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The global burden of age-related cognitive decline and dementia will continue to rise in tandem with our ageing population. This necessitates the discovery of novel biomarkers and candidate drug targets to combat cognitive dysfunction. Blood proteins are important drug targets, and blood samples can be acquired routinely in clinical settings and epidemiological studies. Whereas hundreds of blood proteins are associated with cognitive ability and dementia, we do not understand whether these associations represent correlation or causation. Genome-wide association studies (GWAS) are required to define variants that are associated with blood protein levels. These variants can proxy for candidate disease-markers and assess their causal associations with health outcomes in analysis methods such as Mendelian randomisation. DNA methylation is an epigenetic mechanism that regulates gene expression and is influenced by genetic and environmental factors. Studying the relationship between DNA methylation and protein levels could reveal whether genetic variation or environmental factors likely mediate associations between blood proteins and disease states. The first aim of this thesis is to conduct GWAS and epigenome-wide association studies (EWAS, using DNA methylation) on plasma levels of 422 unique proteins. Using these data, I apply causal inference approaches to determine whether blood proteins are causally associated with Alzheimer's disease risk. Several strategies have been proposed to estimate biological age by leveraging inter-individual variation in DNA methylation profiles. Epigenetic measures of ageing correlate strongly with chronological age. Recently, a novel epigenetic measure of ageing termed 'DNAm GrimAge' was developed to predict one's risk of mortality. DNAm GrimAge is a composite biomarker that incorporates methylation-based predictors of seven blood protein levels and smoking. The relationship between this biomarker of ageing and cognitive decline or dementia is not known. Therefore, the second aim of this thesis is to examine whether DNAm GrimAge associates with measures of brain health and Alzheimer's disease. To conduct these aims, I utilise data from two cohort studies: the Lothian Birth Cohort 1936 (n ≤ 906, LBC1936) and Generation Scotland (n ≤ 9,537, GS). In Chapters 1-3, I provide an overview of cognitive ageing and dementia. I describe GWAS and EWAS on blood protein levels and the development of DNAm GrimAge. In Chapter 4, I detail the population cohorts and main methodologies that are used in this thesis. In Chapter 5, I conduct GWAS and EWAS on plasma levels of 92 neurology-related proteins (n ≤ 750, LBC1936). I identified 41 independent genetic and 26 epigenetic loci that associate with 33 and 9 proteins, respectively. I showed that an immune-related protein, poliovirus receptor (PVR), is causally associated with Alzheimer's disease risk. In Chapter 6, I use a novel Bayesian framework termed BayesR+ to perform an integrated GWAS/EWAS on plasma levels of 70 inflammation-associated proteins (n = 876, LBC1936). Many GWAS and EWAS use linear models, which examine every measured genetic or epigenetic site in isolation. BayesR+ accounts for intercorrelations among genetic and epigenetic sites and the reciprocal influences of these data types. I estimated the contribution of genetic and epigenetic variation towards inter-individual differences in inflammatory protein levels, considered alone and together. There was no evidence for causal associations between blood inflammatory proteins and the risk of Alzheimer's disease. In Chapter 7, I perform a systematic literature review to identify known blood protein correlates of Alzheimer's disease. I then use BayesR+ to conduct an integrated GWAS and EWAS on plasma levels of 282 Alzheimer's disease-associated proteins (n ≤ 1,064, GS). I observed strong evidence for causal associations between two proteins, TBCA and TREM2, and Alzheimer's disease risk. In Chapter 8, I examine associations between DNAm GrimAge and measures of brain health (n ≤ 709, LBC1936). A higher-than-expected DNAm GrimAge associated with poorer performance on cognitive tasks and neurostructural correlates of dementia at age 73. I observed weak evidence to suggest that DNAm GrimAge assessed at age 70 predicts cognitive decline up to age 79. In Chapter 9, I assess whether DNAm GrimAge and other measures of epigenetic ageing predict the prevalence and incidence of common disease states, including Alzheimer's disease (n ≤ 9,537, GS). Epigenetic ageing measures did not predict the prevalence or incidence of Alzheimer's disease. In Chapter 10, I discuss the major findings from this thesis in light of their limitations. The work presented in this thesis helps to detail the molecular regulation of 422 plasma protein levels and their causal associations with Alzheimer's disease. This work also highlights the performance of DNAm GrimAge in predicting indices of cognitive performance and common disease states. By incorporating genetic, epigenetic and protein data in two large-scale epidemiological studies, my findings inform our understanding of relationships between blood proteins and cognitive ageing and dementia.

