Adipose tissue, initially known only for storing excess fat, produces a number of active cytokine-like hormones, collectively known as adipokines or adipocytokines. These molecules are further known to elicit auto-, para- and endocrine functions in the body. In healthy bodies, the cardiovascular endothelium maintains vascular health by critically controlling the interplay between various factors. However, in diseased states such as obesity, owing to numerous metabolic malfunctions, this vascular homeostasis is disrupted. The dysregulated metabolic stimuli perturb vascular homeostasis via initiating or exacerbating the pre-existing inflammatory processes. These inflammatory processes further recruit immune cells to the site of injury, alter cell adhesion molecules expression, and reduce Nitric Oxide levels. These altered mechanisms result in increased blood pressure, endothelial cell migration, proliferation, and apoptosis. In this review article, we aim to evaluate the current literature in understanding the role of Chemerin in vascular health and furthermore, its role in maintaining vascular homeostasis with respect to inflammation, obesity and associated Metabolic Syndrome (MetS) risk factors. For over fifteen years, a growing body of research has been published studying chemerin in the disease states associated with obesity, MetS and cardiovascular disease. Chemerin appears to form an integral link between obesity and related dysfunctional cardiometabolic states as well as in inflammation and immune-system related complications. These combine to suggest a significant Chemerin role in human vascular health and disease.
Simulation studies cycle through the phases of formulation, programming, verification and validation, experimental design and analysis, and implementation. The work presented has been concerned with developing methods to enhance the practice and support for the experimental design and analysis phase of a study. The investigation focussed on the introduction of Artificial Intelligence (AI) techniques to this phase, where previously there existed little support. The reason for this approach was the realisation that the experimentation process in a simulation study can be broken down into a reasoning component and a control of execution component. In most studies, a user would perform both of these. The involvement of a reasoning process attracted the notion of artificial intelligence or at least the prospective use of its techniques.
After a study into the current state of the art, work began by considering the development of a support system for experimental design and analysis that had human intelligence and machine control of execution. This provided a semi-structured decision-making environment in the form of a controller that requested human input. The controller was made intelligent when it was linked to a non-procedural (PROLOG) program that provided remote intelligent input from either the user or default heuristics. The intelligent controller was found to enhance simulation experimentation because it ensures that all the steps in the experimental design and analysis phase take place and receive appropriate input.
The next stage was to adopt the view that simulation experimental design and analysis may be enhanced through a system that had machine intelligence but expected human control of execution. This provided the framework of an advisor that adopted a consultation expert system paradigm. Users were advised on how to perform simulation experimentation. Default reasoning strategies were implemented to provide the system with advisory capabilities in the tasks of prediction, evaluation, comparison, sensitivity analysis, transient behaviour, functional relations, optimisation.
Later the controller and the advisor were linked to provide an integrated system with both machine intelligence and machine control of execution. User involvement in the experimentation process was reduced considerably as support -¿as provided in both the reasoning and control of execution aspects. Additionally, this integrated system supports facilities for refinement purposes that aim at turning the system's knowledge into expertise. It became theoretically possible for other simulation experts to teach the system or experiment with their own rules and knowledge.
The following stage considered making the knowledge of the system available to the user, thereby turning the system into a teacher and providing pedagogical support Teaching was introduced through explanation and demonstration. The explanation facility used a mixed approach: it combined a first time response explanation facility to "how" and "why" questions with a menu driven information system facility for "explain" requests or further queries. The demonstration facility offers tutorials on the use of the system and how to carry out an investigation of any of the tasks that the system can address.
The final part of the research was to collect some empirical results about the performance of the system. Some experiments were performed retroactively on existing studies. The system was also linked to a data-driven simulation package 'hat permitted evaluation using some large scale industrial applications. The system's performance was measured by its ability to perform as well as students with simulation knowledge but not necessarily expertise. The system was also found to assist the user with little or no simulation knowledge to perform as well as students with knowledge.
