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.

Structural behaviour and design of load-bearing falsework

Tne object of this research was to investigate the behaviour of birdcage scaffolding as used in falsework structures, assess the suitability of existing design methods and make recommendations for a set of design rules. Since excessive deflection is as undesirable in a structure as total collapse, the project was divided into two sections. These were to determine the ultimate vertical and horizontal load-carrying capacity and also the deflection characteristics of any falsework. So theoretical analyses were developed to ascertain the ability of both the individual standards to resist vertical load, and of the bracing to resist horizontal load.Furthermore a model was evolved which would predict the horizontal deflection of a scaffold under load using strain energy methods. These models were checked by three series of experiments. The first was on individual standards under vertical load only. The second series was carried out on full scale falsework structures loading vertically and horizontally to failure. Finally experiments were conducted on scaffold couplers to provide additional verification of the method of predicting deflections. This thesis gives the history of the project and an introduction into the field of scaffolding. It details both the experiments conducted and the theories developed and the correlation between theory and experiment. Finally it makes recommendations for a design method to be employed by scaffolding designers.

Design verification and validation in product lifecycle

The verification and validation of engineering designs are of primary importance as they directly influence production performance and ultimately define product functionality and customer perception. Research in aspects of verification and validation is widely spread ranging from tools employed during the digital design phase, to methods deployed for prototype verification and validation. This paper reviews the standard definitions of verification and validation in the context of engineering design and progresses to provide a coherent analysis and classification of these activities from preliminary design, to design in the digital domain and the physical verification and validation of products and processes. The scope of the paper includes aspects of system design and demonstrates how complex products are validated in the context of their lifecycle. Industrial requirements are highlighted and research trends and priorities identified. © 2010 CIRP.

Legal Responses to HIV and AIDs - by James Chalmers

Book review: The Division of Wrongs: A Historical Comparative Study, by eric descheemaeker. Oxford: Oxford University Press, 2009.

Methods and trends of performance benchmarking in UK utility regulation

Regulation is subject to information asymmetries that can lead to allocative and productive inefficiencies. One solution, suggested by Shleifer in 1985 and now adopted by many regulatory bodies round the world, is 'benchmarking', which is sometimes called 'yardstick competition'. In this paper we consider Shleifer's original approach to benchmarking and contrast this with the actual use of benchmarking by UK regulatory bodies in telecommunications, water and the energy sector since the privatizations of the 1980s and early 1990s. We find that benchmarking plays only one part and sometimes a small part in the setting of regulatory price caps in the UK. We also find that in practice benchmarking has been subject to a number of difficulties, which mean that it is never likely to be more than one tool in the regulator's armoury. The UK's experience provides lessons for regulation internationally. © 2006 Elsevier Ltd. All rights reserved.

When promoting positive feelings pays:Aggregate job satisfaction, work design features, and innovation in manufacturing organizations

This study investigates the relationship between aggregate job satisfaction and organizational innovation. In a sample of manufacturing companies, data were gathered from 3717 employees in 28 UK manufacturing organizations about their job satisfaction and aggregated to the organizational level. Data on innovation in technology/processes were gathered from multiple respondents in the same organizations 24 months later. The results revealed that aggregate job satisfaction was a significant predictor of subsequent organizational innovation, even after controlling for prior organizational innovation and profitability. Moreover the data indicated that the relationship between aggregate job satisfaction and innovation in production technology/processes was moderated by two factors: job variety and a commitment to "single status". Unlike previous studies, we conceptualize job satisfaction at the aggregate rather than the individual level and examine innovation rather than creativity. We propose that where the majority of employees experience job satisfaction, they will endorse rather than resist innovation and work collaboratively to implement as well as to generate creative ideas.

A discussion of ethnographic research methods and their relevance for the translation process

In recent years, technologically advanced methodologies such as Translog have gained a lot of ground in translation process research. However, in this paper it will be argued that quantitative research methods can be supplemented by ethnographic qualitative ones so as to enhance our understanding of what underlies the translation process. Although translation studies scholars have sometimes applied an ethnographic approach to the study of translation, this paper offers a different perspective and considers the potential of ethnographic research methods for tapping cognitive and behavioural aspects of the translation process. A number of ethnographic principles are discussed and it is argued that process researchers aiming to understand translators’ perspectives and intentions, how these shape their behaviours, as well as how translators reflect on the situations they face and how they see themselves, would undoubtedly benefit from adopting an ethnographic framework for their studies on translation processes.

