Diffuse beta-amyloid (A beta) deposits and neurons: in situ secretion or diffusion of A beta?

The association between diffuse-type beta -amyloid (AP) deposits and neuronal cell bodies in Alzheimer's disease (AD) and Down's syndrome (DS) could result from the secretion of AP from clusters of neurons in situ or the diffusion of A beta from cell processes, glial cells or blood vessels. To decide between these hypotheses, spatial pattern analysis was used to study the relationship between the degree of clustering of neuronal cell bodies and the presence of diffuse deposits in the temporal lobe of patients with DS. Significant clustering of neuronal cell bodies was present in 17/24 (71%) of brain areas studied. in addition, in 23/24 (96%) of brain areas, there was a positive correlation between the presence of diffuse deposits and the density of neurons. Hence, the data support the hypothesis that diffuse deposits develop in situ mainly as a result of the secretion of A beta by local clusters of neurons rather than by significant diffusion. Furthermore, the size of a diffuse deposit is likely to be determined by the number of neurons within a cluster which secrete A beta. The number and density of neurons could also be a factor determining the evolution of a diffuse into a mature amyloid deposit.

Representation and parameterisation issues in genetic algorithms

A multi-chromosome GA (Multi-GA) was developed, based upon concepts from the natural world, allowing improved flexibility in a number of areas including representation, genetic operators, their parameter rates and real world multi-dimensional applications. A series of experiments were conducted, comparing the performance of the Multi-GA to a traditional GA on a number of recognised and increasingly complex test optimisation surfaces, with promising results. Further experiments demonstrated the Multi-GA's flexibility through the use of non-binary chromosome representations and its applicability to dynamic parameterisation. A number of alternative and new methods of dynamic parameterisation were investigated, in addition to a new non-binary 'Quotient crossover' mechanism. Finally, the Multi-GA was applied to two real world problems, demonstrating its ability to handle mixed type chromosomes within an individual, the limited use of a chromosome level fitness function, the introduction of new genetic operators for structural self-adaptation and its viability as a serious real world analysis tool. The first problem involved optimum placement of computers within a building, allowing the Multi-GA to use multiple chromosomes with different type representations and different operators in a single individual. The second problem, commonly associated with Geographical Information Systems (GIS), required a spatial analysis location of the optimum number and distribution of retail sites over two different population grids. In applying the Multi-GA, two new genetic operators (addition and deletion) were developed and explored, resulting in the definition of a mechanism for self-modification of genetic material within the Multi-GA structure and a study of this behaviour.

Mechanisms of heat and mass transfer to and from single drops freely-suspended in an air stream

A specially-designed vertical wind tunnel was used to freely suspend individual liquid drops of 5 mm initial diameter to investigate drop dynamics, terminal velocity and heat and mass transfer rates. Droplets of distilled, de-ionised water, n-propanol, iso-butanol, monoethanolamine and heptane were studied over a temperature range of 50oC to 82oC. The effects of substances that may provide drop surface rigidity (e.g. surface active agents, binders and polymers) on mass transfer rates were investigated by doping distilled de-ionised water drops with sodium di-octyl sulfo-succinate surfactant. Mass transfer rates decreased with reduced drop oscillation as a result of surfactant addition, confirming the importance of droplet surface instability. Rigid naphthalene spheres and drops which formed a skin were also studied; the results confirmed the reduced transfer rates in the absence of drop fluidity. Following consideration of fundamental drop dynamics in air and experimental results from this study, a novel dimensionless group, the Oteng-Attakora, (OT), number was included in the mass transfer equation to account for droplet surface behaviour and for prediction of heat and mass transfer rates from single drops which exhibit surface instability at Re>=500. The OT number and the modified mass transfer equation are respectively: OT=(ava2/d).de1.5(d/) Sh = 2 + 0.02OT0.15Re0.88Sc0.33 Under all conditions drop terminal velocity increased linearly with the square root of drop diameter and the drag coefficient was 1. The data were correlated with a modified equation by Finlay as follows: CD=0.237.((Re/P0.13)1.55(1/We.P0.13) The relevance of the new model to practical evaporative spray processes is discussed.

A Generic model for the design and analysis of production systems

This dissertation studies the process of operations systems design within the context of the manufacturing organization. Using the DRAMA (Design Routine for Adopting Modular Assembly) model as developed by a team from the IDOM Research Unit at Aston University as a starting point, the research employed empirically based fieldwork and a survey to investigate the process of production systems design and implementation within four UK manufacturing industries: electronics assembly, electrical engineering, mechanical engineering and carpet manufacturing. The intention was to validate the basic DRAMA model as a framework for research enquiry within the electronics industry, where the initial IDOM work was conducted, and then to test its generic applicability, further developing the model where appropriate, within the other industries selected. The thesis contains a review of production systems design theory and practice prior to presenting thirteen industrial case studies of production systems design from the four industry sectors. The results and analysis of the postal survey into production systems design are then presented. The strategic decisions of manufacturing and their relationship to production systems design, and the detailed process of production systems design and operation are then discussed. These analyses are used to develop the generic model of production systems design entitled DRAMA II (Decision Rules for Analysing Manufacturing Activities). The model contains three main constituent parts: the basic DRAMA model, the extended DRAMA II model showing the imperatives and relationships within the design process, and a benchmark generic approach for the design and analysis of each component in the design process. DRAMA II is primarily intended for use by researchers as an analytical framework of enquiry, but is also seen as having application for manufacturing practitioners.

