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Despite the accepted importance of sportspersonship, behaviour contrary to good sportspersonship is regularly observed in sport (Shields, Bredemeier, LaVoi, and Power, 2005). It is surprising therefore, that since the development of a multidimensional definition of sportspersonship in in mid-1990s (Vallerand, Deshaies, Cuerrier, Briere, and Pelletier, 1996; Vallerand, Briere, Blanchard, & Provencher, 1997), research into the subject has stalled somewhat. The purpose of this thesis was to reignite this avenue of research by exploring an existing model, and developing and presenting a superseding model. After a critical analysis of the existing measures of sportspersonship, the compliant and principled sportspersonship scale was developed and validated in a host of studies. Exploratory factor analysis presented an initial model of sportspersonship. This was examined using confirmatory factor analysis and exploratory structural equation modelling. A five-factor, 24-item measure of sportspersonship was presented consisting of (a) compliance towards rules, (b) compliance towards officials, (c) legitimacy of injurious acts, (d) approach towards opponent, and (e) principled game perspective. Studies in the thesis positively relate sportspersonship with moral behaviour, task goal orientation, empathy, agreeableness, and conscientiousness. It is negatively associated with antisocial behaviour and Machiavellianism. These studies support the construct validity of the scale and provide greater theoretical understanding of sportspersonship. Criterion validity is supported through two experimental studies that found that sportspersonship positively predicted prosocial and negatively predicted cheating. Finally, recommendations for enhancing sportspersonship are offered. Overall, the thesis redefines sportspersonship, presents a new multidimensional measure of sportspersonship and evidence of its validity, explores the relationship of sportspersonship to other psychological concepts, and provides a template for assessing and developing measurement scales.

The purpose of this study was to investigate the professional journey from industry practitioner to higher education academic. The research 'mapped' ten new academics' engagement within the institutional and subject team community throughout their first full teaching year within a higher education institute. A comprehensive literature review was undertaken which initially drew on several theoretical perspectives, such as transitions and socialisation, communities of practice and identity formation. These theoretical positions originated from a mini-focus group. The coding from this initial study together with the reflective thoughts of my own first year in academia led me to read certain topic areas. The literature was further developed throughout the course of the study with the data challenging some of the notions that arose from the initial literature sources. Subsequently new literature was identified which supported the data analysis and emergent themes. The study focussed on the lived experiences of new academics through the use of a narrative methodology which acknowledged that lived experiences are socially constructed. Ten new academics were interviewed at four key stages throughout their first full teaching year. The interviews were transcribed and coded, which led to the development of emergent themes. The key themes were scrutinised through writing narrative chronologies for each of the academics. The narrative chronologies laid the foundation for the development of the conceptual model and research findings. From the research findings a new academic progresses through what can be described as three key overlapping phases (The Reciprocal Phase; The Fragile Phase and The Engaged Phase) within the academic milieu. Within these phases the new academic is seeking to establish identity and legitimacy within the boundaries of the academic communities to which they initially belong. Fundamental throughout these phases is the relationship the new academic has with established academics, who act as gatekeepers to academic practice and communities. The research also finds that institutional policies and practices for new academic entry are found to be inadequate and in light of these key findings a number of changes in professional practice are proposed.

An endo-prosthetic replacement (EPR) has been developed that can be lengthened under control from outside the body. This EPR is for use with child bone tumour cases and is to be surgically implanted to replace a section of bone, usually including a joint, which has been resected as part of the treatment for a bone tumour occurring in one of the long bones of a limb. The EPR includes an extendible module that can be adapted for individual patients by the addition of alternative types of artificial joint to suit various tumour sites. The extendible module may be lengthened at frequent intervals during the child's growth years to maintain limb length symmetry. The non-invasive method of lengthening is considered to be a marked improvement on current methods that require a surgical operation each time an extendible EPR requires to be lengthened. Placing the limb into a rotating magnetic field actuates extension. This field acts on a small magnet sealed within the extendible module of the EPR and induced rotation of this magnet drives reduction gearing that turns a power screw to extend telescopic sections. The extension force is sufficient to overcome the expected resistance of body tissues and the extension may be in sufficiently small increments to avoid pain or excessive joint stiffness. Extension can be reversed if necessary. This study considers alternative extension methods and details the reasons for the final selection of the magnetic drive. The study then covers the detailed design of the various elements of the system including a compact and robust gearing mechanism and the equipment that generates the rotating magnetic field. The complete system has been constructed in prototype form and the study is concluded with tests demonstrating that the magnetic drive is capable of reliably extending the telescopic sections of the EPR against simulated in-vivo loading.

The reported incidences of shallow failures on the slopes of highway earthworks have increased in recent years. This Thesis includes a study of the extent of this problem, the likely factors contributing to failure, and presents the results of empirical design and the analysis of the likely mechanism of failure. A survey was conducted, covering a total length of 570km of selected lengths of motorway in England and Wales, which included the principal geologies encountered on the British motorway system, in particular, areas where over-consolidated clays predominate. From the survey, the basic factors that have contributed to shallow failures on the side slopes of embankments and cuttings can be deduced, and attempts are made to quantify any long-term problems. The results show a high incidence of failure associated with the major influences of geology, age of earthworks and geometry of slope, with many more failures occurring on embankments than on cuttings. The slope angles recommended are empirically derived and can be used both in the design of new earthwork side slopes and to identify slopes at risk of failure in existing earthworks. An estimate is made of the extent of failures in the future which suggests that three times as many slopes are likely to fail than have failed so far. To study the mechanisms of failure and the behaviour of over- consolidated clays at extremely low effective stresses, an analytical method is developed which includes a detailed study of non-linear failure envelopes and the fitting of the most representative curve to peak strength data. Also a new rigorous slope stability analysis method is developed which incorporates this type of failure envelope. Back-analyses are conducted for several embankment slopes from which samples have been tested in the laboratory. Results indicate that the critical state strength rather than the peak strength governs the formation of shallow failures.

