S. cerevisiae as a model for studying mutations in the human gene OPA1 associated with dominant optic atrophy and for drug discovery

L’atrofia ottica dominante (ADOA) è una malattia mitocondriale caratterizzata da difetti visivi, che si manifestano durante l’infanzia, causati da progressiva degenerazione delle cellule gangliari della retina (RGC). ADOA è una malattia genetica associata, nella maggior parte dei casi, a mutazioni nel gene OPA1 che codifica per la GTPasi mitocondriale OPA1, appartenente alla famiglia delle dinamine, principalmente coinvolta nel processo di fusione mitocondriale e nel mantenimento del mtDNA. Finora sono state identificate più di 300 mutazioni patologiche nel gene OPA1. Circa il 50% di queste sono mutazioni missenso, localizzate nel dominio GTPasico, che si pensa agiscano come dominanti negative. Questa classe di mutazioni è associata ad una sindrome più grave nota come “ADOA-plus”. Nel lievito Saccharomyces cerevisiae MGM1 è l’ortologo del gene OPA1: nonostante i due geni abbiano domini funzionali identici le sequenze amminoacidiche sono scarsamente conservate. Questo costituisce una limitazione all’uso del lievito per lo studio e la validazione di mutazioni patologiche nel gene OPA1, infatti solo poche sostituzioni possono essere introdotte e studiate nelle corrispettive posizioni del gene di lievito. Per superare questo ostacolo è stato pertanto costruito un nuovo modello di S. cerevisiae, contenente il gene chimerico MGM1/OPA1, in grado di complementare i difetti OXPHOS del mutante mgm1Δ. Questo gene di fusione contiene una larga parte di sequenza corrispondente al gene OPA1, nella quale è stato inserito un set di nuove mutazioni trovate in pazienti affetti da ADOA e ADOA-plus. La patogenicità di queste mutazioni è stata validata sia caratterizzando i difetti fenotipici associati agli alleli mutati, sia la loro dominanza/recessività nel modello di lievito. A tutt’oggi non è stato identificato alcun trattamento farmacologico per la cura di ADOA e ADOA-plus. Per questa ragione abbiamo utilizzato il nostro modello di lievito per la ricerca di molecole che agiscono come soppressori chimici, ossia composti in grado di ripristinare i difetti fenotipici indotti da mutazioni nel gene OPA1. Attraverso uno screening fenotipico high throughput sono state testate due differenti librerie di composti chimici. Questo approccio, noto con il nome di drug discovery, ha permesso l’identificazione di 23 potenziali molecole attive.

A IMPORTÂNCIA DAS TICS E DA EDUCAÇÃO COMO PROCESSO COMUNICACIONAL DIALÓGICO NO ENSINO SUPERIOR: Um Estudo da Universidade Estadual de Mato Grosso do Sul

Esta tese teve por objetivo saber como o corpo docente da Universidade Estadual de Mato Grosso do Sul (UEMS) percebe, entende e reage ante a incorporação e utilização das Tecnologias de Informação e Comunicação (TICs) nos cursos de graduação dessa Instituição, considerando os novos processos comunicacionais dialógicos que elas podem proporcionar na sociedade atual. Metodologicamente, a tese é composta por pesquisa bibliográfica, buscando fundamentar as áreas da Educação e Comunicação, assim como a Educomunicação; pesquisa documental para contextualização do lócus da pesquisa e de uma pesquisa exploratória a partir da aplicação de um questionário online a 165 docentes da UEMS, que responderam voluntariamente. Verificou-se que os professores utilizam as TICs cotidianamente nas atividades pessoais e, em menor escala, nos ambientes profissionais. Os desafios estão em se formar melhor esse docente e oferecer capacitação continuada para que utilizem de forma mais eficaz as TICs nas salas de aula. Destaca-se ainda que os avanços em tecnologia e os novos ecossistemas comunicacionais construíram novas e outras realidades, tornando a aprendizagem um fator não linear, exigindo-se revisão nos projetos pedagógicos na educação superior para que estes viabilizem diálogos propositivos entre a comunicação e a educação. A infraestrutura institucional para as TICs é outro entrave apontado, tanto na aquisição como na manutenção desses aparatos tecnológicos pela Universidade. Ao final, propõe-se realizar estudos e pesquisas que possam discutir alterações nos regimes contratuais de trabalho dos docentes, uma vez que, para atuar com as TICs de maneira apropriada, exige-se mais tempo e dedicação do docente.

