Interaction of peptides, peptidomimetics and other drug candidates with the DI/tripeptide transport system in intestinal epithelial cells, using the in vitro caco-2 cell culture system

An uptake system was developed using Caco-2 cell monolayers and the dipeptide, glycyl-[3H]L-proline, as a probe compound. Glycyl-[3H]L-proline uptake was via the di-/tripeptide transport system (DTS) and, exhibited concentration-, pH- and temperature-dependency. Dipeptides inhibited uptake of the probe, and the design of the system allowed competitors to be ranked against one another with respect to affinity for the transporter. The structural features required to ensure or increase interaction with the DTS were defined by studying the effect of a series of glycyl-L-proline and angiotensin-converting enzyme (ACE)-inhibitor (SQ-29852) analogues on the uptake of the probe. The SQ-29852 structure was divided into six domains (A-F) and competitors were grouped into series depending on structural variations within specific regions. Domain A was found to prefer a hydrophobic function, such as a phenyl group, and was intolerant to positive charges and H+ -acceptors and donors. SQ-29852 analogues were more tolerant of substitutions in the C domain, compared to glycyl-L-proline analogues, suggesting that interactions along the length of the SQ-29852 molecule may override the effects of substitutions in the C domain. SQ-29852 analogues showed a preference for a positive function, such as an amine group in this region, but dipeptide structures favoured an uncharged substitution. Lipophilic substituents in domain D increased affinity of SQ-29852 analogues with the DTS. A similar effect was observed for ACE-NEP inhibitor analogues. Domain E, corresponding to the carboxyl group was found to be tolerant of esterification for SQ-29852 analogues but not for dipeptides. Structural features which may increase interaction for one series of compounds, may not have the same effect for another series, indicating that the presence of multiple recognition sites on a molecule may override the deleterious effect of anyone change. Modifying current, poorly absorbed peptidomimetic structures to fit the proposed hypothetical model may improve oral bioavailability by increasing affinity for the DTS. The stereochemical preference of the transporter was explored using four series of compounds (SQ-29852, lysylproline, alanylproline and alanylalanine enantiomers). The L, L stereochemistry was the preferred conformation for all four series, agreeing with previous studies. However, D, D enantiomers were shown in some cases to be substrates for the DTS, although exhibiting a lower affinity than their L, L counterparts. All the ACE-inhibitors and β-lactam antibiotics investigated, produced a degree of inhibition of the probe, and thus show some affinity for the DTS. This contrasts with previous reports that found several ACE inhibitors to be absorbed via a passive process, thus suggesting that compounds are capable of binding to the transporter site and inhibiting the probe without being translocated into the cell. This was also shown to be the case for oligodeoxynucleotide conjugated to a lipophilic group (vitamin E), and highlights the possibility that other orally administered drug candidates may exert non-specific effects on the DTS and possibly have a nutritional impact. Molecular modelling of selected ACE-NEP inhibitors revealed that the three carbonyl functions can be oriented in a similar direction, and this conformation was found to exist in a local energy-minimised state, indicating that the carbonyls may possibly be involved in hydrogen-bond formation with the binding site of the DTS.

A systems approach to public sector budgeting: the case of the planning, programming, budgeting system for the health and personal social services

The aim of this thesis is to examine the specific contextual factors affecting the applicability and development of the planning, programming, budgeting system (P.P.B.S.) as a systems approach to public sector budgeting. The concept of P.P.B.S. as a systems approach to public sector budgeting will first be developed and the preliminary hypothesis that general contextual factors may be classified under political, structural and cognitive headings will be put forward. This preliminary hypothesis will be developed and refined using American and early British experience. The refined hypothesis will then be tested in detail in the case of the English health and personal social services (H.P.S.S.), The reasons for this focus are that it is the most recent, the sole remaining, and the most significant example in British central government outside of defence, and is fairly representative of non-defence government programme areas. The method of data collection relies on the examination of unpublished and difficult to obtain central government, health and local authority documents, and interviews with senior civil servants and public officials. The conclusion will be that the political constraints on, or factors affecting P.P.B.S., vary with product characteristics and cultural imperatives on pluralistic decision-making; that structural constraints vary with the degree of coincidence of programme and organisation structure and with the degree of controllability of the organisation; and finally, that cognitive constraints vary according to product characteristics, organisational responsibilities, and analytical effort.