This dissertation examines the significance of America’s interactions with stateless actors. It argues that it was groups such as the Muslim Brotherhood, Palestine’s refugees, and ethnic minorities, not the U.S. and Soviet governments, nor the state governments of the region, which dictated how the Cold War unfolded in the Middle East. These groups transformed the policy decisions, strategies, and alliances of both native regimes and the superpowers. Traditionally, historians have looked at the global politics of the Cold War through the lens of state-to-state relations. How have state governments interacted with each other and how did this influence the strategies and alliances of the superpowers? However, this work challenges state-centric models and points to new factors in the history of the United States and the world. Furthermore, much of the literature on groups such as Palestinian refugees and ethnic minorities has characterized them as victims, or actors without agency. Far from victims, this study contends that the Muslim Brotherhood, Palestine’s refugees, and minority groups such as the Armenians and Kurds defined the history of the period and, in key ways, were the primary agents of change. Not only does such research demonstrate the significance of non-state actors with regards to the Cold War, it also highlights the limits of postcolonialism. The non-state groups of this study did not fit into the nation-state system that developed in the Middle East after World War II. While these actors fit within imperial modes of power, the transition from Empire to nation-state left them stateless. As a result, they contested the nation-state system that came into being in the Middle East in the late 1940s and 1950s.

When France began colonizing the North African country of Algeria in 1830, it claimed the Mediterranean as its internal sea and Algeria as a natural extension of France. French propagandists revived Napoleon’s ambition, dating back to his invasion of Egypt in 1798, to transform this notoriously hostile sea into a domesticated “French Lake.” Steamships made this ambition possible; whereas sailing ships had taken three weeks to cross, steamships could make the trip in twenty-four hours. State officials, elite settlers, and businessmen who claimed Algeria as an extension of France literally had to reconfigure the Mediterranean as a French space, bordered by French territory on its northern and southern shores. Steamships played a critical role in shaping modern French imperialism and the Mediterranean. Elites such as state officials, European settlers of Algeria, and steamship companies used steamships as tangible evidence of French mastery of both sea and colony. Algeria’s most prominent shipping company, the Compagnie Generale Transatlantique (French Line), operated an extensive Algerian network from Marseille. The French Line’s ships became “mobile colonies” while evocative advertising shaped perceptions of a French Lake in the Mediterranean. However, the French Line’s commercial preeminence led Algeria’s European settlers to protest virulently against the company, ultimately winning important concessions from the French Line by the 1930s.

This thesis explores how Hong Kong (HK) Christians conceptualise (1) democracy, (2) rights, and (3) faith and civic identity in light of protest movements from 2013 onwards. This thesis identifies two broad categories: pro-establishment Christians (PEC) and pro-democracy Christians (PDC), who generally see each other as incompetent and perhaps lacking in reason. Through an analysis of ethnographic field observations, qualitative primary and secondary interviews, and archival materials from selected published HK theologians and pastors, this thesis suggests a potential first step for HK Christian communities to understand each other on their ideas of public engagement, grounded in language informed by their faith. This thesis proposes using a tool, such as Jens Zimmermann's incarnational humanism, to enable HK Christians to better grant personhood and rationality to those who disagree. This thesis features the lived theology of average, non-clerical HK Christians, making their voices prominent in this research. After summarising HK Christians' interactions with social movements between 1966 and 2016 (Chapter 2), this thesis analyses the theology of representative PEC, Daniel Ng and Paul Kwong, and representative PDC, John Chan and Lap-yan Kung, to set the stage for later sections (Chapter 3). This thesis then analyses field observations and qualitative data with the aim of studying HK Christians' use of democracy, rights, and civic identity, compared with HK Christians' (lack of) use of theological concepts (Chapter 4). Finally, this thesis introduces incarnational humanism, a possible framework for HK Christians to understand 'the other' (Chapter 5). HK Christians wrestle with ideas of liberal democracy, decoloniality, and authoritarianism, which are issues of increasing global importance. This research, utilising tools from theological ethics, social anthropology, and area studies, intends to stimulate further discussions on these issues with those outside of HK.

Women are born with a non-renewable ovarian reserve, which is depleted throughout reproductive life. When this reserve is exhausted, they experience menopause and cease ovulating. Importantly, menopause timing is highly variable and can impact health outcomes in later life. One in 100 women experience menopause before the age of 40. As natural fertility begins to decline 10 years prior to menopause, the age of menopause impacts reproductive options for many women, leading to increased demand for fertility treatments, which have low success rate. This is especially important as more women delay childbearing. Endocrine and imaging tests used in the clinical setting only record changes in ovarian function that have already taken place, thus disabling early prediction and timely identification of women with reduced reproductive lifespan. Human genetic studies have attempted to overcome this problem by identifying genetic markers associated with menopause timing and thus providing substantial insight into the biological mechanisms governing ovarian ageing. However, previous approaches have been largely restricted to assessing common genetic variation, leaving many aspects of the trait biology unexplored. This dissertation describes five distinct projects that advance our understanding of the genetic determinants of female reproductive ageing by employing state-of-art genomic and proteomic technologies with robust functional models. Chapter 3 uses whole exome sequence data to identify rare protein-coding variants associated with menopause timing in ~120K women in the UK Biobank (UKBB), and implicates five novel ANM genes with effect sizes up to ~5 times larger than previously discovered for common variants. Notably, heterozygous loss of ZNF518A shortens reproductive lifespan by delaying puberty timing in girls and reducing ANM by nearly 6 years in carriers, an effect larger than any variation currently tested in clinical genetics for premature ovarian ageing. Furthermore, I provide evidence that ZNF518A is a master transcriptional regulator of ovarian development and establishment of the ovarian reserve in foetal life, thus highlighting novel mechanisms involved in ANM aetiology. I also identify a new cancer predisposition gene, SAMHD1, which has a comparable effect size in women and men to well-established genes such as CHEK2, further reinforcing the link between cancer and reproductive ageing. Finally, I show that mothers with genetic susceptibility to earlier ovarian ageing have a higher rate of de novo mutations in their offspring. This provides direct evidence that female germline mutation rate is heritable and highlights a mechanism for maternal effects on offspring health. Chapter 4 extends the exome sequence analysis to an extreme form of early menopause, i.e. POI, which is often considered a monogenic disorder, with pathogenic mutations reported in ~100 genes. However, such reports are based 5 on small numbers of individuals without independent replication, or/and no functional validation. I systematically evaluate the penetrance of these reported genes in ~120K UKBB women, 2,231 of whom reported ANM before age 40. In this largest study of POI to date, I find limited evidence to support any previously reported autosomal dominant gene. For nearly all these genes I could rule out even modest penetrance, with 97.8% of all identified protein truncating variants found in reproductively healthy women with ANM over 40. In addition, I demonstrate novel haploinsufficiency effects in studied POI genes, including TWNK and SOHLH2. Collectively my results suggest that most POI cases are likely oligogenic or polygenic in nature, which has major implications for future clinical genetic testing and counselling. Chapter 5 presents the first proteogenomic study for the ANM targeting 4,775 distinct proteins measured from plasma samples of 10,713 European ancestry individuals in the Fenland study. Although this analysis did not identify robust protein candidates associated with ANM, it demonstrates the potential of such approaches to discover new biomarkers. Chapter 6 presents the largest genomic meta-analysis for age at menarche on ~566,000 women of European ancestry and 696 genomic loci that contribute to regulation of menarche timing. I use this data to explore biological mechanisms and overlap between genetic architectures of reproductive health outcomes. I provide the first evidence on the enrichment of DDR mechanisms for menarche timing, indicating the involvement of DDR in regulation of both extremes of reproductive lifespan, i.e. menarche and menopause. In addition, I report first gene candidates that I speculate may act via oocyte-specific mechanisms to modify reproductive longevity. I also highlight DDR and other novel mechanisms, including ribosome biogenesis, which impact multiple reproductive health outcomes, such as polycystic ovarian syndrome (PCOS), twinning and number of children (NEB). Finally, I demonstrate the first population genomic evidence on the role of DDR related mechanisms in various anthropometric, metabolic and reproductive health outcomes, indicating that DDR could act as a marker of health outcomes beyond cancer. Combining human genomic evidence with cutting edge CRISPR technology and the In vitro gametogenesis system, in Chapter 7 I investigate the role of PARP-1 in proliferation of primordial germ cells during the establishment of the ovarian reserve. I demonstrate suggestive evidence on the role of PARP-1 in decreasing ANM in women and, paradoxically, that deletion of PARP-1 increases the efficiency of primordial germ cell production in vitro. I speculate that, despite the initial increase in primordial germ cells in the PARP-1 knockout, the quality of these cells could be compromised, thus ultimately limiting the functional ovarian pool. Collectively, these findings provide significant insights into the biological processes of reproductive ageing in women and have the potential to guide future experimental work aimed towards identification of new therapies for enhancing reproductive function and preserving fertility in women, as well as designing intervention strategies to prevent or diminish menopause-related health outcomes.