External audit in the National Health Service in England and Wales:a study of an oversight body's control of auditor remuneration

In the National Health Service (NHS) in England and Wales an oversight body, the Audit Commission (AC), defines the scope of the external auditors’ work, appoints the auditors and has oversight of their fees and audit quality. This heavily regulated audit regime mitigates some of the deficiencies observed in high profile corporate failures. Independence, it has been argued, is influenced by the total auditor remuneration paid by the client. In this study we examine total auditor remuneration in a regulated market which seeks to ensure audit independence and audit quality. In particular we undertake rigorous analysis of auditor remuneration by the type of auditor: We place emphasis on the differentiation between private sector firms and the AC’s in-house auditors (District Audit). Individual private audit firms charge premiums (up to 16%) for particular audit work in identified locations, but no premiums were found when we examined total auditor remuneration. The regime appears to permit efficient operation of the audit market while safeguarding both audit independence and standards.

Designing a support system for aerospace maintenance supply chains

Purpose - To develop a systems strategy for supply chain management in aerospace maintenance, repair and overhaul (MRO). Design/methodology/approach - A standard systems development methodology has been followed to produce a process model (i.e. the AMSCR model); an information model (i.e. business rules) and a computerised information management capability (i.e. automated optimisation). Findings - The proof of concept for this web-based MRO supply chain system has been established through collaboration with a sample of the different types of supply chain members. The proven benefits comprise new potential to minimise the stock holding costs of the whole supply chain whilst also minimising non-flying time of the aircraft that the supply chain supports. Research limitations/implications - The scale of change needed to successfully model and automate the supply chain is vast. This research is a limited-scale experiment intended to show the power of process analysis and automation, coupled with strategic use of management science techniques, to derive tangible business benefit. Practical implications - This type of system is now vital in an industry that has continuously decreasing profit margins; which in turn means pressure to reduce servicing times and increase the mean time between them. Originality/value - Original work has been conducted at several levels: process, information and automation. The proof-of-concept system has been applied to an aircraft MRO supply chain. This is an area of research that has been neglected, and as a result is not well served by current systems solutions. © Emerald Group Publishing Limited.

A test of basic assumptions of Affective Events Theory (AET) in call centre work

Based on data from 2091 call centre representatives working in 85 call centres in the UK, central assumptions of affective events theory (AET) are tested. AET predicts that specific features of work (e.g. autonomy) have an impact on the arousal of emotions and moods at work that, in turn, co-determine job satisfaction of employees. AET further proposes that job satisfaction is an evaluative judgement that mainly explains cognitive-based behaviour, whereas emotions and moods better predict affective-based behaviour. The results support these assumptions. A clear separation of key constructs (job satisfaction, positive and negative emotions) was possible. Moreover, correlations between several work features (e.g. supervisory support) and job satisfaction were, in part, mediated by work emotions, even when controlling for gender, age, call centre type (in-house versus outsourced centres) and call centre size. Predictions regarding consequences of satisfaction and affect were partly corroborated as continuance commitment was more strongly related to job satisfaction than to positive emotions. In addition, affective commitment and health complaints were related to both emotions and job satisfaction to the same extent. Thus, AET is a fruitful framework for explaining why and how specific management strategies used for designing work features influence important organizational attitudes and well-being of employees. © 2006 British Academy of Management.

