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Around half of all type 1 diabetes cases occur in adults but the phenotype of the disease in this age group is poorly understood. A major difficulty studying type 1 diabetes in adults is differentiating cases from type 2 diabetes. The aim of this thesis was to both determine strategies for improving type 1 diabetes classification in adults and evaluate the impact of onset age on clinical phenotype in robustly defined adult-onset type 1 diabetes. Chapter 1 explores the reported characteristics of adult-onset type 1 diabetes and how this varies with case definition. I discuss difficulties classifying adult-onset type 1 diabetes and how this might impact the observed phenotype. Chapter 2 evaluated the commonly reported reduction in positive islet autoantibodies with increasing onset age in type 1 diabetes. We show a significant reduction in genetic predisposition to type 1 diabetes in autoantibody negative adults concluding that most of these cases probably have non-autoimmune diabetes. Chapter 3 examines in adults diagnosed with type 1 diabetes the clinical benefit of measuring and reporting autoantibody results to patients and their clinicians given in Chapter 2 a high proportion without autoantibodies likley have non-autoimmune diabetes. This showed some autoantibody negative cases stopping insulin without detrimental impact on glycaemic control. Chapter 4 explores the conflicted evidence for the loss of HLA (DR15-DQ6) associated protection against type 1 diabetes with increasing onset age. We show that in adults when type 1 diabetes is defined robustly, protection remains. Chapter 5 further builds on the importance of robustly classifying type 1 diabetes in adults. We show that presentation and progression of type 1 diabetes in adults is equivalently severe irrespective of onset age. Chapter 6 evaluated commonly used approaches for defining diabetes type in datasets where biomarkers for diabetes classification are unavailable. This identified the optimum approach to be BMI and Age of diagnosis used continually within a prediction model. We produced an online tool allowing researchers to select the optimum approach for their research question. An overview of the major finding of each chapter, their implications and potential future research are discussed in Chapter 7.

Pollinators are essential to food security but are under threat because of multiple factors including climate change, habitat loss, emerging infectious diseases and pesticide use. Commercial pollinator provision can support threatened pollination services, however, only a few species are currently available. This study assessed the viability of mass-rearing red mason bees (Osmia bicornis) within a lab and greenhouse setting, as well as methods to manipulate the diapausing stage, and thus extend when this species is available to growers. Reproductive rates were too low to be commercially viable, but diapause was successfully extended using fluctuating thermal regimes and could be terminated early using chemical treatment. Climate change was shown to potentially have significant effects on red mason bees, with spring warming likely to advance adult emergence, and delayed winter cooling decreasing survival. Neonicotinoid pesticides impact was then assessed in three species: red mason bees, pollinating flies (Calliphora vicina) and buff-tailed bumblebees (Bombus terrestris). Sub-lethal, field-relevant, doses had a significant impact on thermal activity thresholds of all species, with buff-tailed bumblebees the most vulnerable. Indeed, RNAseq data in this species highlighted disruption of several core processes linked to thermal adaptation. The implications on pollinator phenology, survival, as well as food security are discussed.

This is a portfolio of mixed compositions for a range of musical media. Composition as research is the main theme running throughout the portfolio. Particular focus is given to experimental aspects of composition, in order to see how these function as both creative tools and modes of communication. For example, use of sampling, use of code followed by digital manipulation, conventional notation and unconventional instruments. Some of the compositions are written specifically for performance, one is written specifically as sound design for a film, and others stand as experimental electronic works.

Occupational stress among university and college faculty has significantly increased over the past decade. Employee wellness programs aim to reduce work-related stress through a class of evidence-based activities known as Stress Management Interventions (SMIs). During the COVID-19 pandemic, new challenges in the daily work of academics have simultaneously exacerbated stressful working conditions and exposed shortcomings in traditional face-to-face stress management interventions. Due to time constraints, cost, low scalability, and a high access threshold, the implementation of SMIs on campuses falls short of a national goal set by the United States Department of Health (2010). In addition, existing SMIs are underutilized (Heber et al., 2017). There is a substantial need for more broad-based attention to the health and wellness of university/college faculty, and with the accelerated adoption of work-from-home policies there are calls for the development of internet-based SMIs. This doctoral project investigates evidence and best practice in managing occupational stress among academicians, identifies tools within occupational therapy practice to accommodate remote work, and outlines a development plan to create a cost-effective, internet-based SMI designed for improved administrative implementation and faculty utilization. The program is based on the Person-Environment-Occupation model from occupational therapy literature, which focuses on an individual's performance as shaped by the congruence of their personal domain (e.g., mental and physical health, self-concept, perceived role, cognition), occupational domain (e.g., their work), and their environment (e.g., physical, institutional, social environments) (Law et al., 1996). [The dissertation citations contained here are published with the permission of ProQuest LLC. Further reproduction is prohibited without permission. Copies of dissertations may be obtained by Telephone (800) 1-800-521-0600. Web page: http://www.proquest.com/en-US/products/dissertations/individuals.shtml.]

