'Expanding Horizons': investigating the Glasgow 2014 legacy for young people in the East End of Glasgow

The recent staging of Glasgow 2014 drew universal praise as the ‘Best Games Ever’. Yet the substantial undertaking of hosting the Commonwealth Games (CWG) was sold to the nation as more than just eleven days of sporting spectacle and cultural entertainment. Indeed, the primary strategic justification offered by policymakers and city leaders was the delivery of a bundle of positive and enduring benefits, so-called ‘legacy’. This ubiquitous and amorphous concept has evolved over time to become the central focus of contemporary hosting bids, reflecting a general public policy shift towards using major sporting mega events as a catalyst to generate benefits across economic, environmental and social dimensions, on a scale intended to be truly transformative. At the same time, the academy has drawn attention to the absence of evidence in support of the prevailing legacy rhetoric and raised a number of sociological concerns, not least the socially unequitable distribution of purported benefits. This study investigated how young people living in the core hosting zone related to, and were impacted upon, by the CWG and its associated developments and activities with reference to their socio-spatial horizons, the primary outcome of interest. An ‘ideal world’ Logic Model hypothesised that four mechanisms, identified from official legacy documents and social theories, would alter young people’s subjective readings of the world by virtue of broadening their social networks, extending their spatial boundaries and altering their mind sets. A qualitative methodology facilitated the gathering of situated and contextualised accounts of young people’s attitudes, perceptions, beliefs and behaviours relating to Glasgow 2014. In-depth interviews and focus groups were conducted before and after the Games with 26 young people, aged 14-16 years, at two schools in the East End. This approach was instrumental in privileging the interests of people ‘on the ground’ over those of city-wide and national stakeholders. The findings showed that young people perceived the dominant legacy benefit to be an improved reputation and image for Glasgow and the East End. Primary beneficiaries were identified by them as those with vested business interests e.g. retailers, restaurateurs, and hoteliers, as well as national and local government, with low expectations of personal dividends or ‘trickle down’ benefits. Support for Glasgow 2014 did not necessarily translate into individual engagement with the various cultural and sporting activities leading up to the CWG, including the event itself. The study found that young people who engaged most were those who had the ability to ‘read’ the opportunities available to them and who had the social, cultural and economic capital necessary to grasp them, with the corollary that those who might have gained most were the least likely to have engaged with the CWG. Doubts articulated by research participants about the social sustainability of Glasgow 2014 underscored inherent tensions between the short-lived thrill of the spectacle and the anticipated longevity of its impacts. The headline message is that hosting sporting mega events might not be an effective means of delivering social change. Aspirant host cities should consider more socially equitable alternatives to sporting mega events prior to bidding; and future host cities should endeavour to engage more purposefully with more young people over longer time frames.

The growth prerogative: how does an objective of economic growth influence local planning policy?

This research aimed to explore the privileging of growth and its influence on planning in England. The research examined two contrasting case studies: Middlesbrough Borough Council and Cambridge City Council. The analysis of growth privileging is rooted within a constructionist ontology which argues that planning is about the way in which people construct value relative to the function of land. This perspective enables the research to position growth privileging as a social construction; a particular mental frame for understanding and analyzing place based challenges and an approach which has been increasingly absorbed by the UK planning community. Through interviews with a range of planning actors, the first part of the research examined the state of planning in the current political and economic context and the influence that a privileging of growth has on planning. The second part of the research investigated the merits and feasibility of the capabilities approach as an alternative mental frame for planning, an approach developed through the work of Amartya Sen and Martha Nussbaum. The research results disaggregate the concept of economic growth, based on the responses of interviewees and conclude that it is characterized by homogeneity. Growth is valued, not only because of its economic role, for example, supporting jobs and income but its potential in creating diversity, enriching culture and precipitating transformative change. Pursuing growth as an objective has a range of influences upon planning. In particular, it supports a utilitarian framework for decision-making which values spatial decisions on their ability to support aggregate economic growth. The research demonstrates the feasibility and merits of the capabilities approach as a means with which to better understand the relationship between planning and human flourishing. Based on this analysis, the research proposes that the capabilities approach can provide an alternative ‘mental frame’ for planning which privileges human flourishing as the primary objective or ‘final end’ instead of economic growth.

