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Passively listening to music and other auditory enrichments has been repeatedly demonstrated to be effective at reducing physiological arousal in a wide range of non-human species. Although statistically significant arousal reduction has been demonstrated, the size of this effect in most studies is generally small. To strengthen the previously demonstrated arousal-reducing effects of auditory enrichment, the aims of this thesis are: To understand what specific aspects of auditory enrichment have the greatest influence on arousal in dogs and horses. To determine if dogs have the auditory perceptive abilities that justify any assumptions of musical appreciation. To establish if a positive association with specific music can influence how that music can manipulate arousal in dogs. Classical music with the pitch and tempo altered; music based on the owner's voice; and a range of metronome beats where trialled. Heartrate variability was the primary measure of effect and methods of measurement were validated in both dogs and horses prior to these studies. To test perception, a two-choice go/go selection paradigm was used. Changing the pitch or tempo of music made no difference to the arousal of dogs or horses. Bespoke music based on the owners' voices had an equivalent effect on arousal in dogs as classical music and white noise. Limited testing of perception in dogs failed to demonstrate any ability to discriminate between different tempos, but the results of forming a positive association were suggestive of an increase in effect. An incidental finding was that auditory enrichment was more effective at reducing arousal when used in a noisy environment than when used in a quiet environment. Auditory enrichment has been demonstrated to have an arousal-reducing effect, however, the arousal-reducing effects of auditory enrichment in non-vocal learners may be stemming from simple mechanisms such as acoustic masking and/or the formation of positive associations.

It is commonly recognised that mislocalisation and aggregation of Transactive response DNA- binding protein-43 (TDP-43) occurs in over 97% of amyotrophic lateral sclerosis (ALS) patients and around 50% of fronto-temporal dementia (FTD) patients. However, despite the commonality of this molecular phenotype, its precise role in disease onset and progression remains elusive. Although TDP-43 is an attractive target for therapeutic intervention and diagnostic testing, it has thus far not been possible to exploit either of these approaches. A core problem remains the lack of efficient detection and targeting probes for TDP- 43. A large variety of micrometre-scale TDP-43 inclusions have been described, however, smaller protein assemblies have not been studied in detail. Although traditional ensembleaveraging biochemical techniques fail to deliver information on single nanometre-scale aggregates, single-molecule and super-resolution (SR) methods can be used to circumvent these issues, as has been demonstrated in other neurodegenerative diseases involving protein aggregation. To date, the number of studies employing these techniques to examine TDP-43 is extremely limited. Highly specific and sensitive imaging probes are required for single-molecule measurements and would allow counting and characterisation of individual aggregates. Precise localisation of aggregates in tissue and the cellular milieu could enhance the understanding of TDP-43 relevance in a disease context. Meanwhile, separation of disease- relevant aggregates from physiological TDP-43 in biofluids could assist in the establishment of a reliable biomarker. Aptamers are artificial oligonucleotides capable of binding to specific molecular targets and are attractive alternatives to antibodies with regards to biomolecule labelling. In this study, aptamers targeting TDP-43's RNA recognition motifs (RRM1-2) were designed via the in silico algorithm, catRAPID, and validated in vitro. The highest affinity candidate aptamer, Apt-1, was labelled for fluorescent imaging and used to track the aggregation of a TDP-43 construct. Apt- 1 was capable of generating diffraction limited fluorescence images, as well as SR images at a resolution of 20 nm via Aptamer DNA-points accumulation in nanoscale topography (ADPAINT) and a newly developed technique, dubbed Aptamer-PAINT. To establish if Apt-1 could be used for imaging in biological samples of a complex composition, a comparative study of TDP-43 detection using gold-standard immunohistochemistry (IHC) and Apt-1 fluorescence imaging, was carried out. Despite low-agreement between both techniques, Apt-1 was capable of separating ALS cases from healthy controls based on the number of detected TDP-43 aggregates. Furthermore, Aptamer-PAINT SR images of aggregates could be acquired in tissue with a similar resolution to that achieved in vitro. TDP-43 can be detected in human biofluids, such as serum and cerebrospinal fluid (CSF). SR imaging of CSF samples using Apt-1 was carried out to establish if the number of detected species in samples from ALS patients with TDP-43 proteinopathy was higher than in ALS disease controls. Additionally, size characterisation of the detected species was used to determine differences in the relative distribution of aggregate populations. Overall, the work presented in this thesis demonstrates the development of a new TDP-43 imaging probe capable of characterising aggregate species individually in variety of in vitro and patient-relevant samples. Although these studies are exploratory, they form the basis of establishing a new class of detection probes in the field of ALS and FTD research, and show promise in the development of diagnostic tools. In this manner it is hoped that the developed aptamers will aid researchers and clinicians in understanding the mechanisms of TDP-43 pathology and assist in diagnosing patients.

Rates of developmental deficits in children entering full-time school are increasing in the UK with recent nursery closures and social restrictions exacerbating the situation. Currently, almost half of the children in the United Kingdom (UK) fail to meet typical developmental milestones in communication, language and personal, social, or emotional development at school entry. Numerous risk factors for the development of school readiness have been identified but a key risk factor is dysfunctional parenting practices. Parenting programmes are the most effective interventions to improve early child development, however obstacles to recruitment and engagement often prevent some families, particularly disadvantaged families, from accessing support. School-based and online parenting programmes reduce some of the barriers associated with group-based programmes and may be more accessible and therefore appropriate for families. The Dialogic Book-sharing Programme is a behavioural parenting intervention for parents of young children with developmental deficits in language, communication, attention, and social/emotional understanding. This thesis reports on the first evaluations of the 'Books Together Programme' a Dialogic Book-sharing programme for parents of children aged 3-5 years delivered both in a group format by school staff and subsequently as an online programme. Chapter 1 offers an outline of school readiness and its longer-term impact. Chapter two gives an overview of the origins and background of the 'Book Together Programme' followed by qualitative exploration of the feasibility of the school-based delivery of the programme for parents and schools (Chapter 3). The second study in Chapter four explores the effectiveness of school-based delivery of the programme for parents and children. The next two chapters report the qualitative and quantitative outcomes of the online evaluation study. The 'Books Together Programme' was effective in improving parenting capacity and child development and feedback from schools and parents was positive with all reporting they would continue to use the methods taught. The final chapter of the thesis provides a summary of the research findings and discusses their implications, limitations, and future directions (Chapter 7).

This thesis seeks to make a critical intervention at the intersections of French literary and cultural studies, death and bereavement studies and the Medical Humanities, in order to establish a fuller picture of the role that writing can play in continuing a bond with a deceased child and in establishing a dynamic of care. Drawing on a corpus of predominantly parent-authored grief narratives by Brigitte Barbier, Bernard Chambaz, Marie-Axelle and Benoit Clermont, Max Derhy, Anne Dodemant, Marie Darrieussecq, Philippe Forest, Pierre Jourde, Camille Laurens, Patrick and Véronique Poivre d'Arvor, Georges Salines, Francis Van de Woestyne and Patricia Vergauwen, the thesis argues that the central motivation for parental grief writing is, more often than not, a desire for connection with the deceased child. It then suggests that, by virtue of its atemporality, the text has the potential to generate this connection and facilitate a form of continuing bond between parent and child; that such a continuing bond affords the author, the child and the reader the opportunity to give and receive textual care; and that the manifestations of said care will differ according to the circumstances of the child's death. By engaging with the entangled possibilities of disciplinary boundary crossing, the thesis seeks to inscribe literature within the broader framework of Continuing Bonds, while also moving beyond the mere establishment of the bond to consider its outworking and what is given and received through it, by means of the text. The thesis thus advocates for a productive entangling of disciplinary knowledge, which recognises the rich contribution of the (Medical) Humanities to a deeper understanding of individual and collective experiences of death, grief and mourning, centred around a relationality that transcends the limits of tangibility and offers life-giving and life-enriching care to all those who experience it.

By the end of preschool, children are moral agents. They hold themselves to the same 'objective' normative standards that they hold others to, and behave and expect others to behave according to these standards. Whenever these standards are not upheld, they experience guilt and expect to see it in others, and during the later preschool years, use their culture's shared hierarchy of values to justify their moral judgements (e.g., ruining another's artwork because "I thought it was mine") and to evaluate the reasons others give for theirs. The focus of the current thesis was twofold; to extent the evidence for preschool children's norm-based, agent-neutral sense of morality, and for their awareness of morally (in)appropriate justifications for moral acts. In the first study, I investigated whether children apply impartial norms to their requests for help. Children aged 3 and 5 made a variety of requests for resources that they either did or did not need from an experimenter who either did or did not need them. Results suggest children of both age groups were slower and more hesitant to make an unjustified request (i.e., the child did not need the sticker, but the experimenter did) than a justified request (i.e., the child needed the sticker, but the experimenter did not). Three-year-olds, and 5-year-olds to a lesser extent, also expressed more negative guilt-like emotion when making unjustified requests as measured through changes in body posture. Five-year-olds, on the other hand, relied more on verbal indirect utterances (e.g., "You've got lovely stickers") as opposed to direct ones (e.g., "Can I have that sticker") when making unjustified requests. Already at age 3, this study shows that preschool children are sensitive to the norms around requesting, and use them to evaluate whether or not their requests are fair to recipients. In the second study, I investigated when moral justifications become necessary. Using a partner-choice paradigm, 4- and 5-year-old children were presented with two transgressors, both of whom caused an intent-based accident (unintended action - unintended outcome) or a belief-based accident (intended action - unintended outcome). Both transgressors later apologised, however one also gave a reason for the hurt caused. The results suggest 5-year-olds, but not 4-year-olds, favoured the reason-giving transgressor when the accidents were belief-based, whereas no preference for either transgressor was found when the accidents were intent-based (meaning an apology was suffice). In a follow-up study, the reason given for the belief-related harm was manipulated. One transgressor gave a 'good' reason, the other gave a 'bad' reason. Five-year-olds reliably distinguished between both reasons and preferred the transgressor with the 'good' reason. Thus, older preschoolers realise that some mistakes need or benefit from 'good' explanations, while others can go without. In the third study, I explored the boundaries of moral justifications. Five- and 6-year-old children witnessed a recurring harm that was caused by an apologetic actor who repeated the same reason after each offence (Same Reason condition), gave different reasons (Different Reason condition), or who was present but not personally responsible for the damage done (Baseline condition). The results suggest children of both ages were most trusting of the actor in the Baseline condition, followed by the Different Reason condition, and least trusting in the Same Reason condition. Both ages were also slower to trust the actor in the Same Reason condition as compared to the other two conditions. Thus, preschool children recognise that different reasons should accompany a repeat of the same harm. This study also shows preschool children extend the use of their culture's ordering of moral values to repeat offences. Together, the present studies suggest that before school entry, children already measure themselves against the same normative standards used to evaluate others. They recognise (in)appropriate justifications for solo and repeat moral offences. And even understand which moral acts warrant further explanation and which do not.