Local and systemic delivery of a novel group of inhibitors of transglutaminase enzyme: A potential approach for treating of catheter-related complications and liver fibrosis

The present thesis investigates targeted (locally and systemically) delivery of a novel group of inhibitors of enzyme transglutaminases (TGs). TGs are a widely distributed group of enzymes that catalyse the formation of isopeptide bonds between the y-carboxamide group of protein-bound glutamines and the a-amino group of protein-bound lysines or polyamines. The first group of the novel inhibitors tested were the tluorescently labelled inhibitors of Factor XIIIa (FXIIIa). These small, non-toxic inhibitors have the potential to prevent stabilisation of thrombi by FXIIIa and consequently increase the natural rate of thrombolysis, in addition it reduces staphylococcal colonisation of catheters by inhibiting their FXIIIa¬mediated cross-linking to blood clot proteins on the central venous catheter (CVCs) surface. The aim of this work was to incorporate the FXIIIa inhibitor either within coating of polyurethane (PU) catheters or to integrate it into silicone catheters, so as to reduce the incidence of thrombotic occlusion and associated bacterial infection in CVCs. The initial work focused on the incorporation of FXIIIa inhibitors within polymeric coatings of PU catheters. After defining the key characteristics desired for an effective polymeric-coating, polyvinylpyrrolidone (PVP), poly(lactic-co-glycolic acid) (PLGA) or their combination were studies as polymers of choice for coating of the catheters_ The coating was conducted by dip-coating method in a polymer solution containing the inhibitor. Upon incubation of the inhibitor-and polymer-coated strips in buffer, PVP was dissolved instantly, generating fast and significant drug release, whilst PLGA did not dissolve, yielding a slow and an insufficient amount of drug release. Nevertheless, the drug release profile was enhanced upon employing a blend solution of PVP and PLGA. The second part of the study was to incorporate the FXIIIa inhibitor into a silicone elastomer; results demonstrated that FXIIIa inhibitor can be incorporated and released from silicone by using citric acid (CA) and sodium bicarbonate (SB) as additives and the drug release rate can be controlled by the amount of incorporated additives in the silicone matrix. Furthermore, it was deemed that the inhibitor was still biologically active subsequent to being released from the silicone elastomer strips. Morphological analysis confirmed the formation of channels and cracks inside the specimens upon the addition of CA and SB. Nevertheless, the tensile strength, in addition to Young's modulus of silicone elastomer strips, decreased constantly with an increasing amount of amalgamated CA/ SB in the formulations. According to our results, incorporation of FXIIIa inhibitor into catheters and other medical implant devices could offer new perspectives in preventing bio-material associated infections and thrombosis. The use of tissue transglutaminase (T02) inhibitor for treating of liver fibrosis was also investigated. Liver fibrosis is characterized by increased synthesis and decreased degradation of the extracellular matrix (ECM). Transglutaminase-mediated covalent cross-linking is involved in the stabilization of ECM in human liver fibrosis. Thus, TG2 inhibitors may be used to counteract the decreased degradation of the ECM. The potential of a liposome based drug delivery system for site specific delivery of the fluorescent TG2 inhibitor into the liver was investigated; results indicated that the TG2 inhibitor can be successfully integrated into liposomes and delivered to the liver, therefore demonstrating that liposomes can be employed for site-specific delivery of TG2 inhibitors into the liver and TG2 inhibitor incorporating liposomes could offer a new approach in treating liver fibrosis and its end stage disease cirrhosis.