Sex chromosome mosaicism, including male mosaic loss of chromosome Y (LOY) and female mosaic loss of chromosome X (LOX), is the most common form of clonal haematopoiesis (CH) that can be defined as the age-related clonal expansion of blood cells with somatic mutations. With the decreased cost of sequencing, the development of new bioinformatics methods and the emergence of large cohorts with both genotype and phenotype data, there has been much progress in the detection, causes and consequences of sex chromosome mosaicism especially LOY. On the contrary, the studies of LOX are still very limited. The most recent genome-wide association study (GWAS) to investigate the genetic determinants of LOY in 205,011 males identified 156 independent signals and highlighted a key role for genes involved in cell-cycle regulation and DNA damage response. Population studies typically determine LOY using genotype intensities derived from genotype array data, the accuracy of which varies by the number of Y chromosome probes on the array and are technically noisy. Inaccurate estimation of LOY reduces the power to identify genetic and phenotypic associations with LOY. To overcome these constraints, I developed a robust estimator of LOY , which was derived from several orthogonal approaches using both whole exome sequence and genotype array data. The same method was also implemented for LOX. In chapter 2, in genetic data derived from 205,604 UK Biobank males and 243,765 females, the new method improved the accuracy of LOY/LOX estimation as measured by the strength of association between LOY/LOX and age, smoking status, and polygenic risk of LOY/LOX derived from previous GWAS. In chapter 3, I then used this revised and validated LOY instrument to conduct a new GWAS of LOY status in the UK Biobank. Beyond the previously identified 156 signals, I identified 22 novel LOY-associated loci. I leveraged the shared genetic architecture between LOY and other related traits to improve the power to identify variants associated with the risk of myeloproliferative neoplasm (MPN). Based on available MPN GWAS summary statistics, I identified 13 novel loci reaching genome-wide significance, including locus near PARP1, which encodes an established target of cancer therapy. The method used to detect somatic LOY/LOX can also be used to identify congenital sex chromosome abnormalities. In chapter 4, the detection method and characterisation of male sex chromosome abnormalities were reported, as a similar study on female sex chromosome abnormalities in UK Biobank had already been published. The whole exome sequence also provided the chance to explore the effect of rare non-synonymous variants, which are rarely captured by GWAS arrays. In chapter 5, the first exome-wide association study (ExWAS) for LOY was conducted on over 80,000 men from UK Biobank. As well as CHEK2, which had been identified on a previous GWAS on LOY, a novel gene, GIGYF1, was identified, in which loss-of-function variants increased the risk of LOY and Type 2 diabetes (T2D) by 6-fold. This finding illuminated the potential link between LOY and metabolism. In chapter 6, the first ExWAS of LOX and an extended ExWAS of LOY were performed on over 450,000 samples from UK Biobank. For LOY, the power increase was observed for the two identified genes, CHEK2 and GIGYF1. In addition, loss of function variants in three clonal haematopoiesis of indeterminate potential (CHIP) genes, DNMT3A, TET2 and ASXL1, were negatively associated with LOY. For LOX, rare damaging variants in FBXO10 were identified to increase the risk of LOX. In summary, this thesis shows that the accuracy of estimating LOY/LOX was improved by combining multiple approaches using both GWAS array and whole exome sequence data. Using both GWAS and ExWAS approaches, the thesis further improved the understanding of the genetic causes of sex chromosome mosaicism. This innovative approach improved the power to detect novel mechanisms that regulate clonal mosaicism in blood and can be used to enhance the identification of novel genes associated with the risk of related cancers.