This study investigates the ceramic building materials (CBM) from the UNESCO World Heritage Site of the Roman Baths at Bath, UK. Ceramic building materials from much of Roman Britain are understudied, yet our knowledge of the brick and tile from Bath is not limited solely by a paucity of research, rather than by a lack of synthesis between academic, commercial work, and the study of the Roman Baths itself. This project therefore aimed to create a unified understanding of Roman CBM in the Bath area, bringing together research in Bath and Gloucestershire with novel analyses of the Roman Baths assemblages to develop new understandings of production, procurement and use at the site, local and regional levels. This has been achieved through two strands of research. A range of previous studies in Bath, Gloucestershire and northwest Wiltshire were collated to investigate diachronic supply of CBM to Roman Bath, particularly through the novel integration of finds of stamped and relief-patterned tiles. A survey of the assemblages at the Roman Baths was conducted, and this material subjected to fabric and chemical analyses with portable energy-dispersive X-Ray fluorescence (pXRF) in order to suggest provenance. These analyses yielded significant results when integrated with regional research. At the site level, two major phases of construction at the Roman Baths have been found to be supplied by the Minety kiln site. This has enabled the redating of the construction of the Spring Reservoir Enclosure to the first century, substantially altering the developmental history of the Roman Baths. At the local and regional levels, it is clear that Minety supplied much of Bath and Cirencester, and was important to distant settlements too. This unified picture therefore indicates that centralised production and routine long- distance transport was key to the supply and procurement of these novel building materials in the area of Bath.

The Connect-R is a novel Multi-Robot System that is intended to provide maintenance and servicing capabilities in nuclear environments. The Connect-R system is intended to address the problem of mitigating the effects of radioactive environments by acting as a preliminary robotic deployment that, through its deployment, maximise the useful time in the environment for secondary service robots. The stated mission goal of the Connect-R MRS is to provide structure in unstructured environments, which in reality provides a physical structure within the nuclear environment upon which service robots can traverse the nuclear environment, effectively increasing the efficiency with which they can spend their time, with respect to completing the mission. To realise the underlying ethos of the Connect-R, this work presents a total design of the robotic design whilst discussing the development of the AI system that allows for human-in-the-loop architecture and the tools to support human-system interaction. This thesis presents the principle ethos behind the Connect-R approach in Chapter 3, the Connect-R robotic design in Chapter 4, the AI system in Chapter 5 and the software developed to operate the Connect-R system in Chapter 6. The major contributions of the thesis are the definition and justification of the core approach of the Connect-R system, key design choices to facilitate robot development, the human-intuitive domain representation of the AI system and optimisation measures taken to improve accuracy, scalability and efficiency and also the development of a bespoke software tool that facilitates human-system interaction. This thesis addresses the key challenges in utilising classical AI techniques for full robotic deployment in 3D environments such that the AI system solutions are scalable, human-intuitive and consistently accurate.

How can contemporary companies and corporations, necessarily operating within market-derived norms, act justly in their dealings? Why should they care about doing so? I claim in this thesis that Aristotle's conception of general justice provides an answer to these questions and, claiming the necessity of justice to all ethical deliberation, I propose it as a practicable foundation for the such organizations' ethics. I argue that Aristotle's eudaimonic metaphysics can plausibly be brought to bear on contemporary dilemmas in corporate ethics; and that his particularist approach to ethical deliberation justifies a conception of justice as a point of equipoise, found along several dimensions, always evanescent and demanding of constant attention. Acknowledging the dominance of deontological and utilitarian thinking in contemporary business ethics, I propose an Aristotelian, eudaimonic approach which rests on his teleology and the place of virtue within it. I argue for the primacy of justice as an ethical concern and claim that Aristotle's conception of general (as opposed to particular) justice provides a plausible basis for creating a justice-based corporate ethic. I claim that Aristotelian general justice is analogous to the ancient concept of dikaiosyne , which can be loosely translated into vernacular English as 'doing the right thing'. In chapter 1, I outline the problem I am seeking to address, namely the proliferation of conceptions of justice with which contemporary companies and corporations are expected to deal. I identify two dominant strands of thinking, roughly corresponding to the 'left' and the 'right' in post-French Revolution politics, positing Rawls and Hayek, respectively, as representatives of these traditions. I place companies and corporations within the context of the market - based theories and conventions that underpin contemporary capitalism. In Chapter 2, I introduce Aristotle's teleology and the metaphysics from which he derives his approach to justice. Following his metaphysics, I argue that justice is an ineradicable concern for human beings if they are to have a chance of living a eudaimonic life; and that collective entities such as companies and corporations can partake of these metaphysics, because of the relationship between the collective and the individual. In chapter 3, I summarize Aristotle's approach to justice and propose an interpretation of Aristotelian general justice as a point of equipoise, balanced along many dimensions, and, drawing on his Doctrine of the Mean, consisting in a 'mean of means'. I argue that general justice is the whole of virtue and that it can be conceptualized in a way that can support ethical deliberations in contemporary companies and corporations. In chapter 4, I examine the ways in which justice can be considered in the light of modern schematics of justice, and how this takes place in companies and corporations. I consider the dominant concerns that need to be addressed by any plausible approach to justice in contemporary market economies, such as desert and inequality; and propose ways of considering aspects of contemporary corporate life, such as investments and profits, in terms of Aristotelian general justice. In chapter 5, I consider six intuitively obvious objections to my thesis, namely: that globalization, financialization and the advent of the internet have, respectively and in different ways, rendered it anachronistic; that companies and corporations have no counterparts in the Ancient World, as they are products of industrial capitalism; that the setting for Aristotle's philosophy, the Ancient Greek polis, is irrelevant to modern life; and that Aristotle's character-based ethics are elitist and therefore incompatible with contemporary meritocratic norms. I conclude with some practical proposals for basing corporate ethics on my conception of Aristotelian justice as a point of equipoise.

This thesis investigates the potential for using Web technologies, namely the Document Object Model (DOM), Cascading Style Sheets (CSS), and JavaScript, to describe and control large-scale Internet of Things (IoT) deployments. These are not yet present in the typical home, however, the trajectory of integration between everyday objects and computers suggests that, in future, many homes and commercial spaces will contain thousands of IoT devices. These environments will require complex and scalable orchestration. Web technologies could fulfil these requirements. While there have been many attempts to integrate the IoT with the Web, thus far none have taken advantage of existing technologies to the degree demonstrated here. Several new approaches were explored, each with the aim of representing IoT devices and their components using the DOM, whereafter, CSS was used both to control and store the state of the DOM. The DOM elements became digital twins of the devices they represented, allowing actions upon the DOM to be replicated across the IoT environment it mirrors. Through applying this approach, there is the potential for Web developers to use their existing skills to transition from their current role and become Web of Things (WoT) developers with little effort. The investigation occurred across four experiments, approaching a Web-native solution. The final implementation was tested in a study with experienced Web developers, yielding a positive outcome. Participants showed an interest in the subject matter and quickly learned the skills necessary to implement the technology. Also explored are ideas on how this approach could, in future, be integrated with the social machine of the Web, including with other WoT projects, development communities, and end users. The proposals within this thesis introduce a new concept for modelling the IoT, and, as such, they put forth many avenues for future research. These include the potential to share curated themes for physical environments; to build complex virtual devices from the components of others; and to allow Web pages to spill out into the physical environment they are viewed within.

Over the last three decades, the Chinese hamster ovary (CHO) cell has progressively established itself as a stable, high yielding mammalian expression system for the production of recombinant proteins - in particular monoclonal antibody (mAb) biotherapeutics. Despite the availability of other platforms, CHO cells continue to dominate as the most utilised system due to their scalability, ability to perform post-translational modifications and long history of regulatory approval. Indeed, over 70% of all therapeutic proteins produced are done so using CHO cells in a highly competitive, and ever-expanding biopharmaceutical market valued in excess of US$180 billion per year. The production of recombinant biotherapeutics is typically geared towards selecting cells which provide high levels of expression, enabling cost-efficient production of high product-yielding cells. Nonetheless, there remains a proportion of unpredictably low yielding molecules that require extensive, time-consuming process development. These "difficult-to-express" (DTE) therapeutics significantly increase the cost of manufacture and reduce the speed-to-market of innovative treatments relative to "easy-to-express" molecules. Despite their widespread use, little is known about the spatial proteomic landscape of these industrially important cells, which might reveal information about protein location and protein-protein interactions pertinent to mAb secretion and molecular bottlenecks. This thesis details the cell characterisation of a CHO-K1 production host and two anti-IL-13 recombinant mAb expressing CHO-K1 cells with a 25-fold differential expression yield. This was performed using electron microscopy (Chapter 3) and quantitative tandem mass tag (TMT) labelled proteomics (Chapter 4). Through the optimisation and application of hyperplexed Localisation of Organelle Proteins by Isobaric Tagging (hyperLOPIT); a high-resolution mass spectrometry-based technique, the first, cell-wide proteomic map of the CHO-K1 host is detailed (Chapter 5). This has provided for the unprecedented spatial resolution of thousands of proteins distributed within the CHO-K1 host cell. Furthermore, the hyperLOPIT pipeline was additionally applied to the two recombinant mAb molecules with markedly differing expression characteristics in order to identify changes in subcellular protein localisation (Chapter 6). Together these studies reveal aberrant ultrastructural morphological differences and protein relocalisations between the DTE and ETE antibody-producing cells, leading to the potential for identification of upstream cell engineering targets to improve production and secretion of high-quality recombinant proteins.