Design, modeling and construction of a novel ablative fast pyrolysis reactor and product collection system

The objective of this work was to design, construct and commission a new ablative pyrolysis reactor and a high efficiency product collection system. The reactor was to have a nominal throughput of 10 kg/11r of dry biomass and be inherently scalable up to an industrial scale application of 10 tones/hr. The whole process consists of a bladed ablative pyrolysis reactor, two high efficiency cyclones for char removal and a disk and doughnut quench column combined with a wet walled electrostatic precipitator, which is directly mounted on top, for liquids collection. In order to aid design and scale-up calculations, detailed mathematical modelling was undertaken of the reaction system enabling sizes, efficiencies and operating conditions to be determined. Specifically, a modular approach was taken due to the iterative nature of some of the design methodologies, with the output from one module being the input to the next. Separate modules were developed for the determination of the biomass ablation rate, specification of the reactor capacity, cyclone design, quench column design and electrostatic precipitator design. These models enabled a rigorous design protocol to be developed capable of specifying the required reactor and product collection system size for specified biomass throughputs, operating conditions and collection efficiencies. The reactor proved capable of generating an ablation rate of 0.63 mm/s for pine wood at a temperature of 525 'DC with a relative velocity between the heated surface and reacting biomass particle of 12.1 m/s. The reactor achieved a maximum throughput of 2.3 kg/hr, which was the maximum the biomass feeder could supply. The reactor is capable of being operated at a far higher throughput but this would require a new feeder and drive motor to be purchased. Modelling showed that the reactor is capable of achieving a reactor throughput of approximately 30 kg/hr. This is an area that should be considered for the future as the reactor is currently operating well below its theoretical maximum. Calculations show that the current product collection system could operate efficiently up to a maximum feed rate of 10 kg/Fir, provided the inert gas supply was adjusted accordingly to keep the vapour residence time in the electrostatic precipitator above one second. Operation above 10 kg/hr would require some modifications to the product collection system. Eight experimental runs were documented and considered successful, more were attempted but due to equipment failure had to be abandoned. This does not detract from the fact that the reactor and product collection system design was extremely efficient. The maximum total liquid yield was 64.9 % liquid yields on a dry wood fed basis. It is considered that the liquid yield would have been higher had there been sufficient development time to overcome certain operational difficulties and if longer operating runs had been attempted to offset product losses occurring due to the difficulties in collecting all available product from a large scale collection unit. The liquids collection system was highly efficient and modeling determined a liquid collection efficiency of above 99% on a mass basis. This was validated due to the fact that a dry ice/acetone condenser and a cotton wool filter downstream of the collection unit enabled mass measurements of the amount of condensable product exiting the product collection unit. This showed that the collection efficiency was in excess of 99% on a mass basis.

The design, evaluation and costing of biomass gasifiers

The objective of this study has been to enable a greater understanding of the biomass gasification process through the development and use of process and economic models. A new theoretical equilibrium model of gasification is described using the operating condition called the adiabatic carbon boundary. This represents an ideal gasifier working at the point where the carbon in the feedstock is completely gasified. The model can be used as a `target' against which the results of real gasifiers can be compared, but it does not simulate the results of real gasifiers. A second model has been developed which uses a stagewise approach in order to model fluid bed gasification, and its results have indicated that pyrolysis and the reactions of pyrolysis products play an important part in fluid bed gasifiers. Both models have been used in sensitivity analyses: the biomass moisture content and gasifying agent composition were found to have the largest effects on performance, whilst pressure and heat loss had lesser effects. Correlations have been produced to estimate the total installed capital cost of gasification systems and have been used in an economic model of gasification. This has been used in a sensitivity analysis to determine the factors which most affect the profitability of gasification. The most important influences on gasifier profitability have been found to be feedstock cost, product selling price and throughput. Given the economic conditions of late 1985, refuse gasification for the production of producer gas was found to be viable at throughputs of about 2.5 tonnes/h dry basis and above, in the metropolitan counties of the United Kingdom. At this throughput and above, the largest element of product gas cost is the feedstock cost, the cost element which is most variable.

Design, implementation and control of a small industrial manufacturing system

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