Third sector organisations and social welfare : a study of the role of social service and charitable organisations in Taiwan

This study is about the role and operation of ‘third sector’ organisations (TSOs) within the Taiwanese social welfare context. TSOs have increased dramatically and become actively involved in social service provision. This phenomenon has not only had significant impact on the development and operation of TSOs in Taiwan but it is also of increasing interest to public policy academics. The latter are especially interested in the implications for the government-third sector relationship. This research examines the reasons why TSOs have been established, why they actively participate in social service provision, and their role and operation within the social welfare context of Taiwan. The study has both quantitative and qualitative data. It sampled ‘social service’ and ‘charitable’ organisations (SSCOs), which are the main type of TSOs in Taiwan, to examine their role, operation and interaction with government. Questionnaires were mailed to collect quantitative data first. After the quantitative data were collected and analysed, semi-structured interviews were undertaken to collect qualitative data. The study found that TSOs in Taiwan exist in a highly institutionalised environment, which is affected by traditional Confucian ideas and contemporary Western ideas such as social justice and civil rights. The rapid growth of TSOs has a strong connection with the desire to fill social service gaps left by government and family. TSOs mainly play the role of service provider rather than that of advocate. They cooperate with government in social service provision and have developed different types of symbiotic relationships with government. A ‘resonance effect’ between government and TSOs was also found as they implement social policy.

Intestinal absorption barriers as modelled by p-glycoprotein and cytochrome p450 a34 in caco2 cells

The passage number and origin of two populations of Caco-2 cells influence their enterocyte-like characteristics. Caco-2 cells of passage number >90 from Novartis pharmaceutical company possess higher levels of expression of alkaline phosphatase and P-glycoprotein and a greater cellular uptake of Gly-1.-Pro than those of passage number <40 from the American Type Tissue Culture collection. High P-gp expressing Caco-2 cells have been developed through stepwise selection of the cells with doxonibicin. This newly-developed cell line (hereafter referred to as Type I) possesses approximately twice as much P-gp protein than non-exposed cells, restricts the transepithelial transport of vincristine in the apical-to-basolateral direction whilst facilitating its transport in the reverse direction and accumulates less vincristine than non-exposed cells. There is no apparent evidence of the co-existence of the multidrug resistance protein (MIT) in Type I cells to account for the above-listed observations. Stopping the exposure for more than 28 days decreases the P-gp protein expression in previously doxorubicin-exposed Type I Caco-2 cells and reduces the magnitude of vincristine transepithelial fluxes in both directions to the levels that are almost similar to those of non-exposed cells. Exposing Caco-2 cells to 0.25 JAM la, 25-dihydroxyvitamin D3 induces their expression of cytochrome P450 3A4 protein to the level that is equivalent to that from isolated human jejunal cells. Under the same treatment, doxorubiein-exposed (Type I) cells metabolise naidazolam poorly and less extensively compared to non-exposed cells, suggesting that there is no such co-regulation of P-gp and CYP3A4 in Caco-2 cells. However, there is evidence which suggests CYP3A metabolises mida_zolam into 1- and 4-hydroxymidazolam, the latter may possibly be a P-gp substrate and is transported extracellularly by P-gp, supporting the hypothesis of P-gp-CYP3A4 synergistic roles in keeping xenobiotics out of the body. Doxoru.bicin-exposed (Type I) cells are less effective in translocating L-proline and glycyl-L-proline across the cell mono layers.

Solid-phase combinatorial chemistry and scintillation proximity assays

The Scintillation Proximity Assay (SPA) is a method that is frequently used to detect and quantify the strength of intermolecular interactions between a biological receptor and ligand molecule in aqueous media. This thesis describes the synthesis of scintillant-tagged-compounds for application in a novel cell-based SPA. A series of 4-functianlised-2,5-diphenyloxazole molecules were synthesised. These 4-functionalised-2,5-diphenyloxazoles were evaluated by Sense Proteomic Ltd. Accordingly, the molecules were evaluated for the ability to scintillate in the presence of ionising radiation. In addition, the molecules were incorporated into liposomal preparations which were subsequently evaluated for the ability to scintillate in the presence of ionising radiation. The optimal liposomal preparation was introduced into the membrane of HeLa cells that were used successfully in a cell-based SPA to detect and quantify the uptake of [14C]methionine. This thesis also describes the synthesis and subsequent polymerisation of novel poly(oxyethylene glycol)-based monomers to form a series of new polymer supports. These Poly(oxyethylene glycol)-polymer (POP) supports were evaluated for the ability to swell and mass-uptake in a variety of solvents, demonstrating that POP-supports exhibit enhanced solvent compatibilities over several commercial resins. The utility of POP-supports in solid-phase synthesis was also demonstrated successfully. The incorporation of (4’-vinyl)-4-benzyl-2,5-diphenyloxazole in varying mole percentage into the monomer composition resulted in the production of chemically functionalised scintillant-containing poly(oxyethylene glycol) polymer (POP-Sc) supports. These materials are compatible with both aqueous and organic solvents and scintillate efficiently in the presence of ionising radiation. The utility of POP-Sc supports in solid-phase synthesis and subsequent in-situ SPA to detect and quantify, in real-time, the kinetic progress of a solid-phase reaction was exemplified successfully.In addition, POP-Sc supports were used successfully both in solid-phase combinatorial synthesis of a peptide nucleic acid (PNA)-library and subsequent screening of this library for the ability to hybridise with DNA, which was labelled with a suitable radio-isotape. This data was used to identify the dependence of the number and position of complimentary codon pairs upon the extent of hybridisation. Finally, a further SPA was used to demonstrate the excellent compatibility of POP-Sc supports for use in the detection and quantification of enzyme assays conducted within the matrix of the POP-Sc support.