At this time calcium concentrations of lakes within the boreal region of the world and particularly within Canadian Shield lakes across northern and central Ontario are declining. The base cation Ca2+ is important in activating olfactory neurons in many vertebrates and low environmental Ca2+ has been found to disrupt olfaction. In this study we investigated the effects of calcium decline on the olfactory-mediated behavioural responses of pumpkinseed sunfish (Lepomis gibbosus). In separate field experiments, we exposed juvenile sunfish to conspecific injury-released alarm cue, and food cue in both Plastic Lake and Blue Chalk Lake. We then tested adult sunfish response to juvenile conspecific injury-released alarm cue, and visual stimuli. All of the experiments conducted at Plastic Lake were also repeated with Ca2+ concentrations increased to match Blue Chalk Lake. It has been demonstrated that under low Ca2+ (~ 1 mg/L), response to juvenile conspecific injury-released alarm cue was impaired. In response to food cue there was no significant attraction at Plastic Lake under low or elevated Ca2+ concentrations, there was also no significant attraction under the Ca2+ concentration tested at Blue Chalk Lake. Additionally, after examining adult responses to chemical and visual cues they showed no change in response to alarm cue under any of the Ca2+conditions tested at both Plastic and Blue Chalk Lake. Adults only showed a visual preference in the low Ca2+ concentration tested at Plastic Lake. Our results indicate that calcium decline negatively impacts the olfactory-mediated anti-predator responses of pumpkinseed sunfish. Interruptions in olfactory-mediated behaviour may have major ramifications on aquatic community structure and ecosystem productivity.

The passage of cosmic-ray muons through matter is dominated by the Coulomb interaction with electrons and atomic nuclei. The muons interaction with electrons leads to continuous energy loss and stopping through the process of ionization. The muon's interaction with nuclei leads to angular diffusion. If a muon stops in matter, other processes unfold, as discussed in more detail below. These interactions provide the basis for advanced applications of cosmic-ray muon radiography discussed here, specifically: 1) imaging a nuclear reactor with near horizontal muons, and 2) identifying materials through the analysis of radiation lengths weighted by density and secondary signals that are induced by cosmic-ray muon trajectories. We have imaged a nuclear reactor, type AGN-201m, at the University of New Mexico, using data measured with a particle tracker built from a set of sealed drift tubes, the Mini Muon Tracker (MMT). Geant4 simulations were compared to the data for verification and validation. In both the data and simulation, we can identify regions of interest in the reactor including the core, moderator, and shield. This study reinforces our claims for using muon tomography to image reactors following an accident. Warhead and special nuclear materials (SNM) imaging is an important thrust for treaty verification and national security purposes. The differentiation of SNM from other materials, such as iron and aluminum, is useful for these applications. Several techniques were developed for material identification using cosmic-ray muons. These techniques include: 1) identifying the radiation length weighted by density of an object and 2) measuring the signals that can indicate the presence of fission and chain reactions. By combining the radiographic images created by tracking muons through a target plane with the additional fission neutron and gamma signature, we are able to locate regions that are fissionable from a single side. The following materials were imaged with this technique: aluminum, concrete, steel, lead, and uranium. Provided that there is sufficient mass, U-235 could be differentiated from U-238 through muon induced fission.

Both the Cognitive-Motivational-Relational (CMR) Theory of Emotions and the Broaden-and-Build (BaB) Theory of Emotions are seminal in the domain of psychology. Despite the widespread relevance of their combined core ingredients (that is, stress appraisals, emotions, and coping) to the field of sport psychology, there remain comprehensive gaps in their application to sporting populations, particularly in regards to psychological, neuroendocrine, and athlete performance response. Therefore, the contribution of this thesis was to investigate stress appraisals and emotions in relation to their impact upon psychophysiology and athletic performance through use of five interrelated studies. The CMR theory was examined through cross-sectional and laboratory research, whilst the BaB theory was tested via cross-sectional, longitudinal, and laboratory explorations. Regarding CMR theory, stress appraisals were found to be aligned with both subjective and objective measures of performance, as well as possessing a causal psychophysiological impact within athletes. The temporal orientation of stress appraisals may elicit distinct psychological, neuroendocrine, and performance profiles. Further, in relation to BaB theory, pleasant emotions may have short- and long-term performance and psychological benefits, including 'broadening' one's attention to facilitative coping strategies, 'building' enduring coping resources, and 'undoing' psychological costs incurred from previous unpleasant emotional experiences. Cross-study evidence for the existence of physiological 'success stress' was also discovered. Loss stress appraisals and unpleasant emotions may elicit a performance benefit in some athletes but are also linked with psychophysiological stress. Implications for athletes and their stakeholders, as well as future research recommendations are offered. This thesis represents the first causal examinations of both past-oriented stress appraisals and BaB theory within athletes and can be viewed as a novel contribution to the extant sport psychological literature.

Events in early life have consistently been associated with health outcomes in later life. The ‘developmental origins’ theory first hypothesised that adverse conditions in-utero can lead to physiological adaptations in the developing foetus which have long lasting influences on health. This concept has been extended to early childhood and adolescence, whereby exposures during critical periods of development can impact health throughout the life course of an individual. In particular, a secular trend for a decreasing age of puberty onset has been linked to the global increases in prevalence of cardio-metabolic diseases and cancer. It has been suggested that childhood obesity and lifetime sex hormone exposure may act as key mediating factors in this relationship. As the prevalence of obesity continues to rise globally and consequent comorbidities place an increasing burden on healthcare systems, understanding the mechanisms that link early life events to later life health have become of increasing importance. While environmental exposures are often cited as being highly influential on growth and development, the role of genetics has become gradually more apparent in recent years. This has been aided by the availability of increasingly large data resources. Genetic studies have shown that many developmental traits are highly heritable and share genetic determinants with metabolic and reproductive health outcomes. In this thesis I use data from large-scale, population-based resources to further elucidate the role of genetic and epigenetic factors in explaining observed associations between developmental traits and later life metabolic and reproductive health. I begin by examining the genetic aetiology of puberty timing in men, a key stage of sexual development which is understudied compared to women. I identify 29 novel genes involved in the control of puberty timing, implicating new biological pathways and demonstrate genetic correlations between earlier age of puberty and adverse health in adulthood. I then expand on the theme of genetic discovery by conducting genome-wide association studies (GWAS) for reproductive traits in the UK Biobank study. These outcomes have important societal and public health impacts but many have not previously been investigated from a genetic perspective. I identify over 800 variant-trait associations, highlighting genomic regions with highly pleiotropic influences on a diverse range of reproductive traits. This data is then leveraged to construct a framework for conducting phenome-wide association studies (PheWAS), which is used to explore the extent to which both BMI and sex hormone exposure act as mediating factors to explain the link between earlier puberty and heightened reproductive health risks. I go on to examine mechanisms linking early life markers of development to adult health. I investigate the association between weight at birth and body composition in adulthood, determining that foetal and maternal-specific genetic determinants of birth weight have differential influences on fat and lean mass distribution. Downstream analyses suggest that these operate through distinct biological pathways, adding to our understanding of the association between low birth weight and poor health. Finally, I conduct an epigenome-wide association study (EWAS) as a complementary approach to GWAS for both BMI and puberty timing to identify additional genomic loci associated with both traits. Using EWAS data I present evidence for a casual epigenetic effect on puberty timing, functioning through both BMI-mediated and independent pathways. The findings from this thesis contribute to the understanding of the genetic determinants of early life developmental processes and their relationship with later health, which have important implications for the improvement of individualised disease prevention and management.

