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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
61

Epidemiological and ecological approaches to the study of antimicrobial resistance

Mather, Alison Elizabeth January 2011 (has links)
To date, investigation and policy development relating to antimicrobial resistance (AMR) have focused largely on describing patterns of resistance to individual antimicrobials, often from restricted data sources. What this approach fails to accommodate is the complexity of AMR, such as genetic linkage of resistance determinants, which could potentially lead to inaccurate inference. Novel approaches are therefore required to bring new perspectives on the epidemiology of AMR. These studies take an ecological perspective of AMR, examining several key issues: The relative contribution to AMR from animal and human populations; the potential differences between passive and active surveillance of AMR; the associations of age, antimicrobial treatment and a shared environment with AMR diversity; the relationships between AMR phenotype and genotype; and exploring the additional information provided by DNA sequencing data. Novel ecological and epidemiological approaches were developed to examine long-term passive surveillance data of AMR in Salmonella Typhimurium DT104 (DT104) isolates from concurrently sampled and sympatric human and animal populations in Scotland. By examining the diversity and the phenotypic and temporal relatedness of the resistance profiles, the most likely source of resistance was assessed. The conclusions were that whilst ecologically connected, animals and humans have distinguishable DT104 communities, differing in prevalence, linkage, and diversity. Furthermore, the sympatric animal population is unlikely to be the major source of resistance for human DT104. As robust data are critical to any analysis, the potential differences between data collected by different surveillance types were examined. These systems are not generally designed to detect emerging resistances. The diversity of phenotypic AMR from passive and active surveillance data of poultry Salmonella Heidelberg and swine Salmonella Typhimurium var. 5- isolates derived from animals and foods-of-animal origin were contrasted to assess their suitability for detecting emerging resistance patterns. Results indicated that active and passive surveillance approaches were potentially sampling from distinguishable microbiological communities and are therefore complementary, and that passive surveillance is better at detecting rare profiles. The ecological and epidemiological approach was also applied to a different organism, in a different ecosystem. In order to assess the association of age and antimicrobial exposure with AMR diversity, E. coli from cows and calves on seven dairy farms were examined. There were distinguishable populations of resistance phenotypes on the farms, associated with both age and treatment. Multivariable models were developed to examine simultaneously the association of age, treatment, time, and farm with AMR diversity. These results indicated that there may be particular animal husbandry or farm management practices which influence AMR diversity, and which appear to be different for co-habiting young and adult dairy cattle. The majority of AMR data collected by surveillance systems are phenotypic in nature. However, it is often the underlying genotype that is of interest, which until now could only be achieved with the application of molecular methods. A novel latent class Bayesian model was developed to infer the prevalence of various AMR determinants in a population given a sample of phenotypes, which was applied to animal and human DT104 data. Differences were demonstrated in the estimated prevalences of a number of AMR determinants between the two populations, further supporting the previous observations that the epidemiologies of the organism, the resistance determinants, or both, are distinguishable. To obtain a greater resolution with which to compare AMR in different populations, a second-generation sequencing platform was used to obtain DNA sequencing data from select animal and human DT104 isolates. The objectives were to determine the diversity of the bacteria and of the resistance determinants. Whilst analysis of the resistance determinants is ongoing, preliminary results have suggested that the subtypes of DT104 infecting animals and humans are indeed similar. Overall, these studies comprise application of novel methods and frameworks for the analysis of AMR. The implication of these studies is that greater and more explicit thought is needed regarding the design, collection, analysis, and interpretation of AMR data properly to inform policy.
62

Structural and biochemical insights into members of the kinesin and ubiquitin ligase families

