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The World Health Organisation recommends that resistance exercise be performed at least twice per week to benefit general health and wellbeing. However, resistance exercise is associated with acute muscle damage that potentially can dampen muscle adaptations promoted by chronic resistance training. The extent to which muscle is damaged by exercise is influenced by various factors, including age, training status, exercise type, and - notable to this thesis - sex. To this end, establishing sex-specific management strategies for exercise-induced muscle damage (EIMD) is important to optimise the benefits of exercise. Two EIMD management strategies were focussed on in this thesis: dietary protein supplementation and exercise load manipulation. It was identified in this thesis that research into the impact both of protein supplementation and exercise load on EIMD heavily underrepresent female populations (chapters 3 and 5), despite well-documented sex differences in EIMD responses. Therefore, future research priority should be placed on bridging the sex data gap by conducting high-quality studies centralising around female-focussed and sex-comparative methodological designs. Both peri-exercise protein supplementation and exercise load manipulation in favour of lighter loads were revealed to be effective management strategies for resistance EIMD in males through systematic and scoping review of the current literature (chapters 3 and 5, respectively). Due to a lack of data from females, it is only appropriate for these strategies to be recommended for males at present. To decipher whether protein supplementation and lower exercise loads are beneficial for managing EIMD in females, a randomised controlled trial (RCT) (chapter 4) and a protocol for an RCT (chapter 6) involving male and female participants are presented in this thesis. The incorporation of ecologically-valid resistance exercise in the RCT in chapter 4 highlighted that even mild muscle damage is attenuated in females, reflected in diminished increases in post-exercise creatine kinase concentration and muscle soreness compared with males; however, the reason for this difference requires further investigation. This study, while supporting sex differences, contrasted previous studies, as neither males nor females experienced an attenuation of EIMD during milk protein supplementation. This difference likely owed to the lower severity of muscle damage induced in the current study relative to previous studies, and accordingly, future research should seek to discover alternative management strategies for mild EIMD. A protocol for an RCT examining the impact of exercise load on EIMD in untrained males and females is described in Chapter 6 of this thesis and may be used as guidance for researchers developing similar, sex-comparative studies. It was hypothesised that females will experience attenuated muscle damage relative to males and low-load exercise will induce less muscle damage than high-load exercise in both sexes. A lack of methodological consistency among EIMD studies was a recurring finding throughout this thesis, which posed an issue when attempting to compare between-study outcomes and reach a consensus. Achieving greater uniformity in study designs by adopting comparable methods relating to EIMD markers and time-points of assessment would help improve understanding of the factors influencing the magnitude of EIMD and effective management strategies. While there are limitations with several EIMD markers - for example the variability of biomarkers and subjectivity of perceptual assessments - once the optimal markers are determined, these should be consistently used moving forward. Overall, this thesis has contributed to the current body of knowledge by demonstrating that milk protein ingestion is not an effective management strategy for muscle damage following ecologically-valid resistance exercise; therefore, alternative strategies to mitigate mild muscle damage should be investigated. Further, this work supported previous reports of sex differences in EIMD and indicated that the attenuation of EIMD in females relative to males was not attributed to sex differences in body composition; thus, the aetiology of such differences necessitates further exploration by means of high-quality sex comparative research. Finally, this thesis reached the consensus recommendation that lower exercise loads can be utilised to reduce muscle damage in males; nonetheless, supporting evidence for the application of this recommendation to females is required.

Despite a wealth of evidence identifying criminal victimisation as a reliable predictor of detrimental outcomes across a range of domains of health and wellbeing, the exact mechanism by which these outcomes come about and are determined is not clearly understood. Across three studies, the current research project aims to remedy this gap in our understanding and clarify specifically the way in which criminal victimisation impacts the quality of life of older adults. Study one made use of data taken from wave 3 of the English Longitudinal Study of Ageing (ELSA; Banks et al., 2019) to build a profile of sociodemographic characteristics most associated with having victimisation experience. It was found that amongst older adults, it is the not-so-old, the unmarried, and the more educated who are most likely to report having been victimised at some point in their lives. Study two applied structural equation modelling (SEM) to the same wave 3 ELSA data used in study one to construct and evaluate a theoretical framework of the relationship between victimisation experience, quality of life, and a group of possible mediating variables (social isolation, fear of crime, cognitive function, mental health, and physical health). Of these variables, mental health (specifically a person's level of depression) was the only significant mediator such that victimisation increases depression which, in turn, reduces quality of life. Study three used SEM to extend the theoretical framework identified in study two longitudinally across multiple ELSA waves. The role of depression as a mediator of post victimisation quality of life outcomes was preserved over time. Additionally, victims were found to report increased depression and reduced quality of life almost a decade before nonvictims. The importance of these findings for tackling the negative long-term impacts of criminal victimisation, and the extent to which future research can build on this work, are discussed. Key words: Criminal victimisation, aging, quality of life, depression.

Recently, two new approaches have transformed our understanding of human population history. Firstly, the sequencing of ancient genomes which gives us a snapshot of past genetic variation. We can therefore make inferences from observed genetic signatures present before historical events such as population bottlenecks and natural selection have obscured them from the modern gene pool. Ancient DNA has thus revealed what cannot be determined from modern genomes alone. Secondly, the development of methods that aim to reconstruct population genealogies from genetic variation data. Together with an understanding of how evolutionary processes alter genealogies, this has allowed inference of historical and ongoing processes in real world populations. The latest updates in these approaches now allow us to combine the two and infer genealogies involving both present-day and ancient individuals. In this thesis I present a new method to infer local ancestry along sample chromosomes. The method applies machine learning to tree sequences built from ancient and present-day genomes and is based on a deterministic model of population structure, within which I introduce the concept of 'path ancestry'. I show with extensive simulation that the method is robust to a variety of demographic scenarios and generalises over model misspecification. Subsequent downstream analyses include estimating past effective population size, timing of population specific selection and the time since admixture for individuals. I apply the method to a large ancient DNA dataset covering Europe and West Eurasia to paint all sample chromosomes. I show that the inferred admixture ages are a better metric than sample ages alone for understanding movements of people across Europe in the past.

Brown dwarfs are substellar objects intermediate between stars and planets that are not massive enough to sustain stable hydrogen fusion (< 75M[sub](Jup)). They are a natural outcome of the processes that lead to the formation of stars and planets, and we find them in abundance in every environment we have searched with sufficient depth. Brown dwarfs are not rare; we find a brown dwarf for every 2 -- 5 stars, equating to tens of billions across the Milky Way. However, despite their prevalence, the inherent faintness of brown dwarfs makes studying them challenging. Many fundamental questions about these objects therefore remain unanswered, key among them: how do brown dwarfs form? The overall aim of this thesis has been to work towards this question and better understand the formation of brown dwarfs. To achieve this goal, my research has focused on brown dwarf and star formation in the young cluster, NGC 2264. The aim of studying this cluster was to build the large and well characterised sample of young brown dwarfs needed to answer the outstanding questions in the field of brown dwarf formation. Although NGC 2264 is more distant than the nearest star forming regions, I have shown that it is still accessible for detailed spectroscopic observations of young substellar objects, and crucially has the much larger population that is needed to achieve a robust statistical analysis of the key tracers of brown dwarf formation. I have identified 448 brown dwarf candidates in NGC 2264, based on a combination of NIR colours and additional signatures of youth. I have utilised follow up spectroscopy to show this selection method significantly improves selection efficiency. I find that the star-to-brown dwarf ratio and the slope of the substellar mass function for NGC 2264 are consistent with other young clusters, which points to a uniform IMF across a diverse range of star forming environments. I find no evidence for a variation in the star-to-brown dwarf ratio due to stellar surface density or the presence of OB stars. This rules out brown dwarf formation scenarios that predict strong variations in the relative frequency of brown dwarfs due to environmental conditions. Using Gaia EDR3 kinematics and photometry, I have selected a clean sample of 664 NGC 2264 stellar cluster members and divided these members into north and south sub-clusters using a K-means clustering algorithm. Through comparison with isochrones I have shown that the average age of the northern sub-cluster is ~1 Myr younger than the southern sub-cluster. Using MIR Spitzer data I have classified the disc morphology of the cluster members, based on the slope of their infrared excess. I have shown that despite the younger age of the northern sub-cluster the disc fraction is approximately the same for both the north and south (~ 40%). I attribute this dearth of northern discs to photoevaporation from S Mon, which contains a massive O7 type star - the only O type star in NGC 2264. I have shown that there is a reduction in the local disc fraction up to 1.5 pc away from S Mon, implying that O type stars have a significant and far reaching impact on the local disc lifetime.

This thesis is the first study to focus particularly on francophone life narratives by women from contemporary Tunisia. Due to their innovative methods and original engagement with Tunisian contexts, the texts in this corpus provide us with an opportunity to revisit definitions of the genre of life narrative. Although other scholars have previously employed the figure of the palimpsest in their theoretical discussions of literary and filmic texts (e.g., Genette, Gilbert and Gubar, Dillon, Silverman and Donadey), this is the first time that it has been theorised in relation to the genre of life narrative. My analyses of four Tunisian life narratives across diverse media- a blog by Ben Mhenni (A Tunisian Girl, بنيّة تونسية , 2010-2012); a documentary film by El Fani (Même pas mal, 2012); a photobook by Fellous (Pièces détachées, 2017), and a literary life narrative by Zouari (Le Corps de ma mère, 2016)-allow me to define a new concept of the palimpsestic life narrative as a multi-layered, transnational and relational text in diverse media that takes as its subject an author's life in a complex postcolonial context. I explore the extent to which each female creative practitioner can be seen to overwrite censorship and patriarchal order by adding their own, female-authored, life narrative to the palimpsest of Tunisian history. Additionally, I discuss the degree to which there are internal tensions between the narrative 'layers' of each text, which may work to produce ambiguous identities that resist interpretation and easy classification. Furthermore, I explore the extent to which the figure of the palimpsest can be employed as a mode of reading to envisage the constructed 'selves' that are evoked across this thesis. Finally, I evaluate the degree to which the corpus might be said to enact a politics of palimpsestic identity: a strategy of resistance to monolithic templates for national identity in Tunisia following the 2011 revolution.

Exposure to repetitive mild traumatic brain Injury (r-mTBI) is a substantial risk factor for the development of neurodegenerative diseases, such as Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE). Neuroinflammation is a central component in the secondary injurious response to r-mTBI and has been shown to strongly influence long-term cognitive and functional outcomes following brain injury. As the resident innate immune cells of the CNS, microglia are intricately involved in the neuroinflammatory response that follows TBI. While neuroinflammation has several beneficial functions and is crucial in initiating repair pathways, chronic dysregulated microglial activation and neuroinflammation can propagate further neuronal damage, ultimately leading to neuronal death. Unfortunately, despite mounting evidence linking r-mTBI with progressive neurodegenerative pathologies, there are currently no disease-modifying treatments available to mitigate the consequences of r-mTBI. The persistent nature of microglial activation and neuroinflammation following r-mTBI represents a valuable opportunity to interrogate the mechanisms driving microglial dysfunction. Therefore, in this thesis, I sought to identify microglial-specific therapeutic targets and evaluate their potential to ameliorate the chronic neurodegenerative sequelae of r-mTBI. To achieve this aim, I established and characterized a pre-clinical model of r-mTBI that recapitulates the cognitive deficits, and chronic neuroinflammation observed clinically. Furthermore, I demonstrate that microglia are critical drivers of the neuroinflammatory response to r-mTBI, and through a comprehensive analysis of the microglial transcriptome at sub-chronic and chronic time points I identified dysregulated PPARy signaling as a critical regulator of microglial dysfunction following chronic exposure to r-mTBI. PPARγ is a nuclear transcription factor that is well expressed in immune cells such as microglia. However, there is limited understanding of how PPARy signaling influences microglial pathobiology in the chronic aftermath of repetitive head trauma. To address this, I first investigated how PPARy agonism can influence microglia-mediated inflammation using an in vitro microglial cell model where I found that the PPARy agonist, Pioglitazone, demonstrated beneficial effects on markers of inflammation and microglial metabolism. Furthermore, I assessed the therapeutic potential of a delayed treatment paradigm using Pioglitazone, wherein I observed that treatment reduced microglial-mediated neuroinflammation and ameliorated the cognitive and pathological consequences of r-mTBI. Future studies stemming from this thesis will focus on using cell-specific transgenic models to further investigate the contributions of PPARy signaling to microglial pathobiology following chronic exposure to r-mTBI. Together this collective work has revealed the potential of PPARy as a tractable and viable novel target for neurodegenerative diseases whereby inflammation is a common denominator.