Traumatic brain injuries (TBI) are becoming one of the leading causes of long-term disability worldwide, with more than 200,000 people attending emergency departments in the UK each year following a head injury. This creates immense strain on the individual’s life as well as the healthcare system. The long-term symptoms associated with TBI include depression, anxiety, headaches, dizziness, personality changes, increased aggression, and nausea. These symptoms can lead to job losses, relationship breakdowns and even homelessness. Traumatic brain injuries cannot always be avoided so evidence-based guidelines for suitable and effective rehabilitation interventions are important. The overall aim of this thesis was to pilot an original, multi-component exercise intervention on the mental and physical outcomes in individuals following a TBI. Secondly it aimed to identify disparities in the current rehabilitation guidelines and propose future changes. Finally it intended to lay foundations for a future larger RCT to be conducted across the UK with the implementation of exercise programmes within the community. A systematic review of the literature on the effects of exercise on the quality of life (QOL) in individuals with a TBI can be found in Chapter 3. It found limited conclusive data on the best exercise modality to illicit significant QOL improvements. Therefore, this highlighted the gap in the research and the need for more robust RCTs within this area. Sixteen healthy adults (non-TBI) took part in the first empirical study (Chapter 5) investigating the effects of a 4-week multi-component exercise intervention on physical and health-related quality of life outcomes. The intervention consisted of circuit-based sessions 1x/week working on balance, strength, coordination, and dual-tasking with the second session per week involving aerobic, reaction time and agility exercises. The findings indicated significant improvements in sit-to-stand tests (p = 0.04, g = 0.34) and reaction time on the Fitlight Trainer (p = 0.00, g = 2.94) in the exercise group. This was also the case during the 15-minute cycling time-trial, where the exercise group demonstrated significant improvements in the total distance cycled and average power over the four weeks (p = 0.008, g = 0.24 and p = 0.00, g = 0.28, respectively). These results revealed the opportunity for physical improvements in a TBI population and justified the second empirical study (Chapter 6). The first part of this chapter looked at the TBI admissions into the Hull Royal Infirmary A&E department highlighting trends in patient and injury characteristics. In addition it demonstrated a wide range of potential participants and emphasised the rationale for an exercise rehabilitation programme. The findings from the audit informed the second part of this chapter, where seven participants (with a TBI) were recruited, with four individuals allocated into the novel exercise programme and three into the standard treatment (control) group. The exercise group attended two session a week for twelve weeks. Participants in the exercise group demonstrated significant improvements (decreased scores) in anxiety (p = 0.05) and depression (p = 0.04) compared to the control group as measured using the Hospital Anxiety and Depression Scale (HADS). Health-related QOL score as measured with the SF- 36 revealed significant improvements for role-limited physical (p = 0.02) and vitality domains (p = 0.03) as a result of the exercise intervention. Significant improvements were also recorded for total distance covered during the cycling time trials (p = 0.03), number of sit-to-stands in 30 seconds (p = 0.02), resting heart rate (p = 0.03), and maximum workload during the aerobic fitness test (p = 0.001). An isokinetic dynamometer was used to measure lower limb average power at two angular speeds (60 deg/sec and 180 deg/sec). The exercise group demonstrated significant improvements during both leg extension (p = 0.04) and flexion (p = 0.05) at 180 deg/sec. In the final study (Chapter 7), a qualitative approach was used to understand the main facilitators to exercise following TBI. These included motivation, gaining an understanding of recovery, and improving physical fitness. The barriers to exercise were also explored, such as lack of confidence/ motivation and cost. Overall this thesis demonstrated the potential benefits of a 12-week multi-component exercise intervention on QOL and physical well-being outcomes in a cohort of TBI individuals. It also identified disparities in the current TBI rehabilitation guidelines and proposed future recommendations for long-term support for TBI individuals.

Steam technology radically transformed world shipping in the nineteenth century. Shipping lines established fast and predictable schedules that linked the far reaches of the world to Europe. These sea routes also went hand-in-hand with European imperial expansion; regular, reliable communications between colony and mother country cemented imperial control. To analyze these links, I explore the establishment and operation of shipping lines between France and its most prized colony, Algeria, between 1830 and 1914. The French state fostered this trade through generous subsidies, eventually declaring a monopoly on Franco-Algerian trade in 1889. Far from being a simple story of the French state playing a large role in the affairs of private enterprise, I examine the tensions between political and economic motives to justify these steamship services. These tensions underlying the justifications of linking France and its empire with French ships reveal that the day-to-day operations of these shipping lines were more complex, and more fraught, than previously imagined.