This thesis explores John Burnside's poetic output between 2009 and 2019 encompassing four collections: The Hunt in the Forest (2009), Black Cat Bone (2011), All One Breath (2014), and Still Life with Feeding Snake (2017). I argue that Burnside's later poetry develops his longstanding ecological disposition which is now a unique form of post-secular thought in the face of the climate crisis. I point to the wide-ranging intelligence in his poetry, considering his critical prose writing as well, coalescing around his 2019 monograph on poetry of the twentieth century, The Music of Time. Through his multiple influences, I claim that Burnside's poetry provides an urgent philosophical perspective on our relationship to the natural world and furnishes an understanding of what could constitute peaceful dwelling. I respond to his writing across a breadth of inherited traditions through which his poetry creates a new interdisciplinary approach to the myriad questions about human relationships with animals, plants, and the nonhuman. Across the thesis I explore the idea of ecological grief conditioned by a paradox between the breakdown of the concept of 'oikos' in the relationship between economics and ecology epitomised in part by the financial crash of 2008 which fixes the starting point of my engagement. To do this I ground his poetry in the contingent world of late capitalism and the growing anxieties of technology and ecological crisis, whilst at the same time exploring a suspended temporality which encompasses a spilt catechesis, a pagan sensibility, a folkloric cosmology, and the epochal shift of new timescales prompted by the Anthropocene. From this impasse comes a poetry of grace that bridges both public and private rituals of loss and grief and allows for a compassionate openness towards the urgent questions of ecological crisis.

With cardiovascular diseases (CVD) being the leading cause of death worldwide, computational fluid dynamics can be used to provide insight into the onset and progression of CVD and to improve the design of medical devices. This thesis develops novel cardiovascular simulations to evaluate how the multiphase rheology of blood impacts CVD and the activation of platelets, with an assessment of haemodialysis catheter design. To date all cardiovascular models assume a smooth artery wall, despite microscopic surface roughness being linked to CVD. A simulation of artery roughness showed a greater range in haemodynamic parameters associated with CVD, compared to a smooth wall, with increased residence time in an ultra low-shear environment (< 25 s⁻¹). Stenosed coronary bifurcations were found to exhibit non-Newtonian and multiphase phenomena, with red blood cell residence time in aggregatory low-shear conditions found distal to stenosis. Increased levels of platelet activation and subsequent residence near the plaque highlight the mechanisms of atherothrombosis. Haemodialysis catheters were found to have improved performance with side-holes, however, to ensure long-term patency and reduce the chance of blood clots; the side-holes should be oval shaped, correctly scaled for body diameter, and with an angle-cut profile for optimal surface texture to reduce bio-fouling. Multiphase rheological blood models can be developed to better predict phenomena associated with CVD, yet require additional physical laws governing red blood cell aggregation and near-wall adhesion.

Although mediation has been shown to be effective in helping warring parties to reach agreements to end civil wars, our understanding of how exactly mediators assist the negotiation process remains limited. Existing theories of peace mediation focus on how mediators can help parties to address strategic and cognitive obstacles to reaching a negotiated settlement. A communication perspective, which looks at the process of how the meaning of different aspects of the negotiation process is constructed, has been neglected. In any negotiation, parties compete to impose their preferred meaning on objects of discussion by framing them in a certain way. To advance in their negotiations parties must eventually arrive at a common framing. The puzzle addressed in this PhD thesis is how mediators bring parties' frames into alignment. Based on an analysis of cases of impasses in the 1990-1992 UN-mediated peace negotiations to end the civil war in El Salvador, this thesis develops a theory of mediation as framing. Adapting a general model of social mechanisms developed by Hedström and Swedberg (1998) based on the work of Coleman (1986), it elucidates three underlying mechanisms that explain how mediator framing works. The first is a "situational mechanism" that explains how a mediator with a certain framing capacity, through specific framing actions, causes a negotiating party to form a belief about what framing they should put forward. The second is an "action-oriented" mechanism that explains what kind of change in belief leads a party to reframe. In a third step, a "transformational mechanism" explains how individual parties' acts of reframing interact until their frames align. The theory of mediation as framing proposed in this thesis is an original contribution to the literature on peace mediation, which until now has paid little attention to the concept of framing. By elucidating the underlying mechanisms involved, the thesis also makes original contributions to the wider literature on negotiation and framing. It provides a clear framework that will be of direct practical relevance for mediators interested in understanding when and how framing can be used successfully to advance negotiations.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by the progressive deterioration of upper and lower motor neurons and atrophy of skeletal muscle. Despite advances in genomics methods that have enabled the identification of many ALS risk variants, these account for just 20% of cases. However, many of the associated genes are implicated in mechanisms of RNA homeostasis, inflammation, protein degradation, and vesicular transport, thus providing clues to the underlying pathological pathways involved in the disease. Skeletal muscle is a strongly affected tissue in ALS, and changes in muscle physiology, including chronic denervation and reinnervation of muscle, as well as neuromuscular junction dismantling, are amongst the earliest pathological processes that occur in the disease. Skeletal muscle is now a recognised secretory organ, releasing molecules that can act in an autocrine and endocrine manner. These molecules have been coined myokines and are well established players in intercellular signalling. Muscle has also been shown to secrete extracellular vesicles including exosomes, and these muscle vesicles (MuVs) have been shown to contain cargo proteins, miRNAs and lipids that can alter cellular mechanisms in recipient cells. Indeed, MuVs isolated from ALS patient cell cultures have recently been reported to exert significant levels of toxicity when added to iPSC motor neurons. The work detailed in this thesis contributes further evidence implicating MuVs in ALS pathology, including confirmatory experiments illustrating the neurotoxicity of ALS MuVs to healthy iPSC motor neurons, and demonstration that candidate biomarkers, first identified in MuVs isolated from primary muscle cells, are also increased in the serum of ALS patients. Furthermore, this work describes both a novel immunocapture technique that permits isolation of MuVs from patient serum for the downstream detection of candidate biomarkers, and a MuV lipid quantification assay as a potential biomarker candidate in ALS.

The adhesion protein teneurin is known to control brain development and neuronal migration. Much of the research centered around teneurin thus far has probed its protein binding partners, of which the aGPCR Lphn, and FLRT protein are most extensively studied. One as yet understudied binding partner of the teneurin extracellular domain are the glycosaminoglycan (GAG) macromolecules abundant in the brain extracellular matrix (ECM). These highly charged glycans are made up of five main families: Heparin/ Heparan sulfate (HS); Chondroitin sulfate (CS); Dermatan sulfate; Keratan sulfate; and Hyaluronic acid. These glycans, specifically HS and CS species, have been shown to be important modulators of neuronal migration, as well as factors dictating CNS plasticity and trauma recovery. The work in this thesis proves that binding of HS and CS ligands occurs on a highly charged patch on the large YD-shell scaffold which forms the majority of the teneurin ecto-domain. Two crystal structures were solved here with glycan ligands, proving the binding site contacts 6 Arginine and Lysine residues on the teneurin surface. Subsequent mutation of this binding site abolished binding, and was confirmed by pulldown assay. In vitro cell based migration assays began to unearth the effects of glycan binding of HEK and N2A cell migration, with a view to the effect of glycan binding in the developing brain. This work illustrates the first time teneurin-glycan complexes have been investigated structurally, and represents an introduction into the study of glycobiology with respect to teneurin and how this may control neuronal development.

Anthropogenic activities have caused environmental damage for thousands of years, which has been exacerbated since the industrial revolution. Mining is one such activity that has caused damage to the environment, primarily through the creation of acid-mine drainage (AMD) waters. These are created when pyrite in rocks is exposed to oxygen and water, through mining, causing the formation of sulphuric acid. As the waters become more acidic, metals disassociate from the rocks leading to acidic and metal polluted waters. One such AMD system is Parys Mountain, Wales, where our lab has isolated an acidophilic microalga, Chlamydomonas acidophila - strain PM01. It exhibits higher tolerance levels of copper than other strains of the same species. Whilst tolerance ranges and physiological responses of eukaryotic extremophiles have been well studied, many of their mechanisms of adaptation have yet to be elucidated. PM01 provides a fantastic model to begin to understand some of these tolerance mechanisms. In order to tolerate the harsh conditions of AMD it is likely that C. acidophila has evolved differential responses to both pH differences and metal toxicity to non-adapted organisms, such as Chlamydomonas reinhardtii which is mesophilic in both its pH tolerance and its ability to survive metal toxicity. Firstly, in this thesis the physiological and biochemical responses of PM01 compared to the model organism Chlamydomonas reinhardtii (strain 11/32c) as well as other strains of C. acidophila (strains CCAP 11/136 and CCAP 11/137) were analysed in response to copper. Here it was found that PM01 is capable of growing at much higher copper concentrations than the other strains tested. Also, PM01 shuts down photosystem II after being exposed to copper for 3 hours, without the photosynthetic machinery appearing stressed. Additionally, a 2-stage non-photochemical quenching (NPQ) process was observed, where PM01 has different types of NPQ, depending on the actinic light intensity. The antioxidant capability of PM01 and C. reinhardtii was also measured. PM01 exhibited higher catalase activity, whilst the two isoforms of iron superoxide dismutase show different isoelectric points (pI). It was found that PM01 exhibits high levels of lipid oxidation in both short- and long-term copper stress, whereas C. reinhardtii only exhibited high lipid oxidation under a short-term copper stress. Finally, low lipid oxidation levels were shown in the other C. acidophila species, CCAP strains 11/136 and 11/137. Secondly, fast, high-throughput fingerprinting techniques were used to examine the metabolic and proteomic changes of PM01 and C. reinhardtii in response to copper stress. FT-IR spectroscopy revealed an increase in protein content upon copper exposure in PM01, but a decrease in lipids and carbohydrates. Whilst a similar response was seen in C. reinhardtii it was not to the same extent as PM01. MALDI-TOF mass spectroscopy provided a rapid overview of the proteome. Here protein peaks with a high m/z arising in the long-term copper-stress treated for both PM01 and C. reinhardtii. These protein peaks also suggested that a protein can 'switch' between a single charge and double charge and could play an important role in either metal binding or reactive oxygen species quenching. An in-depth metabolomic analysis using LC-MS techniques reveal greater insights into PM01's adaption to copper through the identification of several key metabolic changes between PM01 and C. reinhardtii. Thiol groups in metabolites such as cysteine and glutathione play a central role in copper adaptation. Additionally, amino acids such as proline, a known osmolyte, was found at elevated levels in PM01. Finally, I conducted a transcriptomic experiment was conducted to observe the global response of PM01 and C. reinhardtii to a long- and short-term copper stress. A whole host of transcripts were differentially expressed under copper stress, however, we managed to find 3 main processes that were altered. Transcripts related to the antioxidant response and lipid breakdown were found to be more highly expressed in C. reinhardtii under a copper stress. Intracellular transport systems and reorganisation was found to be more highly expressed in PM01 under a short- and long-term copper stress. Finally, transcripts related to photosynthesis were found to be reduced in PM01 under both a short- and long-term copper stress. I also found a series of transcripts that were much more highly expressed in the PM01 cells exposed to a short-term copper stress with a wide array of biological functions. These provide an exciting source of potential biological pathways to a copper adaptation. We also investigated individual transcripts of interest, with the putative copper exporter CTP3, being a standout candidate to copper tolerance it was constitutively expressed in PM01 at higher levels than all other C. reinhardtii treatments. This study provides an exciting insight into the copper tolerance mechanisms of PM01, an extremophile microalga that exhibits high copper tolerance levels. In this I have generated large data sets that provide a lot of further avenues for further investigation.