Diabetes Mellitus (DM) is a leading public health priority throughout the world. An estimated 463 million adults currently have DM worldwide. People with DM face an increased risk of several macro and microvascular complications and premature mortality. My thesis aims to estimate trends in hospitalisations and mortality in patients with diabetes over the past 20 years in England. Data were extracted from the Clinical Practice Research Datalink, a primary care database, for 628,811 adults from 1998 to 2018 with diagnosed DM. 313,907 of these adults had their primary care records linked to the Office for National Statistics mortality statistics and Hospital Episode Statistics inpatient admissions data. I identified age, sex matched non-DM adults at a ratio of one to one with the DM study population. I used discretised Poisson regression models, adjusted for age, year, DM status and duration, to estimate annual all-cause death and cause-specific death and hospitalisation rates in adults with and without DM over the past 20-years. I also used Logistic regression models to estimate trends in five-year risk of hospitalisation and mortality for sentinel DM complications following diagnosis. All-cause mortality has declined in adults with DM by approximately 30% from 2001-2018. There were mixed trends in cause-specific mortality with large reductions in cardiovascular disease (CVD) mortality alongside more modest declines in other conditions. This led to cancer becoming the leading cause of death in adults with DM. There were mixed trends across cause groupings in hospitalisation rates over a similar period. There were declines in DM-specific aetiological complications including CVD, amputations, and DM itself alongside increases in infections, cancers, and respiratory conditions. During this period, the 5-year risk of hospitalisation for sentinel DM-specific aetiological complications after diagnosis generally declined with the largest reductions in AMI and stroke hospitalisation risk. Changes in the composition of absolute and excess mortality and hospitalisation in adults with DM means that therapeutic, clinical and preventative programmes should be broadened to reflect the diverse set of causes driving persistent excess mortality and morbidity in this patient group.

Strong galaxy-scale gravitational lensing provides a powerful means of studying galaxy formation, constraining cosmology and understanding the evolution of large-scale structure. The presence of a foreground lensing galaxy deflects the light rays of a background source into multiple images, with their configuration dependent upon the lens mass distribution. Modelling of this distribution to reproduce the lensed images not only aids in measuring the dark matter content of the foreground galaxy, but allows for the reconstruction of the background source in order to study high-redshift galaxy populations. Modelling is typically performed by relatively slow parametric parameter-fitting techniques requiring manual inspection. However, upcoming large-scale surveys like the Legacy Survey of Space and Time (LSST) and Euclid will discover tens of thousands of strong lenses, with this vast quantity driving the growing use of automated machine learning for both identifying and modelling such systems extremely quickly. Convolutional neural networks (CNNs) can extract information from lensed images in order to predict parameters of the lens mass model, but require large simulated data sets for training and testing. In this thesis, I explore the effectiveness of deep learning CNNs for estimating strong galaxy-scale lens mass model parameters when applied to upcoming wide-field survey data, investigating the practicalities they face and comparing and combining them with conventional modelling methods. I construct a CNN and train it on my own simulated lensing images with the imaging characteristics of the Euclid VIS band, LSST r-band, and LSST gri multiband. The CNN is trained to predict parameters of a smooth singular isothermal ellipsoid (SIE) projected mass profile that would best fit the observed image. Multiple aspects of this method are investigated, beginning with a comparison of its accuracy and reliability when applied to the survey data sets. The impact of multiband imaging is analysed, as well as the impact of lens light subtraction commonly performed by conventional modelling techniques. I show that for images including lens galaxy light, the CNN recovers the lens model parameters with an acceptable accuracy, with precision improved on average by 34 ± 5 per cent when lens light is subtracted. Additionally, the inclusion of multiband data improves performance regardless of lens light subtraction. While similar accuracies and precision are obtained for single epoch Euclid VIS and LSST r-band data sets, adding g- and i-band images to the latter increases precision by 24 ± 2 per cent without lens light and by 20 ± 2 per cent with lens light. I also examine the gains in performance through stacking images, and the impact of lens mass-light alignment. For the latter, when orientation and ellipticity of the lens light profile are allowed to differ from those of its mass profile, just as with real galaxies, the network performs most consistently when trained with a moderate amount of scatter between the two profiles. I next seek ways of improving the method for application to real images, starting by implementing an existing technique to create a new Bayesian CNN that can predict both model parameters and their uncertainties. New data sets are then simulated for training and testing the network, allowing the network to either predict parameters of the SIE profile or predict those of the more general elliptical power law profile. To examine how the CNN performs at fitting these profiles to more complex mass models, these data sets feature a range of increasingly realistic lensing systems, from smooth parametric mass and light profiles to featuring real background sources, complex hydrodynamically-generated foreground mass distributions and line-of-sight structure. In order to assess the suitability of the Bayesian CNN as a whole, I compare its performance when tested on these data sets to that of a conventional fitting method: the semilinear inversion technique PyAutoLens. In addition, I present a method for combining the network with such inversion methods where the CNN provides initial priors on the latter's parameters. Across the test sets, I find that the CNN achieves errors 19 ± 22 per cent lower than when applying PyAutoLens blindly. Compared to PyAutoLens alone, the initial centring of its priors on CNN-predicted parameters instead achieves 27 ± 11 per cent lower errors. If the prior widths are additionally initialised according to CNN-predicted Bayesian uncertainties, errors are reduced further to 37 ± 11 per cent as the uncertainties help it to avoid local minima in parameter space, with errors also 17 ± 21 per cent lower than the CNN by itself. While the CNN is undoubtedly the fastest modelling method, the combination of the two increases the speed of conventional fitting alone by a factor of 1.73 and 1.19 with and without CNN-predicted uncertainties, respectively. This, combined with greatly improved precision, highlights the benefits obtainable through combining neural networks with conventional techniques in order to achieve an efficient automated modelling approach. I finish off this thesis by discussing the scientific applications requiring such an approach, and examining how tightly these methods can constrain cosmological parameters through the modelling of double source plane lenses to aid in our understanding of the Universe.

Many adults living with and beyond cancer (LWBC) are impacted by the multitude of toxicities associated with chemotherapy treatment. For example, platinum based chemotherapy (PBC) is known to cause ototoxicity, presenting as hearing loss and tinnitus. There is a paucity of good-quality information and support offered to patients who experience ototoxicity, which can subsequently lead to many being undiagnosed and untreated. In order to identify gaps in the literature, a systematic review was carried out. The systematic review aimed to collect evidence about the prevalence and severity of chemo-therapy-induced hearing loss and tinnitus. However, no reliable prevalence, incidence or severity of ototoxicity was reported, though those with ototoxicity reported having a lower quality of life (QoL). To seek further information, grey literature in the form of online health forums was explored to identify what people experiencing ototoxicity were discussing with one another. The forum review gave a unique insight into online forums and people's thoughts about ototoxicity and their experiences. Six major themes emerged from the forum review, including the nature of ototoxicity, time of experienced ototoxicity, information on ototoxicity, quality of life, therapies and online social support. These two reviews then led to the development of two clinical studies: the first being a mixed method study identifying the severity and the impact of QoL in those living with the effects of ototoxicity. Results from the qualitative aspect found that more aware-ness is needed surrounding ototoxic effects and the impact this has on QoL, specifically, social QoL. Furthermore, experiences with clinicians have a major role in determining whether people receive guidance and support for their symptoms. Clinical staff that do not engage, refer or offer support can have a negative impact on the QoL of their patients, compared to those that listen and offer guidance. Second, a cross-sectional study was developed to identify the prevalence and severity of ototoxicity using ex-tended high-frequency audiometry in patients who received platinum based chemo-therapy. This study recruited 7 participants prior to being suspended due to COVID-19 research restrictions. Finally, two online surveys were developed to identify acceptability of an ototoxicity monitoring programme for those undergoing chemotherapy. One survey was targeted at those who had received chemotherapy, the other was aimed at healthcare professionals specialising in hearing. The surveys showed that many people were unaware of ototoxicity as a side effect of chemotherapy, and that healthcare professionals such as ENTs and Audiologists did not unanimously agree on an ototoxicity monitoring proto-col, or which department is responsible for monitoring ototoxicity. Ototoxicity is an understudied, yet important late effect of platinum based chemotherapy and more information, awareness and support is needed for adults living with and beyond cancer.