TRIB2 in normal and malignant hematopoiesis - a transcription factor network

Hematopoiesis is the tightly controlled and complex process in which the entire blood system is formed and maintained by a rare pool of hematopoietic stem cells (HSCs), and its dysregulation results in the formation of leukaemia. TRIB2, a member of the Tribbles family of serine/threonine pseudokinases, has been implicated in a variety of cancers and is a potent murine oncogene that induces acute myeloid leukaemia (AML) in vivo via modulation of the essential myeloid transcription factor CCAAT-enhancer binding protein α (C/EBPα). C/EBPα, which is crucial for myeloid cell differentiation, is commonly dysregulated in a variety of cancers, including AML. Two isoforms of C/EBPα exist - the full-length p42 isoform, and the truncated oncogenic p30 isoform. TRIB2 has been shown to selectively degrade the p42 isoform of C/EBPα and induce p30 expression in AML. In this study, overexpression of the p30 isoform in a bone marrow transplant (BMT) leads to perturbation of myelopoiesis, and in the presence of physiological levels of p42, this oncogene exhibited weak transformative ability. It was also shown by BMT that despite their degradative relationship, expression of C/EBPα was essential for TRIB2 mediated leukaemia. A conditional mouse model was used to demonstrate that oncogenic p30 cooperates with TRIB2 to reduce disease latency, only in the presence of p42. At the molecular level, a ubiquitination assay was used to show that TRIB2 degrades p42 by K48-mediated proteasomal ubiquitination and was unable to ubiquitinate p30. Mutation of a critical lysine residue in the C-terminus of C/EBPα abrogated TRIB2 mediated C/EBPα ubiquitination suggesting that this site, which is frequently mutated in AML, is the site at which TRIB2 mediates its degradative effects. The TRIB2-C/EBPα axis was effectively targeted by proteasome inhibition. AML is a very difficult disease to target therapeutically due to the extensive array of chromosomal translocations and genetic aberrations that contribute to the disease. The cell from which a specific leukaemia arises, or leukaemia initiating cell (LIC), can affect the phenotype and chemotherapeutic response of the resultant disease. The LIC has been elucidated for some common oncogenes but it is unknown for TRIB2. The data presented in this thesis investigate the ability of the oncogene TRIB2 to transform hematopoietic stem and progenitor cells in vitro and in vivo. TRIB2 overexpression conferred in vitro serially replating ability to all stem and progenitor cells studied. Upon transplantation, only TRIB2 overexpressing HSCs and granulocyte/macrophage progenitors (GMPs) resulted in the generation of leukaemia in vivo. TRIB2 induced a mature myeloid leukaemia from the GMP, and a mixed lineage leukaemia from the HSC. As such the role of TRIB2 in steady state hematopoiesis was also explored using a Trib2-/- mouse and it was determined that loss of Trib2 had no effect on lineage distribution in the hematopoietic compartment under steady-state conditions. The process of hematopoiesis is controlled by a host of lineage restricted transcription factors. Recently members of the Nuclear Factor 1 family of transcription factors (NFIA, NFIB, NFIC and NFIX) have been implicated in hematopoiesis. Little is known about the role of NFIX in lineage determination. Here we describe a novel role for NFIX in lineage fate determination. In human and murine datasets the expression of Nfix was shown to decrease as cells differentiated along the lymphoid pathway. NFIX overexpression resulted in enhanced myelopoiesis in vivo and in vitro and a block in B cell development at the pre-pro-B cell stage. Loss of NFIX resulted in disruption of myeloid and lymphoid differentiation in vivo. These effects on stem and progenitor cell fate correlated with changes in the expression levels of key transcription factors involved in hematopoietic differentiation including a 15-fold increase in Cebpa expression in Nfix overexpressing cells. The data presented support a role for NFIX as an important transcription factor influencing hematopoietic lineage specification. The identification of NFIX as a novel transcription factor influencing lineage determination will lead to further study of its role in hematopoiesis, and contribute to a better understanding of the process of differentiation. Elucidating the relationship between TRIB2 and C/EBPα not only impacts on our understanding of the pathophysiology of AML but is also relevant in other cancer types including lung and liver cancer. Thus in summary, the data presented in this thesis provide important insights into key areas which will facilitate the development of future therapeutic approaches in cancer treatment.