Klejnot, Marta January 2013 (has links)
The thesis focuses on characterisation of two different protein families, kinesins and ubiquitin ligases, that are involved in different biological processes. Kinesins constitute a superfamily of microtubule-based motor proteins, fulfilling important cellular functions, ranging from intracellular transport to cell division. They also play a role in primary cilia and Hedgehog signalling. Ubiquitin ligases are enzymes that catalyse the transfer of ubiquitin to the lysine residues of the substrate. Marking protein substrates with ubiquitin alters their functions and fates. With nearly 700 different ubiquitin ligases in humans, they control a vast array of cellular processes. The first part of this thesis summarises results relating to kinesins. Protocols for creation of a panel of kinesin motor domains, a useful tool for anti-mitotic inhibitors specificity testing are presented. Furthermore, biochemical, kinetic and structural features of a poorly described kinesin motor protein - Kif15 are reported. Kif15's motor domain structure is described and compared to Eg5's catalytic core. Moreover, the influence of Eg5 inhibitors on Kif15 ATPase activity is investigated. Scouting for small molecules targeting Kif15 is also performed. Kif15 interaction with microtubules in various nucleotide-bound states is characterised. The possibility of a secondary microtubule binding site in the tail of Kif15 is examined. The binding of Kif15 with partner proteins is also investigated. Additionally the high-resolution structure of the human Kif7 motor domain is presented, providing the first step towards structural characterisation of this Kinesin-4 family member. The second part of this thesis concerns a ubiquitin ligase, Trim28. Trim28 was first reported as a transcription corepressor, working by recruiting proteins that drive the heterochromatin state, whilst its mechanism of action as a ubiquitin ligase remains elusive. Attempts to crystallise and determine the three-dimensional structure of Trim28 are described. Additionally, Trim28 functioning as an E3 ubiquitin ligase, and its interactions with E2s, KRAB domains of various zinc finger proteins and with the Mage-C2 protein are investigated. The results provide the foundation for future studies on Trim28.
63

Identification of night eating behaviour and investigation into its characteristics in an obese population

Cleator, Jacqueline January 2011 (has links)
Background Night Eating Syndrome (NES) was characterised in 2003 as comprising; morning anorexia, evening hyperphagia, night-time awakenings, consumption of high calorie snacks during awakenings and an absence of other eating disorders (ED). Method An identification study was conducted in a hospital–based UK obesity clinic with 81 individuals undertaking a diagnostic interview and completing a proposed screening tool. Full NES (n=7) and partial NES (n=24) individuals were combined into one Night Eating Behaviour (NEB) group (n=31) and compared to all other participants (n=50). NEB characteristics were identified through qualitative thematic analysis of interview data, based on techniques used by Grounded Theorists. NEB individuals (n=28) were compared with matched controls. In a separate prevalence study, night-eating, sleep quality and suspected Obstructive Sleep Apnoea (OSA) were estimated in 103 participants using the Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale and a validated Night Eating Questionnaire. Correlational analysis was also performed. Results In the identification study, full NES was rare (9%). Comparison of the NEB and non-NEB group showed significant differences in mood (p=0.001), work status (p= 0.03), perceived lack of control over eating (p= 0.03) and variability in sleep duration (p<0.01). The study tool successfully identified NEB, but not other ED. Interview analysis identified the compulsive nature of night-eating and chaotic eating patterns. A variety of physical factors affected night-time awakenings. The matched control comparison showed no difference in levels of significant life events, childhood-onset obesity and poor sleep quality. Prevalence study results showed; suspected NES 14.6% (n=15), based on a lower cut score of >25, 3.9% (n=4), based on a higher cut score of >30, poor sleep quality 74% (n= 76) and suspected OSA 32% (n= 33). A strong relationship (r = 0.55, p = < 0.001) between night-eating and poor sleep quality was found, with day-time sleepiness having no influence over this relationship. Conclusion Comparison of the study findings with new NES criteria (2010) shows poor differentiation between NES and morbid obesity. In obese populations, a shift of focus is proposed to an alternative ‘Impaired Sleep Syndrome’ of which night-eaters may be a sub-group, often with severe depression. Night-eaters also exhibit too many features of other ED for this relationship to be ignored.
64

The impact of diabetes on cardiac remodelling after myocardial infarction : potential role of thyroid hormone signalling