Veterinary care can be essential for maintaining the physical health of horses and yet the impact of veterinary care on a horse's emotional state and how that influences their behavioural responses has not been investigated previously. The term horses is used to describe both horses and ponies. Adverse behavioural responses are unwanted, not only for equine welfare but because veterinarians are frequently injured by the horses they are working with, each sustaining on average around 7-8 significant injuries over the courses of their careers. This study evaluated which aspects of veterinary care horses find stressful, their common behavioural responses in this context and potential ways of improving how they perceive veterinary care. In the context of a veterinary examination, horses are limited in which behavioural responses they can express as they will be restrained to a greater or lesser degree. To determine the range of behavioural responses that may occur and their usefulness in assessing emotional state in the veterinary clinic, a two round Delphi process was undertaken. In the first-round participants from the field of Equitation Science (n=16), Equine Veterinarians (n=10) and Animal Behaviour and Welfare Scientists (n=7) evaluated 11 videos of horse's behavioural responses to veterinary care. They assigned a score to the degree of stress they perceived each horse to be experiencing and described any behavioural indicators of stress as free text. There was poor agreement on the perceived degree of stress the horses were experiencing and different behavioural indicators were reported by different individuals. The behavioural indicators (41) identified in round one were then re-presented to the participants in a second round where 34/41 indicators were considered useful measures of the horse's stress response in this context. A feasibility study was then undertaken to determine the best measures of arousal and valence in the context of a veterinary clinic. Horses presenting for veterinary care at an equine hospital (n=30) were filmed during various veterinary interactions (Events) with the horses and the footage was evaluated using a detailed inventory of behavioural responses. Principle component analyses were performed, results of which suggested that the most common behavioural responses to veterinary care were characterised by freeze or flight. Evaluation of the feasibility of different measures of arousal (salivary cortisol, surface eye temperature and heart rate variability) were undertaken on the same cohort of horses. Salivary cortisol concentrations highlighted that horses were in a state of elevated arousal, likely as a consequence of transportation, even before veterinary care commenced. Elevated cortisol concentrations were maintained, most likely due to exposure to veterinary Events, but the lag between an individual Event and concentration peaks / return to baseline meant this was not feasible measure in this context. Surface eye temperature provided data that varied in real time and showed variation between horses and between individual Events. The main limitation of using this measure was the practical challenges trying to capture usable, in focus, and therefore accurate, thermal images of the eye as many horses did not remain still during Events. Heart rate variability parameters (HRV) provided data that varied in real time and showed variation between horses and between individual Events. Moreover, it could be collected remotely and regardless of any behavioural response. In the feasibility study HRV data were collected using a Polar heart rate monitor. However, validation against an ECG showed the Polar to be inaccurate, even following artefact correction. Even when an ECG was used subsequently, manual R peak detection and documentation of arrhythmias was essential to ensure accurate data for HRV analyses were generated. The methodology developed in the feasibility study was used to evaluate the responses of 60 horses undergoing veterinary care in the same equine hospital. The proportion of time a horse was 'stressed' was calculated based on the sum total of time in any negative affective state over total time. This study found marked variation regarding which veterinary Events horses appeared to find stressful, both within and between individuals. For example, 13/15 veterinary Events resulted in a range of time an individual horse was scored as 'stressed'. Negative behavioural responses were characterised by freeze or flight but also fidgeting behaviours, which are well described in other species but poorly documented in horses. Aggressive 'fight' responses occurred very infrequently. Further research is required to determine whether training of equine veterinarians to recognise subtle behavioural indicators, across the range of responses (freeze, flight, fidget or fight), can be used to improve equine welfare and reduce the likelihood of occupational injuries. With regard to evaluation of individual Events: • One of the most arousing stimuli, based on behavioural response and elevated heart rate, in the veterinary environment was the sound or sight of another horse walking past and so minimising this stimulus where possible is recommended. • Horses are frequently walked onto a weigh bridge upon entering the equine hospital and this commonly evoked a behavioural response characterised by freeze or flight and elevated heart rate. It is less than ideal that their first experience in a novel environment and first interaction with staff may be a negative one. Weighing a horse after other veterinary Events have been completed or development of a low stress technique would likely be of benefit. • The use of feed during diagnostic local anaesthesia appeared to minimise the proportion of time an equid was scored as 'Stressed' compared to when it was not used and so is recommended. • Horses were scored as more 'Stressed' when an I.V. injection was administered by a student or nurse in comparison to a veterinarian. Investigation of training to try to mitigate this response should be undertaken. The final study in this thesis evaluated the way in which learning theory could be applied in veterinary practice. Classical counter conditioning was used prior to diagnostic local analgesia (nerve blocks) and the impact on the horse's stress response was investigated. Twenty-seven cases presenting for lameness evaluation were recruited and randomly assigned to a control or treatment group. In the treatment group the provision of feed (unconditioned stimulus) was paired with someone approaching (conditioned stimulus) the limb. In the control group 14 horses received 24 nerve blocks, in the treatment group 13 horses received 35 nerve blocks. Restraint during the nerve block was at the discretion of the veterinarian performing the procedure. Video footage of horses during the nerve block was evaluated using a fixed list method Qualitative Behaviour Assessment by 5 observers blinded to treatment group. They scored the treatment group as being in a more positive affective state (at ease, relaxed and confident) than the control group (nervous, tense and fearful). However, the difference between groups was only statistically significant once other significant contributing factors such as the type of block were included in the multivariable model. This highlights that many different factors are contributing to how a horse perceives veterinary Events such as nerve blocks but that classical counter conditioning can be used to help horses perceive them more positively. In summary, a horse's perception of veterinary care will vary markedly between individual animals but also within an individual. Constant evaluation of the horse's emotional state, based on an understanding of subtle indicators of negative affect, will allow the veterinary team to modify their approach and optimise care of the individual. In addition, it is possible to promote a positive affective state even during aversive procedures such as nerve blocks. This can be achieved in a real-life scenario using classical counter conditioning.

Human respiratory syncytial virus (HRSV) is a common cause of respiratory tract infections (RTIs) globally. Of those infected, 25%-40% aged ≤1 year develop severe lower RTIs leading to pneumonia and bronchiolitis, with ~10% requiring hospitalisation. There is currently no HRSV vaccine and clinically approved treatments are only moderately effective. New and more effective anti-HRSV strategies are urgently required. It is established that viruses require cellular ion channels to infect cells. Ion channels are a diverse class of transmembrane proteins that selectively allow ions across membranes, influencing a multitude of cellular processes. Modulation of these channels by viruses is an important host-pathogen interaction that regulates critical stages of the virus multiplication cycle including entry, replication, and egress. Cellular chloride (Cl-) channels are large family of ion channels which were historically overlooked, however the importance of these proteins, especially within the respiratory tract, is now being revealed. This thesis examined the role of Cl- channels during HRSV infection. Utilising GFP-expressing HRSV in combination with an extensive panel of channel-specific pharmacological inhibitors, a critical requirement for calcium (Ca2+)-activated chloride channels (CaCCs) during HRSV infection was highlighted. For the first time, a role for TMEM16A as a host-factor was revealed and the channel was implicated as a post-exposure antiviral target. An investigation into the mechanisms underpinning the relationship between HRSV and TMEM16A revealed that the channel was involved at the genome replication and/or transcription stage of infection, and evidence suggested that this interaction may occur at or near the Golgi, in HRSV replication factories. Lastly, a role for TMEM16A was described within the HRSV-mediated production of antiviral protein interferon γ-induced protein 10 (IP-10), which supported a hypothesis wherein HRSV sequestered TMEM16A for genome replication, and simultaneously prevented the cellular antiviral response. Therefore, these findings have revealed TMEM16A as an exciting target for future host-directed antiviral therapeutics.

This thesis presents the first critical edition of a Syriac manuscript housed in the John Rylands Library (Manchester)-class mark Ms. Syr. 52-which contains a compendium of magico-medical lore known as the Book of Protection. The edition consists of the following: a transcription of the Syriac text; an English translation; philological notes; a commentary contextualising each passage; and a glossary in which all the word forms used in the text are listed and parsed. The edition is preceded by an introduction to the Book of Protection and a literature review outlining previous research published on Syriac magic. Following the edition is a discussion in three chapters, which aims to evaluate claims made by previous scholars that the Book of Protection is closely related to the magico-medical traditions of late antique, medieval, and ancient Mesopotamia. Chapter one examines this question with regard to praxis, finding that the practices associated with the Book of Protection often represent the continuation of longstanding regional traditions with roots extending back to ancient Mesopotamia. Chapter two examines the question with regard to texts, finding that the majority of texts compiled in the Book of Protection reflect a distinctly Syriac Christian magico-medical tradition which first flourished in the medieval period. Chapter three contextualises these findings, considering the historical circumstances which facilitated praxis to be passed down from one generation to the next with little alteration, and those which encouraged or necessitated innovation of magico-medical texts. The conclusion reached is that the scribes who produced the texts in the Book of Protection did not seek to simply preserve antecedent traditions. Rather, they actively engaged with their sources-compiling, redacting and acculturating them-in order to develop a magico-medical tradition that was considered efficacious but also appropriate for the needs and wants of the Syriac Christian community.

Concerns have been raised over many years about both the number of teachers leaving the profession and those suffering from physical or mental ill-health, and the impact of this on students and schools as well as on teachers themselves. "Resilience" is a concept which has been used in many disciplines to explain why some people appear to have successfully navigated challenging situations, and teacher resilience has become the focus of a growing body of international research. Whilst it is often presented as a critical factor for teacher retention, student achievement and teacher wellbeing, there is no universal definition for teacher resilience, and relatively few recent empirical studies which seek the views of teachers on this concept. This thesis investigates the experiences of eight long-serving teachers in England (with careers ranging from 14 to 25 years) to gain a better understanding of what has sustained them through their teaching career, as well as the challenges they have experienced, and how this relates to current conceptualisations of teacher resilience. Teacher-created visual timelines were used to support in-depth interviews, where participants provided considerable detail about the complexities of their journeys as they navigated their careers. Interview and timeline data were analysed using a dual analysis approach to create detailed, complex and nuanced findings. Findings from this study indicate that teachers face multiple challenges throughout their careers, and these challenges are greatest when they involve more than one dimension of teachers' practical, cognitive and emotional workload. Teachers are sustained by a combination of environment-centred, role-centred and person-centred factors, with this mix of factors depending on context at different points in time. Findings highlight the impact of school leadership on multiple environmental factors within the school culture and conditions, whilst person-centred factors include teachers' approach to the role, encompassing agency, acceptance, hope and perseverance. This research also identifies the significance of transitions between schools as a critical moment of vulnerability, which has not previously received attention in the educational research literature. Findings also illustrate the individual nature of the relationship between teachers and their environments, and the temporal nature of the balance between challenges and supporting factors. By suggesting teacher resilience is both idiosyncratic and dynamic, this research indicates that both teachers and schools may benefit from better understanding the factors which have the greatest impact on individual teachers at a particular moment in time. Other implications are also proposed for teacher trainers, schools and policymakers, and future directions for research are recommended.

Successful embryo implantation is a trade-off between a receptive endometrium and a good quality embryo. Endometrial glands are important for successful pregnancy, creating a favourable uterine environment for the implanting embryo. The 3D structure and gene expression profile of endometrial glands during endometrial receptivity are yet to be determined. The European Society of Human Reproduction and Embryology guidelines suggest recurrent pregnancy loss occurs in approximately 2% of women. While the pathogenesis of recurrent pregnancy loss remains unclear, it has been associated with reduced endometrial gland secretions and altered endometrial receptivity. In this thesis, multi-modal 3D imaging and RNA sequencing are applied to the endometrium from control women and women with recurrent pregnancy loss, to identify 3D structural alterations and a gene expression profile of endometrial glands during the implantation window. This thesis takes a multi-scale approach to investigating endometrial glands. Beginning with the relationship between endometrial glands and endometrial stromal cells in whole endometrium, investigating endometrial glands only, and finally glandular ciliated cell components. This thesis used 3D imaging to further our understanding of the spatial relationships between stromal cells and endometrial glands and their relationship to recurrent pregnancy loss. Quantitative 3D distance maps demonstrated for the first time that endometrial cells from women who experience recurrent pregnancy loss have altered 3D spatial relationships compared to controls. This 3D spatial information may help understand the underlying biology and the changes that are observed in disease states. Endometrial function may underlie a range of fertility disorders and these 3D imaging approaches could ultimately lead to more informative diagnostic testing and new treatments. 3D imaging provided insight into glandular structure and was combined with high-speed video to quantify endometrial gland cilia movements. This study made a number of observations that would not have been obvious from 2D imaging. One of these was that microvesicles appear to be forming on the tips of glandular microvilli. Secretion of glandular microvesicles into the uterine lumen may help mediate a favourable uterine environment during embryo implantation. The microvillus surface of the glandular lumen was interspersed with ciliated cells. The role of glandular cilia is not clear but it is hypothesised that they may facilitate the movement of microvesicles to the uterine lumen. The cilia beat pattern observed in endometrial glands from controls and women with recurrent pregnancy loss however, was uncoordinated. High-speed video could be developed in the future and provide a fast diagnostic of glandular cilia function. This thesis used 3D imaging and RNA sequencing to further our understanding of the gene expression profile of endometrial glands and glandular beta-tubulin from women with recurrent pregnancy loss. Differentially expressed genes were identified in endometrial glands from women with recurrent pregnancy loss compared to controls and beta-tubulin enrichment in glandular ciliated cells was established. Combined 3D imaging and gene expression analysis also demonstrated that beta-tubulin isoforms were altered on a gene transcript level and a protein level in endometrial glands from women with recurrent pregnancy loss. Combining 3D imaging and gene expression data allows gene expression changes to be located in endometrial tissue. Teasing out beta-tubulin changes in the glandular ciliated epithelium could lead to specific endometrial gland biomarkers of a recurrent pregnancy loss phenotype. This multi-scale and multi-modal approach has established a four dimensional view of endometrial glands during the window of implantation. Alterations in the endometrial gland architecture and their spatial relationship to the endometrial stroma could be associated with recurrent pregnancy loss. This new approach can be applied to other patient groups who suffer from unsuccessful pregnancy, such as infertility and recurrent implantation failure, and in future, contribute to the development of diagnostics.