TRIB2 in human AML: a biological and clinical investigation

Acute myeloid leukemia (AML) involves the proliferation, abnormal survival and arrest of cells at a very early stage of myeloid cell differentiation. The biological and clinical heterogeneity of this disease complicates treatment and highlights the significance of understanding the underlying causes of AML, which may constitute potential therapeutic targets, as well as offer prognostic information. Tribbles homolog 2 (Trib2) is a potent murine oncogene capable of inducing transplantable AML with complete penetrance. The pathogenicity of Trib2 is attributed to its ability to induce proteasomal degradation of the full length isoform of the transcription factor CCAAT/enhancer-binding protein alpha (C/EBPα p42). The role of TRIB2 in human AML cells, however, has not been systematically investigated or targeted. Across human cancers, TRIB2 oncogenic activity was found to be associated with its elevated expression. In the context of AML, TRIB2 overexpression was suggested to be associated with the large and heterogeneous subset of cytogenetically normal AML patients. Based upon the observation that overexpression of TRIB2 has a role in cellular transformation, the effect of modulating its expression in human AML was examined in a human AML cell line that expresses high levels of TRIB2, U937 cells. Specific suppression of TRIB2 led to impaired cell growth, as a consequence of both an increase in apoptosis and a decrease in cell proliferation. Consistent with these in vitro results, TRIB2 silencing strongly reduced progression of the U937 in vivo xenografts, accompanied by detection of a lower spleen weight when compared with mice transplanted with TRIB2- expressing control cells. Gene expression analysis suggested that TRIB2 modulates apoptosis and cell-cycle sensitivity by influencing the expression of a subset of genes known to have implications on these phenotypes. Furthermore, TRIB2 was found to be expressed in a significant subset of AML patient samples analysed. To investigate whether increased expression of this gene could be afforded prognostic significance, primary AML cells with dichotomized levels of TRIB2 transcripts were evaluated in terms of their xenoengraftment potential, an assay reported to correlate with disease aggressiveness observed in humans. A small cohort of analysed samples with higher TRIB2 expression did not associate with preferential leukaemic cell engraftment in highly immune-deficient mice, hence, not predicting for an adverse prognosis. However, further experiments including a larger cohort of well characterized AML patients would be needed to clarify TRIB2 significance in the diagnostic setting. Collectively, these data support a functional role for TRIB2 in the maintenance of the oncogenic properties of human AML cells and suggest TRIB2 can be considered a rational therapeutic target. Proteasome inhibition has emerged as an attractive target for the development of novel anti-cancer therapies and results from translational research and clinical trials support the idea that proteasome inhibitors should be considered in the treatment of AML. The present study argued that proteasome inhibition would effectively inhibit the function of TRIB2 by abrogating C/EBPα p42 protein degradation and that it would be an effective pharmacological targeting strategy in TRIB2-positive AMLs. Here, a number of cell models expressing high levels of TRIB2 were successfully targeted by treatment with proteasome inhibitors, as demonstrated by multiple measurements that included increased cytotoxicity, inhibition of clonogenic growth and anti-AML activity in vivo. Mechanistically, it was shown that block of the TRIB2 degradative function led to an increase of C/EBPα p42 and that response was specific to the TRIB2-C/EBPα axis. Specificity was addressed by a panel of experiments showing that U937 cells (express detectable levels of endogenous TRIB2 and C/EBPα) treated with the proteasome inhibitor bortezomib (Brtz) displayed a higher cytotoxic response upon TRIB2 overexpression and that ectopic expression of C/EBPα rescued cell death. Additionally, in C/EBPα-negative leukaemia cells, K562 and Kasumi 1, Brtz-induced toxicity was not increased following TRIB2 overexpression supporting the specificity of the compound on the TRIB2-C/EBPα axis. Together these findings provide pre-clinical evidence that TRIB2- expressing AML cells can be pharmacologically targeted with proteasome inhibition due, in part, to blockage of the TRIB2 proteolytic function on C/EBPα p42. A large body of evidence indicates that AML arises through the stepwise acquisition of genetic and epigenetic changes. Mass spectrometry data has identified an interaction between TRIB2 and the epigenetic regulator Protein Arginine Methyltransferase 5 (PRMT5). Following assessment of TRIB2‟s role in AML cell survival and effective targeting of the TRIB2-C/EBPα degradation pathway, a putative TRIB2/PRMT5 cooperation was investigated in order to gain a deeper understanding of the molecular network in which TRIB2 acts as a potent myeloid oncogene. First, a microarray data set was interrogated for PRMT5 expression levels and the primary enzyme responsible for symmetric dimethylation was found to be transcribed at significantly higher levels in AML patients when compared to healthy controls. Next, depletion of PRMT5 in the U937 cell line was shown to reduce the transformative phenotype in the high expressing TRIB2 AML cells, which suggests that PRMT5 and TRIB2 may cooperate to maintain the leukaemogenic potential. Importantly, PRMT5 was identified as a TRIB2-interacting protein by means of a protein tagging approach to purify TRIB2 complexes from 293T cells. These findings trigger further research aimed at understanding the underlying mechanism and the functional significance of this interplay. In summary, the present study provides experimental evidence that TRIB2 has an important oncogenic role in human AML maintenance and, importantly in such a molecularly heterogeneous disease, provides the rational basis to consider proteasome inhibition as an effective targeting strategy for AML patients with high TRIB2 expression. Finally, the identification of PRMT5 as a TRIB2-interacting protein opens a new level of regulation to consider in AML. This work may contribute to our further understanding and therapeutic strategies in acute leukaemias.