Both the computation and the detection of Gröbner bases require a criterion that decides whether a set of polynomials is a Gröbner basis. The most fundamental decision criterion is the reduction of all S-polynomials to zero. However, S-polynomial reduction is expensive in terms of time and storage, so a number of researchers have investigated the question of when we can avoid S-polynomial reduction. Certain results can be considered "combinatorial", because they are criteria on the leading terms, which are determined by integers. Our research builds on these results; this thesis presents combinatorial criteria for Gröbner bases. The first part of this thesis reviews the relevant literature on Gröbner bases and skipping S-polynomial reduction. The second part considers criteria for skipping a fixed number of S-polynomial reductions. The first two theorems of part two show howto apply Buchberger's criteria to obtain necessary and sufficient conditions for skipping all S-polynomial reductions, and for skipping all but one S-polynomial reductions. The third theorem considers the question of skipping all but two Spolynomial reductions; we have found that this problem requires new criteria on leading terms. We provide one new criterion that solves this problem for a set of three polynomials; for larger sets, the problem remains open. The final part of this thesis considers Gröbner basis detection. After a brief review of a previous result that requires S-polynomial reduction, we provide a new result which takes a completely different approach, avoiding S-polynomial reduction completely. Throughout the latter two parts, we provide some statistical analysis and experimental results.

Despite the growing interest into the role of physiotherapists providing psychological interventions within anterior cruciate ligament (ACL), literature surrounding goal setting practices within this field is minimal. The main purpose of this research was to explore physiotherapists' approaches, training and beliefs into goal setting practices used within ACL rehabilitation. The thesis consisted of seven chapters, two of which were empirical studies. The empirical chapters aimed to gain further insight into physiotherapists understanding on the psychological aspects of patients following ACL surgery, theoretical knowledge of goal setting, experiences of implementing goals, training received on goal setting and future training needs. Study four involved a UK cross sectional online survey of one hundred and twenty four physiotherapists (N=124). The survey provided an insight of perceptions and goal setting approaches used within ACL rehabilitation. These findings were further explored in study five which involved a UK semi-structured interview study including twenty four physiotherapists (N=24), using an inductive approach. Study five provided a much deeper understanding in to physiotherapist's goal setting practices, training and experiences within ACL rehabilitation and also revealed issues surrounding the initial consultation process. The research findings were conceptualised into a theoretical, innovative goal setting model. The goal of this model is to outline a multi-phase conceptual model of an appropriate ACL rehabilitation goal setting strategy for physiotherapists in an attempt to guide both practice, teaching and research.

Human ageing is accompanied by characteristic metabolic and endocrine changes, including altered hormone profiles, insulin resistance and deterioration of skeletal muscle. Obesity and diabetes may themselves drive an accelerated ageing phenotype. Untangling the causal web between ageing, obesity and diabetes is a priority in order to understand their aetiology and improve prevention and management. The role of biological ageing in determining the risk of obesity and associated conditions has often been examined using mean leukocyte telomere length (LTL), a marker of replicative fatigue and senescence. However, considering phenotypes which represent different domains of biological and functional ageing as exposures for obesity and related traits could allow the elucidation of new understudied phenotypes relevant to cardio-metabolic risk in the wider population. This PhD considers the causal role of (1) hand grip strength (HGS), a marker of overall strength and physical functioning, and (2) resting energy expenditure, an indicator of overall energy metabolism and the major component of daily energy expenditure, in cardio-metabolic risk. I also characterise a new and readily-quantifiable marker of age-related genomic instability, mosaic loss of the Y chromosome (mLOY). Observational evidence implicates each of these phenotypes in cardio-metabolic conditions and intermediate phenotypes. However, it is not possible to infer causality from these observational associations due to confounding and reverse-causality. Mendelian randomisation offers a solution to these limitations and can allow the causal nature of these relationships to be investigated. Using population-based data including UK Biobank, this thesis presents the first large-scale genetic discovery effort for each trait and provides new biological insight into their shared and separate aetiology. I used identified variants to investigate the bidirectional causal associations of each trait with cardio-metabolic outcomes, intermediate phenotypes and other related traits such as frailty and mortality. In total I identified 16 loci for hand grip strength, 19 for mLOY, and one signal for REE. I have shown that HGS is likely to be causally linked to fracture risk, and I have identified the important shared genetic architecture between mLOY, glycaemic traits and cancer. I have also demonstrated that at least one known genetic variant contributing to obesity risk acts partially via reduced REE. Overall the findings of my PhD contribute to our wider understanding of the aetiological role of ageing processes in metabolic dysfunction, and have implications for both basic science and translational applications.

The Catholic Church is one of the largest providers of medical care in the US, with 1 in 6 acute-care beds residing in a Catholic hospital. One third of these hospitals are in rural or underserved areas in the US, and advocacy for the vulnerable is a central platform of the Catholic Healthcare Association. Despite this, the Church has been under attack for allegedly putting women at risk of injury or death due to the care restrictions concerning reproductive health stipulated in the Ethical and Religious Directives (ERDs). Additionally, scholars are questioning the distinctiveness of the Catholic healthcare mission in practice, pointing to the increased homogenization of Catholic and non-Catholic hospitals. For these reasons, it is necessary to assess if and how women are being harmed in Catholic hospitals and, if there is harm being done, if there is a way to prevent these harms while preserving the Catholic Social Tradition in medicine. In carrying out this assessment, I read the current literature closely to explore both the origins and the practical consequences of these ethical conflicts. Subsequently, I use Chris Durante's "pragmatic perspectivism" to formulate a proposal that considers both Catholic medical ethics and secular medical ethics on the same plane. The proposal suggests the adoption of an alternative and complementary lens for Catholic health care. Using this framework would allow the Church to pursue its health care mission in a fuller sense, unencumbered by the inertia of the medical industry towards homogenization due to legal and economic pressures. It also provides the potential for Catholics to more easily receive Catholic care in all hospitals, not just those under Catholic sponsorship. Importantly, it would also prevent any American woman from being practically forced to receive Catholic care, circumventing many of the ethical conflicts present in the current system.