This thesis examines the responsibilities, remuneration, roles, and representations of manorial officials, those who were unfree peasants who were elected to manage and supervise the lord's lands and tenants. Using a combination of economic, social, and cultural approaches, this work explores how officialdom on the manors of Glastonbury was influenced by a manor's local structure, such as its degree of rurality, as well as how officialdom changed across the period c. 1250 - 1400. The source material used in this thesis has been from an examination of the manorial source material from the Abbey of Glastonbury. This has predominantly been the accounts, court rolls, and custumals, for the manors of Ashbury, Ashcott, Damerham, Glastonbury, and Nettleton. This thesis has also utilised a variety of source material beyond the manorial record, such as art, literature, and treatises, in order to explore the wider cultural representations and perceptions of officialdom in combination with the manorial documentation. Chapter 1 explores the structure of manorial officialdom and the responsibilities of each manorial officer at Glastonbury. Chapter 2 utilises a quantitative methodology to examine how officials were remunerated at each manor. Chapter 3 employs a quantitative and qualitative approach to analyse the activities of officials upon the manor and how they were treated by the hallmoot courts. Chapter 4 explores the variety of ways in which manorial officials were depicted in art and literature in order Ito examine the contemporaneous perceptions of officialdom. A number of key conclusions have been found in this work. The structure of officialdom at Glastonbury was flexible, utilised to adapt to local structures and the impacts of wider socio-economic events in the fourteenth century. Officialdom played a vital role in mediating the carefully negotiated interplay between the central, seigneurial administration and the local manors, and executing important economic and administrative decisions. Officials were both of the peasantry but also distinct in their role as representatives of the seigneurial authority, as is shown in both the manorial record and art and literature of the period. This study has also demonstrated that officialdom can be used as a lens through which to explore and understand the changes and developments on the medieval manor due to external factors.

Acoustic emission (AE) is widely used for condition monitoring of critical components and structures. Conventional AE monitoring techniques use piezo-electric AE sensors to detect elastic stress waves emitted from a source, such as a propagating crack. These sensors are often surface mounted and secured in place using magnetic hold-downs or adhesive tape to monitor structural components. Coupling sensor and structural components is achieved with the use of an appropriate ultrasonic couplant due to the high frequency signals emanating from an AE event (up to 1 MHz). The couplant is crucial to permit an efficient transfer of elastic waves between damage source and sensor. Piezo-electric sensors tend to be relatively bulky, so cannot be embedded into composite materials. The embedding process protects sensors against environmental stresses, prolonging operational lifetime and enhancing device sensitivity. In addition, piezo-electric AE sensors are affected by electromagnetic interference meaning that when required in challenging conditions such as in flammable or explosive environments, AE sensors need to be manufactured as intrinsically safe. Fibre-optic acoustic emission sensors (FOAES) offer several advantages over conventional piezoelectric AE sensors. FOAES can be both surface-mounted to various materials or embedded into composites owing to their small size and acrylate coating relieving the stress concentration around the sensor. The immunity of FOAES to electromagnetic interference makes these sensors attractive for condition monitoring across a wide range of operational environments. This is because the FOAES employs light at the sensing region to interrogate elastic stress waves instead of electrical components used in piezo-electric AE sensors. This study discusses the approach employed for manufacturing sensitive and reproducible FOAES in addition to methods used to characterise them. Towards the end of the investigation, a comparison between AE signals captured using both conventional piezo-electric sensors and FOAES is also provided.

Crystalline and amorphous structures have been investigated using a range of modelling methods within this body of work to understand the behaviour of disordered grain boundary regions. The oxide systems considered are ZrO₂ formed as a passivation layer on the Zr based nuclear fuel cladding, and UO₂, used as nuclear fuel. This work aims to analyse whether amorphous grain boundary regions may be stabilised due to the inclusion of dopants or impurities at the boundary, impacting the grain boundary properties and therefore the material performance during manufacture and/or operation. Undoped and doped oxide systems were simulated successfully, and structural analysis found that amorphous structures were distinctly different to the crystalline counterpart, not only in their arrangement but also in other material properties. Native oxide bonds were retained in undoped systems, with coordination environments being similar. Dopant channels were formed upon introducing dopants into the amorphous systems, affecting the connectivity of the network. Oxygen was the fastest diffusing species in all systems analysed in Chapter 4 (ZrO₂) and Chapter 6 (UO₂). Diffusion of oxygen ions in amorphous undoped ZrO₂ and UO₂ systems was predicted to be much faster than that observed in the crystalline counterparts, over the temperature ranges simulated. This result highlights the difference in properties observed in amorphous regions that may be formed along the grain boundaries, in comparison to the crystalline bulk. The diffusion mechanism in amorphous systems can be considered as a structural re-arrangement of ions to accommodate diffusion events, opposite to the more defined vacancy or interstitial diffusion mechanisms observed in crystalline systems. This relates well with the range of activation energies often observed in amorphous systems, due to the disorder in amorphous systems impacting the activation energy landscape of the system. For the first time, the thermodynamic stability of undoped and doped amorphous oxide systems was investigated by assessing their configurational entropies. Crystalline and amorphous ZrO₂ systems were computed, and Voronoi tessellations were conducted on these systems to quantify the configurational entropy with increasing temperature. Enthalpy calculations were conducted using density functional theory, and by combining both enthalpy and entropy terms, the Gibbs free energy of reaction was computed successfully. This corroborates experimental literature reports of grain boundary complexions. Further utilisation of this novel approach will be useful in predicting fuel performance at high temperatures and understanding the corrosion mechanism along disordered grain boundary regions in ZrO₂.

Important decision making problems are increasingly addressed using computer models for complex real world systems. However, there are major limitations to their direct use including: their complex structure; large numbers of inputs and outputs; the presence of many sources of uncertainty; which is further compounded by their long evaluation times. Bayesian methodology for the analysis of computer models has been extensively developed to perform inference for the physical systems. In this thesis, the Bayesian uncertainty analysis methodology is extended to provide robust decision support under uncertainty. Bayesian emulators are employed as a fast and efficient statistical approximation for computer models. We establish a hierarchical Bayesian emulation framework that exploits known constrained simulator behaviour in constituents of the decision support utility function. In addition, novel Bayesian emulation methodology is developed for computer models with structured partial discontinuities. We advance the crucial uncertainty quantification methodology to perform a robust decision analysis developing a technique to assess and remove linear transformations of the utility function induced by sources of uncertainty to which conclusions are invariant, as well as incorporating structural model discrepancy and decision implementation error. These are encompassed within a novel iterative decision support procedure which acknowledges utility function uncertainty resulting from the separation of the analysts and final decision makers to deliver a robust class of decisions, along with any additional information, for further consideration. The complete toolkit is successfully demonstrated via an application to the problem of optimal petroleum field development, including an international and commercially important benchmark challenge.

The aim of this thesis is to write a 'music novel' for children and by doing so examine some of the many ways words and music play a role in storytelling. A music novel can be studied critically and to write one is ultimately a creative act. Academic scholarship on literary representations of music has so far been primarily focused on attending to the presence and representation of Western classical music in adult literary texts. Eminent leaders in the field include Delia da Sousa Correa, Emily Petermann, and Werner Wolf. Research into music in children's fiction has not been undertaken to such an extent. This thesis takes a first step towards readdressing this gap in knowledge, taking as examples children's novels by Aimee Lucido (In the Key of Code, 2019), Philip Reeve (Railhead, 2015), and Lewis Carroll (Alice's Adventures in Wonderland, 1865); and a more recent, contemporary adult novel by Matthew Herbert (The Music - A novel through sound, 2018). My detailed analysis centres on how music contributes to the construction and development of these works, as well as music that has made use of fiction as a compositional device in György Ligeti's Nonsense Madrigals (1988-93). The theoretical framing of my study draws on work by Roland Barthes, John Cage, Jean-Jacques Nattiez, and Patricia Waugh. Underdog, my music novel aimed at readers aged eight years and over, is my creative response to the questions this thesis raises. The two soundscapes that accompany the novel are musical paratexts born from Underdog that help unite the words with the music beyond the printed page. I provide a critical reflection on the inspirations behind Underdog which serves as a bridge into critical case studies that investigate what happens when one art form (music) has infiltrated the other (fiction) as part of what Jean-Jacques Nattiez calls the poietic process. My study demonstrates that the literary techniques used in fiction to imitate music, regardless of genre, are shared. These traits include references to pop and classical music embedded in the text, imitation of motifs and numerical musical patterns associated with a particular piece of music, and individual pieces of music that underpin the construction of a literary work.

