Systems biology approach to study permeability of paracetamol and its solid dispersion

Physiological changes that take place at cellular level are usually reflective of their level of gene expression. Different formulation excipients have an impact on physiological behavior of the exposed cells and in turn affect transporter genes, enterocyte-mediated metabolism and toxicity biomarkers. The aim of this study was to prepare solid dispersion of paracetamol and evaluate genetic changes that occur in Caco-2 cell lines during the permeability of paracetamol alone and paracetamol solid dispersion formulations. Paracetamol-PEG 8000 solid dispersion was prepared by melt fusion method and the formulation was characterised using differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FTIR). Formulation of solid dispersion resulted in the conversion of crystalline drug into an amorphous form. Permeability studies showed that paracetamol absorption was higher from the solid dispersion formulation. DNA microarrays analysis was carried out in order to investigate the involvement of any efflux/uptake transporters in paracetamol or its solid dispersion permeability. Neither transporter carriers nor efflux proteins were found to be involved in the absorption of paracetamol or its PEG solid dispersion. Gene expression analysis established that paracetamol toxicity was potentially reduced upon formulation into solid dispersion when ATP binding cassette (ABC) and solute carrier transporter (SLC) genes were analyzed.

A comparison of variational and Markov chain Monte Carlo methods for inference in partially observed stochastic dynamic systems

In recent work we have developed a novel variational inference method for partially observed systems governed by stochastic differential equations. In this paper we provide a comparison of the Variational Gaussian Process Smoother with an exact solution computed using a Hybrid Monte Carlo approach to path sampling, applied to a stochastic double well potential model. It is demonstrated that the variational smoother provides us a very accurate estimate of mean path while conditional variance is slightly underestimated. We conclude with some remarks as to the advantages and disadvantages of the variational smoother. © 2008 Springer Science + Business Media LLC.

Everyday tactics and spaces of power: the role of informal economies in post-Soviet Ukraine

Utilising de Certeau's concepts of daily life and his delineation between strategies and tactics as everyday practices this paper examines the role of informal economies in post-Ukraine. Based on 700 household surveys and seventy-five in-depth interviews, conducted in three Ukrainian cities, the paper argues that individuals/households have developed a wide range of tactics in response to the economic marginalisation the country has endured since the collapse of the Soviet Union. Firstly, the paper details the importance of informal economies in contemporary Ukraine while highlighting that many such practices are operated out of necessity due to low wage and pension rates and high levels of corruption. This challenges state-produced statistics on the scale of economic marginalisation currently experienced in the country. By exploring a variety of these tactics the paper then examines how unequal power relations shape the spaces in which these practices operate in and how they can be simultaneously sites of exploitation and resistance to economic marginalisation. The paper concludes pessimistically by suggesting that the way in which these economic spaces are shaped precludes the development of state policies which might benefit the economically marginalised.

The end of transition?:The role of informal economies in the post-Soviet space

This book challenges the accepted notion that the transition from the command economy to market based systems is complete across the post-Soviet space. While it is noted that different political economies have developed in such states, such as Russia’s ‘managed democracy’, events such as Ukraine gaining ‘market economy status’ by the European Union and acceding to the World Trade Organisation in 2008 are taken as evidence that the reform period is over. Such thinking is based on numerous assumptions; specifically that economic transition has defined start and end points, that the formal economy now has primacy over other forms of economic practices and that national economic growth leads to the ‘trickle down’ of wealth to those marginalised by the transition process. Based on extensive ethnographic and quantitative research, conducted in Ukraine and Russia between 2004 - 2007, this book questions these assumptions by stating that the economies that operate across post-Soviet spaces are far from the textbook idea of a market economy. Through this the whole notion of ‘transition’ is problematised and the importance of informal economies to everyday life is demonstrated. Using case studies of various sectors, such as entrepreneurial behaviour and the higher education system, it is also shown how corruption has invaded almost all sectors of the post-Soviet every day.