The purpose of this study is (1) to explore the theological significance of Berdyaev's idea of human creativity and to determine its relation to a Christian doctrine of salvation, and (2) to identify the major theological presuppositions which undergird this idea, compare them with the thought of Paul Tillich and L. Harold DeWolf, and evaluate them. The study engages the thought of Berdyaev at its most inclusive and determinative point--his dualism of spirit and nature. It then narrows to an investigation of the content and meaning which is given to the idea of "spirit." On the basis of theological meanings which appear, the preliminary conclusion is drawn that the main theological concern of Berdyaev's teaching on human creativity involves the problem of a particular understanding of man's relationship to God Following a study of Berdyaev's doctrines of God and man, and an identification of the marks of the creative experience of God and its cosmic consequences, the conclusion is dram that Berdyaev, in his teaching on human creativity, seeks to give an interpretation of the meaning of Christian salvation. [TRUNCATED]

Rapid, sensitive and selective detection and identification of pathogens is required in the prevention and recognition of problems related to food security. Salmonella is one of the dangerous foodborne pathogens. The identification of specific volatile organic compounds (VOCs) produced by Salmonella may contribute in providing a fast and accurate detection method for Salmonella in food samples. In this study, VOCs liberated by Salmonella strains have been identified and quantified via head space-solid phase microextraction coupled to gas chromatography/mass spectrometry (HS-SPME GC/MS). The dominant chemical class of volatiles liberated from Salmonella strains was alcohol compounds. In addition, ester and ketone compounds were also detected. The most sensitive VOCs detected were ethyl octanoate (LOD = 62.0 ng/mL and LOQ = 207 ng/mL) and ethyl decanoate (LOD = 66 ng/mL and LOQ = 219 ng/mL) with the lowest LOD and LOQ when using Rappaport-Vassiliadis Soya peptone (RVS) broth media and polar SPME fiber with polar GC column. The type of culture medium was found to affect the liberated VOCs. For example, 2-heptanone was not detected when S. london and S. stanley were grown in TSB but they were detected and quantified when using BHI as growth media. Also, 1-octanol was detected and quantified in all strains when Salmonella grown in TSB and BHI, and did not detected in all strains when RVS was used as growth media. The research has been extended to include the addition of specific enzyme substrates to the culture medium (RVS). The enzyme substrates are either commercially available or have been synthesised to allow exogenous VOC detection. The specific enzymes targeted in Salmonella were α-galactosidase, C-8 esterase and pyrrolidonyl peptidase. The enzyme substrates used are phenyl α-D-galactopyranoside, 2-chlorophenyl octanoate and L-pyrrollidonyl fluoroanilide respectively. All, except pyrrolidonyl peptidase, are known to give a positive response to Salmonella. This developed methodology was initially applied to pure cultures of S. stanley to evaluate the feasibility of the approach. The developed approach shows potential for future application in food samples to detect and identify Salmonella species in food samples of a level as low as 100 CFU/mL within a 5 h incubation at 37 ºC by the detection of the liberated VOCs. Subsequently the methodology was applied to a range of food samples (milk, cheese, eggs and chicken). It was found that all food samples were Salmonella free; however, false positive was detected due to the presence of other pathogens in the food samples. Inhibition of some of these pathogens in milk and cheese samples was achieved with the addition of 5 mg/L vancomycin and 10 mg/L of novobiocin. To improve the method specificity, it was necessary to deviate from the standard method and use Salmonella selective RVS broth in pre-enrichment step than using non selective one (BPW). This results in a successful detection of Salmonella contamination on milk samples and cheddar cheese samples. However, failed in detect Salmonella in other cheeses. Inhibition of resistant pathogens (Streptococcus salivarius ssp. Thermophilus, Lactobacillus rhamnosus and Enterococcus faecalis) using another combination of selective agents (vancomycin 10 mg/L, novobiocin 10 mg/L, erythromycin 0.75 mg/L and lithium chloride 15 g/L) failed. This study highlighted the benefits of the use of specific enzyme substrates along with antibiotics into Salmonella VOC analysis to improve the specificity of Salmonella detection method. The results of VOC analysis of specific enzymes inherent within Salmonella could be extended to develop a selective portable sensor approach to be used in food production.

Members of the Mycobacterium abscessus complex (MABSC) are a highly antibiotic-resistant complex of organisms within the genus Mycobacterium, increasingly acknowledged as a significant cause of lung infection in patients with cystic fibrosis (CF) and associated with poor clinical outcomes. Current methods of isolation of MABSC are hindered by the fact that they grow at a slower rate in culture than other microorganisms with many patient samples having to be discarded due to the overgrowth of more rapidly growing species. Decontamination of samples has shown to have an adverse effect upon the viability of MABSC, therefore improvements in the isolation of MABSC are urgently required in order to offer the possibility of a more rapid and accurate diagnosis. A novel medium (RGM) was developed for the isolation of MABSC. Commercially available pre-poured media were compared with RGM and challenged with isolates of rapidly growing mycobacteria and other species. In addition, in a multi-centre study sputum samples collected from patients with CF were inoculated onto RGM medium, BCSA and standard automated liquid culture method and assessed for growth. RGM demonstrated superior sensitivity over currently used methods without any requirement for decontamination and could easily be incorporated into any laboratory alongside routine culture for other CF pathogens. Chromogenic and fluorogenic substrates were investigated for the possibility of differentiating between subspecies within the MABSC complex. However, the results established that these would not provide any additional benefit to RGM. Possible environmental sources were explored in order to establish how patients with CF were acquiring MABSC. Although person-to-person transmission has been suggested, there are very few reports to substantiate this at present and many questions remain unanswered. In this study, MABSC was not isolated from any of the environments screened. Finally, a selection of antimicrobials were investigated against MABSC with the purpose of ascertaining susceptibility and whether any may be used for a more successful treatment outcome. There were no clinically applicable results therefore further work is required in this area. To conclude, RGM is a novel culture medium, which can be embedded alongside routine culture for other CF pathogens without any requirement for decontamination. This means that all respiratory samples submitted from patients with CF can be conveniently cultured for NTM, considerably improving the service offered to clinicians and patients. Furthermore, it is likely that formal AFB culture methods could be replaced by use of such a medium, potentially enabling substantial savings in terms of materials and labour time.