Kalofutis, Christos January 2012 (has links)
Diabetes (DM) increases mortality after myocardial infarction and deteriorates post-ischaemic cardiac remodelling. This study investigated possible implications of thyroid hormone (TH) signalling in either reducing or preventing this response. TH signalling has a regulatory role in metabolism, cardiac function, growth and ischaemic stress. Acute myocardial infarction (AMI) was induced in age–match healthy control rats (AMI-C) and in streptozotocin (STZ)-induced type I diabetic (DM) animals (DM+AMI) using 35 mg/kg body weight while sham operated animals served as controls (SHAM). The results show that AMI in tissue hypothyroidism caused significant down-regulation of TH receptors, TRα1 and TRβ1, in the diabetic myocardium without changes in T3, T4 levels in plasma. This response was associated with increased expression of β-MHC and distinct changes in cardiac function and geometry. Ejection fractions (EF%) was decreased in DM-AMI as compared to DM+AMI animals. Systolic and diastolic chamber dimensions were increased without concomitant increase in wall thickness and thus, WTI (the ratio of LVIDd/2*Posterior Wall thickness), an index of wall stress, was significantly elevated. The absence of wall thickening in DM+AMI hearts was associated with changes in stretch-induced kinase hypertrophic signalling p38 MAPK. In contrast, ERK, p-ERK and p-p38 MAPK levels were not changed in DM+AMI as compared to non-infarcted hearts (DM+SHAM). TH administration after AMI prevented hypothyroidism and resulted in decreased β-MHC expression, increased wall thickening and normalized wall stress, while stretch-induced p38 MAPK activation was restored. The results show that diabetes can exacerbates post-ischaemic cardiac remodelling and tissue hypothyroidism and TH treatment can prevent this response and improve cardiac haemodynamics.
65

Behavioural analysis of 6-hydroxydopamine rodent models of Parkinson's disease

Heuer, Andreas January 2012 (has links)
The aims of this thesis were to characterise further lesion-induced impairments in unilateral rodent models of Parkinson’s disease (PD) on a more cognitive level and to investigate the effects of cell replacement therapies on these tests. Chapter 3.1 deals with the effects of dopamine depletion on a lateralised choice reaction time task in the Skinner box as this apparatus is more widely available than the 9-hole boxes on which initial studies have been based. Unilateral near complete lesions of the nigro-striatal pathway induced a stable side bias that was comparable to the lesion-induced deficits that have been reported in the 9-hole box apparatus. Chapter 3.2 reports on the effects of similar lesions on a more spatial reaction time task and the effects of engraftment of dopamine rich tissue in the denervated striatum. The lesions induced a spatial bias that was only marginally improved by the cell transplantation, clearly showing the limitations of ectopic graft placement. Nevertheless, small but significant improvements on that task could be shown as grafted animals performed with higher accuracy and had reduced movement times compared to the lesion only counterparts. Chapter 3.3 explores the lesion-induced deficit in more detail by implementing an error correction rule on the operant task to enforce a change in the animals’ response strategy. The results of this chapter confirmed earlier findings, that the dopamine depletion produced by the lesion gives rise to a strong near hole bias on the contralateral side which did not recover, even with extensive post lesion testing, i.e. the lesion-induced deficit is most likely to be caused by a misrepresentation of response space, rather than caused by a shift in response strategy. The second strand of this thesis focuses on the development of mouse models of similar dopamine-depleting lesions that are typically used in rat models of PD. In Chapter 3.4 the three most common lesion models are compared to each other on an extensive battery of simple motor tests. The aim was both to characterise the behavioural impact of dopamine depletion in different sites, as well as to identify appropriate hand tests, capable of distinguishing lesions greater than 70% depletion. The differences and similarities between lesions were evaluated and correlations between behavioural performance and nigral cell loss were observed. In Chapter 3.5 I developed parameters which allowed application of the lateral choice reaction time task to mouse models of dopamine depletion. Here I demonstrate the effects of two lesions, either to the medial forebrain bundle or the substantia nigra, on the same task conducted in mice. Lesioned mice of the former group displayed a stronger deficit largely because of the larger dopamine depletion. Subsequently, in Chapter 3.6 I characterise the effects of primary fetal tissue grafts on the previously established model and task. Primary fetal tissue was able to ameliorate some of the lesion-induced deficits on an operant choice reaction time task and a series of simple motor screens. The results of both strands of research in the present thesis have implications for the understanding of the cognitive and motor deficits that are induced by the most commonly used lesion model of PD and for the parameters that can be recovered by cell replacement therapies. The primary fetal tissue will serve as a baseline, against which future stem cell based therapies can be measured
66