This study represents the first practical attempts to use the expert system framework to model the processes involved in simulation experimentation. The framework described in this thesis has been implemented as a prototype advisory system called WES (Warwick Expert Simulator). The thesis concludes that the framework proposed is robust for this purpose.
This qualitative study was positioned within an emerging scientific field concerned with empirical explorations into theologies of grace. The theoretical framework was provided by the SIFT approach to biblical hermeneutics, an approach rooted in reader-perspective hermeneutical theory and in Jungian psychological type theory, that explores the distinctive readings of sensing perception and intuitive perception and the distinctive readings of thinking evaluation and feeling evaluation. The empirical methodology was provided by developing a research tradition concerned with applying the SIFT approach to biblical text. In this study, a group of 32 Anglican clergy were invited to work in type-alike groups to explore biblical theologies of grace. Dividing into three workshops according to their preferences for sensing and intuition, the clergy explored the messages of grace in Matthew 6: 25-30 (birds and lilies). Dividing into three workshops according to their preferences for thinking and feeling, the clergy explored the messages of grace in Matthew 20: 1-15 (labourers in the vineyard). The rich data gathered from these workshops generated insight into contemporary theologies of grace and also confirmed the hypothesis that scriptural reading and interpretation may be shaped by the reader's psychological type preference.
This thesis explores the nucleophilic thiol-yne reaction as a crosslinking method for the synthesis of hydrogel materials under biologically relevant conditions. The reaction, using simple functional groups, can be carried out without the use of an external catalyst. This thesis aims to portray the immense potential this reaction has in creating hydrated polymer networks for a wide range of biomedical applications. In the review of the literature (Chapter 1), the popularity and future of hydrogels in tissue engineering has been discussed and the advantages of using alkyne functional groups to crosslink polymers has been highlighted. The main aim of this thesis is to further develop the nucleophilic thiol-yne reaction and to prepare poly(ethylene glycol) (PEG) hydrogel materials with superior performance for application as tissue engineered scaffolds (e.g. extracellular matrix (ECM) mimics or injectable scaffolds). This aim has been approached through a variety of experimental pathways in this thesis demonstrating the suitability of this reaction in the biomaterials field.
In Chapter 2, the nucleophilic thiol-yne reaction has been presented as a highly efficient chemistry for producing robust, high water content hydrogels which could be repeatably compressed without hysteresis. Through a straightforward blending process of PEG thiol precursors, the material properties were easily tuned to a range of relevant biological environments. In a similar manner, using the PEG precursors to tune the resultant properties, Chapter 3 addresses the swelling profiles of the thiol-yne hydrogels. By increasing the number of hydrophobic crosslinking points within the networks, nonswelling, cytocompatible hydrogel material were created when immersed in aqueous environments.
The monoaddition product of the nucleophilic thiol-yne reaction results in a vinyl thioether bond which can favour different isomers, depending on the reaction conditions. To exploit this in hydrogel synthesis, Chapter 4 describes the formation of sterecontrolled hydrogels. Significantly, an impressive range of mechanical properties was achieved, without affecting the structure or swelling behaviour of the materials.
To achieve a structure with more advantageous properties (e.g. self-healing and stretchability) thiol-yne interpenetrating networks (IPNs) were synthesised through the inclusion of natural polymer hydrogels (Chapter 5). These IPNs achieved the advantageous properties required in a simple and effective manner, while retaining the characteristics already exhibited by these materials. To improve on this aim, the thiol-yne PEG hydrogels successfully encapsulated breast cancer cells with enhanced viability compared to the widely used radical thiol-ene reaction (Chapter 6). Controlled matrix degradation allowed for cell proliferation and the formation of cell clusters.
Chapter 7 investigates the kinetics of the nucleophilic thiol-yne reaction with different activating groups (e.g. adjacent group to the alkyne), to reduce the toxicity of the PEG alkyne precursors and degradation of the resultant thiol-yne hydrogels. This chapter highlights key requirements of the functionalisation reaction to form alkyne and thiol precursors for successful hydrogel synthesis.
Chapter 8 provides a summary of the key findings from Chapters 2-7 and Chapter 9 states the experimental procedures of this thesis.