Despite Africa accounting for ~20% of the global cattle population, prevalence estimates and related risk factors of bovine tuberculosis (bTB), caused by Mycobacterium bovis, are still poorly quantified in many countries across the continent. Control of bTB in Africa is difficult due to poor monitoring of cattle movements and limited abattoir surveillance. Also M. bovis is zoonotic and risk factors for transmission include living in close contact with cattle and consumption of unpasteurised milk. Cattle keeping is integral to some rural populations in Cameroon and understanding the epidemiology of bTB in cattle populations is important both to bovine and public health. Detection of bTB in cattle is difficult due to variability of immune responses to M. bovis infection. The interferon-γ (IFN-γ) assay maybe useful to estimate bTB prevalence and identify bTB risk factors in Cameroon. However its performance can vary at different stages of bTB pathogenesis and in different cattle populations. Recently Fasciola hepatica co-infections have been reported to suppress IFN-γ responses in M. bovis infected cattle but the potential effect with F. gigantica co-infections on bTB prevalence estimates in Cameroon is unknown. An abattoir study was conducted in Cameroon to assess the performance of the IFN-γ assay. In 2012-13; 2064 slaughtered cattle were sampled from Bamenda abattoir (North West Region; NWR) and Ngaoundere abattoir (Vina Division; VD). Individual animal data was collected from routine meat inspection including identification of bTB and Fasciola pathology. Cattle were also tested for bTB using the IFN-γ assay and an M. bovis antibody ELISA. In the absence of a gold-standard diagnostic, the IFN-γ assay was compared to other diagnostic tests to assess agreement and identify factors that affected performance of the assay. Agreement between IFN-γ assay, TB lesion identification and an M. bovis antibody ELISA was poor-moderate, probably partly related to differences in immune response detected. A presence of Fasciola gigantica also increased the odds of false negative IFN-γ assay results. On further investigation co-infected cattle had increased odds of TB lesions and reduced IFN-γ responses that potentially could lead to ~20% reduction in test sensitivity. In an attempt to take into account the potential impact of F. gigantica, when estimating bTB prevalence, an antibody ELISA was developed to detect the exposure in live cattle. To highlight the awareness of disease in cattle-rearing communities, estimate prevalence and identify risk factors of bTB in cattle populations; two cross-sectional studies were conducted in 2013. A stratified clustered cross-sectional study of pastoral cattle herds, in the NWR and the VD, sampled 1448 pastoral cattle reared by 100 pastoralists. A smaller cross-sectional study sampled 60 dairy cattle from 46 small-holder co-operative dairy farmers. Individual animal data and herd-level data were collected and animals were screened by both the single comparative intradermal skin test (SCITT) and IFN-γ assay. Awareness of zoonotic TB was low yet consumption of raw milk was high in cattle-keeping communities highlighting the need for accurate bTB prevalence estimates. Despite the high awareness of the clinical presentation of bTB, clinical signs identified by pastoral herdsmen were not associated with cattle being bTB positive. The SCITT was used to compare two manufacturers cut offs for the IFN-γ assay, ≥0.05 and ≥0.1, and highlighted that these two diagnostics may detect different populations of bTB positive cattle. Using the IFN-γ assay at ≥0.1, bTB prevalence was highest in dairy cattle (21.67%) and was also present in pastoral cattle in the NWR and VD (11.33% and 6.55% respectively). Importantly, as F. gigantica is endemic in Cameroon and its influence could mean the true prevalence of bTB could be higher. Female pastoral cattle were at lower odds of being IFN-γ assay positive potentially due to immunosuppressive factors had lower odds of disease. Husbandry practices also decreased the odds of being IFN-γ assay positive such as drinking from streams, antelope and contact with herds at grazing. Age increased the odds of pastoral cattle being IFN- assay positive potentially being a confounder to chronicity of bTB and other co-infections may influence IFN-γ responses. Dairy cattle herds had different risk factors for being IFN- positive likely due to differences in husbandry practices. Considering the potential risk to public health of M. bovis this thesis highlights the extent of bTB across two major cattle keeping regions in Cameroon and the public health risk in cattle-rearing communities. Furthermore the relationship between Fasciola co-infection and IFN- responses to M. bovis described has potential implications for bTB diagnosis in cattle populations where the parasite is present across the globe.