Beyond orientalism: 'The Stranger' and 'Colonial Cosmopolitanism' in the romantic period novel

Going beyond Orientalism in its examination of novels dealing with British colonisation in the West, as well as the East Indies, the postcolonial frame of my thesis develops recent theorisations of the Romantic ‘stranger’. Analysing a range of novels from the much anthologised Mansfield Park (1814), to less well-known narratives such as John Thelwall’s The Daughter of Adoption (1801) and Sir Walter Scott’s Saint Ronan’s Well (1823), my thesis seeks to account for a model of ‘colonial cosmopolitanism’ within fiction of the period. Considering the cosmopolitan dimensions of the transferential rhetoric of slavery, my thesis explores the ways in which, Jane Austen, Amelia Opie and Maria Edgeworth consider the position of women in domestic society through a West Indian frame. Demonstrating the need for reform both at home and abroad, such novels are representative of a fledgling cosmopolitanism that is often overlooked in current criticism. In seeking to account for ‘colonial cosmopolitanism’ as a new model for reading fiction composed during the Romantic period, my thesis attempts to add further nuance to current understandings of sympathetic exchange during the process of British colonisation. In chapters four and five I will develop my analysis of novels dealing with colonial expansion in the Caribbean to consider novels which deal with the Indian subcontinent. Although stopping short of questioning colonial expansion, discourses of ‘colonial cosmopolitanism’, as my thesis demonstrates, provided a foundation for humanitarian and cultural engagement which was mutually transformative for both the coloniser and the colonised.

