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.

An investigation of the dynamic characteristics of a bolted-rotor system

A Jeffcott rotor consists of a disc at the centre of an axle supported at its end by bearings. A bolted Jeffcott rotor is formed by two discs, each with a shaft on one side. The discs are held together by spring loaded bolts near the outer edge. When the rotor turns there is tendency for the discs to separate on one side. This effect is more marked if the rotor is unbalanced, especially at resonance speeds. The equations of motion of the system have been developed with four degrees of freedom to include the rotor and bearing movements in the respective axes. These equations which include non-linear terms caused by the rotor opening, are subjected to external force such from rotor imbalance. A simulation model based on these equations was created using SIMULINK. An experimental test rig was used to characterise the dynamic features. Rotor discs open at a lateral displacement of the rotor of 0.8 mm. This is the threshold value used to show the change of stiffness from high stiffness to low stiffness. The experimental results, which measure the vibration amplitude of the rotor, show the dynamic behaviour of the bolted rotor due to imbalance. Close agreement of the experimental and theoretical results from time histories, waterfall plots, pseudo-phase plots and rotor orbit plot, indicated the validity of the model and existence of the non-linear jump phenomenon.

Aspects of design for a spare parts provisioning system

This thesis describes an investigation by the author into the spares operation of compare BroomWade Ltd. Whilst the complete system, including the warehousing and distribution functions, was investigated, the thesis concentrates on the provisioning aspect of the spares supply problem. Analysis of the historical data showed the presence of significant fluctuations in all the measures of system performance. Two Industrial Dynamics simulation models were developed to study this phenomena. The models showed that any fluctuation in end customer demand would be amplified as it passed through the distributor and warehouse stock control systems. The evidence from the historical data available supported this view of the system's operation. The models were utilised to determine which parts of the total system could be expected to exert a critical influence on its performance. The lead time parameters of the supply sector were found to be critical and further study showed that the manner in which the lead time changed with work in progress levels was also an important factor. The problem therefore resolved into the design of a spares manufacturing system. Which exhibited the appropriate dynamic performance characteristics. The gross level of entity presentation, inherent in the Industrial Dynamics methodology, was found to limit the value of these models in the development of detail design proposals. Accordingly, an interacting job shop simulation package was developed to allow detailed evaluation of organisational factors on the performance characteristics of a manufacturing system. The package was used to develop a design for a pilot spares production unit. The need for a manufacturing system to perform successfully under conditions of fluctuating demand is not limited to the spares field. Thus, although the spares exercise provides an example of the approach, the concepts and techniques developed can be considered to have broad application throughout batch manufacturing industry.

Design of an expandable manufacturing simulator through the application of object-oriented principles

In analysing manufacturing systems, for either design or operational reasons, failure to account for the potentially significant dynamics could produce invalid results. There are many analysis techniques that can be used, however, simulation is unique in its ability to assess detailed, dynamic behaviour. The use of simulation to analyse manufacturing systems would therefore seem appropriate if not essential. Many simulation software products are available but their ease of use and scope of application vary greatly. This is illustrated at one extreme by simulators which offer rapid but limited application whilst at the other simulation languages which are extremely flexible but tedious to code. Given that a typical manufacturing engineer does not posses in depth programming and simulation skills then the use of simulators over simulation languages would seem a more appropriate choice. Whilst simulators offer ease of use their limited functionality may preclude their use in many applications. The construction of current simulators makes it difficult to amend or extend the functionality of the system to meet new challenges. Some simulators could even become obsolete as users, demand modelling functionality that reflects the latest manufacturing system design and operation concepts. This thesis examines the deficiencies in current simulation tools and considers whether they can be overcome by the application of object-oriented principles. Object-oriented techniques have gained in popularity in recent years and are seen as having the potential to overcome any of the problems traditionally associated with software construction. There are a number of key concepts that are exploited in the work described in this thesis: the use of object-oriented techniques to act as a framework for abstracting engineering concepts into a simulation tool and the ability to reuse and extend object-oriented software. It is argued that current object-oriented simulation tools are deficient and that in designing such tools, object -oriented techniques should be used not just for the creation of individual simulation objects but for the creation of the complete software. This results in the ability to construct an easy to use simulator that is not limited by its initial functionality. The thesis presents the design of an object-oriented data driven simulator which can be freely extended. Discussion and work is focused on discrete parts manufacture. The system developed retains the ease of use typical of data driven simulators. Whilst removing any limitation on its potential range of applications. Reference is given to additions made to the simulator by other developers not involved in the original software development. Particular emphasis is put on the requirements of the manufacturing engineer and the need for Ihe engineer to carrv out dynamic evaluations.