A methodology for analysis and control of discrete event dynamic systems

The rapid developments in computer technology have resulted in a widespread use of discrete event dynamic systems (DEDSs). This type of system is complex because it exhibits properties such as concurrency, conflict and non-determinism. It is therefore important to model and analyse such systems before implementation to ensure safe, deadlock free and optimal operation. This thesis investigates current modelling techniques and describes Petri net theory in more detail. It reviews top down, bottom up and hybrid Petri net synthesis techniques that are used to model large systems and introduces on object oriented methodology to enable modelling of larger and more complex systems. Designs obtained by this methodology are modular, easy to understand and allow re-use of designs. Control is the next logical step in the design process. This thesis reviews recent developments in control DEDSs and investigates the use of Petri nets in the design of supervisory controllers. The scheduling of exclusive use of resources is investigated and an efficient Petri net based scheduling algorithm is designed and a re-configurable controller is proposed. To enable the analysis and control of large and complex DEDSs, an object oriented C++ software tool kit was developed and used to implement a Petri net analysis tool, Petri net scheduling and control algorithms. Finally, the methodology was applied to two industrial DEDSs: a prototype can sorting machine developed by Eurotherm Controls Ltd., and a semiconductor testing plant belonging to SGS Thomson Microelectronics Ltd.

The development of hard real-time systems using a formal approach

Hard real-time systems are a class of computer control systems that must react to demands of their environment by providing `correct' and timely responses. Since these systems are increasingly being used in systems with safety implications, it is crucial that they are designed and developed to operate in a correct manner. This thesis is concerned with developing formal techniques that allow the specification, verification and design of hard real-time systems. Formal techniques for hard real-time systems must be capable of capturing the system's functional and performance requirements, and previous work has proposed a number of techniques which range from the mathematically intensive to those with some mathematical content. This thesis develops formal techniques that contain both an informal and a formal component because it is considered that the informality provides ease of understanding and the formality allows precise specification and verification. Specifically, the combination of Petri nets and temporal logic is considered for the specification and verification of hard real-time systems. Approaches that combine Petri nets and temporal logic by allowing a consistent translation between each formalism are examined. Previously, such techniques have been applied to the formal analysis of concurrent systems. This thesis adapts these techniques for use in the modelling, design and formal analysis of hard real-time systems. The techniques are applied to the problem of specifying a controller for a high-speed manufacturing system. It is shown that they can be used to prove liveness and safety properties, including qualitative aspects of system performance. The problem of verifying quantitative real-time properties is addressed by developing a further technique which combines the formalisms of timed Petri nets and real-time temporal logic. A unifying feature of these techniques is the common temporal description of the Petri net. A common problem with Petri net based techniques is the complexity problems associated with generating the reachability graph. This thesis addresses this problem by using concurrency sets to generate a partial reachability graph pertaining to a particular state. These sets also allows each state to be checked for the presence of inconsistencies and hazards. The problem of designing a controller for the high-speed manufacturing system is also considered. The approach adopted mvolves the use of a model-based controller: This type of controller uses the Petri net models developed, thus preservIng the properties already proven of the controller. It. also contains a model of the physical system which is synchronised to the real application to provide timely responses. The various way of forming the synchronization between these processes is considered and the resulting nets are analysed using concurrency sets.

Analysis and optimisation of the performance of nonlinear optical communication systems

We investigate the feasibility of simultaneous suppressing of the amplification noise and nonlinearity, representing the most fundamental limiting factors in modern optical communication. To accomplish this task we developed a general design optimisation technique, based on concepts of noise and nonlinearity management. We demonstrate the immense efficiency of the novel approach by applying it to a design optimisation of transmission lines with periodic dispersion compensation using Raman and hybrid Raman-EDFA amplification. Moreover, we showed, using nonlinearity management considerations, that the optimal performance in high bit-rate dispersion managed fibre systems with hybrid amplification is achieved for a certain amplifier spacing – which is different from commonly known optimal noise performance corresponding to fully distributed amplification. Required for an accurate estimation of the bit error rate, the complete knowledge of signal statistics is crucial for modern transmission links with strong inherent nonlinearity. Therefore, we implemented the advanced multicanonical Monte Carlo (MMC) method, acknowledged for its efficiency in estimating distribution tails. We have accurately computed acknowledged for its efficiency in estimating distribution tails. We have accurately computed marginal probability density functions for soliton parameters, by numerical modelling of Fokker-Plank equation applying the MMC simulation technique. Moreover, applying a powerful MMC method we have studied the BER penalty caused by deviations from the optimal decision level in systems employing in-line 2R optical regeneration. We have demonstrated that in such systems the analytical linear approximation that makes a better fit in the central part of the regenerator nonlinear transfer function produces more accurate approximation of the BER and BER penalty. We present a statistical analysis of RZ-DPSK optical signal at direct detection receiver with Mach-Zehnder interferometer demodulation