This thesis explores the relationship between radical politics and the local state in the context of left urban government, through a case study of the 'new urban left' administration of the Greater London Council (GLC) from 1981 to 1986. Drawing on a critical historical study consisting of archival and oral history material, the GLC experience provides a lens through which to examine the potential, limits, and contradictions of radical urban movements developing political alternatives through the local state. Looking at how left activists pursued an alternative municipal politics, how they negotiated constraints, and how they experienced the contradictions of being 'in-and-against-the-state', the thesis develops an argument for looking beyond a binary conception of state and society. To capture different elements of working in-and-against the spaces of power, the thesis develops three linked conceptual frames each focused on different scales of analysis: 'urban state activism', highlighting the contestation of urban political economy; 'reflexive autonomy', emphasising the relational quality between constraint and agency and bringing into view both the limits and possibilities of pursuing radical politics within the local state; and 'activist state work', exploring the practical labour in the boundary-bridging world of radicals within the state, spanning the distinct yet overlapping roles and values of activism and officialdom. Productive possibilities for anti-capitalist social change can be found in the contradictions, gaps and fissures that emerge from political contestation within local government. The GLC study informs an argument for rethinking existing habitual binaries in radical left state-critical thought, chiefly in separating state from society and splitting left strategies into abstention or reformism. The thesis argues for antagonistic engagement with local states, and for attention to the everyday micro-politics of pursuing activism through the practical labour of statehood, which contributes to 'new municipalist' thinking on renewing left strategies for urban transformation.

This thesis considers the increased entanglement of contemporary French self-writing and theorising in the 2000s, with particular reference to questions of gender, sex and sexuality. The study of modern French autobiography has long emphasised the intimate connection between developments in intellectual thought and formal experimentation. Yet while the belated reception of queer theory and gender studies in France has generated significant critical interest, how these paradigms are both absorbed into and reconjugated by life writing has yet to be extensively examined. Attending to this omission, this thesis focuses on the generically hybrid works of four contemporary writer-theorists - Anne F. Garréta, Paul B. Preciado, Virginie Despentes and Didier Eribon - who make implicit and explicit use of theoretical precepts gleaned from gender studies and queer theory so as to narrate, reinterpret and retheorise the self. In so doing, this thesis establishes 'autotheory' - a genre which has gained recent critical interest to describe Anglophone texts that blend autobiography with theory - in the French context, arguing that its emergence marks a formal and ideological rupture with the predominant mode of autofiction. Chapter one establishes the critical ascendance and political valence of confessional French autofiction in the 1990s and 2000s through a reading of Anne F. Garréta's faux autofiction, Pas un jour (2002). Bringing Lauren Berlant's concept of the 'juxtapolitical' into conversation with Garréta's baroque Oulipian textuality and her own literary criticism, this chapter considers the psychoanalytic diagnostic of desiring and gendered subjectivity contained by the genre and its potential for renewal. Chapter two addresses the underexplored Derridean impulses of Paul B. Preciado's Testo Junkie (2008) to argue that Preciado rewrites the self beyond any one 'genre' through a deconstructive method of contamination, in which theory is both absorbed into and secreted out of the textual 'body'. Chapter three re- positions Virginie Despentes's King Kong Théorie (2004) as a work of 'low theory' that refuses to be confined to subject-centred realm of memoir and instead excavates a comprehensive theory of the sex-gender regime from Despentes's exposure to sexual violence, sex work and pornography. Yet the chapter also examines the possible limitations of theorising in the first-person by narrowing in on the text's racial lacunae. The final chapter discusses Didier Eribon's Retour à Reims (2009) as a work that demonstrates the autotheoretical undertow of the older French tradition of 'autosocioanalyse'. Blending sociological theory with his own anti-psychoanalytic queer theories, Eribon inverts the primacy of interiority in his project of self-knowing, even as this rejection of the psychoanalytic reproduces the self's opacity. French autotheory emerges as a lens through which to consider the divisions between the universal and the particular, the abstract and the embodied, the first-person and the political.

Since its development, electrospray ionization (ESI) for the analysis of thermally labile, polar compounds and particularly biomolecules has been extremely useful. Not all compounds can be easily protonated and electron ionization (EI) is still a widely used ionization method for compounds like hydrocarbons. However, the low-pressure environment of the EI source requires complex and expensive vacuum systems and inlets. Therefore, a source which can ionises non-polar compounds while operating at atmospheric pressure would be highly advantageous. In this thesis I have undertaken development and characterisation of four prototype atmospheric pressure glow discharge ionization sources for the analysis of compounds not normally amiable to ionization by conventional atmospheric pressure ionization sources. A helium micro-glow discharge source ("Prototype V") operated using a direct current power supply was studied and its discharge characterised. Its current-voltage relationship increased linearly which is typical of the abnormal glow regime while thermal imaging showed it had a "cold" discharge. Prototype V was successfully interfaced with a Xevo G2-S time-of-flight and a Xevo TQ-S triple quadrupole (Waters Corp, Wilmslow, UK) and used with a range of sample introduction methods, initially a solids probe, but later APCI and ESI probes. These probes enabled prototype V to readily integrate with separation sciences; specifically liquid chromatography was demonstrated for complex mixture analysis. Prototype V exhibited high analytical sensitivity in the nanogram range in both positive and negative modes and could ionize a wide range of compound chemistries from polar to non-polar. In particular it showed sensitivity to non-polar compounds in negative-ion mode when compared to ESI. This gives the source the potential to operate in conjunction with a range of sample inlets and in combination with other ionization techniques as part of a multimodal platform to analyse the widest range of samples and a step towards a universal source.

Tumour Necrosis Factor-alpha (TNF-α) is one of the main drivers of inflammatory bowel disease (IBD). Regulating the actions of this pro-inflammatory cytokine through selective antagonism using an anti-TNF-α monoclonal antibody (mAb) provides effective therapy for IBD. These agents are administered and then distributed systemically in a condition localised to the gastrointestinal tract. Induction of anti-drug antibodies and other undesirable side effects limit their use. This research aimed to optimise the production of ovine anti-TNF-α polyclonal antibodies (PcAb) and demonstrate their in vitro functionality to develop a therapeutic oral product for IBD treatment. The choice of adjuvants and immunisation schedules for the production of ovine anti-TNF-α PcAb was optimised. The novel product's binding, functional potency, and binding kinetics were compared to a licenced anti-TNF-α mAb, infliximab. Functional activity of ovine anti-TNF-α PcAb on TNF-α-dependent tight junction protein (TJP) modulation and cell architecture was assessed in a co-culture human tissue equivalent model of inflammation. This study demonstrates that CoVaccine HTTM adjuvant generates significantly greater ovine neutralising PcAbs directed against human TNF-α as compared to Freund's (with BrijTM-35) adjuvant. Additionally, the use of CoVaccine HT™ is associated with fewer reactions at injection sites. Ovine anti-TNF-α PcAb have broad functionality, as they bind and neutralise murine TNF-α, whilst a mAb, infliximab, does not. BiacoreTM studies demonstrated that the binding kinetics (KD, Ka and Kd) of ovine anti-TNF-α PcAb and infliximab are not significantly different. Additionally, cellular functional binding studies suggest that ovine anti-TNF-α PcAb bind both free and membrane-bound TNF-α. Functional activity of the novel ovine anti-TNF-α PcAb was demonstrated in an in vitro co-culture model of inflammatory disease. During inflammation, ovine anti-TNF-α PcAb protect Caco-2 monolayer integrity and maintain ZO-1 and occludin localisation. Additionally, they maintain F-actin distribution, cytoskeletal structure and cell architecture. The findings of this study indicate that ovine anti-TNF-α PcAb are functional and comparable to the monoclonal agent, infliximab, and supports their further development as a pharmacologically active component of an oral IBD treatment.

Background: Alternative provision (AP) for permanently excluded YPs of compulsory school age typically takes the form of pupil referral units (PRUs). PRUs ultimately aim to support and prepare YPs for a timely and successful reintegration to mainstream provision. Documented reintegration failures highlight a need for research that targets AP outcomes and informs reintegration practice. Methods/Participants: A systematic literature review (SLR) synthesises the existing research evidence regarding the reintegration experiences of YPs. Eight studies, including one international study, were critically appraised and synthesised following PRISMA guidelines. An empirical investigation, adopting an exploratory multiple case study methodology investigates stakeholders' reintegration experiences within the local context through individual interviews. Preliminary interview data and reintegration documentation were additionally gathered. Analysis/Findings: The SLR identified three global themes: outcomes of reintegration; factors that support reintegration (facilitators); factors that limit reintegration success (barriers). The findings were configured into a chronological reintegration journey model. Paper Two provides a detailed overview of both case studies, with constant comparative thematic analysis findings presented. The findings lead to a discussion of the overarching commonalities and differences of the case studies and a reintegration model that builds upon the findings of Paper One. Conclusion/implications: Paper One considers implications for reintegration practice and provides recommendations for future research. Paper two considers the use of a reintegration practice framework in supporting practitioners involved within the reintegration journeys of YPs. Recommendations of approaches for addressing reintegration facilitators and barriers, considering the role of educational psychologists, are discussed with implications for future research. Paper Three discusses evidence-based practice in relation to the role of practitioner psychologists. Plans for dissemination of findings, and professional practice implications, are discussed.

