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Parkinson's disease is an archetypal sporadic neurodegenerative disease: it is age-related and results in region-specific neurodegeneration with intracellular inclusions in many of the remaining neurones. Despite three decades of intense study, disease modifying therapies remain beyond the horizon, reflecting our understanding of the pathological process and the intrinsic challenges that the degenerative diseases of the brain present. Dysfunction in a number of cellular systems has been implicated in the development of Parkinson's disease. Protein homeostasis in terminally differentiated neurones is of particular import; unlike most other cells, they have no progeny with which to gift troublesome proteins. The ubiquitin proteasome system is the cell's main regulated proteolytic pathway and observations from neuropathological, genetic and animal studies have consistently found evidence that it may be aetiologically important in Parkinson's disease. Using a Cre/loxP approach Psmc1, which encodes an essential component of the 26S proteasome, was spatially deleted in catecholaminergic neurones in mice. This model reproduced both the region-specific neuronal loss and intraneuronal inclusions that define the sporadic human disease. In this work, I describe the further characterization of this unique model and use it to test hypotheses regarding the nature of the process that leads to these neuropathological features. Specifically, I show that in response to Psmcl deletion genes encoding sub- units of the 26S proteasome are up-regulated; using whole-genome microarray analysis I identify differentially expressed transcripts in micro dissected brain regions and then use the model to demonstrate that α-synuclein is not essential for the neurodegeneration or inclusion formation that result from Psmc1 deletion. These data underline the relevance of this model to the study of the pathogenesis of Parkinson's disease and identify avenues for further investigation.

Understanding of the 'market' for property development is critical to the procedure of property research. But this market's constitution is fundamentally derived from the end users of property - namely the occupiers / tenants. It in turn, therefore, becomes appropriate that an endeavour into property research explores what determines occupiers' / tenants' choice of location. By exploring the underlying logic and reasoning that the 'end users' of property bring to their decision-making we may come to a better understanding of the market. Science parks in the UK, and indeed globally, are typically predicated upon the ideal of 'proactively' accommodating the needs of their occupying companies. Such companies are for the most part small, start-up enterprises for whom the science park developer / manager actively makes provisions of facilities and services as well as physical accommodation, that may nurture and enhance the prospects of potentially vulnerable business ventures. It is therefore evident that the concept of science parks is founded upon principles that would bridge the gap between 'property developer' and 'property user'. It is apparent that these 'principles' would heighten knowledge and understanding of the market for the property that is science parks. Implicit to the science park concept, then, is recognizance that property and in particular its management concerns far more than mere considerations for its physical, fiscal and quantitative characteristics; the success or otherwise of a property development is distinctly influenced by the perceptions and qualities that are attached to the property. Such perceptions and qualities are, thus, distinct players in the determination of location. The research therefore takes as its focus the predominantly perception borne qualitative variables that act as location determinants. Consequent to literature review and piloting surveys a system of classification, (categories), of science park tenants for analysis is developed and a host of location determinants / variables was derived for inclusion in the 'main survey'. Via the administration of the 'main' questionnaire survey to occupiers of science park premises throughout the United Kingdom these qualitative variables are examined. The survey methodology introduces measurement and thus quantitative assessments of, what are termed, 'primary', 'secondary' and 'minor' determinants of location, but the qualitative origin of these determinants is not treated disparagingly. Indeed a central contention of the thesis is that if true knowledge and understanding of the 'market' is to be achieved the underlying logic and reasoning for the quantitative responses to the qualitative variables / determinants must be pursued. The analysis therefore is conducted through narrative, description and circumspection for the sources of response to the inquiry. 11 Abstract Having exercised such circumspection in consideration of the sources of response, propositions are made as to the nature of location determinants for each of the categories of science park tenant, (respondent), that have been generated through review and piloting. These propositions are, then, in turn checked for their veracity against a further, independent sample of science park tenants. That is - a follow-up survey is conducted the results of which are used to check the extent to which agreement exists between the two independent samples. With high degrees of agreement between the main survey results and those of the follow-up survey, the propositions may be upheld as valid representations of location determinants for science parks in the UK. The primary findings, pursuant to this procedure, would indicate that though science parks are predicated upon principles of altruistic origin in their support for the initiation of new, high technology orientated business, commercial realities may be seen to impinge upon such altruism. Consequently the tenants of science park premises are found to be only limitedly motivated by the additional facilities and services that may be offered by science parks. Instead they are found to be more distinctively motivated, (i.e. their location is determined), by fundamental and basic concerns for adequacy, appropriateness and the affordability of their premises.

In this thesis we shall be concerned with the study of models which arise as a consequence of adopting discrete regularisations for various Euclidean space quantum field theories. Specifically, we employ a random triangulation of the continuum space, and define the fields only over nodes or links of the mesh. Lattice field theories, together with the Renormalisation Group, are introduced in the first chapter. Continuum physics is shown to depend on the positions and stabilities of zeroes of the β-function, which in turn requires a knowledge of the critical behaviour of the associated statistical model. In Chapter 2. we examine a theory of Dirac fermions in 2 + 1 dimensions on a random lattice. We investigate the behaviour of the 2-pt function and fermion condensate in the absence of any background gauge field. The results indicate certain doubling problems, generic to regular lattice formulations of fermion field theories, are evaded, at least at tree graph level. We then go on to examine the fermion vacuum currents in the presence of background fields with non-zero winding number. We are able to demonstrate the existence of a Chern-Simon's topological term in the gauge field effective action which yields parity violating vacuum currents. The magnitude of these are in agreement with certain continuum calculations. The final chapter concerns the properties of random surfaces. The particular class of models chosen originate as discretisations of Polyakov's string. The partition function is approximated by a sum over all possible random triangulations and an integral over vertex positions. The sum over random lattices is intended to mimick the functional integral over intrinsic metrics encountered in the continuum, and the model may also be pictured as 2D quantum gravity coupled to a scalar field. We consider the phase structure of the models when two forms of extrinsic curvature are added to the standard action. Monte-Carlo simulation indicates that with one type of curvature term a strong 2nd order phase transition exists at finite coupling, leading to a new continuum limit for the model possessing long-range correlation properties. With the other type a much weaker higher order transition is observed. In this case the surface will be crumpled at long distance. We discuss the implications of these results for continuum surfaces.