Analytical first order comparison of amplitude and phase noise in single and dual Mach-Zehnder interferometer detection schemes for DQPSK transmission systems

An analytical first order calculation of the impact of Gaussian white noise on a novel single Mach-Zehnder Interferometer demodulation scheme for DQPSK reveals a constant Q factor ratio to the conventional scheme.

An exploratory study of management accounting and control systems in a developing country

This thesis reports on the results of case studies in four commercial banks in Nigeria. The study focuses how management accounting and control systems (MCS) operate in the four banks. The study is motivated by the dearth of literature on management accounting practices in the developing world in general and in Nigeria in specific. The case study approach adopted in conducting the research was useful in exploring the dynamics of the MCS in the organisations. Data was gathered from two sources. First, semi-structured interviews were conducted with managers at the head office, regional office and branches of each bank. The participants were selected from different backgrounds and managerial levels to provide broader understanding of the operations of the MCS. Second, various internal and external documents were reviewed to provide supporting evidence for the interview results. New institutional sociology (NIS) provided the theoretical framework to understand the results. NIS provided explanations for how the MCS in the four banks were shaped by diverse external and internal factors. The key factors identified as shaping the operations of the MCS were the need to comply with the regulatory environment (coercive isomorphism), the need to maintain social and cultural support (normative isomorphism) and the need to imitate successful organisations in order to appear legitimate (mimetic isomorphism). The study also examines the interplay between the institutional forces, market forces and infra-organisational power relations. This analysis is necessary to overcome the criticism of NIS that it downplays the role of market forces, agency and intra-organisational relations. The findings of the study have implications for understanding the operations of MCS in the developing world.

An Investigation into the adoption and implementation of computer aided production management systems:using the Rogers model of adoption and implementation and a social constuctionist account of technology

The research investigates the processes of adoption and implementation, by organisations, of computer aided production management systems (CAPM). It is organised around two different theoretical perspectives. The first part is informed by the Rogers model of the diffusion, adoption and implementation of innovations, and the second part by a social constructionist approach to technology. Rogers' work is critically evaluated and a model of adoption and implementation is distilled from it and applied to a set of empirical case studies. In the light of the case study data, strengths and weaknesses of the model are identified. It is argued that the model is too rational and linear to provide an adequate explanation of adoption processes. It is useful for understanding processes of implementation but requires further development. The model is not able to adequately encompass complex computer based technologies. However, the idea of 'reinvention' is identified as Roger's key concept but it needs to be conceptually extended. Both Roger's model and definition of CAPM found in the literature from production engineering tend to treat CAPM in objectivist terms. The problems with this view are addressed through a review of the literature on the sociology of technology, and it is argued that a social constructionist approach offers a more useful framework for understanding CAPM, its nature, adoption, implementation, and use. CAPM it is argued, must be understood on terms of the ways in which it is constituted in discourse, as part of a 'struggle for meaning' on the part of academics, professional engineers, suppliers, and users.

Modulation of certain 5-HT-related behaviours by serotonergic and noradrenergic systems