Extratropical cyclones and their associated extreme precipitation and wind cause large damage and loss of life over Europe. When such extremes occur at the same time and same place they can cause even greater risks. Knowing more about the frequency and spatial pattern of these extremes over Europe and their relationship to cyclones is important for forecasting, the (re)insurance industry and emergency planners. This thesis takes both an Eulerian and a Lagrangian perspective to investigate compound precipitation and wind extremes over Europe and within cyclones. Observational data including ERA5 as well as a high resolution climate model, GloSea5, is used to do this. Over Europe high co-occurrence is found over western coasts and low co-occurrence is found over eastern coasts. These results are found to be robust over different timescales and datasets. Cyclones are found to be strongly associated with compound extremes, given an extreme co-occurring event the chance of a cyclone being nearby is more than 70% for much of Europe. Using an objective feature tracking method, insight into the frequency, spatial pattern and footprint size of extremes within cyclones from a Lagrangian perspective is given. Wind extreme footprints have almost double the area of precipitation and are 5 times larger than compound. The spatial pattern of extremes does not vary much during a cyclones lifecycle, however, the frequency does. The frequency of extreme wind peaks at maximum intensity, within the cold conveyor belt to behind the cold front. The frequency of precipitation and compound extremes peak 6 hours before maximum intensity, ahead of the cyclone centre, in the warm conveyor belt and warm front. The spatial structure of extremes within cyclones are very consistent and vary little with seasonality, intensity and speed. The frequency of extremes and footprint size however varies largely. GloSea5 is evaluated against ERA5, to find out how well it can represent extremes from both an Eulerian and Lagrangian perspective and to be used to investigate unprecedented extremes using the UNSEEN method. Substantial differences in magnitude are found between precipitation and wind extremes between the datasets, however, compound extremes compare well spatially over Europe. GloSea5 represents the general structure of extremes within cyclones well. However, extremes at the cyclone centre tend to be overestimated and regions with the largest frequencies of extremes are underestimated, particularly within cyclones at maximum intensity. Despite biases in GloSea5 it is shown to have a reasonable representation of the storm tracks over Europe and the North Atlantic and can simulate the variability in cyclone frequency well. Although GloSea5 underestimates the number of storms over Europe there are still winters in GloSea5 with unprecedented number of storms for some locations. Extreme storm seasons over Europe and over particular locations arise from a variety of winter mean circulation types. GloSea5 has shown that it can replicate circulation patterns that appear feasible in and similar to the real world. Stormy seasons in GloSea5 are found that produce circulation patterns that are unrealised in the observational record. These large scale dynamics drive large numbers of storms over Central and Southern Europe. GloSea5 represents the size of extreme wind, precipitation and compound footprints very well. It is possible in the current climate to get storms with footprints of extremes almost double the size of that seen historically.

The Indian subcontinent (ISC) was targeting visceral leishmaniasis (VL) for elimination by 2020, with Bihar, an endemic state in India a major focus of the campaign. Current diagnostics for VL such as the direct agglutination test (DAT) and rK39 tests detect antibodies, making it difficult to distinguish between past or current infection, particularly in the absence of clinical symptoms or typical VL. Asymptomatic Leishmania infections (ALI) outnumber symptomatic infections on the ISC and people living with human immunodeficiency virus (PLHIV) have a higher risk of developing symptoms of VL with high treatment failure, relapse, and mortality, presenting a major challenge for both clinical management and elimination. PLHIV and asymptomatic individuals are of importance to VL elimination, particularly where the reservoir host is thought to be anthroponotic. Diagnostics that enable the detection of ALI, diagnosis of acute VL and Leishmania-HIV co-infections, monitoring VL treatment, and surveillance are needed. The Leishmania antigen enzyme-linked immunosorbent assay (ELISA) (Clin-Tech, UK) measures antigenuria, therefore identifying antigens excreted in urine during current infections, potentially allowing monitoring of VL treatment response, and predicting treatment failure and relapse in PLHIV. Testing urine is non-invasive and has the potential to replace invasive tissue aspiration. Real-time polymerase chain reaction (qPCR) is a highly sensitive technique to detect Leishmania donovani (L. donovani) kinetoplast DNA (kDNA). Similarly, loop-mediated isothermal amplification (LAMP) is a technique used to amplify DNA suitable for resource-poor settings. However, the clinical utility of the Leishmania antigen ELISA and molecular techniques in asymptomatic and symptomatic L. donovani infections with and without HIV has not been fully established in an elimination setting. In this thesis, I describe the prevalence and determinants of ALI, and the utility and diagnostic accuracy of the Leishmania antigen ELISA, DAT, LAMP, and qPCR for the detection of ALI in a cohort of 720 contacts of people with VL and PKDL in Bangladesh (chapter 2). Further, I describe the prevalence and determinants of ALI, and examine the utility of the Leishmania antigen ELISA, qPCR, rK39 rapid diagnostic test (RDT), and rK39 ELISA for the detection of ALI in a cohort of 1,300 PLHIV in India (chapter 3). The latter cohort were followed for 18 months to evaluate the rate and risk factors for disease progression from ALI to VL in PLHIV and to determine the utility of the Leishmania antigen ELISA, qPCR, rK39 RDT, and rK39 ELISA as markers of progression (chapter 4). I then describe the potential use of these assays as diagnostic and test of cure assays for VL in a cohort of HIV co-infected patients in India (chapter 5). In a final chapter, I screened a panel of thirteen monoclonal antibodies for the development of an alternative antigen detection test and evaluated other available antigen detection assays (chapter 6).

Horses were an important, and almost ubiquitous, component of many British Late Pliocene and Pleistocene ecosystems. Study of them has, however, been hampered by their highly convoluted taxonomy. This research describes horse fossils of the genus Equus from their first entry into the British mainland (over 2.6 million years ago) until approximately 12 thousand years ago. The earliest British Pliocene finds of stenonoid ('zebra-like') horses appear to pre-date first appearance records in many areas of Eurasia. Unlike several previously proposed biostratigraphical schemes for fossil European Equus, the earliest British material represents not one, but several species. Several species also continue to occur throughout the Early Pleistocene and early Middle Pleistocene, and this is likely to reflect an adaptive radiation of stenonoid horses subsequent to their entry into the Old World. Caballoid ('true' horses) first appear in Britain during the early Middle Pleistocene and, with the exception of very rare occurrences of the 'European ass', Equus hydruntinus, replace the stenonoid horses throughout the late Middle and Late Pleistocene. All of the British material studied is compared with samples from major mainland European localities, and this study confirms the presence of several species previously named using continental material. However, several significant differences between the British and European forms are also identified in this analysis, possibly due to the environmental conditions experienced by horses at the extreme north-west of their European distribution. The study also identified apparent gaps in the occurrence of horses in Britain. Some of these may be due to hiatuses in the stratigraphical sequence, but others appear to be due to factors such as very harsh environmental conditions during glacial stages and changes in sea level preventing their entry. Several possible reasons for the observed changes in size and form are presented. Additionally, forms that differ from the continental horses are described, including in the Late Pliocene deposits and around 200,000 years ago. The work concludes with suggestions for extending this research and for combining its findings with those from other fields.

This thesis explores the potential of the material turn in strategy studies to explore how nonhuman 'things' contribute to strategy production. Drawing on the ontologies and methodologies of the strategy-as-practice and actor-network theory domains, the empirical research informing this thesis is an immersive mixed methods ethnographic study in a higher education school of art and design conducted over a period of 24 months. The study combines observation and a qualitative interview protocol to build four explorative case study narratives that consider various aspects of material agency in strategy production. Analysis and discussion inform a re-theorising of strategy production that foregrounds the agency of materials beyond that of human intent, providing a counterpoint to prevailing approaches that centre the affordances 'things' offer to human action and suggesting instead a novel extension to strategy studies that emphasises emancipatory critique of normative organisational practices and ontologies.

This project follows the ghost of Gothic British masculinity across the ocean in the period of classical cinema. It examines the ways in which British stars were offered as an alternative to the American ideal of muscular, anti-intellectual, tough male identity. British men on film allowed Hollywood a glimpse in a mirror, a dark, haunted mirror, where identity might be fractured, damaged, liberated, queered or feminised. In a period dominated by two world wars and a Great Depression, identities of all types were being challenged and filmmakers used Britishness to allow this tension to seep into cinema. This project uses the lens of the Gothic as a method of uncovering the hidden history that is embedded in many films. The uncanny and the sublime, shadows and mirrors, portraits, decadent iconography and dark doubles all dominate in these cinematic texts. At a time when the Production Code made it necessary for subversive content to be well hidden, films contained embedded secret codes and invited possible alternative readings. Bringing together film scholarship with literary theorists this thesis offers fresh perspectives on historical cinematic meanings. This study presents a detailed analysis of British male stardom as it emerged in the period of early talkies. It details the ways in which the male stars, Ronald Colman, Basil Rathbone and George Sanders were presented in fan publications. It presents the contradictions inherent in their fan discourse and allows for consideration of the queerness that American culture seemed to accept was part of British - and European - male identity.

Let D be division algebra over its center C, let σ be an endormorphism of D, let δ be a left σ-derivation of D, and let R=D[t; σ, δ] be a skew polynomial ring. We study the structure of a class of nonassociative algebras, denoted by Sf, whose construction canonically generalises that of the associative quotient algebras R/Rf where f ∈ R is right-invariant. We determine the structure of the right nucleus of Sf when the polynomial f is bounded and not right invariant and either δ = 0, or σ = idD. As a by-product, we obtain a new proof on the size of the right nuclei of the cyclic (Petit) semifields Sf. We look at subalgebras of the right nucleus of Sf, generalising several of Petit's results [Pet66] and introduce the notion of semi-invariant elements of the coefficient ring D. The set of semi-invariant elements is shown to be equal to the nucleus of Sf when f is not right-invariant. Moreover, we compute the right nucleus of Sf for certain f. In the final chapter of this thesis we introduce and study a special class of polynomials in R called generalised A-polynomials. In a differential polynomial ring over a field of characteristic zero, A-polynomials were originally introduced by Amitsur [Ami54]. We find examples of polynomials whose eigenring is a central simple algebra over the field C ∩ Fix(σ) ∩ Const(δ).