Enabling innovation:knowledge control, sharing and coordination boundaries in UK and German manufacturing

We investigate how boundaries in knowledge control, sharing and co-ordination influence UK and German manufacturing firms’ innovation intensity (an indicator of the volume of product change) and product life (an indicator of the pace of generational change). In general UK plants more commonly face knowledge control boundaries related to plant ownership or control, while German plants more commonly face boundaries related to knowledge sharing and knowledge co-ordination between functional groups. Our empirical results emphasise the importance of the strategic management of innovation. Knowledge control boundaries – related to external ownership, group membership and decision making autonomy – have a weak negative influence on plants’ innovation outcomes. Strategic decisions relating to multifunctional working and networking are found to be more important in overcoming knowledge sharing and co-ordination boundaries. Knowledge sharing boundaries, related to plant or company boundaries, prove most important where a plant has no in-house R&D capability. Knowledge co-ordination boundaries related to functional or multi-functional working have strong but differential effects on different innovation output measures: functional boundaries increase product life in both countries, and in Germany maintaining functional boundaries is also associated with increased innovation intensity.

Does role clarity explain employee-perceived service quality? A study of antecedents and consequences in call centres

Purpose – Role clarity of frontline staff is critical to their perceptions of service quality in call centres. The purpose of this study is to examine the effects of role clarity and its antecedents and consequences on employee-perceived service quality. Design/methodology/approach – A conceptual model, based on the job characteristics model and cognitive theories, is proposed. Key antecedents of role clarity considered here are feedback, autonomy, participation, supervisory consideration, and team support; while key consequences are organizational commitment, job satisfaction and service quality. An internal marketing approach is adopted and all variables are measured from the frontline employee's perspective. A structural equation model is developed and tested on a sample of 342 call centre representatives of a major commercial bank in the UK. Findings – The research reveals that role clarity plays a critical role in explaining employee perceptions of service quality. Further, the research findings indicate that feedback, participation and team support significantly influence role clarity, which in turn influences job satisfaction and organizational commitment. Research limitations/implications – The research suggests that boundary personnel in service firms should strive for more clarity in perceived role for delivering better service quality. The limitations are in sample availability from in-house transaction call centres of a single bank. Originality/value – The contributions of this study are untangling the confusing research evidence on the effect of role clarity on service quality, using service quality as a performance variable as opposed to productivity estimates, adopting an internal marketing approach to understanding the phenomenon, and introducing teamwork along with job-design and supervisory factors as antecedent to role clarity.

Cause, effect and benefits of a standardised corporate visual identity system of UK companies operating in Malaysia

Investigates the degree of global standardisation of a corporate visual identity system (CVIS) in multinational operations. A special emphasis of this research is accorded to UK companies operating in Malaysia. In particular, the study seeks to reveal the reasons for developing a standardised CVIS; the behavioural issues associated with CVIS; and the determination in selecting a graphic design agency. The findings of the research revealed that multinational corporations in an increasingly corporate environment adopted a standardised CVIS for several reasons, including, aiding the sale of products and services, creating an attractive environment for hiring employees, and increasing the company’s stature and presence. Further findings show that the interest in global identity was stimulated by global restructuring, merger or acquisition. The above trends help explain why increased focus has been accorded to CVIS over the past five years by many UK companies operating in Malaysia. Additional findings reveal that both the UK design agencies and in-house design department are used in the development of the firms’ CVIS.

Exploitation of fibre characteristics in temperature sensing and radio-over-fibre applications