The modulation of 5-hydroxytryptamine (5-HT)-related head-twitchbehaviour by antimigraine drugs and migraine triggers was examined inmice. The antimigraine drugs examined produced either inhibition or noeffect on 5-HT-related head-twitching. On the basis of these resultsit is suggested that 5-HT-related head-twitching is unlikely to beuseful in the preclinical screening and discovery of systemically-activeantimigraine agents. The migraine triggers examined, tyramineand beta-PEA initially produced a repeatable complex time-relatedeffect on 5-HT-related head-twitching, with both inhibition andpotentiation of this behaviour being observed, however, when furtherexamination of the effect of the migraine triggers on 5-HT-relatedhead-twitching was attempted some time later the effects seeninitially were no longer produced. The effect of (±)-1-<2, 5-dimethoxy-4-iodophenyl)-2-aminopropane,((±)DOl), on on-going behaviour of mice and rats was examined. Shakingbehaviour was observed in both species. In mice, excessive scratchingbehaviour was also present. (±)DOl-induced scratching and shakingbehaviour were found to be differentially modulated by noradrenergicand serotonergic agents, however, the fact that both behaviours wereblocked by ritanserin (5-HT2/5-HT1c receptor antagonist) and inhibitedby FLA-63 (a dopamine-beta-oxidase inhibitor which depletesnoradrenaline), suggests the pathways mediating these behaviours mustbe convergent in some manner, and that both behaviours require intact5-HT receptors, probably 5-HT2 receptors, for their production. Ingeneral, the behavioural profile of (±)DOI was as expected for anagent which exhibits high affinity binding to 5-HT2/5-HT1c receptors.Little sign of the 5-HTl-related '5-HT syndrome' was seen in eithermice or rats. The effect of a variety of noradrenergic agents on head-twitchinginduced by a variety of shake-inducing agents was examined. A patternof modulatory effect was seen whereby the modulatory effect of thenoradrenergic agents on 5-hydroxytryptophan <5-HTP) (and in some cases, 5-methoxy-N,N-dimethyltryptamine (5-MeODMT)) was found to be the opposite of that observed with quipazine and (±)DOI. The relationship between these effects, and their implications for understanding the pharmacology of centrally acting drugs is discussed.

Modelling manufacturing planning and control systems:the application of object-oriented principles and discrete-event simulation

Manufacturing planning and control systems are fundamental to the successful operations of a manufacturing organisation. 10 order to improve their business performance, significant investment is made by companies into planning and control systems; however, not all companies realise the benefits sought Many companies continue to suffer from high levels of inventory, shortages, obsolete parts, poor resource utilisation and poor delivery performance. This thesis argues that the fit between the planning and control system and the manufacturing organisation is a crucial element of success. The design of appropriate control systems is, therefore, important. The different approaches to the design of manufacturing planning and control systems are investigated. It is concluded that there is no provision within these design methodologies to properly assess the impact of a proposed design on the manufacturing facility. Consequently, an understanding of how a new (or modified) planning and control system will perform in the context of the complete manufacturing system is unlikely to be gained until after the system has been implemented and is running. There are many modelling techniques available, however discrete-event simulation is unique in its ability to model the complex dynamics inherent in manufacturing systems, of which the planning and control system is an integral component. The existing application of simulation to manufacturing control system issues is limited: although operational issues are addressed, application to the more fundamental design of control systems is rarely, if at all, considered. The lack of a suitable simulation-based modelling tool does not help matters. The requirements of a simulation tool capable of modelling a host of different planning and control systems is presented. It is argued that only through the application of object-oriented principles can these extensive requirements be achieved. This thesis reports on the development of an extensible class library called WBS/Control, which is based on object-oriented principles and discrete-event simulation. The functionality, both current and future, offered by WBS/Control means that different planning and control systems can be modelled: not only the more standard implementations but also hybrid systems and new designs. The flexibility implicit in the development of WBS/Control supports its application to design and operational issues. WBS/Control wholly integrates with an existing manufacturing simulator to provide a more complete modelling environment.

The Evaluation of health and safety auditing systems

The specific objective of the research was to evaluate proprietary audit systems. Proprietary audit systems comprise question sets containing approximately 500 questions dealing with selected aspects of health and safety management. Each question is allotted a number of points and an organisation seeks to judge its health and safety performance by the overall score achieved in the audit. Initially it was considered that the evaluation method might involve comparing the proprietary audit scores with other methods of measuring safety performance. However, what appeared to be missing in the first instance was information that organisations could use to compare the contrast question set content against their own needs. A technique was developed using the computer database FileMaker Pro. This enables questions in an audit to be sorted into categories using a process of searching for key words. Questions that are not categorised by word searching can be identified and sorted manually. The process can be completed in 2-3 hours which is considerably faster than manual categorisation of questions which typically takes about 10 days. The technique was used to compare and contrast three proprietary audits: ISRS, CHASE and QSA. Differences and similarities between these audits were successfully identified. It was concluded that in general proprietary audits need to focus to a greater extent on identifying strengths and weaknesses in occupational health and safety management systems. To do this requires the inclusion of more probing questions which consider whether risk control measures are likely to be successful.