A practical MEMS gravimeter

The ability to measure tiny variations in the local gravitational acceleration allows – amongst other applications – the detection of hidden hydrocarbon reserves, magma build-up before volcanic eruptions, and subterranean tunnels. Several technologies are available that achieve the sensitivities required (tens of μGal/√Hz), and stabilities required (periods of days to weeks) for such applications: free-fall gravimeters, spring-based gravimeters, superconducting gravimeters, and atom interferometers. All of these devices can observe the Earth tides; the elastic deformation of the Earth’s crust as a result of tidal forces. This is a universally predictable gravitational signal that requires both high sensitivity and high stability over timescales of several days to measure. All present gravimeters, however, have limitations of excessive cost (£70 k) and high mass (<8 kg). In this thesis, the building of a microelectromechanical system (MEMS) gravimeter with a sensitivity of 40 μGal/√Hz in a package size of only a few cubic centimetres is discussed. MEMS accelerometers – found in most smart phones – can be mass-produced remarkably cheaply, but most are not sensitive enough, and none have been stable enough to be called a ‘gravimeter’. The remarkable stability and sensitivity of the device is demonstrated with a measurement of the Earth tides. Such a measurement has never been undertaken with a MEMS device, and proves the long term stability of the instrument compared to any other MEMS device, making it the first MEMS accelerometer that can be classed as a gravimeter. This heralds a transformative step in MEMS accelerometer technology. Due to their small size and low cost, MEMS gravimeters could create a new paradigm in gravity mapping: exploration surveys could be carried out with drones instead of low-flying aircraft; they could be used for distributed land surveys in exploration settings, for the monitoring of volcanoes; or built into multi-pixel density contrast imaging arrays.

Re-imagining the theology of human sexuality in the Methodist Church: the use of narrative in theological methodology

This thesis proposes the development of a narrative methodology in the British Methodist Church. Such a methodology embraces and communicates both felt experience and critical theological thinking, thus producing and presenting a theology that might have a constructive transformative impact on wider society. In chapter one I explore the ways in which the Church speaks in public, identify some of the challenges it faces, and consider four models of engagement. If the Church is to engage in public discourses then I argue that its words need to be relevant and connect with people’s experiences. To ground the thinking I focus on the context of the British Methodist Church and explore how the Church engages in theological reflection through the lens of its thinking on issues of human sexuality. Chapter two reviews how theological reflection is undertaken in the British Methodist Church. I describe how the Methodist Quadrilateral of Scripture, tradition, reason and experience remains a foundational framework for theological reflection within the Methodist Church and consider the impact of institutional processes and the ways in which the Methodist people actually engage with theological thinking. The third and fourth chapters focus on how the British Methodist Church has produced its theology of human sexuality, giving particular attention to the use of personal and sexual stories in this process. I find that whilst there has been a desire to listen to the stories of the Methodist people, there has not been a corresponding interrogation or analysis of their stories so as to enable robust and constructive theological reflection on these experiences. Using resources from Foucauldian approaches to discourse analysis, I critique key statements and the processes involved in their production, offering an analysis of this body of theological thinking and indicating where possibilities for alternative ways of thinking and acting arise. The proposed methodology draws upon resources from social science methodologies, and in chapter five I look at the use of personal experience and relevant strategies of inquiry that prompt reflection on the hermeneutical process and employ narrative approaches in undertaking, analysing and presenting research. The exploration shows that qualitative research methodologies offer resources and methods of inquiry that could help the Church to engage with personal stories in its theological thinking in a robust, interrogative and imaginative way. In chapter six an examination of story and narrative is undertaken, to show how they have been understood as ways of knowing and how they relate to theological inquiry. Whilst acknowledging some of the limitations of narrative, I indicate how it offers constructive possibilities for theological reflection and could be a means for the British Methodist Church to engage in public discourse. This is explored further in chapter seven, which looks in more detail at how the British Methodist Church has used narrative in its theological thinking, and outlines areas requiring further attention in order for a narrative theological methodology to be developed, namely: attention to the question ‘whose experience?’; investigation of issues of power and the dynamics involved in the process of the production of theological thought; how personal stories and experiences are interrogated and how narrative is constructed; and how narrative might be employed within the Methodist Quadrilateral. The final chapter considers the advantages and limitations of such an approach, whether the development of such a method is possible in the Methodist Church today and its potential for helping the Church to engage in public discourse more effectively. I argue that this methodology can provoke new theological insights and enable new ways of being in the world