The development of sensing devices is one of the instrumentation fields that has grown rapidly in the last decade. Corresponding to the swift advance in the development of microelectronic sensors, optical fibre sensors are widely investigated because of their advantageous properties over the electronics sensors such as their wavelength multiplexing capability and high sensitivity to temperature, pressure, strain, vibration and acoustic emission. Moreover, optical fibre sensors are more attractive than the electronics sensors as they can perform distributed sensing, in terms of covering a reasonably large area using a single piece of fibre. Apart from being a responsive element in the sensing field, optical fibre possesses good assets in generating, distributing, processing and transmitting signals in the future broadband information network. These assets include wide bandwidth, high capacity and low loss that grant mobility and flexibility for wireless access systems. Among these core technologies, the fibre optic signal processing and transmission of optical and radio frequency signals have been the subjects of study in this thesis. Based on the intrinsic properties of single-mode optical fibre, this thesis aims to exploit the fibre characteristics such as thermal sensitivity, birefringence, dispersion and nonlinearity, in the applications of temperature sensing and radio-over-fibre systems. By exploiting the fibre thermal sensitivity, a fully distributed temperature sensing system consisting of an apodised chirped fibre Bragg grating has been implemented. The proposed system has proven to be efficient in characterising grating and providing the information of temperature variation, location and width of the heat source applied in the area under test.To exploit the fibre birefringence, a fibre delay line filter using a single high-birefringence optical fibre structure has been presented. The proposed filter can be reconfigured and programmed by adjusting the input azimuth of launched light, as well as the strength and direction of the applied coupling, to meet the requirements of signal processing for different purposes in microwave photonic and optical filtering applications. To exploit the fibre dispersion and nonlinearity, experimental investigations have been carried out to study their joint effect in high power double-sideband and single-sideband modulated links with the presence of fibre loss. The experimental results have been theoretically verified based on the in-house implementation of the split-step Fourier method applied to the generalised nonlinear Schrödinger equation. Further simulation study on the inter-modulation distortion in two-tone signal transmission has also been presented so as to show the effect of nonlinearity of one channel on the other. In addition to the experimental work, numerical simulations have also been carried out in all the proposed systems, to ensure that all the aspects concerned are comprehensively investigated.

Radioimmunoassay of insulin and glucagon with studies on the obese hyperglycaemic syndrome in mice

Sensitive and precise radioimmunoassays for insulin and glucagon have been established. Although it was possible to employ similar precepts to the development of both hormone assays, the establishment of a reliable glucagon radioimmunoassay was complicated by the poor immunogenicity and instability of the peptide. Thus, unlike insulin antisera which were prepared by monthly injection of guinea pigs with crystalline insulin emulsified in adjuvant, the successful production of glucagon antisera was accomplished by immunisation of rabbits and guinea pigs with glucagon covalently linked to bovine plasma albumin. The conventional chloramine-T iodination with purification by gel chromatography was only suitable for the production of labelled insulin. Quality tracer for use in the glucagon radioimmunoassay was prepared by trace iodination, with subsequent purification of monoiodinated glucagon by anion exchange chromatography. Separation of free and antibody bound moieties by coated charcoal was applicable to both hormone assays, and a computerised data processing system, relying on logit-log transformation, was used to analyse all assay results. The assays were employed to evaluate the regulation of endocrine pancreatic function and the role of insulin and glucagon in the pathogenesis of the obese hyperglycaemic syndrome in mice. In the homozygous (ob/ob) condition, mice of the Birmingham strain were characterised by numerous abnormalities of glucose homeostasis, several of which were detected in heterozygous (ob/+) mice. Obese mice exhibited pancreatic alpha cell dysfunction and hyperglucagonaemia. Investigation of this defect revealed a marked insensitivity of an insulin dependent glucose sensing mechanism that inhibited glucagon secretion. Although circulating glucagon was of minor importance in the maintenance of hyperinsulinaemia, lack of suppression of alpha cell function by glucose and insulin contributed significantly to both the insulin insensitivity and the hyperglycaemia of obese mice.

Acquisition and management of technology in Malaysian companies

This thesis is about the acquisition and diffusion of imported technology. Writers in the field of technology development in developing countries have always recognised that technical progress depends on the diffusion of imported technology and its applications to the provision of products and processes (Rosemberg, 1982). Despite the massive importation of technology by Malaysian companies, little effort has been made to study and understand the diffusion system in local companies. This study analyses: The problems associated with the acquisition of technology, highlighting the technology strategies adopted by the suppliers of technology; the diffusion pattern and key characteristics of the diffusion process; and major factors affecting the diffusion of technology. The policy implications are examined and the framework to manage the diffusion process within the enterprises is suggested. The findings indicated that the diffusion process is not one of passive acceptance but involves systematic efforts to acquire and diffuse the imported technology. A strong system of diffusion in companies had enabled a rapid diffusion of imported technology resulting in higher levels of technical capability. On the other hand, weakness in the company's diffusion system led to limited diffusion and slow technical progress. Characteristics of diffusion system are analysed and discussed extensively. The thesis attempts to develop the idea of `in-house system of diffusion' associated with the acquisition and development of imported technology. It argues for the development ofa stronger theoretical framework on the diffusion and development of technology particularly in countries like Malaysia which relies extensively on the importation of foreign technology.