This thesis argues that a sense of nation and race emerged within a global, eighteenth century East India Company world. Taking as its starting point the premise that identity matrices formed and reacted in concert with each other across the globe, the thesis contends that the eighteenth-century Indo-Persian culture of Bengal acted upon the Company elite. With their multicultural lifestyles these Company men transgressed the norms of their homeland. At the same time, a belief in the moral superiority of British sovereignty as it manifested through Company rule, helped these Britons to distinguish themselves from both Europeans and Bengalis in South Asia. Using imperial biography as the vehicle, the thesis interrogates these global forces through the cultural symbols that one man, the East India Company servant and Governor General, John Shore, adopted and the codes of conduct that he followed. The thesis examines his public papers, Company minutes and private letters to triangulate the historical forces that made this Briton in empire. After 1785, with an evangelical conversion, marriage to an English wife, and the impeachment of Warren Hastings, Shore began to reacquaint himself with his nation of origin. At the same time, he started to reframe his Bengali identity, as something to condemn and expunge. When he rose to the Supreme Council in 1786 and then to Governor General in 1793, as a man of influence Shore returned his representations of nation and race back to Britain through his public writings and acts. This thesis contributes a person-centred methodology to the analysis of the global forces of history. It shows that by unravelling the meanings of the cultural signs that elite, imperial men seeded into their public and private writings, historians can dissect the mechanisms of colonial power.

This thesis examines the nature of attitudes held by students, members of the public, and volunteers towards individuals who have been convicted of a sexual offence, and considers the importance of better understanding these attitudes. This is explored within a group of individuals who volunteer within a community-based initiative providing support to those who have committed a sexual offence, along with their motivations for initially choosing to volunteer in such a programme. The experiences of those individuals within the programme who have been convicted of a sexual offence (Core Members) are also reviewed. Chapter 1 presents a general introduction to the concepts of sexual offending, Circles of Support and Accountability (CoSA), and attitudes. Chapter 2 consists of a literature review regarding the experiences of Core Members (CMs) participating in a CoSA. Chapter 3 then presents a critique of a scale designed to measure attitudes towards individuals who have been convicted of a sexual offence and examines its validity, reliability, and the way in which it has been used within research. Chapter 4 presents an empirical research study regarding volunteers within CoSA. Their attitudes towards people who have committed a sexual offence are assessed and compared to both undergraduate students and members of the wider public. Their perceptions are also measured following exposure to vignettes depicting different types of sexual offences. Volunteers' motivations for joining the programme are also considered through Thematic Analysis. Additional reliability data regarding the attitudinal measure, the Attitudes towards Sexual Offenders scale (ATS; Hogue, 1993), is then presented within this chapter. Finally, Chapter 5 presents an overall summary of the thesis. The implications of the main findings are discussed, as well as potential directions for future research.

We are now in the era of high precision particle physics, spurred on by a wealth of new data from the Large Hadron Collider (LHC). In order to match the precision set by modern experiments and test the limits of the Standard Model, we must increase the sophistication of our theoretical predictions. Much of the data available involve the interaction of protons, which are composite particles. These interactions are described by combining perturbative Quantum Chromodynamics (QCD) with parton distribution functions (PDFs), which encapsulate the non-perturbative behaviour. Increasing accuracy and precision of these PDFs is therefore of great value to modern particle physics. PDFs are determined by multi-dimensional fits of experimental data to theoretical predictions from QCD. Uncertainties in PDFs arise from those in the experimental data and theoretical predictions, as well as from the fitting procedure itself. Those in the theory come from many sources. Here we consider two of the most important: the first are missing higher order uncertainties (MHOUs), arising due to truncating the predictions' perturbative expansion; the second are nuclear uncertainties, due to difficulty making predictions in a nuclear environment. In this thesis we consider how to include theory uncertainties in PDF fits by constructing a theory covariance matrix and adding this to the experimental one. MHOUs are estimated and included as a proof of concept in next-to-leading order PDFs. We find that these capture many of the important features of the known PDFs at the next order above. We then investigate nuclear uncertainties, estimate their magnitude and assess their impact on the PDFs. Finally, we consider how to make predictions with theory uncertainties using PDFs which themselves include theory uncertainties. Here there are correlations between the PDFs and the predictions, which can lead to a shift in the predictions and their uncertainties, which can significantly improve their accuracy and precision.

Immunity and metabolism are closely intertwined. Immune responses are resource-demanding and metabolic changes are therefore required to the supply the immune system with the required energy and raw materials. In pathological infections where the immune response becomes dysregulated, these metabolic changes can contribute to pathology. Work using the model organism Drosophila melanogaster has been productive in uncovering how the immune system regulates metabolism, but details of actual metabolic changes that occur during infection, and their functions, are poorly known. This project sought to uncover the metabolic changes that occur during the Drosophila innate immune response to infection and understand the consequences of these changes. By combining mass spectrometry-based metabolomic analysis with the genetic analysis of Drosophila, I found that the immune response to systemic bacterial infection caused an increase in nitrogenous waste metabolism. Further investigations suggested that this increase in nitrogenous waste is due to an increase in the upregulation of endogenous protein degradation via an ESCRT-III mediated process. Expression of CHMP2B, encoding a core ESCRT-III component, was indicated to be required in the fat body for optimal translation of antimicrobial peptide transcripts. Together these data suggest a model in which the fly upregulates endogenous protein degradation in order to rapidly provide in-demand amino acids for immune effector production, with catabolism of the resulting excess amino acids causing an in increase in nitrogen waste metabolism. This project has thus revealed a profound metabolic change induced by a successful immune response in Drosophila. As the cost of this change is the degradation of the host's own protein, this a probable mechanism of metabolic pathology in the context of a dysregulated immune response. Studying the etiology of such metabolic pathology will contribute to our understanding of conditions underpinned by metabolic dysregulation, such as sepsis and infection-induced cachexia.

Background Maternal mental health problems and substance misuse are key risk factors for child maltreatment and are common among children entering care in England. Better evidence about the health needs of women whose children enter care is needed to inform prevention and service responses across the family courts, children's social care and healthcare. Methods I used area-level and person-level linked administrative data from health, children's social care and family justice in England. First, I performed an ecological analysis of the association between maternal health before birth and infant entry into care using national data. Next, I used linked mental health and substance use service use and family court data for 3226 women in court proceedings concerning their child(ren)s entry into care in the South London and Maudsley NHS Foundation Trust catchment. I generated evidence on the type, severity and timing of health problems and identified predictors for returning to court with a new child. Results Parts of England with higher prevalence of maternal history of mental health, substance misuse or violence-related hospital admission among births had higher rates of infant entry into care, adjusting for potential confounders. Among women in proceedings in the SLaM catchment, 66% (of 3226) linked to a SLaM patient record and 54% were known to SLaM before their first recorded set of proceedings. Women who linked had high rates of schizophrenia spectrum disorders, personality disorders and substance misuse, compared to other female SLaM patients. They also had two-fold higher expected mortality rates, adjusted for age, and higher rates of service disengagement. I found six common trajectories of SLaM inpatient and outpatient contact among women in proceedings, which revealed that many (53%) women had little or no service contact around proceedings despite most having a SLaM referral. I found that being younger, having a young child in proceedings, and having parental responsibility curtailed or terminated were most predictive of returning to court with a new infant. Conclusions Mental health problems and substance misuse are common among women involved in proceedings, with healthcare needs often acute and complex. Given the scale of this issue, family law and social care policy reform is needed to ensure adequate and timely treatment for maternal mental health problems.

Undertaking IELTS (International English Language Testing System), a high-stakes, on-demand English language proficiency test, is a rite of passage for many non-native English-speaking individuals to demonstrate linguistic readiness for academic, emigrational, or vocational ambitions in Anglophone countries. Some self-directed test-takers who lack awareness of how to prepare for and succeed in the Writing module solicit written feedback (WF) via social networking services on rehearsed writing, in the hope outside expertise can provide a judgment of written readiness, suggest ways to close gaps in performance, develop test-taking skills, and enhance familiarity with task expectations. The present case study explores how four candidates preparing for IELTS Writing Task 2 engaged affectively, behaviourally, and cognitively with asynchronous, electronic written feedback provided by the researcher and how their beliefs mediated such engagement. Data was collected over four months from two sources: three rounds of rehearsed essay writing and semi-structured interviews taking place after each round. The study found that, despite detailed written feedback that explained and exemplified required performance, engagement was insufficient to bridge deficits in written performance across the project. Cognitively, learners did not always understand the intentions behind comments or what actions to take to resolve problematic textual features within how the task is assessed, leading to restricted written progress. Behaviourally, meaningful improvements in lexicogrammatical accuracy were not apparent across compositions, while notable content changes between drafts meant many errors went uncorrected. Processing WF tended to be at the surface-level, accompanied by few supplementary learning activities that the participants deemed of limited value. Affectively, the WF was highly valued and deemed confidence-building, contributing an activating effect. A range of personal-, task-, and strategy-related beliefs, some of which appeared naïve or ill-informed, impacted on how the learners engaged with the WF. The implications for practitioners of IELTS Writing preparation and test-takers are discussed.

Official statistics and media reports highlight the high prevalence rate of sexual victimisation among young adults in the UK. However, academic research in this area is behind that of other countries, such as the United States, and investigations conducted in the UK fail to compare student and non-student populations. Using a Pragmatic philosophical foundation, as well routine activity theory and cognitive distortion theory as theoretical frameworks, the project aimed to better understand sexual victimisation and perpetration by identifying the prevalence rates among 18-30-year-olds, exploring the extent that demographical/risk factors are related to victimisation or perpetration, as well as identify how sexual consent is related to reported victimisation/perpetration. A mixed methodology was used in two phases to holistically explore the research questions by combining quantitative and qualitative methods. Phase one used a large-scale quantitative questionnaire in three parts (prevalence/demographical vulnerability, risk factors and consent), which was completed by 544 18-30-year-old adults. Each area of the questionnaire was analysed separately to highlight significant factors that were more common among reported victims or perpetrators of a number of sexual assault and rape types. Binominal logistical regression was then conducted in stages to determine the predictability of these factors on victimisation and the extent they can explain the variance between victims and non-victims. Significant factors included gender, marital status, dating app use and attitudes towards pornography. Phase two then built upon phase one by conducting two focus group discussions with 8, 18-30-year-old adults concerning their thoughts and observations surrounding phase one findings. The discussions yielded interesting themes, such as those who are vulnerable to assault or rape and the dangers of sexting and online dating etc. As a result of these findings a visual model of victimisation and perpetration was developed. The implications of this project are the contribution the findings have to our theoretical understanding of sexual victimisation/perpetration among a young adult population and provide information that can be used in support/prevention strategies, as well as highlight how a mixed methods approach can be beneficial.