Respiratory complex I (NADH:ubiquinone oxidoreductase) is a crucial metabolic enzyme that couples the free energy released from NADH oxidation and ubiquinone reduction to the translocation of four protons across an energy-transducing membrane, contributing to the proton motive force used to synthesise ATP. Although structural knowledge of complex I is now extensive, the mechanisms by which it captures the redox energy for proton translocation, and the mechanisms and pathways of the proton pumps, remain elusive. In this thesis, the α- proteobacterium Paracoccus denitrificans is developed and presented as a powerful model system for understanding mitochondrial complex I, combining interrogative biophysical and structural characterisation with the potential for mutagenesis in every subunit. First, aiming to establish conditions for studying the thermodynamic reversibility of P. denitrificans complex I, activation of ATP hydrolysis by the unidirectional F1FO-ATP synthase of P. denitrificans was investigated by the deletion of potential inhibitory subunits and treatment with potential chemical activators. While no conditions were found in which ATP hydrolysis could be sufficiently activated to drive complex I in reverse, insights were gained into the regulatory mechanism of P. denitrificans ATP synthase and the inhibitory role of Mg-ADP. Next, a strain of P. denitrificans containing an alternative NADH dehydrogenase, a bypass enzyme, was generated to facilitate the creation of deleterious complex I variants. In addition, a purification tag was engineered onto complex I, enabling its rapid purification. The isolated complex I was thoroughly characterised and its reconstitution into proteoliposomes was optimised, expanding the toolkit available for the study of complex I variants. The structure of the enzyme was also partially resolved by cryo-EM. The well-resolved map of the hydrophilic domain revealed a novel supernumerary subunit and demonstrated that P. denitrificans complex I exists entirely in the so-called 'active' state. However, due to conformational heterogeneity, the cryo-EM map was poorly resolved in the membrane domain, preventing detailed structural modelling of the complete enzyme. Finally, single point variants in the Nqo13 (ND4) subunit of complex I were generated to investigate: (1) key residues in the energy propagation pathway; (2) coordination to the lateral helix of Nqo12 (ND5); and (3) a potential hydration channel controlled by a gating mechanism. Comprehensive characterisation of the variants revealed insights into all three components of the mechanism. Furthermore, no variants were identified that pump fewer than four protons per NADH oxidised, emphasising the tight coupling between ubiquinone reduction and proton translocation, which is conserved even when the rate of catalysis is compromised.

Oesophageal cancer continues to be associated with a poor prognosis. Proton beam therapy's distinct physical characteristics widen the therapeutic ratio in oesophageal cancer and has the potential to improve outcomes. This thesis aims to examine how proton beam therapy may improve outcomes in oesophageal cancer and documents efforts to expand its role. In Chapter 2, a comprehensive systematic literature review demonstrates the paucity of high-quality evidence in this field. Following this, a series of radiotherapy planning studies investigates potential dosimetric advantages of proton beam therapy for distal oesophageal cases. In chapter 3, proton beam therapy is shown to reduce lung and heart dose compared to photon radiotherapy. Normal tissue complication probability modelling establishes that this may reduce the risk of treatment related pulmonary and cardiac toxicity. Chapter 4 demonstrates that spleen dose constraints may successfully be introduced in oesophageal cancer for proton and photon plans, potentially resulting in lower lymphopenia rates and greater immune sparing. Chapter 5 highlights the impact of different beam arrangements on dose to organs at risk and individual cardiac substructures. The latter half of the thesis highlights work underpinning the development of novel clinical trials of proton beam therapy in oesophageal cancer. Chapter 6 details the work of creating a radiotherapy delineation protocol by comparing two established protocols in a delineation comparison study, showing that geometric expansion of volumes results in more consistent target volumes compared to 'free-hand' delineation. In chapter 7, public and patient involvement work is shown to inform and refine the design of a two new trials of proton beam therapy in oesophageal cancer. A final chapter discusses and summarises the current areas of interest in this field, expanding on current trial development work and future directions.

This thesis presents a search for Higgs Portal Scalars (HPS) and Heavy Neutral Leptons (HNL) decaying in the MicroBooNE liquid argon time projection chamber (LArTPC). The measurement was performed using data collected in-time with the Neutrino at the Main Injector (NuMI) beam with a total exposure corresponding to 7.01 × 10²⁰ protons on target. Mono-energetic HPS and HNL would be produced from kaons decaying at rest in the NuMI hadron absorber, before travelling ~100 m to the MicroBooNE detector where they decay. A single selection and search strategy is used to target decays of HPS to µµ pairs and HNL to µπ pairs. The results are expressed as limits, at the 90% confidence level, on the mixing angles that control the rates of production and decay for each new particle. For the HNL model, upper limits are set on the mixing parameter |Uµ4|² in the range [12.9 × 10⁻⁸, 0.54 × 10⁻⁸] for HNL with masses in the region 246-385 MeV. For the HPS model, limits on the scalar-Higgs mixing angle θ² are set, excluding a region with a lower boundary between [31.3 × 10⁻⁹, 1.09 × 10⁻⁹] and an upper boundary between [2.50 × 10⁻⁵, 5.05 × 10⁻⁹] for scalars with a mass of 212-275 MeV. These results set the first constraints in this region of parameter space from a dedicated experimental search for HPS.

Quantum thermodynamics aims to build a theory of thermodynamics starting from the theory of quantum mechanics. The natural framework for this formulation of thermodynamics is the theory of open quantum systems. Open quantum system theory concerns the dynamics of a quantum system interacting with a quantum environment. Its techniques are suited to treating the dynamical, nonequilibrium processes that are of central importance to quantum thermodynamics. We give an introduction to the techniques of open quantum systems in Chapter 1. In quantum thermodynamics, work is an inherently stochastic quantity, and as well as its average behaviour we will look at its fluctuations and the underlying probability distribution that governs the fluctuations. Chapter 2 considers a finite-time quantum Otto engine. To operate at finite-time and simultaneously remove the quantum analogue to friction, a shortcut to adiabaticity protocol is applied. This suppresses nonadiabatic transitions in the system and minimises dissipated work. Any experimental realisation of such a system will be affected by an imperfect control of the driving protocol. We model these fluctuations of the control field with a Gaussian white noise process, and find that the noise is particularly detrimental to performance at short cycle times. At these short cycle times it would appear that it is disadvantageous to use the shortcut protocol. White noise is often an over-simplification of a stochastic process. Noise will generally be correlated with itself at different moments of time - this is referred to as coloured noise. In an extension of the analysis in Chapter 1, the third chapter is concerned with an isolated work protocol disturbed by coloured Gaussian noise. We find expressions for the first two moments of work for such a system. We then look at a particular model: a stochastic, driven harmonic oscillator and show that the average, non-Markovian dynamics of this model can be calculated exactly. This makes it an excellent test case for the analysis of quantum work in the presence of classical noise. We find non-monotonic behaviour of the work moments with the correlation time of the noise. In Chapter 4, we move beyond looking at work moments to calculating the distribution of work itself. We look at a driven two-level system interacting strongly with a heat bath. Most previous studies of work statistics of open systems have considered weakly-coupled systems. We work in a polaron frame which allows us to extend the weak-coupling analysis to the strong-coupling regime. We focus on driving protocols which give near-adiabatic unitary dynamics for the system. We find quantitative and qualitative differences to the weak-coupling theory: an overall broader distribution but with "sharper" features.

Ranavirus is a genus of large double-stranded DNA viruses (family Iridoviridae) that parasitise three taxonomic classes of poikilothermic vertebrates. They are important wildlife pathogens of conservation and economic concern, posing significant threat to amphibian biodiversity and aquaculture commerce. Despite substantial advances since their discovery in the 1960s, the evolutionary history of ranaviruses remains poorly characterised. The aim of this thesis is to advance the characterisation of Ranavirus evolutionary dynamics to contemporary standards. A large whole-genome dataset was collated and scrutinised, combining all publicly available material with a novel collection of isolate genomes. Cutting-edge microbial genomics tools were applied to gain insight into ranavirus genetic diversity, phylogeography, and genome evolution. Delineation of the Ranavirus pan-genome served as a foundation to conduct phylogenetic and population genetic analyses. Where the limitations of alignment-based methodologies were met, alignment-free techniques were employed to make full use of all genomic information. Phylogenetic reconstructions uncovered unique genetic diversity incompatible with current taxonomic demarcations amongst several lineages of Ranavirus. Pervasive genetic recombination was detected across the genus, and certain lineages contained a high degree of ancestral polyphyly. Recurrent patterns linked to animal trade and aquaculture were detected. Extensively polyphyletic viruses were isolated from captive animals, and population genetic analysis revealed ancestry components shared by ranaviruses isolated from farmed animals on separate continents. Finally, phylodynamic analysis suggests human-mediated translocation of FV3-like ranaviruses began more than a century before present. The inadequacies of current Ranavirus taxonomy are highlighted by this work, and suggests a substantial diversity remains to be characterised. The processes by which ranaviral genetic diversity is generated appears particularly dynamic, with significant contributions made via recombination between distinct linages. Altogether, this thesis underscores the vital impact trade and captive rearing of fish and herpetofauna have had on the global spread of ranaviruses and their processes of genetic diversification. Finally, these results suggest that anthropogenic influences commenced decades earlier than previously thought, likely upon the acceleration of modern globalisation.