Assessing the effects of subpopulations on the application of forensic DNA profiling

Clark, Dan January 2013 (has links)
Currently, UK forensic service providers (FSPs) tend to employ three geographically-broad databases when estimating profile frequencies based on a standard SGM Plus® DNA profile. These estimations will typically include correction factors to take into account issues such as substructuring of populations and sampling inefficiencies. It has been shown previously that regional genetic variation within the UK ‘Caucasian’ population is negligible but consideration has to be made for profiles which may originate from an individual of a more genetically isolated population. Samples were collected from Indian, Pakistani and UK (white British) donors; as well as Kalash individuals, a small population from the Khyber Pakhtunkhwa region in the North West of Pakistan. These were profiled using the SGM Plus® and Identifiler® kits and databases for each population were compiled. The greatest pairwise FST was seen between the Kalash and Indian population at 2.9 %. Allele frequency data were collected for each population and each sample’s profile frequency was estimated against all other databases to see whether samples reported a more conservative profile frequency (higher match probability) in their cognate database or in that of another population. A combined database comprising the Indian, Pakistani and previously published Bangladeshi data was also formed and used to calculate the level of correction required to make all samples of a population report a more conservative profile frequency in this combined database as opposed to their cognates. At the standard FST correction of 3 % – the minimum correction used by some FSPs, 94 % of the UK samples reported a more conservative profile frequency in the South Asian database; the lowest proportion that did so from all four populations. The Kalash dataset required the highest correction factor at FST = 12 % to make 100 % of samples report more conservative match probabilities when measured against the combined database. It was established that the current levels of correction applied to profile frequency calculations were more than sufficient; with random match probabilities remaining in the order of less than one in one billion for all samples in all databases with a correction of FST = 5 %. Although significant pairwise FST differences were observed as well as significant differentiation between populations across all SGM Plus® loci, no evidence of substructuring was detected using a program which employs a Bayesian probabilistic clustering approach, STRUCTURE, likely due to an insufficient number of samples and number of loci tested. Marked differences were seen in allele frequencies of the Kalash population, which also exhibited the highest affiliation to their cognate database, at least 80 %, with or without correction. AMOVA analysis also confirmed the greatest variance between groups was seen when the Kalash were kept as a separate entity from the other South Asian populations. Although current UK practice for applying FST correction prior to estimating STR match probabilities seems generous, there will be occasions when an estimation may appear less conservative when based on a broad database. Conversely, in this study, the one in one billion match probability ceiling threshold was not exceeded for any sample being compared to all databases. Therefore, although consideration should be given to a suspect’s reference population prior to frequency estimation, the current correction factors applied should be sufficient in the vast majority of cases. In instances where partial profiles are obtained, this caused little effect on the estimation of geographic origin, compared to full profiles, with the populations used in this study.
67