The appalling failings at the Mid-Staffordshire trust highlighted by Francis in 2013, prompted a renewed focus upon compassionate healthcare. Consequently, compassion and delivering compassionate care, although, not a new concept in midwifery, formal study in undergraduate curricula is relatively novel. Therefore, those responsible for undergraduate courses, have needed to consider how students may be educated about and for compassion. As midwifery education involves practice learning, consideration also needs to be given to this aspect. This presented an opportunity to learn from midwifery students who were about to, or already had been formally taught about compassion and who had spent varying lengths of time in their midwifery practice placements. A mixed methods approach was utilised and included: data collection via a free writing exercise prior to new students' studying about compassion. Students in all years of the course were surveyed via a self-completion questionnaire, including questions eliciting both qualitative and quantitative data. Finally, focus groups comprising three semi-structured interviews were facilitated separately and with a sample of volunteer students from all years of the midwifery course. Thematic analysis was used to interpret the qualitative findings. Wenger's (1998) Communities of Practice, Social Learning Theory offered a useful lens to make sense of and analyse the data's findings. The quantitative data show to what extent the students reported that being taught about compassion had increased their understanding. Furthermore, it shows how much or how little being taught about compassion had prepared the students for clinical practice and subsequently to what degree clinical practice had informed their learning about and for compassion. The results show that the majority of students reported formal study about and for compassion had increased their understanding. The midwifery practice placements also supported students' learning about and for compassion. Therefore, the formal teaching about compassion during undergraduate midwifery education is recommended. Three distinct yet interrelated phases emerged and the findings show that students' brought their pre-professional life experiences to the classroom and clinical practice; they continued to learn both formally and informally, depending upon the situations they found themselves in. These findings have significant implications for students, midwifery educators, clinical midwives supporting student learning and Heads of midwifery who have an overall responsibility for students' practice learning in the maternity services.

The overarching theme of this thesis was to explore if and how sexual reproduction in fungi could be exploited for disease control and strain improvement. Work focussed on two distantly related members of the Pezizomycotina; Pyrenopeziza brassicae, an important pathogen of Brassica napus (oilseed rape) and other Brassica species; and Penicillium roqueforti, the famous species used for commercial production of blue cheeses. First, investigations were undertaken to characterise a putative lipid hormonal compound, "Sex Factor" (SF), involved in controlling the switch between asexual and sexual reproduction in Pyrenopeziza brassicae, the causative agent of light leaf spot in Brassica plant species. SF shows promise as a novel disease control agent because of its reported ability to repress asexual sporulation, an important factor in the spread of disease. Crude SF was extracted from mated cultures of P. brassicae and it was confirmed via bioassays that extracts were able to repress asexual sporulation in this species. By contrast, asexual sporulation of North American "Lineage 2" isolates of P. brassicae was unaffected by SF. Biochemical purification work including the use of LC-MS then identified 16-(β-D-Glucopyranosyloxy)-2,15-dihydroxyhexadecanoic acid as a putative candidate for being an active component of crude SF. Finally, progress was made towards identifying key genes which may be involved with regulation of asexual and sexual development. Overall, this work has provided new insights into the asexual and sexual biology of P. brassicae, and laid the groundwork for developing new methods of disease control against this important fungal pathogen. Secondly, investigations were made to characterise sexual progeny of Penicillium roqueforti. A sexual cycle has only recently been discovered in this species, and therefore it was of academic and of commercial interest to determine whether sex can lead to the production of progeny with novel characteristics relevant to blue cheese production. Four pairs of parental isolates and respective progeny were screened for proteolytic activity and lipolytic activity, and production of certain secondary metabolites. It was found that up to 91 % of progeny had altered proteolytic activities and up to 55 % had altered lipolytic activities, compared to parental isolates. No progeny were found to have novel secondary metabolite production capacity, although significant variation was detected, suggesting novelty may be found with further screening. Thus, it was demonstrated that strains of P. roqueforti with alterations in desirable characteristics can be generated via the sexual cycle. These results may encourage the use of sexual reproduction for strain improvement of this species and other species used in industrial settings. Third, work was undertaken to characterise lipase genes involved in blue cheese maturation given that the genetic basis of the lipolytic system of P. roqueforti, the most important factor in determining the flavour of blue cheese, was largely unknown. Nine putative lipase genes were identified in silico, five of which were found to be more than two-fold upregulated in model blue cheese conditions. Concurrently, a "laboratory strain" of P. roqueforti (ku70::pyrG) was developed which allowed for more efficient genetic manipulation than would be possible using a wild type strain. This laboratory strain was then used to generate lipase knockout strains which led to the identification of two genes, lipD and lipI, which encode for lipases that likely constitute the main extracellular lipolytic activity of P. roqueforti. Finally, the expression of these key genes was determined in parental isolates and sexual progeny of P. roqueforti. Novel expression profiles were found for lipD, indicating that sexual reproduction can lead to variation in lipolytic activity by alteration of gene expression. The development of a laboratory strain more amenable to genetic manipulation will be of interest to researchers working on this species who can now conduct genetic characterisation studies more easily. In addition, identification of lipD and lipI will allow more specific screening for strains which show desired expression levels of or mutations within these genes, and could therefore be of interest to blue cheese producers.

Natural Flood Management (NFM) measures are being implemented across the UK and Europe in an effort to reduce flood impacts in a cost-effective and sustainable manner. Presently, NFM measures are often constructed without consideration of their geomorphological impact. There is also little evidence for NFM measures such as Runoff Attenuation Features (RAFs), which include leaky barriers, having an impact at larger (> 10 km2) catchment scales and for extreme events (> 100 year return period). This thesis examines both the hydrological and geomorphological effects of RAFs through; (i) morphodynamic modelling of RAFs of differing shapes, sizes and quantities at catchment scale (~41 km2) for an extreme event (120 year return period), (ii) comparison between a morphodynamic model and geomorphological processes estimated from outputs of a hydraulic model, which enables (iii) hydraulic modelling of differences in leaky barrier design. The results indicate that a RAF can be designed to increase water storage and floodplain connectivity. However, hydrologically beneficial designs can produce erosion and deposition and scour to the feature itself. These effects are all localised and at catchment scale no notable peak discharge reduction was observed. Thus relying solely on RAFs will only likely reduce localised, low magnitude flooding and future research should look to strengthening this argument alongside increasing understanding of structure failure within networks of RAFs. Qualitatively, the geomorphological outputs derived from CAESAR-Lisflood (a morphodynamic model) and HEC-RAS 2D (a hydraulic model) agreed with each other. However, methodological refinement is needed before hydraulic model outputs can be repurposed into geomorphological process estimations on a wider, national scale with little detailed validation. Overall, the HEC-RAS 2D methodology should be used to consider local problems requiring a high spatial resolution including changes in infrastructure design. CAESAR-Lisflood should be used to consider catchment dynamics and where NFM measures induce bed morphology changes.

This thesis investigated positive and negative sleep appraisals for excessively long and short sleep duration disturbances commonly experienced by those with bipolar spectrum mood swings. Chapter 1 provides a background of the literature and the proposal of the Integrative Cognitive Sleep Model (ICSM). The ICSM is a subset of the Integrative Cognitive Model and proposes that positive and negative sleep appraisals for excessively long and short sleep durations play a key role in the development and maintenance of insomnia, hypersomnia and reduced need for sleep. Specifically, endorsing more of these conflicting appraisals will drive sleep fluctuation. Chapter 1 outlines the aims and hypotheses designed to test this new model while Chapter 2 is a review of the methodologies undertaken in order to achieve the aims and hypotheses. Study 1 (Chapter 3) provides a scoping review of the literature to identify the available sleep cognition measures. This study highlighted a significant gap in the knowledge base since no measures were identified for hypersomnia or reduced need for sleep. Study 2 (Chapter 4) is a Delphi method study with research and clinical professionals in the field of BD to generate appraisal statements for a new measure that will aid in testing the proposed ICSM. The statements generated in Study 2 informed the new Positive and Negative Sleep Appraisal Measure (PANSAM). Study 3 (Chapter 5) is a series of validity and reliability statistical tests to establish initial psychometric robustness for the PANSAM. The results highlighted four expected subscales: positive and negative appraisals for both short and long sleep durations. Study 3 also evidenced good convergent validity with validated measures for mood, sleep, and mood and sleep cognitions. Study 4 (Chapter 6) was a clinical study with participants who met criteria for either bipolar spectrum, unipolar depression or were non-clinical. It was hypothesised the PANSAM would discriminate between all three participant groups, with higher scores for those in the bipolar spectrum group due to their increased vulnerability to mood and sleep disturbances. This hypothesis was only partially supported since there was no statistically significant difference between the clinical groups, but both had statistically significantly higher PANSAM scores than the non-clinical control group. Finally, the ICSM was tested more directly in several different ways. Study 3 (Chapter 5) conducted a hierarchical regression to test the incremental validity of the PANSAM on subjective poor sleep quality, over and above age, gender, bipolar tendency and a commonly used sleep cognition measure for insomnia. The results highlighted the subscale for positive appraisals for sleeping more (representing sleep as a safety behaviour) was significant. To test the ICSM more robustly, Study 5 (Chapter 7) was devised to test the hypothesis that the PANSAM would predict subjective (sleep diary) and objective (actigraphy) total sleep time variability. Additionally, a second hierarchical regression was conducted in this study to test the incremental validity of the PANSAM on the sleep variability variables over and above bipolar tendency and the same commonly used sleep cognition measure for insomnia. The results of Study 5 (Chapter 7) showed the PANSAM was statistically significantly predictive of objective total sleep time variability only but did not uphold incrementally. The findings from these studies suggest the PANSAM offers unique contributions to sleep cognition research. Clinical implications and future research ideas are discussed.

This thesis focuses on fast and sensitive readout of mechanical motion to answer questions in the foundations of physics. By coupling a silicon nitride membrane to different readout cavities I have explored the thermodynamic costs of time keeping and carried out a bench-top experiment to put bounds on the theory of classical channel gravity. In order to reach these aims, I have developed real time displacement measurements of the motion of a nm-thick silicon nitride membrane. For this, a lumped element LC circuit is capacitively coupled to the metallized silicon nitride membrane. This approach allows for the estimation of key parameters without the need for frequency matching or cryogenic cooling. I demonstrate electromechanical characterization of several mechanical modes of the silicon nitride membrane. In addition, I show optomechanically induced transparency on chip in this high loss cavity. The real time displacement measurements of the membrane's motion allow the device to be operated as a thermomechanical clock and to be used to investigate a thermodynamic trade-off in a nanoscale clock. The system follows a trade-off derived for the idealised quantum setting, indicating a fundamental universality of a relation previously predicted to hold in the quantum regime. This system is compatible with cryogenic temperatures, allowing me to actuate and detect the resonance frequency of a membrane at low temperatures. At these temperatures, one can perform tests of the theory of classical channel gravity which models the gravitational interaction as a classical measurement channel. The theory predicts a density dependent heating effect due to the gravitational interactions within the membrane itself. Bounds could be put on this theory using a membrane capacitively coupled to a 3D superconducting microwave cavity which has a much higher Q factor than the LC circuit. With this cavity, I achieved 10 mHz resolution of the mechanical signal, which is required for an accurate estimation of the mode temperature and thus to put bounds on the theory.