In response to DNA damage, cells decrease global rates of protein synthesis to conserve energy and selectively translate mRNAs of proteins involved in the DNA damage response. Doxorubicin is a widely used chemotherapeutic that induces double strand DNA breaks. It might be expected that doxorubicin-induced DNA damage would rapidly inhibit global protein synthesis through the phosphorylation of eIF2α, as has been observed in response to UVB-induced DNA damage. However, in MCF10A cells, a delay of 9 hours was observed between DNA damage recognition and protein synthesis inhibition. Furthermore, eIF2α phosphorylation was not observed until 12 hours, and global protein synthesis inhibition was subsequently shown to be independent of eIF2α phosphorylation status. An alternative regulator of translation initiation is the mTORC1 target protein 4E-BP1. Doxorubicin-induced mTORC1 inhibition preceded eIF2α phosphorylation and correlated with the inhibition of global protein synthesis, suggesting that the DDR signalled through mTOR to regulate protein synthesis. Experiments using p53-/- MCF10A cells suggested that doxorubicin-induced mTORC1 inhibition was mediated by p53 activity, and p53-/- cells were shown to be more sensitive to doxorubicin-induced cell death. Interestingly, doxorubicin-and catalytic-inhibition of mTORC1 activity mediated the phosphorylation of eIF2α in a signalling mechanism that may be dependent on PP6, DNA-PKcs and GCN2 or PERK. Importantly, eIF2α phosphorylation was absent in response to doxorubicin in p53-/- cells, whereas catalytic inhibition of mTORC1 activity enhanced eIF2α phosphorylation. These data suggested a mechanism where p53-mediated mTORC1 inhibition signalled to enhance the phosphorylation of eIF2α.

The standard view of Greek tyranny is that it was a unique phenomenon in the ancient Greek world, representing neither continuity nor a long-lived institution. The turannoi are generally described as illegitimate leaders who seized power with the support of the lower classes, usurping the rule of the aristocrats. This school of thought locates the origins of Greek tyranny in the supposed changes in the economic and social climate around the seventh and sixth centuries B.C. Although the image of the tyrant as a populist leader has come under attack in recent years, there has been no attempt to challenge the theory that tyranny was a new phenomenon in the seventh and sixth centuries. This thesis contends that the turannoi were not a new form of ruler born from the supposed turmoil of this period. In reality, the word turannos came to represent a new way of thinking about an old style of leadership. This thesis shows that the Greek tyrants represented a continuation of the form of leadership practised by the Homeric basileis. As new ideas about law and order were formed in the seventh century, such as limited terms of office and magistrates with divided powers, these basileis began to be seen as a negative force by those engaging with the new political concepts and institutions. This change in attitude caused the traditional basileis to become the polar opposite of what was thought to be good for the polis, and not at all compatible with eunomia. Their apparent irreverence towards dikaiosune was at odds with the political atmosphere of the Archaic and Classical Greek polis. These rulers were not seen as representing continuity or a traditional form of rule, but became abhorrent to those practising the new ways of law and politics, attracting the label turannos.

This study attempts to identify the causal mechanisms linking social inequality and physical (im)mobilities, by way of a case study analysis. Adopting a methodological approach of critical realism, the focus of this study lies not with aggregate analyses of transport behaviour, but with qualitative judgements based on mixed-methods regarding the links between mobility, place, and identity, as they are played out in a deprived (though partially gentrified) neighbourhood. Following an examination of the Labour government's Social Exclusion Unit's work on transport inequalities (Making the Connections, 2003), I will attempt to link current trends in class analysis to the problematic of mobility and inequality, giving particular attention to the Bourdieusian inspired concepts of 'network capital' (Urry, 2007) and 'elective belonging' (Savage et al, 2005). In attempting to relate sociological theory to the level of individual experience, this work tends towards the ideographic, as against the macro analyses of authors such as Bauman, Beck, Castells, and Giddens. To locate this case study site within the broader array of social processes, a careful description of its contextual attributes will be undertaken, focusing especially on the impact of the mobility of capital (and of regional 'uneven development', Massey, 1995), and the restructuring of urban space around modernist planning ideals (Jacobs, 1961). The substantive empirical data presented in two chapters deals with everyday and residential mobilities, respectively. In the first of these chapters I engage with Urry's concept of network capital and, by relating its constituent components to the forms of capital conceived of by Bourdieu, question the independence of this form from other axes of stratification and especially from social class. In the second analysis chapter I thematically explore identity, belonging and residential mobility by reference to perceptions of the locality, discourses around regeneration, residential mobility narratives and residential mobility more specifically in relation to the transition to adulthood. This chapters ends with the assertion of the necessity of a conceptual antonym to Savage et al's 'elective belonging' that recognises the difficulty in achieving such a state for actors occupying more marginal class positions. To conclude the thesis, I will revisit the aims of the thesis and demonstrate how a search for causal mechanisms draws attention to the overwhelmingly structural reasons for the experience of unequal mobilities in a disadvantaged UK inner-city neighbourhood.