Over-expression of indolamine-2,3-dioxygenase 1 (IDO1) and programmed death-ligand 1 (PD-L1) are common phenotypes of immunoresistant cancers. The expression of IDO1 and PD-L1 is mediated by the janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway in response to stimulation by interferon-gamma (IFN gamma), with tumoral signalling specifically transduced via JAK2. IDO1's role in tumour immunoresistance is mediated by both depletion of its substrate, L-tryptophan, and by metabolites derived from its product, N-formyl-L-kynurenine. The mechanism of IDO1-mediated dioxygenation of L-tryptophan to N-formyl-L-kynurenine proceeds by either a radical or electrophilic-based mechanism. Radicals adjacent to cyclopropane rings undergo ring-opening driven by relief of ring strain, with the rate of ring-opening dependent on the stability of the resulting radical. A series of cyclopropane-containing IDO1 substrate mimics were designed to divert the hypothesised radical dioxygenation mechanism, potentially resulting in enzyme inhibition resulting from either a mechanistic 'dead-end' or covalent inactivation of the protein. Based on tryptophan and tryptamine, 1,2-cyclopropanated analogues were synthesised via a 1,3-dipolar cycloaddition of an amino acrylate and a indolo-diazo species or the Rh-catalysed cyclopropanation of a terminal olefin. Complimentary spirocyclic cyclopropane analogues of tryptophan and tryptamine were accessed via cyclodialkylation of 3-indoleacetonitrile. A library of sulfenylindoles was also synthesised to divert late-stage metabolic intermediates in a non-radical dependent manner. The synthesised inhibitors were exposed to IFN gamma-stimulated SCOV-3 cells and demonstrated a broadly poor ability to inhibit IDO1 turnover of tryptophan. Novel cell-free assays were developed to ascertain whether the reduced reactivity was related to compound cell-permeability and to further probe the mechanistic-detail of IDO1. A promising IDO1 inhibitor was identified in the cell-free assays and the further evaluation of the candidate is described. Study of JAK2's role in tumour immune escape has been complicated by inhibitors direct effects on immune cells, which is thought to be mediated by inhibition of other JAK family members. Proteolysis targeting chimeras (PROTACs) have the ability to degrade proteins within cells by harnessing the ubiquitin-proteasomal system. Based on FDA-approved JAK2 ligand fedratinib, a series of PROTACs were synthesised. The synthesised PROTACs were evaluated in JAK2-expressing HeLa cells. Degradation of JAK2 in HeLa cells was not observed in the preliminary western-blot analysis - future investigations of JAK2 PROTACs is discussed.

This thesis contributes new evidence and analyses on the effects of cash transfers on adolescent school attendance, work participation and marital status. The mixed-methods study investigates the effects of Nepal's Old Age Allowance (OAA), an unconditional cash transfer, on adolescents who co-reside with older persons using primary data from a household survey (n=2018) and in-depth interviews (IDI) (n=55) conducted in Rautahat district in the Terai region. The quantitative analysis exploits the age criteria for OAA eligibility to isolate its effects on co-resident adolescents. Using a hybrid thematic approach, IDIs are used to elucidate whether and how the OAA was factored into household decision-making and its relation to other factors that influence decisions about adolescents' lives. The findings show that the OAA supports households to fulfil existing preferences for adolescents, which depend on the socioeconomic status, decision-making dynamics and religion of the household, the type and quality of local schools, the nature of local credit markets, and gendered social norms and expectations attached to transitions to adulthood. For many adolescents, this means increased access to school, whether public, private, or religious. However, some households support adolescents to access private school by taking loans in anticipation of OAA eligibility but fail to sustain the costs in the face of delays in registration and receipt of the first payments. Some out-of-school adolescents are prevented from engaging in paid work. However, other households use the OAA to accelerate transitions to adulthood, supporting economic migration of older boys and expediting the formalisation of marriage of older girls. This study makes five main contributions to the literature. First, studies on income effects on access to education tend to consider school as a homogenous entity, but the findings show that a UCT can expand school choice with different effects for different types of school. Second, the findings on adolescent marriage are novel for a dowry context and should prompt the research and policy literature to recognise the possibility that UCTs can increase the risk of early marriage. Third, this study provides unique evidence on the role of cash transfers in leveraging loans for human capital investment and marriage. Fourth, the study examines the dynamics of household decision-making in relation to causal processes and shows that variation in outcomes according to the gender of the cash transfer recipient may stem from differences in bargaining power and economic opportunity as much as from differences in preferences. Finally, most studies on cash transfers often fail to account for the complexity in people's lives which may lead to blunt or erroneous conclusions. This study shows that adopting the tenets of a critical realist perspective and placing decision-making about the outcomes of interest at the centre of the analysis focuses attention on the diverse contextual factors that shape the effects of cash transfers on individual household members, and provides for richer and more nuanced findings.