Development of an integrated reverse osmosis-greenhouse system driven by solar photovoltaic generators

The development of a system that integrates reverse osmosis (RO) with a horticultural greenhouse has been advanced through laboratory experiments. In this concept, intended for the inland desalination of brackish groundwater in dry areas, the RO concentrate will be reduced in volume by passing it through the evaporative cooling pads of the greenhouse. The system will be powered by solar photovoltaics (PV). Using a solar array simulator, we have verified that the RO can operate with varying power input and recovery rates to meet the water demands for irrigation and cooling of a greenhouse in north-west India. Cooling requires ventilation by a fan which has also been built, tested and optimised with a PV module outdoors. Results from the experiments with these two subsystems (RO and fan) are compared to theoretical predictions to reach conclusions about energy usage, sizing and cost. For example, the optimal sizing for the RO system is 0.12–1.3 m2 of PV module per m2 of membrane, depending on feed salinity. For the fan, the PV module area equals that of the fan aperture. The fan consumes <30 J of electrical energy per m3 of air moved which is 3 times less than that of standard fans. The specific energy consumption of the RO, at 1–2.3 kWh ?m-3, is comparable to that reported by others. Now that the subsystems have been verifi ed, the next step will be to integrate and test the whole system in the field.

Stand-alone groundwater desalination system using reverse osmosis combined with a cooled greenhouse for use in arid and semi-arid zones of India

In many areas of northern India, salinity renders groundwater unsuitable for drinking and even for irrigation. Though membrane treatment can be used to remove the salt, there are some drawbacks to this approach e.g. (1) depletion of the groundwater due to over-abstraction, (2) saline contamination of surface water and soil caused by concentrate disposal and (3) high electricity usage. To address these issues, a system is proposed in which a photovoltaic-powered reverse osmosis (RO) system is used to irrigate a greenhouse (GH) in a stand-alone arrangement. The concentrate from the RO is supplied to an evaporative cooling system, thus reducing the volume of the concentrate so that finally it can be evaporated in a pond to solid for safe disposal. Based on typical meteorological data for Delhi, calculations based on mass and energy balance are presented to assess the sizing and cost of the system. It is shown that solar radiation, freshwater output and evapotranspiration demand are readily matched due to the approximately linear relation among these variables. The demand for concentrate varies independently, however, thus favouring the use of a variable recovery arrangement. Though enough water may be harvested from the GH roof to provide year-round irrigation, this would require considerable storage. Some practical options for storage tanks are discussed. An alternative use of rainwater is in misting to reduce peak temperatures in the summer. An example optimised design provides internal temperatures below 30EC (monthly average daily maxima) for 8 months of the year and costs about €36,000 for the whole system with GH floor area of 1000 m2 . Further work is needed to assess technical risks relating to scale-deposition in the membrane and evaporative pads, and to develop a business model that will allow such a project to succeed in the Indian rural context.