Regional and national variation in Arabic handwriting

Al-Hadhrami, Ahmed Abdullah Nasser January 2013 (has links)
It has been established in a number of research publications that a careful study of general handwriting features based on class characteristics could indicate either the place or the country where the writer was first taught to write. Using these studies as the basis, this research was carried out explicitly to understand the characteristics of Arabic handwriting. The aim of this study was to determine the presence of any particular features or characteristics that may be common to individuals of a given region or nationality. This was done by obtaining samples of handwriting collected from individuals of four countries including; Jordan, Morocco, Oman and Tunisia, where Jordon and Oman are considered to be Eastern Arab world and Morocco and Tunisia in the Western Arab world. An attempt was made to establish whether it was possible to determine either the region or nationality of the writer of an Arabic passage of text, based on the formation and the style of the handwriting using specific Arabic characters. Different steps were taken towards the identification of the class characteristics of Arabic handwriting in this study starting with the collection of 600 handwriting samples from the participants in four Arabic countries employing; 150 handwriting samples from each. Ten different characters and one word were selected for examination, with more than one form of each character in different positions being identified and the handwriting samples classified accordingly. In total, 221 class characteristics were identified from the samples based on different criteria including the shape, number of strokes, pen movement and starting point. Tests of association using chi-squared on individual characters showed that the p-value is less than 0.001 in every case. Correspondence analysis was used to produce a plot of relative similarities where the different countries appear as discernible, but overlapping groups. ANOSIM showed these groups to be statistically different (R = 0.321 p = 0.0002, 1000 permutations). Tree analysis was used to create a classification system and blind tests were conducted to test the accuracy of the classification system. On the basis of the statistics used, significant differences were found in character forms used by the individuals from the four Arabic countries, suggesting that either region or nationality of the writer may potentially be predicted with a useful degree of accuracy. Though the samples were obtained from only four countries out of a total of 22 Arab countries and only ten characters and one word out of 28 characters were chosen in this study, the results obtained are valuable and useful, particularly to Forensic Document Examiners (FDEs). In turn this could be implemented in practice in a situation where a questioned document containing Arabic text is presented and the suspected author could have come from one of the four considered countries.
68

Characterisation of embryonic ventral mesencephalon grafts in a rat model of Parkinson's disease

Fjodorova, Marija January 2013 (has links)
The work discussed in this thesis adds further knowledge regarding the survival of embryonic dopaminergic grafts, derived from the rat ventral mesencephalon, in the rat model of Parkinson’s disease, in terms of the populations of cells involved, their distribution within the grafts, and how these are affected by the donor age and the host environment in to which they are implanted. The current data further reinforce the notion that harvesting ventral mesencephalic tissue at embryonic day 12 (E12) before the peak of dopamine neurogenesis yields more dopamine cells in the grafts and, more importantly, also yields more nigral A9 type dopamine neurons, which are an important determinant for functional recovery. Following on from this, commitment of dopamine neural precursor cells to the two dopamine neuron phenotypes, and how this is affected by the host environment was investigated, by grafting rat E12 and E14 ventral mesencephalon tissue into different cerebral targets. Brain regions were chosen that receive either the nigral A9 type dopamine, ventral tegmental A10 type dopamine or noradrenaline innervation. The yield of A9 type dopamine neurons was found to be influenced both by the environment within the graft and by the host environment in the transplantation site to a higher extent than the yield of A10 type dopamine neurons. Dopaminergic progenitors procured from rat embryos at E12 were shown to have a greater potential to proliferate post-grafting and differentiate into mature dopamine neurons as compared to embryos at E14. In vivo proliferation of younger precursor cells significantly contributed to the higher yields of the A9 type dopamine neurons in the grafts. If this improved yield of the A9 type dopamine neurons could be reproduced in human trials, fewer human donors might suffice to produce functional grafts in Parkinson’s disease patients.
69

Biomarkers for arthritis : regulation of extracellular transglutaminase activity by non-conventional export