Self-regulation of health and safety in a Local Authority with particular reference to safety representatives, supervisors and safety committees

The Report of the Robens Committee (1972), the Health and Safety at Work Act (1974) and the Safety Representatives and Safety Committees Regulations (1977) provide the framework within which this study of certain aspects of health and safety is carried out. The philosophy of self-regulation is considered and its development is set within an historical and an industrial relations perspective. The research uses a case study approach to examine the effectiveness of self-regulation in health and safety in a public sector organisation. Within this approach, methodological triangulation employs the techniques of interviews, questionnaires, observation and documentary analysis. The work is based in four departments of a Scottish Local Authority and particular attention is given to three of the main 'agents' of self-regulation - safety representatives, supervisors and safety committees and their interactions, strategies and effectiveness. A behavioural approach is taken in considering the attitudes, values, motives and interactions of safety representatives and management. Major internal and external factors, which interact and which influence the effectiveness of joint self-regulation of health and safety, are identified. It is emphasised that an organisation cannot be studied without consideration of the context within which it operates both locally and in the wider environment. One of these factors, organisational structure, is described as bureaucratic and the model of a Representative Bureaucracy described by Gouldner (1954) is compared with findings from the present study. An attempt is made to ascertain how closely the Local Authority fits Gouldner's model. This research contributes both to knowledge and to theory in the subject area by providing an in-depth study of self-regulation in a public sector organisation, which when compared with such studies as those of Beaumont (1980, 1981, 1982) highlights some of the differences between the public and private sectors. Both empirical data and hypothetical models are used to provide description and explanation of the operation of the health and safety system in the Local Authority. As data were collected during a dynamic period in economic, political and social terms, the research discusses some of the effects of the current economic recession upon safety organisation.

Human performance modelling as an aid in the process of manufacturing system design

Manufacturing system design is an ongoing activity within industry. Modelling tools based on Discrete Event Simulation are often used by practitioners during this design cycle. However, such tools do not adequately model the behaviour of 'direct' workers in manufacturing environments. There is an important need to expand the capability of modelling to include the relationships between human centred factors (demography, attitudes, beliefs, etc), their working environment (physical and organizational), and their subsequent performance in terms of productive routines. Therefore, this paper describes research that has formed a pilot modelling methodology that is an important first step in providing such a capability.

Human performance modelling as an aid to manufacturing system design

Once the factory worker was considered to be a necessary evil, soon to be replaced by robotics and automation. Today, many manufacturers appreciate that people in direct productive roles can provide important flexibility and responsiveness, and so significantly contribute to business success. The challenge is no longer to design people out of the factory, but to design factory environment that help to get the best performance from people. This paper describes research that has set out to help to achieve this by expanding the capabilities of simulation modeling tools currently used by practitioners.

Omnigen:providing electricity, food preparation, cold storage and pure water using a variety of local fuels

We describe a polygeneration system that can run on neat plant oils, such as Jatropha and Pongamia, or standard diesel fuel. A prototype has been constructed using a compression ignition engine of 9.9 kW shaft output. It consumes 3 L/h of fuel and will produce 40 kg/h of ice by means of an adsorption refrigerator powered from the engine jacket heat. Steaming of rice, deep and shallow frying, and other types of food preparation heated by the exhaust gas have been demonstrated. In addition, the feasibility of producing distilled water by means of multiple-effect distillation powered by the engine waste heat is shown. Overall plant efficiency and potential savings in greenhouse gas emissions are discussed. © 2012 Elsevier Ltd.