Current treatments of cultural heritage as an object of moral concern (whether it be the heritage of mankind or of some particular group of people) have tended to treat it as a means to ensure human wellbeing: either as ‘cultural property’ or ‘cultural patrimony’, suggesting concomitant rights of possession and exclusion, or otherwise as something which, gaining its ethical significance from the roles it plays in people’s lives and the formation of their identities, is the beneficiary at most of indirect moral obligations. In contrast, I argue that cultural heritage, as something whose existence can go well or badly, can itself qualify as a moral patient towards which we may have obligations which need not be accounted for in terms of subsequent benefits to human beings. Drawing inspiration from environmental ethics and suggesting that heritage, like an ecosystem, is a complex network of interrelations which invites a holistic understanding, I develop a framework for thinking about cultural heritage which shows how such a thing can feature in our ethical reflections as intrinsically worthy of respect in spite of its most obvious differences from the ‘natural’ world: the very human origins of cultural heritage and its involvement with human life in all its forms. As part of the development of this framework I consider the epistemic difficulties which arise when for all our holistic sophistication we do find ourselves in the predicament of having to judge the moral worth of some item of heritage, possibly someone else’s heritage and possibly something which we find ourselves disposed to value more because of than despite any mysteries surrounding it. I conclude by offering some tentative illustrations of how such a framework might operate in the practical course of normative moral reasoning about what should be done with items of cultural heritage.

This thesis explores the expansion of British television in the 1950s and 1960s and its relationship to social and cultural change. During this period, television developed into an industry and mass medium and this coincided with a cultural shift from a seemingly consensual society of post-war austerity to a society characterised by fragmentation, individualism and consumerism. By combining a re-examination of existing histories of British television with a discussion of television programmes and sociological theory, this thesis explores the complex relationship between the expansion of television and that social and cultural change. The thesis shows how television represented these changes, and how it presented competing discourses about consumer culture in a range of programmes including action adventure series, pop music and women's programmes. It also demonstrates how television promoted class and cultural conflict in its individual programmes such as situation comedies and dramas, and through juxtaposition of high and low cultural vales, themes and forms in its mixed programme schedule. By looking at issues such as intimacy, performance, authenticity and sociability, the thesis argues that television promoted its own status as an increasingly centralised cultural form. It proposes that television established social categories which became embedded and naturalised over time, and this created the potential to define social experience. The thesis therefore concludes that the examination of the expansion of television in the 1950s and 1960s is of importance for understanding the operation of media power today.

This thesis concerns the automated synthesis of separation processes. A single multi- component stream is to processed to give one or more pure component product streams. A list of units are available for the task and the aim is to find the optimal flowsheet structure in terms of cost. Implicit enumeration (IE) has been used to tackle the synthesis problem. The main advantage of this approach is that IE does not require the development of a superstructure. A disadvantage of using IE is that it is necessary to discretise the values of unit operating conditions in order for there to be a finite search space (Fraga et al., 2000). The user may not have any idea of the effect of the discretisations on the quality of the solution. In addition, the optimal solution may be missed between the discrete values chosen. The purpose of this work is to address these issues. Interval analysis is used to bound the effects of this discretisation. This allows the cost of each particular flowsheet to be bounded based on the level of discretisation used. The technique is demonstrated by bounding the effect of discretisation on the synthesis of distillation flowsheets. The use of runs with progressively finer uniform discretisation lead to the isolation of the optimal structure. This result leads to the development of an adaptive algorithm that changes the discreti sation profile in response to bounding information from downstream in the search. The algorithm operates recursively and isolates the optimal process structure for each stream encountered. This builds up to the isolation of the overall optimal process structure for the feed process stream. The effectiveness and performance of the new algorithm are evalu ated using two very different separation problems. The first is a distillation sequence and the second a separation of a protein from a biological stream.

The management of architects within architectural businesses has been identified as an issue influencing the future behaviour of architectural practices. This work goes on to develop and apply a qualitative model (based on systems theory) which enables deeper research into architects' businesses. The modelling of goals at strategic, management and individual levels in the firm are introduced into a Case Study Series. The results are analysed and presented in the form of a social efficiency map. The thesis explores the modelling of multiple goal- seeking behaviour within firms. The work justifies behaviour at individual level using a fulfilment model (explaining personality as based on a single force toward growth and actualisation). Existing models of business behaviour are used to explain business behaviour at management and strategic levels in the firm. A rigorous selection of firms included in the series of Case Studies is undertaken. This enables a process of contrast comparison and replication. Initially this work builds on research by the RIBA (undertaken in 1993) and the RIBA's findings from their Case Studies of traditional, muitidisciplinary, named, and commercial architectural business. This is the basis for the propositions examined in this research. The research concludes by comparing the results of the Social Efficiency Map by triangulation with questionnaires and a technique of participant as observer (using an vnopportunistic method of sampling) to strengthen the findings. The model proves effective in capturing the 'world view 1 of architects, based on propositions developed from the RIBA study and those emerging from the Case Studies Series. The implications are applied in the wider sense of the construction industry entire. The systems theory model is extended to facilitate discussion. Recommendations are made regarding the wider problem of 'perceptions' by firms in the construction industry and the permeability of these firms towards change introduced into this wider environment described.