Adamczyk, Magdalena January 2013 (has links)
Transglutaminase 2 (TG2) is an enzyme with a predominant role in cell stress response and tissue repair. Dramatically increased production of this enzyme is associated with early changes in arthritis, and the activity of the protein has been shown to directly contribute to both inflammatory and degenerative arthritis, although through distinct molecular mechanisms. Aberrant TG2 activity during joint disease might lead to protein modifications that are not normally present in extracellular matrix components. Those novel epitopes can possibly serve as a qualitative biomarker besides their potential role in disease pathogenesis. TG2 is released from cells via a non-conventional route, and this mechanism controls its extracellular activity. This pathway is likely to be shared with other proteins undergoing alternative secretion, many of which are potent biological signaling molecules. The aim of this project is to investigate whether non-classical secretion of TG2 is mediated by activation of the ligand-gated ion channel 7 (P2X7R) in analogy to interleukin-1β processing and release. Specifically, we are exploring whether ATP, a P2X7R agonist, which might be released from damaged cells at the sites of injury, triggers active release of TG2 from cells. To test this hypothesis we first employed macrophage and breast cancer cell models, where P2X7R is endogenously expressed, to look for involvement of ATP signaling in TG2 externalization through microvesicle shedding. By establishing HEK293 cells stably expressing P2X7R we show for the first time that introduction of functional P2X7R alone is sufficient to reconstitute rapid non-conventional TG2 export in a cell model. P2X7R activation induced time-dependent release of TG2 but not other cytoplasmic proteins, and this response was blocked by a selective P2X7R inhibitor. TG2 release was dependent on Ca2+ influx triggered by P2X7R activation and might be related to P2X7R-dependent membrane pore formation. These results provide a mechanistic explanation for a link between active TG2 release and inflammatory responses.
70

Studies on oligopeptidase B of Leishmania major

Munday, Jane Claire January 2008 (has links)
Peptidases of Leishmania are acknowledged virulence factors. It is hypothesised that peptidases are crucial for the survival of Leishmania in its hosts and that many could be potential targets for new antileishmanial drugs. As such, the investigation of peptidase activity in live Leishmania promastigotes was proposed as a valuable approach by which to increase knowledge on particular peptidases. In order to complete this investigation, it was decided to use short peptidyl fluorogenic substrates, which only fluoresce once the bond linking the peptide to the fluorescent moiety is cleaved. These allow detection of peptidase activity by quantifying the release of the fluorescent moiety. Detection of peptidase activity in live Leishmania using the fluorogenic substrate Bz-R-AMC proved fruitful, enabling study of the activity of the serine peptidase oligopeptidase B (OPB) in live L. major promastigotes. OPB is a member of the Family S9 peptidases, the prolyl-oligopeptidases, which are taxonomically restricted to plants, bacteria and trypanosomatid flagellates. In African and American trypanosomes, OPB has been shown to have important roles: OPB is a virulence factor in Trypanosoma cruzi, mediating entry into host cells, and OPB is released into the serum by African trypanosomes, where it cleaves host blood factors. In this study, the inhibition profile of L. major OPB has been determined and OPB has been localised to the cytosol, the site of hydrolysis of Bz-R-AMC. Immunoprecipitation of OPB confirmed that OPB was the sole peptidase responsible for the hydrolysis of Bz-R-AMC and anti-OPB antibodies were found to inhibit the hydrolysis of Bz-R-AMC. Inhibitors of OPB could also kill Leishmania promastigotes, suggesting OPB could be a valuable drug target. However, genetic manipulation of OPB was successful, with mutants over-expressing OPB and opb null mutants produced. OPB is thus not essential for the growth of promastigote L. major, though the opb null mutants did have a defect in metacyclogenesis, in survival in macrophages and a reduced ability to induce lesions on the footpads of mice. A role in amastigote differentiation or survival in macrophages was also suggested. OPB is thus likely to be a virulence factor, though not essential, and thus not suitable as a primary drug target. A number of avenues require further investigation, including the need for re-expression of OPB in the opb null mutants to confirm that lack of OPB is indeed responsible for the phenotypic deficiencies of the null mutants. Other important areas requiring attention are investigation of the role of OPB in amastigote differentiation or survival, investigation of the reported release of OPB by promastigotes, and identification of the physiological substrate of OPB.

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