Pattern integration in the normal and abnormal human visual system

The processing conducted by the visual system requires the combination of signals that are detected at different locations in the visual field. The processes by which these signals are combined are explored here using psychophysical experiments and computer modelling. Most of the work presented in this thesis is concerned with the summation of contrast over space at detection threshold. Previous investigations of this sort have been confounded by the inhomogeneity in contrast sensitivity across the visual field. Experiments performed in this thesis find that the decline in log contrast sensitivity with eccentricity is bilinear, with an initial steep fall-off followed by a shallower decline. This decline is scale-invariant for spatial frequencies of 0.7 to 4 c/deg. A detailed map of the inhomogeneity is developed, and applied to area summation experiments both by incorporating it into models of the visual system and by using it to compensate stimuli in order to factor out the effects of the inhomogeneity. The results of these area summation experiments show that the summation of contrast over area is spatially extensive (occurring over 33 stimulus carrier cycles), and that summation behaviour is the same in the fovea, parafovea, and periphery. Summation occurs according to a fourth-root summation rule, consistent with a “noisy energy” model. This work is extended to investigate the visual deficit in amblyopia, finding that area summation is normal in amblyopic observers. Finally, the methods used to study the summation of threshold contrast over area are adapted to investigate the integration of coherent orientation signals in a texture. The results of this study are described by a two-stage model, with a mandatory local combination stage followed by flexible global pooling of these local outputs. In each study, the results suggest a more extensive combination of signals in vision than has been previously understood.

Investigating local delivery by road to retail and non-retail customers in the UK logistics sector

Over recent years, hub-and-spoke distribution techniques have attracted widespread research attention. Despite there being a growing body of literature in this area there is less focus on the spoke-terminal element of the hub-and-spoke system as being a key component in the overall service received by the end-user. Current literature is highly geared towards discussing bulk optimization of freight units rather than to the more discrete and individualistic profile characteristics of shared-user Less-than-truckload (LTL) freight. In this paper, a literature review is presented to review the role hub-and-spoke systems play in meeting multi-profile customer demands, particularly in developing sectors with more sophisticated needs, such as retail. The paper also looks at the use of simulation technology as a suitable tool for analyzing spoke-terminal operations within developing hub-and spoke systems.

Extra compensation for inventive employees:is our system equitable, unbiased and motivating?

There is a presumption that invention is good. It provides us with innovative goods, services and ways of doing things leading to greater employment, wealth and health. This article looks at the two recent UK cases regarding statutory extra compensation that may be awarded to employee inventors under the Patents Act 1977. Most universities worldwide and many companies have individual inventor reward schemes. Researchers now work in teams made up of both industry and academic researchers who are often based in different countries where different legal regimes apply. Is leaving the decision to award employees extra financial compensation up to individual companies unfair, unequal and de-motivating? Is having differing legislative systems in different European countries counter productive and a barrier to economic growth? There must be a balance between the inventor and the innovator. Do we have it right and if not what should it be? Legislation: Patents Act 1977 s.39 , s.40 , s.41 Cases: Kelly v GE Healthcare Ltd [2009] EWHC 181 (Pat); [2009] R.P.C. 12 (Ch D (Patents Ct)) Shanks v Unilever Plc [2010] EWCA Civ 1283; [2011] R.P.C. 12 (CA (Civ Div))

Analytical BER performance in differential n-PSK coherent transmission system influenced by equalization enhanced phase noise

Long-haul high speed optical transmission systems are significantly distorted by the interplay between the electronic chromatic dispersion (CD) equalization and the local oscillator (LO) laser phase noise, which leads to an effect of equalization enhanced phase noise (EEPN). The EEPN degrades the performance of optical communication systems severely with the increment of fiber dispersion, LO laser linewidth, symbol rate, and modulation format. In this paper, we present an analytical model for evaluating the performance of bit-error-rate (BER) versus signal-to-noise ratio (SNR) in the n-level phase shift keying (n-PSK) coherent transmission system employing differential carrier phase estimation (CPE), where the influence of EEPN is considered. Theoretical results based on this model have been investigated for the differential quadrature phase shift keying (DQPSK), the differential 8-PSK (D8PSK), and the differential 16-PSK (D16PSK) coherent transmission systems. The influence of EEPN on the BER performance in term of the fiber dispersion, the LO phase noise, the symbol rate, and the modulation format are analyzed in detail. The BER behaviors based on this analytical model achieve a good agreement with previously reported BER floors influenced by EEPN. Further simulations have also been carried out in the differential CPE considering EEPN. The results indicate that this analytical model can give an accurate prediction for the DQPSK system, and a leading-order approximation for the D8PSK and the D16PSK systems.