This study sits within a wider research agenda, the aim of which is to develop a novel psychological therapy programme designed to target hopelessness and compromised self-esteem in young people recently diagnosed with a psychotic illness. The aspiration is to develop a programme that is experienced as accessible and engaging and perceived to be of value. It is anticipated that that process will progress through several stages and a number of iterations. The primary objectives of this specific piece of research were to undertake a first piloting of the Therapy Programme, gather evaluative feedback from participant-service users, and fine-tune the approach. The secondary objective was to explore the perceived value of the programme with regard to ‘proof of concept’. The research design combined the methodological rigour of Interpretative Phenomenological Analysis with a mixed-methods focus on data, underpinned by the philosophical paradigm of critical realism. Quantitative data was collected through the completion of outcome measures pre, during and post-therapy. Qualitative data was gathered through the facilitation of semi-structured feedback interviews with participant-service-users shortly after the completion of each of their Therapy Programmes. Participants were followed-up at 2 years from the commencement of their therapy to ascertain the subsequent trajectory of their lives and to explore reflections on their experiences of the programme from a perspective of temporal distance. Eight Early Psychosis Service clients were recruited to receive the Therapy Programme. Three withdrew from the therapy. Another completed the Programme, but failed to complete all of the research requirements. One completer-participant experienced a psychotic relapse shortly before the end of therapy. The principal purposes of the research were the elicitation of critical reflections on the Therapy Programme and meaningful recommendations for its improvement. There was some evidence of reticence amongst participants regarding the expression of critical statements. Where more critical observations were expressed, they focussed primarily on the relative balance and chronological ordering of different elements. The consensus recommendation was for the ‘pure’ elements of the approach, including direct attention to the cognitive-constructs of hope and self-esteem, to proceed the consideration of more applied goals. There was a strong collective recommendation to allocate more attention to addressing unhelpful illness narratives. A Participant Handbook, written as a resource for those involved in the therapy, was positively received with regard to design. Participants, however, recommended significant change to the complexity of its content. Of the four completer-participants, three showed substantial improvements in reported hope, self-esteem and wellbeing over the period in which the therapy was delivered. Those gains were sustained at follow-up. The participant who experienced a psychotic relapse showed limited improvements on all measures at the end of the treatment period, but had progressed significantly at follow-up. In each case, reported scores on the outcome measures were supported by substantial success in negotiated life-goals. Participant feedback regarding the programme, post-therapy and at follow-up, was generally very positive, with all participants identifying causal connections between the therapy, achievement of therapy and life goals, and subsequent improved outcome scores. To accommodate a priority focus of qualitative data, participant numbers were small and there was no access to normative or comparative data for the service user population. The limitations of the sample size were compounded by a high rate of attrition. The delay to follow-up introduced additional confounding variables. As a consequence of the study-design, therefore, quantitative data can only be regarded as providing indicative evidence of reported improvements across the measures of wellbeing. It cannot be said to evidence a causal connection between therapy and identified improvements or to support statements regarding the efficacy of the approach. Finally, although participants were recruited explicitly to be collaborators in the evaluation and betterment of the Therapy Programme, reflections appeared to be somewhat biased towards a validation of the approach and critical evaluations, although present, were limited. The credibility of these observations is, further, undermined by the design-decision to have the therapist conduct the post-therapy feedback interviews. The primary objective of the research was to generate meaningful recommendations for the improvement of the Therapy Programme. That purpose was achieved. The secondary objective was to consider the programme with regard to ‘proof of concept’. Subject to the limitations detailed above, the level of improvement reported over the period in which the therapy was offered, together with the fact that those gains had not been lost at follow-up, tentatively supports an argument for further development of the programme.

Globally, practical approaches to managing flood hazards are moving away from mitigation solely at the point of the impact, and towards an integrated catchment-scale approach which considers flood source areas, flow pathways of flood waters and impacted communities. The current method for managing the fluvial flood risk in Nepal, however, generally involves localised structural interventions in affected areas using a static and reactive approach. This method does not create long term resilience to the hazards. There is therefore the need to rely less on these large-scale structural measures and focus instead on sustainable and non-structural measures for flood mitigation that allow the catchments and communities within them to be more resilient. The three-stage, end-to-end approach developed in this thesis provides a process to help shift towards an integrated catchment management for flood hazard reduction in Nepal. The approach centres on identifying flood water source areas within the catchment and spatially targeting flood management measures in these locations. Consideration is also given to the potential impact of future, flow magnitude increasing, land cover change such as deforestation and the abandonment of terraced agriculture that is evident in many Nepali catchments. Stage 1 adopts SCIMAP-Flood, a catchment-scale decision support framework that identifies critical source areas for flood waters. The framework uses maps flood water generating areas based on spatial rainfall patterns and land cover, the incorporation of travel times across a catchment, and modelling of hydrological connectivity. Outputs are used to create catchment-scale flood management scenarios which target flood source areas; tested flood management measures include targeted afforestation, check dams in key sub-catchments and abandoned terrace restoration. In Stage 2 the flood management scenarios are assessed using CRUM3, a physically-based, spatially distributed, catchment-scale hydrological model. The impact of the flood management measures can be evaluated throughout the catchment using the modelled change in discharge. Stage 3 uses LISFLOOD-FP, a 2D flood inundation model, to establish the change flood inundation patterns at key flood impacted communities within the catchment from the created flood management scenarios. Stage 2 and Stage 3 utilise a coupled hydrological-hydraulic modelling approach with the results from the CRUM3 model entering the LISFLOOD-FP model as inflow hydrographs. The approach is applied to the East Rapti catchment, a 3,084 km2 sub-catchment of the Nayarani River in southern central Nepal. The catchment contains three river flow gauges (Lothar Khola [catchment area - 169 km2], Manahari Khola [427 km2] and Rapti River [471 km2]) placed within the main sub-catchments and eight rainfall gauges. Additional data used to drive the approach was attained from global datasets and acquired during fieldwork. This thesis has researched the potential effectiveness of the implementation of flood management interventions at the catchment-scale and evidences an alternative approach to flood management that is applicable in both Nepal and the wider Himalayan Region. Based on the integrated modelling approach, the results predict that the high flow magnitudes in the East Rapti catchment can be reduced through a catchment-scale approach. However, even with a combined approach of large scale spatially targeted afforestation and check dam implementation (Q99.9 decrease of ≤5.3%), the use of solely catchment-scale flood management approaches to combat flood hazard might not be effective at reducing the flood impact to at-risk communities. A significant outcome from the catchment-scale modelling work was that there is a far greater potential for land use change to increase, rather than reduce through mitigation, flow magnitudes in the East Rapti catchment. The model results suggest that any land within the East Rapti catchment that is altered from existing forest will contribute to increasing the flow magnitude (Q99.9 increase of up to 48.2%).

In complex unstructured environments such as under the canopy of densely forested areas, autonomous and intelligent unmanned aerial vehicle (UAV) flight continues to be an unaddressed challenging problem. The main predicament in the development of a system supporting autonomous and intelligent fly lies primarily due to the lack of an available dataset. During this research, a method was developed to enable rapid data labelling in real-time, which is suitable for data gathered from most mounted cameras (handheld, ground vehicles and/or UAV), regardless of their resolution. Leveraging this dataset creation capability, the proposed trail following approach outperforms the state-of-the-art approaches for trail navigation within a complex forest canopy environment. Additionally, extensive testing demonstrated that the proposed approach does not suffer loss of performance even when replacing the camera between flights. Another issue with navigating in such an environment (i.e. under the canopy) is the lack of generalisation across varying domains (i.e. farmland, deserts, savanna etc). This is further aggravated by seasonal environmental variations such that a model trained during summer will not be generalised to the same environment during the winter. To solve this issue a multi-task approach presents a deep neural network which eliminates the need to follow a trail, by providing the UAV with the ability to identify the safest area to navigate, regardless of the existing altitude and whether or not a trail is visible in the scene. This new approach increases the navigational control from three to six DoF (Degrees of Freedom). Furthermore, the final results demonstrated superior performance for navigation than the comparators approach. Besides autonomously navigating in the environment, an intelligent UAV is expected to increase its resourcefulness by mapping while simultaneously exploring the environment. This would facilitate the commencement of search and rescue operations to be carried by either one or a swarm of intelligent UAV. This research entailed the development of a grid-based map that can store the position of obstacles and trails within the search area, while allowing onboard processing. Additionally, this approach adopts a hybrid network that combines Reinforcement Learning and Online Learning to improve navigability, exploration and adaptability to unseen environments, thus allowing search and rescue operations to be extended without requiring offline training. Overall, this research aims to investigate new and efficient ways for intelligent UAV to perform an end-to-end operation and achieve real-time mapping and autonomous navigation in an unstructured environment. The findings in this research are important in that they culminate into three extensively tested approaches for navigation and exploration that can be deployed either on a ground control station or on-board of a UAV.

Nuclear fusion, a potentially world-changing energy source, has been the subject of dedicated research for over half a century. With a focus on scientific research, development has principally been via publicly funded programmes led by government laboratories in which strategy and innovation are largely overlooked. Consequently, and without intention, the commercial aspects of development on such programmes are left until later, and routes that are not well-suited to commercialisation are pursued. The recent emergence of privately funded fusion start-ups with the explicit goal of commercialisation is disrupting the fusion innovation paradigm. The purpose of this thesis is to characterise the fusion start-up innovation approach and to apply Technology Roadmapping to help fusion start-ups overcome challenges in the commercialisation process. Strategic challenges in the availability, supply, and use of critical natural resources are specifically analysed. The research takes an interdisciplinary engineering systems approach, using mixed methods to connect innovation, technology management and strategy to the fusion paradigm. The thesis deploys innovation theory via contextual analysis, with parallels to the space exploration sector, to find that fusion start-ups operate on an agile innovation model. Technology Roadmapping is applied to a fusion start-up case study with Tokamak Energy Ltd, and the process is adapted to the hardware-based agile innovation approach. The impact of roadmapping on planning, innovation management and communication are examined. Via forecasting models and literature-based analysis, key commercial challenges for critical fusion resources – specifically deuterium, tritium, lithium-6, beryllium, lead and helium – are characterised. A new innovation space for commercial tritium breeding blankets is identified. In conclusion, this thesis characterises a paradigm shift in fusion commercialisation. It provides a framework for the innovation approach, an applied roadmapping process, and highlights key resource criteria yielding recommendations to drive commercial fusion missions forward.

This thesis investigates the emergence of the Green Party in the United Kingdom from its creation in 1973 up until the 1979 general election. The party was first called PEOPLE, then the Ecology Party from 1975 before changing its name again to the Green Party in 1985. The thesis focuses upon the creation and early history of the party, considering the reasons for its emergence. Studies of the UK Greens have examined several areas including their membership, ideology and internal structure. They have not considered in detail the question of why the party emerged. There are more general theories and ideas about the emergence and development of green parties as a phenomenon across numerous countries. Not only do such accounts fail to fully engage with the specific details of the UK case. They have also been the subject of comprehensive criticism, calling into doubt their broader merit as explanations for the emergence of green parties. This thesis employs historical methods to provide insights into the causes of the party’s coming into being. It focuses in particular on the party’s founders and early members, looking at their background, the influences on their thinking, and their perceptions, ideas and views. Two main types of sources have been used which together represent the most comprehensive study of the party’s history to date. First, 50 oral interviews were conducted with individuals who joined the party between 1973-79. Most of these participants had never previously been interviewed for research into the party. Secondly, thousands of archival documents relating to the party from this period, which were retrieved from public archives and personal collections of papers, have been consulted. A considerable amount of this archive material had not previously been accessed by researchers. The thesis rejects monocausal explanations for the party’s emergence. Instead it identifies several important motivations. It does, however, place particular emphasis on some dynamics in the period leading up to and during the party’s inception: the increase in concrete environmental problems as a result of population growth and economic development, increased public and media attention on the environment and, in particular, the emergence of an environmental or ecological ideological project without which the party’s existence simply would not have made sense. The first and most obvious original contribution to knowledge which this thesis makes is in enhancing understanding of the Greens in the UK. This is important because they have achieved the rare feat within the British party system of breaking out of obscurity and establishing themselves as a small but significant and, seemingly, stable force which therefore merits investigation. The nature of the method employed here, including extensive use of interviews and accessing longstanding party activists’ private papers, means this was one of the last chances to conduct such work. This thesis will provide a valuable record for future researchers. More generally, the party’s emergence during the 1970s was part of a wider set of developments in the form of the fragmentation of the UK party system, the emergence of a broader environmental movement in Britain and internationally, and the collective emergence of green parties across the world. All of these developments have had longstanding and significant political impacts. The research conducted for this thesis enriches academic understanding of them.