This portfolio provides an insight into the development of a trainee sport psychology practitioner’s journey through the Professional Doctorate in Sport and Exercise Psychology at Liverpool John Moores University. The portfolio provides evidence, through a combination of consultancy, research, and reflective practice, of how the trainee sport psychology practitioner successfully meets the competencies (professional standards, consultancy, research, and dissemination) of the British Psychological Society’s (BPS) Stage Two training pathway. The three applied case studies and one applied teaching case study provide a critical and reflective insight into the work conducted with elite athletes and coaches from a variety of sports. These applied consultancy experiences allowed the trainee practitioner to develop a coherent and congruent philosophy of practice, which can now be confidently delivered across contexts and cultures. Throughout these applied experiences, the trainee practitioner was able to demonstrate diversity in their training by working with multiple sports (gymnastics, triathlon, wrestling, rugby-league, football, and golf). The reflective log highlights the critical moments experienced by the author throughout this journey, which support the development of a coherent personal and professional identity. The two empirical papers and systematic review attempt to bridge the gap between theory and practice by exploring topics such as; use of psychology within the coaching context, importance of reflective practice for optimal practitioner development, and the impact critical moments have on the practitioner individuation journey of applied sport psychology practitioners. The research, combined with the opportunities to disseminate at conferences and as a Lecturer of Sport Psychology, allowed the author to understand how his values and beliefs transferred across his consultancy, teaching, and research.

This thesis reassesses the evidence surrounding Edward Irving’s controversial teaching about the doctrine of the incarnation. Irving was a controversial figure in his own day and his legacy has been contested ever since he was dismissed from the ministry of the Church of Scotland for teaching that Christ had a ‘fallen’ human nature. This thesis re-examines the emergence and significance of Irving’s teaching. It evaluates the scholarly consensus that his distinctive Christology was a stable feature of his thought and argues the case that his thinking in this area did change significantly. Methodologically, this thesis draws on some aspects of Quentin Skinner’s work in the importance of context (Chapter Two) to understand Irving as he really was, rather than in terms of his later significance. In the light of this, Irving’s biography is examined in Chapter Three, before moving into a discussion of the influential part played by Samuel Taylor Coleridge in Irving’s intellectual development (Chapter Four). The second half of the thesis then moves on to consider the development of Irving’s Christology and the questions surrounding its provenance and development (Chapters Five and Six). Finally, in Chapter Seven, possible sources of explanation for Irving’s distinctive ideas about the Incarnation are exhibited and assessed. The argument of this thesis is that Edward Irving developed an account of the Incarnation that was essentially novel, in response to the Romantic ideas that he had derived from Coleridge. In accordance with Coleridge’s assessment, it is argued that this derivation was rendered more complex by Irving’s incomplete apprehension of Coleridge’s underlying philosophy. Nonetheless, it is argued that Edward Irving’s teaching presented a Romantic version of Christ, and that this distinctive conception owes more to the times in which Irving lived than to the theological tradition to which he claimed adherence.