The big 4 in Bangladesh:caught between the global and the local

Purpose- This article explores the work practices of Big 4 firms in Bangladesh with the aim of exploring the extent to which Global Professional Service Firms can be thought of as being genuinely ‘global’. Methodology/Approach- Interviews were undertaken with the vast majority of Big 4 partners in Bangladesh. These interviews explored a number of themes related to the professional service work context in Bangladesh and the relationship between local and global firms. Findings- The central finding of this paper is that although the Big 4 have a long-established presence in Bangladesh, local societal factors heavily influence the realities of work for accountants there. In most cases the Big 4 firms establish correspondent firms (instead of full member firms) in Bangladesh and tend to offer restricted service lines. Additionally, the paper identifies professional, commercial and cultural barriers to greater Big 4 involvement in the local market. Conceptually, the chief contribution of this paper is to explore how the effects of globalising capitalism and standardised ‘best practices’ in global professional service work are mediated through the societal effects of Bangladeshi society, resulting in the Big 4 having only a tentative presence in the Bangladeshi market. Research implications- The findings cast doubt on the extent to which self-styled Global Professional Service firms are truly ‘global’ in nature. Future work examining the Big 4, or accounting more generally, in the context of globalization, would do well to pay greater attention to the experience of professionals in emerging markets. Originality/Value- Whilst there has been much work looking at accounting and accountants in the context of globalization, this work has tended to privilege ‘core’ western empirical settings. Very little is known about Professional Service Firms in ‘peripheral’ or emerging markets. Furthermore, this study extends the application of the System, Society and Dominance framework by mapping the interactions and dynamics of these three sources of influence in the setting of PSFs.

Towards probabilistic synchronization of local controllers

The traditional use of global and centralised control methods, fails for large, complex, noisy and highly connected systems, which typify many real world industrial and commercial systems. This paper provides an efficient bottom up design of distributed control in which many simple components communicate and cooperate to achieve a joint system goal. Each component acts individually so as to maximise personal utility whilst obtaining probabilistic information on the global system merely through local message-passing. This leads to an implied scalable and collective control strategy for complex dynamical systems, without the problems of global centralised control. Robustness is addressed by employing a fully probabilistic design, which can cope with inherent uncertainties, can be implemented adaptively and opens a systematic rich way to information sharing. This paper opens the foreseen direction and inspects the proposed design on a linearised version of coupled map lattice with spatiotemporal chaos. A version close to linear quadratic design gives an initial insight into possible behaviours of such networks.

Control of pattern formation by time-delay feedback with global and local contributions

We consider the suppression of spatiotemporal chaos in the complex GinzburgLandau equation by a combined global and local time-delay feedback. Feedback terms are implemented as a control scheme, i.e., they are proportional to the difference between the time-delayed state of the system and its current state. We perform a linear stability analysis of uniform oscillations with respect to space-dependent perturbations and compare with numerical simulations. Similarly, for the fixed-point solution that corresponds to amplitude death in the spatially extended system, a linear stability analysis with respect to space-dependent perturbations is performed and complemented by numerical simulations. © 2010 Elsevier B.V. All rights reserved.

A DEA-based incentives system for centrally managed multi-unit organisations

In multi-unit organisations such as a bank and its branches or a national body delivering publicly funded health or education services through local operating units, the need arises to incentivize the units to operate efficiently. In such instances, it is generally accepted that units found to be inefficient can be encouraged to make efficiency savings. However, units which are found to be efficient need to be incentivized in a different manner. It has been suggested that efficient units could be incentivized by some reward compatible with the level to which their attainment exceeds that of the best of the rest, normally referred to as “super-efficiency”. A recent approach to this issue (Varmaz et. al. 2013) has used Data Envelopment Analysis (DEA) models to measure the super-efficiency of the whole system of operating units with and without the involvement of each unit in turn in order to provide incentives. We identify shortcomings in this approach and use it as a starting point to develop a new DEA-based system for incentivizing operating units to operate efficiently for the benefit of the aggregate system of units. Data from a small German retail bank is used to illustrate our method.