Carbohydrates are essential for bacterial survival. As well as being taken up and used as a carbon source, they are synthesised by bacteria to protect them from environmental stresses and assist in colonisation of new environments. Bacteria possess a range of mechanisms to modify the diverse carbohydrate structures that they synthesise, a key example being O acylation. Acylation of bacterial carbohydrates can have applications in processes such as antigenic variation, osmoregulation, virulence and cell division, and can also have transferrable applications in clinical and industrial processes. The aim of this research was to investigate the mechanism of carbohydrate O-acylation by Acyltransferase_3 (AT3) domain containing proteins OafA and OafB of the bacterial pathogen Salmonella. These proteins contain a membrane bound AT3 domain fused to an extra cytoplasmic SGNH domain. They O-acetylate different residues in the variable repeating carbohydrate O-antigen of lipopolysaccharide. The research presented in this thesis demonstrates that both the AT3 and SGNH domains are required for O-antigen acetylation in these proteins. It also highlights functional residues that support a conserved mechanism of transmembrane acyl group transport by AT3 domain-containing proteins, and suggests residues within the AT3 domain specifically adapted for function with a fused SGHN domain. Furthermore, structural and functional characterisation of the SGNH domain of OafA and OafB supports the hypothesis that this domain is responsible for the final step of acetyl group transport to the carbohydrate acceptor in this system, and also identifies how acceptor substrate specificity is achieved by this domain. These findings have allowed a refined mechanistic model for AT3-SGNH fused proteins to be defined, enhancing our understanding of an important family of acyltransferase proteins which are found across all domains of life. This work therefore provides a framework for understanding and potentially manipulating these proteins, to enable carbohydrates of clinical and industrial significance to be engineered.

The general acceptance of the – often fatal – risks associated with high–speed transport, can be seen as a global public health issue. In the UK, ‘survivors’ groups’ are condemnatory about the trivialisation of road death by a system of justice which overlooks victims’ rights and increases the suffering of the bereaved. For those who suffer the loss of a family member in a road collision, the traumatic and complicated grief they experience sees them as ‘co–victims’ of such a death. This difficulty is compounded when they find that the collision event is deemed to be non–culpable, forcing them to encounter part of the Justice System in England and Wales which is little known and less understood: the coronial system. As an administrative system encapsulating the inquest, the coronial system sets itself up to establish the ‘truth’ of how a person has died in order to categorise, commit to record and ultimately register a sudden death, while at the same time investigating without apportioning blame. From the moment of the death, through the initial coronial investigation and into the inquest hearing itself, a number of mismatches between what the bereaved expect – both morally and symbolically – from the State and what it seeks to provide, are apparent. Policymakers’ reforms and coroners’ comportment have attempted to balance these needs, and families’ ability to cope with their grief is moderated by their agency and outlook. However, in investigating whether the emotions of the bereaved were negatively impacted by the coronial system, this thesis examines the proposition that the process and the conduct of those working within it, amounts not only to an acceptance by the State of a road death, but moreover as a justification for it. In so doing, the thesis aims to confirm or deny the status of the bereaved not only as co–victims, but as secondary victims of that system.

Right iliac fossa (RIF) pain is the largest source of acute referrals to the general surgical take. Most previous studies concentrate on retrospective analysis of patients who have had an appendicectomy. This study has two aims. The first is to investigate the factors affecting the diagnostic pathway of all patients referred with RIF pain. The second is to implement and evaluate a clinical decision support tool (CDST) integrated into a specific RIF pain clerking proforma. All patients over the age of 15, without a previous appendicectomy, who were referred acutely to the general surgeons were eligible for the study. Data was collected prospectively on all patients during initial, pilot and implementation stages. 605 patients were included in the study. 292 patients were included in the evaluation of the clinical decision support tool. The majority of patients presenting with RIF pain do not have appendicitis. The most frequent diagnosis is non-specific abdominal pain. Use of the CDST significantly improved the agreement of the senior clinician plan with that of the junior clinician's plan (p≤0.0001). There is no change in the frequency of imaging requests with the CDST but the proportion of CT scans being requested by junior clinicians is significantly increased (p=0.0342). This study provides new and updated information on the factors affecting the diagnostic pathway of patients presenting with RIF pain. It is the largest study to look at this cohort and is more applicable to current practice than the previous studies. The implementation of a novel CDST has been shown to significantly improve the decision making of junior clinicians when used within a specific RIF pain pathway. Further work needs to be done with a larger study to look for further improvements to the diagnostic pathway and to understand and improve the poor uptake by junior doctors.

Street-involved children and young people in northern Tanzania have left home to make a life for themselves on the street. While they consider leaving home necessary for improving their prospects, many discover that life on the street is more challenging than they had expected. This research is based in northern Tanzania and, using grounded theory methodology, engaged 55 street-involved children and young people, former street-involved children, social workers and community members in group and individual interviews to learn more about the role relationships play street-involved children and young people's lives. Following nine months of fieldwork, data collection, open coding, constant comparison and theoretical abstraction, this thesis has identified four key areas of concern for street-involved children and young people in northern Tanzania. These four areas identify that; (1) children and young people after they leave home have broken the intergenerational contract with their families and are left responsible for meeting their own needs; (2) while children seem satisfied with the freedom and opportunity to earn money when they first arrive on the street, after time they aspire for better paid and well-respected jobs which are often inaccessible to them; (3) children and young people face certain change points during their life trajectories on the street; and, (4) after children have aged into young people, some become disenchanted due to their perceived lack of opportunities on the street and become involved in heavy drug use: the children and young people consider this 'giving up on life'. Underpinning the challenges that children and young people face on the street is an absence of someone who will share responsibility for them and grant them access to opportunities beyond the street. This thesis argues that providing street-involved children and young people with supportive relationships will expand their options and future prospects.

Volume one contains three research chapters. The first chapter presents a systematic review of the literature examining the outcomes of Dialectical Behaviour Therapy (DBT) for individuals with Intellectual Disabilities (ID). The second chapter is an empirical research study, exploring the experiences of DBT in a community setting for individuals with ID. The third chapter presents a public dissemination document, which provides a brief overview of the systematic review and empirical paper. An accessible summary of the main findings from the empirical paper was also developed for the individuals who participated in the research.

The absence of speech in Angelman syndrome is striking and widely recognised by those familiar with the syndrome but the specificity of communicative impairment is not well documented. This research delineated the expressive communication profile in Angelman syndrome, through comparisons to typical development and examining variability across the genetic aetiologies of Angelman syndrome, which were areas identified as requiring further research through a scoping review. In the second study, an informant-based report on speech and gestures showed that in individuals with Angelman syndrome, speech production was significantly impaired whereas gesture presence and use was comparable to that seen in typically developing children matched for comprehension. In an observational study, fine-grained analysis of gesture and prelinguistic communication in Angelman syndrome showed that these aspects emerged in a reliable and consistent pattern across individuals, which aligned with the emergence in typical development. However, this was not the case for speech. In all studies, differences across deletion and non-deletion aetiologies were found for gesture and prelinguistic communication, with individuals with a non-deletion aetiology having greater expressive communication abilities but both groups showing significantly impaired speech. Together, these findings identify an isolated speech production impairment in Angelman syndrome, which is dissociated from gestures and prelinguistic communication abilities and cannot be accounted for by level of disability. This research contributes to the understanding of the communication profile of Angelman syndrome and the role of the UBE3A gene in speech production.

Background: Fatigue is an important symptom for people with axial spondyloarthritis (axSpA). Current measurement relies on a single item visual analogue scale of fatigue severity that provides a limited assessment of fatigue. This thesis sought to improve the understanding and measurement of axSpA-fatigue and capture what matters to patients. Coupled with current evidence and patient and clinician involvement, I developed a novel patient-reported outcome measure (PROM) for use in both clinic and research. Methods: The four-phase mixed-methods research process was: i) a systematic review to identify whether there was a need for a new PROM; ii) phenomenology-based semi-structured interviews to develop a lived experience and measurement framework; iii) item (question) generation and refinement; and iv) a psychometric evaluation of the new PROM. A patient research partner group was incorporated throughout the project as co-producers of the PROM. Results: The systematic review identified 9 PROMs of limited quality and relevance to axSpA-fatigue. Interviews with patients identified 'achieving balance' as an active process of integrating axSpA symptoms and fatigue into daily life through three themes: having energy, engaging in everyday life and making sense of axSpA. Energy emerged as a related but distinct component in axSpA-fatigue experience. The measurement framework of axSpA-fatigue consisted of four domains (symptoms, impact, psychological/emotional wellbeing, self-management) which underpinned the content of a 30-item PROM. Psychometric evaluation showed that the PROM is good quality, producing a four domain (fatigue, energy, symptoms, control) 18-item short form version - the Warwick Axial Spondyloarthritis measure of faTigue and Energy (WASTEd). Conclusion: The WASTEd is a co-produced, axSpA-fatigue specific PROM. Its use will help make visible the work patients do to balance their axSpA and fatigue symptoms and support the development of appropriate interventions. Further psychometric testing of the WASTEd is required to determine evidence of its reliability (test-retest) and responsiveness.