Nutrient sensing neurons are unique in coupling changes in the concentration of nutrients to changes in neuronal activity. These neurons typically exist in regions of the brain where the blood brain barrier is fenestrated, such as the arcuate nucleus of the hypothalamus. Glucose and leucine are nutrients known to be sensed by neurons in this brain region, but the mechanisms by which they are sensed, and cells that sense them require further study. Using calcium imaging of adult neuron cultures from the mouse mediobasal hypothalamus, I demonstrated that leucine bidirectionally regulates neuronal activity in a neurochemically heterogeneous population of neurons, including AgRP/NPY and POMC neurons. Using pharmacological tools, I demonstrated, unexpectedly, that this acute sensing is independent of mTOR and leucine metabolism, known pathways involved in leucine sensing in vivo. Leucine sensing is LAT1 independent. The response principally relies on calcium entry into the cell across the plasma membrane, but IP3 sensitive calcium stores play a role in neurons inhibited by leucine. Using phosphoTRAP and single cell RNA sequencing, I aimed to identify a molecular marker for leucine sensing cells to allow their manipulation in vivo. PhosphoTRAP, and subsequent pharmacological studies identified a T Type calcium channel may be a marker for leucine sensing cells. AgRP neurons are essential for feeding, and also play roles in controlling glucose homeostasis. Using chemogenetics to selectively activate these neurons, I demonstrated, in contrast to a similar, recently published study, that blood glucose concentrations did not rise upon activation of these neurons. A subpopulation of AgRP neurons express glucokinase, and some AgRP neurons are glucose inhibited, but the role of glucokinase in these neurons has not been characterised. Our lab generated an AgRP neuron specific glucokinase knock out mouse line. Preliminary results suggest 18 – 25 week old female AgRP glucokinase knock out mice may have altered glucose tolerance, but conclusions can only be drawn once further mice have been phenotyped, and the success of the glucokinase knock out from AgRP neurons has been confirmed.

Adsorption isotherms in chromatography are critical in determining the separation of solutes during column separations. Multicomponent protein adsorption isotherms, which are relevant during the downstream processing of biopharmaceutical products, have received limited study historically. The studies and methodologies which have been assessed have mainly focused on small, simple, chromophore containing proteins which have limited applicability to industrially relevant bio-therapeutics. The reasons why this area of study has received limited attention include the experimental effort associated with generating such large data sets as well as the difficulty in obtaining data of good enough quality. The work explored here presents and optimises the deployment of highthroughput chromatography formats as well as automated liquid handling systems in order to elucidate adsorption isotherms of proteins. Additionally, alternative rapid analytical methods involving the collection of protein UV spectra in conjunction with multivariate data analysis have been applied to quantify protein mixtures. These rapid high-throughput methods decrease the experimental effort associated with multicomponent isotherm studies. 3 binary isotherms and 1 ternary isotherm have been studied for larger, non-chromophore containing model proteins. The propagation of error in single component and multicomponent isotherms has been investigated to understand what drives the propensity for error as well as methods to mitigate problematic regions of investigation. The fitting of the multicomponent ion exchange isotherms across multiple salt levels to isotherm formalisms proved elusive which precluded their application for in silico modelling of column separation. Short of that a heuristic optimisation of a binary mixture was achieved quantifying eluted fractions using the UV spectra multivariate method.

Introduction: Low rectal cancer management presents a unique challenge. On one hand more radical measures are required to address poor oncological outcomes and on the other hand there is a need to avoid unacceptably high permanent colostomy rates and suboptimal post-treatment function. This thesis investigates radiological, surgical, pathological and quality of life factors in low rectal cancer, in order to predict outcomes and provide a patient-tailored approach to low rectal cancer management. Methods: The majority of data presented within this thesis will be from the ongoing Low Rectal Cancer Study (MERCURY II). This multidisciplinary study prospectively collected surgical, radiological, pathological and QoL data in consecutive patients undergoing treatment for low rectal cancer. In addition, a multicentre crosssectional quality of life study was performed. This was designed to evaluate post-operative bowel function using patient reported outcome measures (PROMs). Results: Analysis from 279 low rectal cancer patients from the MERCURY II study suggested that MRI assessment of the low rectal plane (mrLRP) guided selection for pre-operative therapy and for restorative resection. MRI assessment contributed to the low (9%, 25/279) pathological circumferential resection margin (pCRM) involvement; significantly lower than the pre-stated target of ≤15% and lower than published studies. Multivariate analysis identified three other predictors for pCRM involvement: tumour ≤4cm from the anal verge; anterior quadrant tumour invasion; and MRI evidence of EMVI. This thesis also validates the English translation of a Danish PROM (LARS score). This data was also used to predict for post-operative bowel-related quality of life (BQoL) impairment following a restorative anterior resection. Finally, the UK LARS data was used to develop a model that predicts post-operative bowel dysfunction (POLARS) with external validation with Danish data. Future Work: The predictors for pCRM involvement require external validation. Future studies should also explore the relationship between these predictors and long-term survival. The POLARS and the LARS score should be used in clinical practice to identify patients who may benefit from additional support for postoperative bowel dysfunction. The value of the post-treatment MRI requires further investigation and the TRIGGER trial has been designed for this purpose.