tool life and surface roughness and very limited influence on material removal. By last tool life can be judged either from tool life or volume of material removal.

DISCUS : end-to-end network design for ubiquitous high speed broadband services

Fibre-to-the-premises (FTTP) has been long sought as the ultimate solution to satisfy the demand for broadband access in the foreseeable future, and offer distance-independent data rate within access network reach. However, currently deployed FTTP networks have in most cases only replaced the transmission medium, without improving the overall architecture, resulting in deployments that are only cost efficient in densely populated areas (effectively increasing the digital divide). In addition, the large potential increase in access capacity cannot be matched by a similar increase in core capacity at competitive cost, effectively moving the bottleneck from access to core. DISCUS is a European Integrated Project that, building on optical-centric solutions such as Long-Reach Passive Optical access and flat optical core, aims to deliver a cost-effective architecture for ubiquitous broadband services. One of the key features of the project is the end-to-end approach, which promises to deliver a complete network design and a conclusive analysis of its economic viability. © 2013 IEEE.