Glioblastoma multiforme is the most frequently occurring primary brain tumour and it carries a dismal prognosis. Despite surgical intervention and aggressive chemo-radiotherapy the median survival of patients is just under 15 months. Very little progress has been made with regards to improving patient survival therefore novel therapeutic interventions are required. Vaccination offers an attractive option for the therapeutic treatment of GBM, with activated T-cells previously being shown to access tumours located within the brain resulting in improved survival in pre-clinical murine models of GBM. Several vaccine platforms have been developed and tested in GBM patients, however many of these therapies fail during clinical trials and as of 2019 no immunotherapeutic treatments have been approved for use in the GBM setting. One major obstacle to overcome when using the immune system to treat GBMs is the highly immunosuppressive phenotype these cancers have. GBMs frequently express immunosuppressive checkpoints that prevent anti-tumour T-cell activity. Immune checkpoint blockade has recently gained approval for the treatment of malignant melanoma, lung cancer, head and neck cancer, lymphoma, bladder cancer and kidney cancer. The utilisation of immune checkpoint blockade as a monotherapy improves survival in small subsets of patients however it is not a completely curative treatment modality. Therefore it is of great interest to see if combining immune checkpoint blockade with vaccine therapy can boost anti-tumour immunity by stimulating T-cells and preventing the inhibitory signals from tumour cells that prevent T-cell killing. Examination of GBM tumour tissues and cell lines revealed that a large proportion of GBMs express the immunogenic antigens Tyrosinase-related protein-2 (TRP-2) and Wilms’ tumour 1 (WT-1). It was also revealed that these tumours expressed several immunosuppressive proteins with PD-L1, HLA E and HLA-G expression being observed in tissues and cell lines studied. It was also revealed that when GBM cell lines were treated with the immune stimulating cytokine IFNγ they up-regulated the immunosuppressive proteins PD-L1 and IDO. The ImmunoBody® DNA plasmid vaccination encodes an IgG antibody molecule that acts as a carrier protein for the peptide targets of interest, these peptides are engrafted into the complementarity determining regions of the antibody. This method of vaccination generates a strong-immune response via direct and cross-presentation. Pre-clinical testing using the humanised HHDII/DR1 C57BL/6 mouse model revealed that a HLA-A2 specific TRP-2 and a HLA-A2 specific WT-1 directed ImmunoBody® vaccine generated a strong peptide specific immune response. When both vaccinations were given simultaneously this strong TRP-2 and WT-1 directed immune response was equivalent to when each vaccine was given alone meaning that epitope dominance is not a factor when targeting these two antigens. Using the HHDII/DR1 humanised mouse the effects of this dual ImmunoBody® vaccination regime was tested both prophylactically and therapeutically. In these proof of concept experiments the B16 HHDII/DR1 Luc2 cell line was utilised. This cell line expresses both TRP-2 and WT-1 antigens and it has the chimeric HLA-A2 HHDII/DR1 MHC molecule meaning it presents HLA-A2 specific peptides. When the dual ImmunoBody® vaccination regime was used prophylactically it significantly improved the survival of mice intracranially implanted with B16 HHDII/DR1 Luc2 cells compared to sham vaccinated mice. In the therapeutic setting the addition of an anti-PD-1 blocking antibody to the dual vaccination regime improved survival of B16 HHDII/DR1 Luc1 tumour bearing mice when compared to dual vaccinated mice receiving PD-1 isotype control antibody and control sham vaccinated mice that received PD-1 isotype antibody. Analysis of tumour infiltrating lymphocyte populations revealed that dual vaccination increases CD8+ T-cell infiltrate into these intracranial tumours with these cells showing increased cell surface expression of the activation markers CD25 and CD69. The dipeptide carnosine was also used to treat GBM cells in vitro, this molecule has previously been shown to have anti-tumour activity. When carnosine was used to treat GBM cells it led to reduced mitochondrial metabolism and migration of these cells. These properties make carnosine an attractive adjunct to immunotherapy. Overall these results provide promise for the use of ImmunoBody® vaccination with immune checkpoint blockade for the treatment of GBM. Whilst immune cells can actively access tumours systemically administered checkpoint antibodies don't cross the blood-brain-barrier freely, therefore in order for these therapies to be further developed methods for improving brain penetrance of checkpoint inhibitors needs to be explored.

This thesis constitutes an explanation for how a reconceptualization of primary physical education (PPE) as a practice of care might contribute to human flourishing and well-being. The research is presented as an account of what worked for me, as a teacher educator, as I investigated and theorised my PPE practice in higher education (HE) and in primary schools. In doing so, I aimed to generate understanding of new or improved processes that might encourage trainee and qualified teachers to become more confident and competent in their teaching of PPE, alongside greater understanding about what the concept `care' means and how it is practised. The thesis contains a narrative of personal and collaborative learning throughout three interconnected action research cycles. The guiding principles of action research, which seek to generate knowledge through collaborative research for personal and social improvement, provided the necessary means to realise my educational values of care, inclusion and emancipation in action and the development of caring relationships. Each cycle explores the emergence of a more humanistic-orientated practice as I moved from a conceptual form of caring about standards of teaching and people's performance within PPE, towards a more inclusive, trusting and communal practice that values the process of learning and encourages people to care with one another. The research presents the possibility for practitioners to critique their own practice to allow personal and professional tensions to emerge and be negotiated and tested, demanding appropriate and contextualised choices to be made in regard to the well-being of self and others. It also offers potential connections between personal values and research-based curriculum aims and purposes which may contribute to new forms of thinking among those teaching PPE, Higher Education personnel and policy makers, so a caring practice as a basis for social action for emancipatory change may develop.

This thesis is concerned with the interaction between assessment and agency. The context in which the research took place is an English for Academic Purposes (EAP) department of a UK university, specifically its summer pre-sessional courses which prepare and assess postgraduate international students' academic language for their degree programmes. The specific focus of this thesis is the negative impacts of academic writing assessment practices within this context on students' ability to a) exercise agency in learning and assessment situations b) conceptualise themselves as developing writers. The research was underpinned by a critical realist perspective, which allowed educational assessment to be seen as a layer of societal structure with the potential to enable and constrain individual and social agency. An action research methodology in iterative cycles over three consecutive years was employed to investigate and intervene. As a response to the negative impacts identified in a reconnaissance cycle in 2013, I designed and implemented a processfolio assessment for academic writing to facilitate student agency around assessment. The first intervention took place in 2014 with my own class of 14 students; the second in 2015 widened the participation to three classes (46 students) and three teachers including myself. Due to the necessity for flexibility in methods of data collection in this context, a range of methods and analysis was employed in each cycle. Data sets generated through both intervention cycles were the processfolios themselves and interviews with students and teachers. Benefits deriving from the processfolio were that students both demonstrated and reported high levels of self-efficacy and awareness of writing as a both a social practice and an individual metacognitive process. In keeping with the aims of action research underpinned by a critical realist approach to agency, the students showed a growing critical consciousness of the potential of EAP assessment to constrain or enable their understandings of writing, and their relationships with themselves, peers, teachers, and the academy. Participating teachers' tacit assumptions about assessment practices and EAP writing pedagogies were also disrupted. Moreover, through a reflexive process, my own understanding of the original intention of the processfolio shifted. For practical and philosophical reasons, it should not be a replacement assessment tool to foster better learning behaviours. Rather, I conclude that the processfolio should be used on the pre-sessional to mitigate the negative impacts of assessment by creating conditions for a continuous dialectic between agency and structure. These findings imply that this approach to action research in assessment writing in EAP can contribute to a greater understanding of the mediating conditions which shape assessment practices.

Hereditary spastic paraplegias (HSPs) are genetically inherited neurological diseases characterised by the distal axonal degeneration of corticospinal neurons. Of the 80 genes currently associated with HSP, mutations in SPAST, encoding the protein spastin, are by far the most common cause of pathology. Spastin functions as a microtubule remodelling enzyme by using energy derived from ATP hydrolysis by its ATPase domain. The location of this activity is governed by spastin's localisation domains which mediate recruitment to membrane sites including endosomes and the ER. In this thesis I aimed to elucidate the function of spastin at these sites, as well as to analyse the resulting effects on the cell surface proteome. Through this work, I have shown that spastin functions to mediate the fission of endosomal recycling tubule and have confirmed spastin's localisation to ER exit sites, but show using synchronised secretion assays that spastin is dispensable for generalised cargo secretion of at least 2 classes of secretory cargo. Finally, through quantitative cell surface proteomics, I show that mutation of spastin's ATPase domain induces substantial remodelling of the cell surface proteome, and through this have generated a list of pathological candidates whose change in surface abundance could drive the pathogenicity of spastin-HSP.

Purpose Investigate changes in retinal structure and function caused by multiple sclerosis (MS) using established and novel modes of image acquisition and analysis, in order to identify candidate biomarkers of disease. Use longitudinal analysis to determine the rate at which changes to the retinal anatomy occur and whether this rate-of-change alters throughout the MS disease course. Method Within the Anne Rowling Regenerative Neurology Clinic (Royal Infirmary of Edinburgh), 72 MS participants (53 female, 19 male, age range 20-79, median age 44) and 80 healthy volunteers (HV) (61 female, 19 male, age range 23-73, median age 38) received spectral domain optical coherence tomography (SD-OCT) and ultra-wide field scanning laser ophthalmoscope (UWF-SLO) scans at baseline. Within the MS group, 16 (9 right eyes and 10 left eyes) had at least one clinically diagnosed episode of optic neuritis (ON). Follow up scans were taken at approximately 3, 6 and 12-month intervals over the course of two years. Visual acuity (VA) as an indicator of retinal function was also measured at each visit using Sloan letter charts at 100% and 2.5% illumination. Through proprietary software, automatic segmentation of SD-OCT images quantified changes to retinal nerve fibre layer (RNFL) thickness and macular volume. Novel image processing algorithms specifically adapted to semi-automatically segment the vasculature in UWF-SLO images (using multi-scale filtering and supervised classification) allowed for measurement of vessel diameter. Data from the 3 participant groups (MS (no ON), MS (ON) and HV) was first tested statistically for significant differences. Linear regression modelling with the inclusion of disease, sex, length-of-disease and age as predictors was then used to estimate the true effects of disease on the retinal anatomy without confounders. Results Baseline data showed that individuals with MS (no ON) have a reduced RNFL thickness in all peripapillary regions and a reduced macular volume when compared with HVs. The reduction in RNFL thickness was seen globally in both eyes (OS: -10μm, OD: -11μm, p<0.001) but was greatest in the inferior temporal region (OS: -15μm, OD: -13μm, p<0.01). In the MS (ON) group the reduction in RNFL thickness was even greater, again being largest in the inferior temporal region (OS: -29μm, OD: -24μm). Linear regression models confirmed the effect of disease on RNFL thickness and macular volume with significant coefficients in all regions but the inferior nasal. Follow-up analysis showed that the MS (no ON) group had a larger annual rate-of-thinning of the RNFL than HVs in the majority of regions, the largest difference being in the inferior nasal (OS: -1.32μm/year, OD: -1.06μm/year, p<0.05) and superior nasal (OS: - 1.11μm/year, OD: -1.13μm/year, p<0.05) regions. Retinal arteries were shown to have a significantly reduced diameter in only the inferior nasal quadrant, where the greatest reduction in vessel width was found (OS: -0.005mm, OD: - 0.007mm, p<0.05). For mean venous width, the inferior nasal quadrant of the right eye also showed a statistically significant difference between the two groups (OS: -0.005mm, OD: - 0.005mm). Linear regression models were more frequently significant for arterial rather than venous data, despite both vessel types having significant disease coefficients in the inferior nasal quadrant. Follow-up data was inconclusive on the effect that disease has on the annual rate-of-change of vessel thinning. Median baseline high contrast VA (OS: -6, OD: -3, p< 0.05) and low contrast VA (OS: -6, OD: -6, p<0.01) scores were significantly reduced in the MS (no ON) group when compared to HVs. In this study, MS seemed responsible for a 1 line drop in both high contrast and low contrast VA scores in the MS (no ON) group. A significant difference between the HV group and MS (ON) group was only found in the median low contrast VA score of the left eye (OS: -21, OD: -4, p< 0.05). As with vessel analysis, follow-up data showed no significant rates-of-change in VA score. Conclusions At baseline, the RNFL and blood vessels of the retina were significantly thinner in the MS (no ON) group when compared to HVs in particular regions. Consistent with previous reports in the literature, both RNFL and macular volume showed a significant decrease in individuals with MS (no ON). However, this is the first study to show that both arteries and veins in the retinal periphery also have a reduced width in the inferior nasal quadrant. Such changes in the retinal anatomy correlate with a drop in visual function as measured by VA. An increased annual rate of RNFL thinning was also seen in participants with MS (no ON) indicating that anatomical changes occur over time rather than acutely, however this rate-of-change is largest early in the disease course. A similar pattern was observed with the rate at which macular volume decreases in individuals with MS (no ON). Whether changes to the retinal blood vessels occur over time was not determinable within this study, due to the effect size being too small for the number of participants recruited. Future studies should focus on replicating findings pertaining to retinal blood vessels and determining when in the MS disease course these changes occur.