Clinical decision support system for point of care use: ontology driven design and software implementation

OBJECTIVES: The objective of this research was to design a clinical decision support system (CDSS) that supports heterogeneous clinical decision problems and runs on multiple computing platforms. Meeting this objective required a novel design to create an extendable and easy to maintain clinical CDSS for point of care support. The proposed solution was evaluated in a proof of concept implementation. METHODS: Based on our earlier research with the design of a mobile CDSS for emergency triage we used ontology-driven design to represent essential components of a CDSS. Models of clinical decision problems were derived from the ontology and they were processed into executable applications during runtime. This allowed scaling applications' functionality to the capabilities of computing platforms. A prototype of the system was implemented using the extended client-server architecture and Web services to distribute the functions of the system and to make it operational in limited connectivity conditions. RESULTS: The proposed design provided a common framework that facilitated development of diversified clinical applications running seamlessly on a variety of computing platforms. It was prototyped for two clinical decision problems and settings (triage of acute pain in the emergency department and postoperative management of radical prostatectomy on the hospital ward) and implemented on two computing platforms-desktop and handheld computers. CONCLUSIONS: The requirement of the CDSS heterogeneity was satisfied with ontology-driven design. Processing of application models described with the help of ontological models allowed having a complex system running on multiple computing platforms with different capabilities. Finally, separation of models and runtime components contributed to improved extensibility and maintainability of the system.

Modelling and experimental verification of a solar-powered liquid desiccant cooling system for greenhouse food production in hot climates

Experiments and theoretical modelling have been carried out to predict the performance of a solar-powered liquid desiccant cooling system for greenhouses. We have tested two components of the system in the laboratory using MgCl2 desiccant: (i) a regenerator which was tested under a solar simulator and (ii) a desiccator which was installed in a test duct. Theoretical models have been developed for both regenerator and desiccator and gave good agreement with the experiments. The verified computer model is used to predict the performance of the whole system during the hot summer months in Mumbai, Chittagong, Muscat, Messina and Havana. Taking examples of temperate, sub-tropical, tropical and heat-tolerant tropical crops (lettuce, soya bean, tomato and cucumber respectively) we estimate the extensions in growing seasons enabled by the system. Compared to conventional evaporative cooling, the desiccant system lowers average daily maximum temperatures in the hot season by 5.5-7.5 °C, sufficient to maintain viable growing conditions for lettuce throughout the year. In the case of tomato, cucumber and soya bean the system enables optimal cultivation through most summer months. It is concluded that the concept is technically viable and deserves testing by means of a pilot installation at an appropriate location.

Understanding institutional conversion:the case of the National Reporting and Learning System

This article focuses on one type of institutional change: conversion. One innovative approach to institutional change, the “political-coalitional approach”, acknowledges that: institutions can have unintended effects, which may privilege certain groups over others; institutions are often created and sustained through compromise with external actors; and institutions’ external context can vary significantly over time, as different coalitions’ power waxes and wanes. This approach helps explain the conversion of one institution drawn from the UK National Health Service, the National Reporting and Learning System. However, the shift of this system from producing formative information to facilitate learning to promote safer care, towards producing summative information to support resource allocation decisions, cannot be explained merely by examining the actions of external power coalitions. An internal focus, which considers factors that are normally viewed as “organisational” (such as leadership and internal stability), is also required.

Basic principles of design and functioning of multifunctional laser diagnostic system for non-invasive medical spectrophotometry

The devising of a general engineering theory of multifunctional diagnostic systems for non-invasive medical spectrophotometry is an important and promising direction of modern biomedical engineering. We aim in this study to formalize in scientific engineering terms objectives for multifunctional laser non-invasive diagnostic system (MLNDS). The structure-functional model as well as a task-function of generalized MLNDS was formulated and developed. The key role of the system software for MLNDS general architecture at steps of ideological-technical designing has been proved. The basic principles of block-modules composition of MLNDS hardware are suggested as well. © 2011 Copyright Society of Photo-Optical Instrumentation Engineers (SPIE).