Development of a computerised library system in the construction industry

This thesis examines the ways that libraries have employed computers to assist with housekeeping operations. It considers the relevance of such applications to company libraries in the construction industry, and describes more specifically the development of an integrated cataloguing and loan system. A review of the main features in the development of computerised ordering, cataloguing and circulation control systems shows that fully integrated packages are beginning to be completed, and that some libraries are introducing second generation programs. Cataloguing is the most common activity to be computerised, both at national and company level. Results from a sample of libraries in the construction industry suggest that the only computerised housekeeping system is at Taylor Woodrow. Most of the firms have access to an in-house computer, and some of the libraries, particularly those in firms of consulting engineers, might benefit from computerisation, but there are differing attitudes amongst the librarians towards the computer. A detailed study of the library at Taylor Woodrow resulted in a feasibility report covering all the areas of its activities. One of the main suggestions was the possible use of a computerised loans and cataloguing system. An integrated system to cover these two areas was programmed in Fortran and implemented. This new system provides certain benefits and saves staff time, but at the cost of time on the computer. Some improvements could be made by reprogramming, but it provides a general system for small technical libraries. A general equation comparing costs for manual and computerised operations is progressively simplified to a form where the annual saving from the computerised system is expressed in terms of staff and computer costs and the size of the library. This equation gives any library an indication of the savings or extra cost which would result from using the computerised system.

How capabilities in operations can influence green production:exploring the issues

This research presents case material of companies within the UK that are attempting to be “Green” in their operations processes. We assess their aspirations by plotting capabilities through their supply networks under five key headings: Strategy; Production planning and procurement; In-house production; Logistics; and Human resource management within operations. We build upon the work of Azzone and Noci, 1998 and Azzone et al., 1997 and we present insights into companies whose commitment to Green Production ranges from “the company tries to delay the adoption of green programs” through to the company adopts a “radical approach to environmental issues.” In doing so we see how operations capabilities in a range of parameters can play a central and pivotal role in achieving some of the aspirations of Green Production within companies.

Computationsl modelling of dimethyl ether separation and steam reforming in fluidized bed reactors