This thesis is divided into two parts; the first part describing the synthesis and evaluation of novel fluorogenic enzymatic substrates for microorganism detection, and the second part investigating the synthesis of thiophenes with extended conjugation as fluorescent labels with potential applications in antimicrobial susceptibility testing. ‘Spacer’ substrates were identified as a method of incorporating a phenolic fluorophore (ArOH) into an enzymatic substrate designed at targeting aminopeptidase activity. Substrates of the general structure ArO-spacer-AA were therefore synthesised (AA = amino acid). The action of aminopeptidases on these substrates would therefore result in fragmentation, liberating the phenolic fluorophore. The spacer group of choice was para-aminobenzyl alcohol (PABA), as it has been widely used as such for the synthesis of prodrugs. After condensation of the amine group of PABA with either Boc-L-alanine or pyroglutamic acid and subsequent chlorination of the benzylic alcohol giving the corresponding benzyl chloride, 2-(2-hydroxyphenyl)benzothiazole and 2-(2-hydroxyphenyl)benzoxazole were attached using a Williamson ether synthesis to produce the Boc-protected substrates. After removal of the Boc groups, the substrates produced strongly fluorescent colonies with Gram-negative bacteria. Also investigated were a series of fluorogenic substrates, both with and without ‘spacer’ methodology, designed for the detection of nitroreductase activity but little activity was observed with bacteria. Three BODIPY-derived substrates were also prepared and evaluated for detecting nitroreductase and esterase activity. These substrates showed good activity in agar media when the agar plates were post-treated with acid resulting in the generation of strong colour and fluorescence. The second section of this thesis focuses on antimicrobial susceptibility testing. Two types of substrates possessing highly conjugated thiophene cores were synthesised: hydrazides and D-amino acids. The hydrazides are expected to label dead cells by reacting with aldehyde groups that are produced by protein carbonylation. The D-amino acid series of compounds are expected to be incorporated into the cell walls of growing bacteria, and hence live cells can be labelled. The thiophene core structures were chosen to have excitation wavelengths of approximately 488 nm because this excitation wavelength is commonly used in flow cytometry. Results from fluorescence measurement testing indicate that both sets of cell labelling substrates synthesised have an excitation wavelength of roughly 450 – 460 nm with emission wavelengths ranging from 480 nm to as high as 520 nm.

Cystic Fibrosis (CF) is the most common autosomal recessive genetic disorder in the UK. A mutation in the CFTR gene, alters a Cl- transporter protein resulting in dehydration at epithelial surface and a thick mucus layer that provides a nutrient rich environment ideal for opportunistic bacteria to colonise. Bronchiectasis (BR) is similar symptomatically to CF, with localised dilations and inflammation events of the bronchial tree that can be linked to lung trauma or allergy. Pseudomonas aeruginosa (Pa) is the most common opportunistic pathogen in CF that correlates to lowered lung function. Burkholderia cepacia complex (Bcc) species have been shown to be more problematic to clear than Pa, due to increased antimicrobial resistance and progression to Cepacia syndrome that can be fatal. These opportunistic bacteria and their genome plasticity allows adaptation to the lung and can correlate to pathogenicity of chronic infection which is associated with poor clinical outcomes. As adaptation to the lung environment is such a key aspect of chronic bacterial infection in the lung this study focuses on the temperate phages infecting Pa and Bcc. Temperate phages once integrated into the bacterial chromosome have been shown in other bacterial backgrounds to aid bacterial adaptation through increasing rates of recombination. They have also been previously characterised to aid positive selection by carrying genes that aid bacterial survival, aiding evolution of both the bacterium and phage. The aim of this project was to characterise temperate bacteriophages chemically induced from 94 Pa (47 associated with CF and 47 with BR patients), 47 Bcc isolates (associated with CF patients). This study focuses on 3 key areas. The first studies how phages induced from Pa and Bcc infect isolates from patients at different stages of chronic infection. All the bacterial isolates used in this study had at least one inducible lysogenic phage, in some instances polylysogens. Infectivity through Pa phage cross infection showed that adult CF phage were more infective across the Pa panel. Paediatric CF phages showed an infection profile similar to that of Pa phage induced from BR patients > 10 years after clinical diagnosis. Pa phage associated with BR patients < 10 years after clinical diagnosis showed the least infection across the Pa panel. Secondly, isolating and purifying temperate phages can be difficult and time consuming as phages that induce from the bacterial host in high numbers can mask secondary or tertiary phages. Importantly identifying individual phages can be complex, as a sensitive bacterial host is needed to isolate and propagate. This study uses novel genomic approaches to overcome this problem and separate mixed phage communities using k-mer abundance. Stratified phages have been annotated and compared for similarities that link to the clinical aetiology of the bacteria that carried that phage. Finally, this study begins to map genetic traits that may aid phage longevity in a microbial system. A model has been previously characterised with lytic phages where Ig-like domains or BAM motifs may explain how phages bind to complex carbohydrates in mucus. When evaluating the incidence of BAM, Ig-like domains in temperate phage DNA sequences isolated in this study we identify an increase in BAM motifs, that may correlating to the evolution of disease in both CF and BR. This aids the proposed BAM model and the evolution of temperate phages interacting at mucosal surfaces.

The aim of my work was to identify additional genetic and non-genetic factors influencing female reproductive ageing in humans. Although approximately 50% of population variation in age at menopause is due to genetics, less than 3% of variation had been accounted for by common genetic variants. Of non-genetic risk factors, only smoking had consistently been found to have a strong effect on age of menopause. In the wider context of female reproduction, our understanding of the role of genetics in determining sex hormone levels was limited. By combining the results of research in these different areas, I hoped to improve our knowledge of the biology of female reproductive ageing. Chapter 1 is an introduction in which I discuss the biology of menopause, describe relationships with health and present current knowledge regarding non-genetic and genetic risk factors influencing menopause age. Chapter 2 is an analysis of the associations between non-genetic risk factors occurring in early life with early menopause. We identified an association between multiple births and early menopause, connecting events pre-birth, when the oocyte pool is formed, with reproductive ageing in later life. Chapter 3 is a genome-wide association study to identify genetic variants associated with levels of nine sex hormone related phenotypes. We highlighted loci of relevance to reproductive function, which suggested overlaps in the genetic basis of hormone regulation. Chapter 4 is a genome-wide association study of menstrual cycle length. We showed that a common genetic variant related to follicle stimulating hormone levels and age at menopause is associated with several reproductive traits including length of menstrual cycle. Chapter 5 is an investigation of the relationship between differences in length of normal FMR1 triplet repeat alleles and timing of menopause. We found no association between the length of normal FMR1 alleles and timing of menopause, contradicting the results of smaller studies and replicating a null result in another large study. Chapter 6 is large genome-wide meta-analysis to identify common and low-frequency genetic variants associated with age at menopause. We identified 44 regions containing 54 independent common signals and two rare missense alleles of large effect. Finally, in Chapter 7 I evaluate how this work has benefitted our knowledge of female reproductive ageing and describe directions for future research.