Anomalies in stiffness and damping of a 2D discrete viscoelastic system due to negative stiffness components

The recent development of using negative stiffness inclusions to achieve extreme overall stiffness and mechanical damping of composite materials reveals a new avenue for constructing high performance materials. One of the negative stiffness sources can be obtained from phase transforming materials in the vicinity of their phase transition, as suggested by the Landau theory. To understand the underlying mechanism from a microscopic viewpoint, we theoretically analyze a 2D, nested triangular lattice cell with pre-chosen elements containing negative stiffness to demonstrate anomalies in overall stiffness and damping. Combining with current knowledge from continuum models, based on the composite theory, such as the Voigt, Reuss, and Hashin-Shtrikman model, we further explore the stability of the system with Lyapunov's indirect stability theorem. The evolution of the microstructure in terms of the discrete system is discussed. A potential application of the results presented here is to develop special thin films with unusual in-plane mechanical properties. © 2006 Elsevier B.V. All rights reserved.

Combining an enterprise resource planning system and informality:a study of efficiency and flexibility complmentarity [sic]

DUE TO COPYRIGHT RESTRICTIONS ONLY AVAILABLE FOR CONSULTATION AT ASTON UNIVERSITY LIBRARY AND INFORMATION SERVICES WITH PRIOR ARRANGEMENT One of the current research trends in Enterprise Resource Planning (ERP) involves examining the critical factors for its successful implementation. However, such research is limited to system implementation, not focusing on the flexibility of ERP to respond to changes in business. Therefore, this study explores a combination system, made up of an ERP and informality, intended to provide organisations with efficient and flexible performance simultaneously. In addition, this research analyses the benefits and challenges of using the system. The research was based on socio-technical system (STS) theory which contains two dimensions: 1) a technical dimension which evaluates the performance of the system; and 2) a social dimension which examines the impact of the system on an organisation. A mixed method approach has been followed in this research. The qualitative part aims to understand the constraints of using a single ERP system, and to define a new system corresponding to these problems. To achieve this goal, four Chinese companies operating in different industries were studied, all of which faced challenges in using an ERP system due to complexity and uncertainty in their business environments. The quantitative part contains a discrete-event simulation study that is intended to examine the impact of operational performance when a company implements the hybrid system in a real-life situation. Moreover, this research conducts a further qualitative case study, the better to understand the influence of the system in an organisation. The empirical aspect of the study reveals that an ERP with pre-determined business activities cannot react promptly to unanticipated changes in a business. Incorporating informality into an ERP can react to different situations by using different procedures that are based on the practical knowledge of frontline employees. Furthermore, the simulation study shows that the combination system can achieve a balance between efficiency and flexibility. Unlike existing research, which emphasises a continuous improvement in the IT functions of an enterprise system, this research contributes to providing a definition of a new system in theory, which has mixed performance and contains both the formal practices embedded in an ERP and informal activities based on human knowledge. It supports both cost-efficiency in executing business transactions and flexibility in coping with business uncertainty.This research also indicates risks of using the system, such as using an ERP with limited functions; a high cost for performing informally; and a low system acceptance, owing to a shift in organisational culture. With respect to practical contribution, this research suggests that companies can choose the most suitable enterprise system approach in accordance with their operational strategies. The combination system can be implemented in a company that needs to operate a medium amount of volume and variety. By contrast, the traditional ERP system is better suited in a company that operates a high-level volume market, while an informal system is more suitable for a firm with a requirement for a high level of variety.

Thermalized polarization dynamics of a discrete optical-waveguide system with four-wave mixing

Statistical mechanics of two coupled vector fields is studied in the tight-binding model that describes propagation of polarized light in discrete waveguides in the presence of the four-wave mixing. The energy and power conservation laws enable the formulation of the equilibrium properties of the polarization state in terms of the Gibbs measure with positive temperature. The transition line T=∞ is established beyond which the discrete vector solitons are created. Also in the limit of the large nonlinearity an analytical expression for the distribution of Stokes parameters is obtained, which is found to be dependent only on the statistical properties of the initial polarization state and not on the strength of nonlinearity. The evolution of the system to the final equilibrium state is shown to pass through the intermediate stage when the energy exchange between the waveguides is still negligible. The distribution of the Stokes parameters in this regime has a complex multimodal structure strongly dependent on the nonlinear coupling coefficients and the initial conditions.