This study presents a computational fluid dynamic (CFD) study of Dimethyl Ether (DME) gas adsorptive separation and steam reforming (DME-SR) in a large scale Circulating Fluidized Bed (CFB) reactor. The CFD model is based on Eulerian-Eulerian dispersed flow and solved using commercial software (ANSYS FLUENT). Hydrogen is currently receiving increasing interest as an alternative source of clean energy and has high potential applications, including the transportation sector and power generation. Computational fluid dynamic (CFD) modelling has attracted considerable recognition in the engineering sector consequently leading to using it as a tool for process design and optimisation in many industrial processes. In most cases, these processes are difficult or expensive to conduct in lab scale experiments. The CFD provides a cost effective methodology to gain detailed information up to the microscopic level. The main objectives in this project are to: (i) develop a predictive model using ANSYS FLUENT (CFD) commercial code to simulate the flow hydrodynamics, mass transfer, reactions and heat transfer in a large scale dual fluidized bed system for combined gas separation and steam reforming processes (ii) implement a suitable adsorption models in the CFD code, through a user defined function, to predict selective separation of a gas from a mixture (iii) develop a model for dimethyl ether steam reforming (DME-SR) to predict hydrogen production (iv) carry out detailed parametric analysis in order to establish ideal operating conditions for future industrial application. The project has originated from a real industrial case problem in collaboration with the industrial partner Dow Corning (UK) and jointly funded by the Engineering and Physical Research Council (UK) and Dow Corning. The research examined gas separation by adsorption in a bubbling bed, as part of a dual fluidized bed system. The adsorption process was simulated based on the kinetics derived from the experimental data produced as part of a separate PhD project completed under the same fund. The kinetic model was incorporated in FLUENT CFD tool as a pseudo-first order rate equation; some of the parameters for the pseudo-first order kinetics were obtained using MATLAB. The modelling of the DME adsorption in the designed bubbling bed was performed for the first time in this project and highlights the novelty in the investigations. The simulation results were analysed to provide understanding of the flow hydrodynamic, reactor design and optimum operating condition for efficient separation. Bubbling bed validation by estimation of bed expansion and the solid and gas distribution from simulation agreed well with trends seen in the literatures. Parametric analysis on the adsorption process demonstrated that increasing fluidizing velocity reduced adsorption of DME. This is as a result of reduction in the gas residence time which appears to have much effect compared to the solid residence time. The removal efficiency of DME from the bed was found to be more than 88%. Simulation of the DME-SR in FLUENT CFD was conducted using selected kinetics from literature and implemented in the model using an in-house developed user defined function. The validation of the kinetics was achieved by simulating a case to replicate an experimental study of a laboratory scale bubbling bed by Vicente et al [1]. Good agreement was achieved for the validation of the models, which was then applied in the DME-SR in the large scale riser section of the dual fluidized bed system. This is the first study to use the selected DME-SR kinetics in a circulating fluidized bed (CFB) system and for the geometry size proposed for the project. As a result, the simulation produced the first detailed data on the spatial variation and final gas product in such an industrial scale fluidized bed system. The simulation results provided insight in the flow hydrodynamic, reactor design and optimum operating condition. The solid and gas distribution in the CFB was observed to show good agreement with literatures. The parametric analysis showed that the increase in temperature and steam to DME molar ratio increased the production of hydrogen due to the increased DME conversions, whereas the increase in the space velocity has been found to have an adverse effect. Increasing temperature between 200 oC to 350 oC increased DME conversion from 47% to 99% while hydrogen yield increased substantially from 11% to 100%. The CO2 selectivity decreased from 100% to 91% due to the water gas shift reaction favouring CO at higher temperatures. The higher conversions observed as the temperature increased was reflected on the quantity of unreacted DME and methanol concentrations in the product gas, where both decreased to very low values of 0.27 mol% and 0.46 mol% respectively at 350 °C. Increasing the steam to DME molar ratio from 4 to 7.68 increased the DME conversion from 69% to 87%, while the hydrogen yield increased from 40% to 59%. The CO2 selectivity decreased from 100% to 97%. The decrease in the space velocity from 37104 ml/g/h to 15394 ml/g/h increased the DME conversion from 87% to 100% while increasing the hydrogen yield from 59% to 87%. The parametric analysis suggests an operating condition for maximum hydrogen yield is in the region of 300 oC temperatures and Steam/DME molar ratio of 5. The analysis of the industrial sponsor’s case for the given flow and composition of the gas to be treated suggests that 88% of DME can be adsorbed from the bubbling and consequently producing 224.4t/y of hydrogen in the riser section of the dual fluidized bed system. The process also produces 1458.4t/y of CO2 and 127.9t/y of CO as part of the product gas. The developed models and parametric analysis carried out in this study provided essential guideline for future design of DME-SR at industrial level and in particular this work has been of tremendous importance for the industrial collaborator in order to draw conclusions and plan for future potential implementation of the process at an industrial scale.

Openness, knowledge, innovation and growth in UK business services

We explore the causal links between service firms' knowledge investments, their innovation outputs and business growth based on a bespoke survey of around 1100 UK service businesses. We combine the activity based approach of the innovation value chain with firms' external links at each stage of the innovation process. This introduces the concept of 'encoding' relationships through which learning improves the effectiveness of firms' innovation processes. Our econometric results emphasise the importance of external openness in the initial, exploratory phase of the innovation process and the significance of internal openness (e.g. team working) in later stages of the process. In-house design capacity is strongly linked to a firm's ability to absorb external knowledge for innovation. Links to customers are important in the exploratory stage of the innovation process, but encoding linkages with private and public research organisations are more important in developing innovation outputs. Business growth is related directly to both the extent of firms' service innovation as well as the diversity of innovation, reflecting marketing, strategic and business process change.