Polycomb repressive complex 2 (PRC2) has a well characterised role in maintaining gene silencing and is essential for normal development, tissue homeostasis and is frequently dysregulated in cancer. The classical role of PRC2 is to catalyse post-translational modification of histone tails, with tri-methylation of Histone 3 lysine 27 strongly associated with gene silencing. Recent studies have highlighted additional non-classical roles for PRC2 including methylation of non-histone substrates, direct transcriptional activation and association with cell signalling cascades. Here I show that loss of core PRC2 components results in reduced Wnt signalling in embryonic stem cells (ESCs). Mouse ESCs that lack Suz12 show virtually undetectable canonical Wnt signalling. ESCs lacking Suz12 fail to differentiate. Intriguingly, efficient downregulation of pluripotency genes, but failure of induction of lineage specific genes is observed. In addition to the contribution to canonical Wnt signalling, beta-catenin also complexes with E-cadherin at cell surface adherens junctions. Importantly, altered E-cadherin localisation is observed in PRC2 null ES cells. E-cadherin localisation is normalised at cell-cell contacts between PRC2 mutant and wild type ES cells when grown together. Normalisation of E-cadherin localisation occurs concomitant to reestablishment of canonical Wnt signalling, and rescue of neuronal differentiation. The dual residency protein Afadin, a constituent of the intracellular adherens junction complex is also shown to have altered subcellular localisation in the absence of Jarid2 or Suz12. Taken together these results suggests a potential non-classical role for PRC2 in regulation of the adherens junctions, which in turn modifies the contribution of cadherin associated beta-catenin to Wnt signalling, and differentiation.

This thesis provides a Lacanian psychoanalytic study of the phenomena of unconscious generational transmission. It proposes a model of transmission without trauma, specifically a model of the effects produced as a result of generational transmission which can be described as unconscious, but wherein neither these effects nor their cause can be adequately described as 'traumatic'. The domain of trauma studies has traditionally dominated that of 'transmission studies', so that transmission is often taken to be an epiphenomenon of trauma. This thesis will argue for the opposite: transmission should be considered the primary and central phenomenon. It will argue that transmission phenomena exhibit the repetition of a signifier - the primary organising element of the unconscious -linking different aspects of the subject's lifeworld and prehistory, around which idiosyncratic significations are formed. It will propose that the presence of certain conditions - all of which function to establish what will be termed the 'Family Line', a construction which renders sensical the subject's place in a generational lineage - are determinative of generational transmission as an unconscious process. These conditions are specified as a) the presence of a debt; b) the necessity for an 'accounting' in relation to this debt or similar asymmetry in family relations; c) the doubling or superimposition of a loss; and d) the supplementation of a lack in the Other through a principle of sacrifice on the part of the subject. Clinical examples are used throughout, and the relevance for clinical practice of the proposed new model for unconscious generational transmission is specified.

Carl Schmitt has recently become a popular figure in humanities scholarship. In this turn, contemporary culture has amplified Schmitt's insights about sovereignty, states of emergency and political decisions. His ideas have particularly disturbed and excited literary theorists, who use his writings as a methodological resource for approaching 21st century literary fiction. This type of critical work does not fully take into account Schmitt's own encounters with, and exercises in, literature, art and cultural criticism. Concomitantly, nor does it understand his relationship to the literary cultures of his time and the artistic context within which he wrote his major philosophical works. In Europe and America, Schmitt's life as a writer, stretching from the 1910s to the 1970s, is dominated by the aesthetic revolution of modernism. Using this framing, my thesis asks: Does Schmitt's concept of sovereignty- of 'he who decides on the exception'-transform understandings of modernism? If so, how does this transformation attend to genres, forms and styles in ways that answer questions about sovereignty? How is sovereignty depicted in modernist literature? In response, this thesis analyses three works by definitive authors of literary modernism: Virginia Woolf's Orlando (1928), William Faulkner's The Wild Palms (1939) and Samuel Beckett's "Ping" (1967). It argues that these fictions respond to questions of sovereignty through their deployment of various, ironic aesthetic and representational techniques. Woolf's mocking satire of melancholy ironizes sovereign authority as epoch-defining. Faulkner's genresplicing, contrapuntal novel identifies failure as a contingent response to absolute sovereignty. Beckett's prose short explores the relationship between anticipation and the human search for sovereign representation. The methods I am exercising in this thesis speak within continuing and ever more complicated debates about sovereignty.

This study investigates the Japanese learning of foreign English teachers in Japan. Foreign English teachers are an example of a previously under-explored group of migrant language learners due to the linguistic capital they draw from being English speakers which in turn gives them access to employment positions in Japan. This study used a mixed methods approach and combined three data collection methods. In the Diary Study, nine teachers who had been in Japan for less than 1 year wrote weekly reflective diaries and took part in monthly interviews. For the Linguistic Biographies, thirteen long-term teachers who had been in Japan for over 5 years took part in two semi-structured interviews. In the L2 Motivational Self Survey, 227 teachers took a survey about their attitudes to learning Japanese. The Diary Study found that it was difficult for newly arrived teachers to manage their Japanese learning because of the pressure of self-directing language learning while living and working in Japan. For these teachers, exercising agency about their learning and having access opportunities to use Japanese were important in helping them maintain Japanese engagement. The Linguistic Biographies data found that a teacher's attitude to learning and using Japanese learning influenced whether a learner could stay engaged with Japanese learning. These teachers' Japanese learning was affected by the commitments that came with being a long-term migrant. The L2 Motivational Self Survey found that Dörnyei's L2 Motivational Self System was present in the experiences of foreign English teachers in Japan, but it was not possible to fit their responses stably during Structural Equation Modelling analysis. For both groups of foreign English teachers in Japan, managing Japanese learning while living and working in Japan was influenced by the how each learner valued Japanese learning, the linguistic capital that Japanese learning had for them and investment by communities in them as Japanese speakers. This shows that dominant ideologies that exist within a context and the L2 Learning Experience play a major role in whether teachers can maintain consistent language learning. This suggests that Dörnyei's L2 Motivational Self System does not fully account for the motivations of foreign English teachers in Japan learning Japanese.

This thesis contains simulation work carried out in order to understand the effect of modifying the hohlraum environment and the consequences of these modifications on the performance of an inertial confinement fusion capsule. Simulations were carried out using the radiation hydrodynamic codes HYADES and h2d. In addition, a view-factor code was developed in order to calculate the radiation symmetry for different hohlraum designs. Firstly, h2d was used to study the effect of lining the inside of a hohlraum with a mid-Z element, in this case copper, on the X-ray drive produced. A reduction in the hard X-ray component of the drive was found and attributed to the inclusion of the liner. The mechanism by which this reduction occurs was investigated and is outlined within this work. Secondly, the consequences of including a mid-Z liner were investigated by using HYADES to perform 1D implosions of capsules. A hohlraum with a reduced high energy X-ray content will be able to drive a capsule that contains lower levels of dopant. Implosions of capsules containing several different dopant concentrations were compared with regards to the ignition threshold energy in order to assess the benefit of using a lined hohlraum. Finally, a method for tailoring the X-ray drive symmetry in hohlraums via albedo-profiling of the hohlraum wall was investigated using a view-factor method. Symmetry control in geometries relevant to laser-driven and z-pinch driven hohlraums was obtained by using this method with the extent presented in the final results section of this thesis.

Tree crown morphology and arrangement in three-dimensional space is a key driver of forest dynamics, determining not only the competitiveness of an individual but also the competitive effect exerted on neighbouring trees. Many theoretical frameworks aim to predict crown morphology from first principles and assumptions of Euclidean form and ultimately infer whole forest stand structure and dynamics but paucity in data has limited vigorous testing. Tree crowns are also not rigid in form and due to their sessile nature, must morphologically adapt to immediate abiotic and biotic surroundings to enhance survival. The characterisation of tree structure has been limited by the simplicity and associated error of traditional crown measurements. This project uses Terrestrial Laser Scanning data collected from a water limited Mediterranean forest community in Spain to highlight methodological opportunities presented by TLS in understanding forest structure and also the various developments required to extract ecologically meaningful metrics from these data. It then applies these novel metrics to answer questions about how tree crowns scale with size, the effects of competition and how plasticity in shape and arrangement interacts with light capture at the individual and plot scales. Modification to existing code as well as bespoke development were required to segment and calculate individual metrics from trees in this forest type. Accurate measures of crown morphology highlighted allometric scaling deviations from theoretical predictions and intra-specific differences in response to competition, calculated using more representative neighbourhood metrics. Inter-specific differences in crown plasticity and significant effects of size (height) were also evident, along with trade-offs between morphological plasticity and crown size. Light capture was positively affected by plasticity with inter-specific differences highlighting various biomass allocations strategies species undertake to acquire light. At the plot scale, mixed-genus plots intercepted less direct light and were structurally more complex rather than more volume filling.

The problem this dissertation addresses is at face a simple one: in the very specific case of Hebrews 7.1-3, what interpretive move is the author using to interpret the Old Testament, when he offers a comparison between Jesus and the mysterious figure of Melchizedek? However, the answer quickly becomes complicated due to the inadequacy of our terminology, where "typology" and "allegory" - the most common interpretive moves assigned to Hebrews 7.1-3 in the scholarship - take on medieval or modern meanings rather than definitions available to the ancient authors themselves. This dissertation explores the historical background to figural and non-literal readings of sacred texts, considering in turn Greek, Jewish, and Christian readers. Each group of readers considered provides necessary context for interpretive activity in Hebrews. Greek allegorists provide the idea of a religiously or philosophically encoded text via the Homeric allegorists and their critic Plato. They also provide the actual ancient definition of the term "allegory", as a rhetorical trope involving extended metaphor and poetic hinting by an author, which might include techniques ranging from metonymy to numerology to concept-for-concept substitution. Jewish allegorists - Aristeas, Aristobulus, and Philo - make the distinctive move to seeing a text as encoded not by a human poet like Homer or Orpheus, but by the great divine Author, God. When turning to Christian allegorists, a natural touchstone is Paul - who uses the term allegory in Galatians - but Jesus himself and (Pseudo)-Barnabas also provide very important context for distinctively Christian allegorical reading, particularly involving the Christological fulfilment of hints laid by God in the sacred history of the Old Testament (that is, "typology"). Trajectories in allegorical exegesis in early Christianity are considered, to examine the latent tendencies within the form. Finally, the definitions and understanding gained are turned to use in analysing exegesis in Hebrews, where 7.1-3 - and several other texts - are read against the background of Hellenistic literary allegory.

Monitoring near real-time national solar PV output is an increasingly important part of operating an electricity system. Monitoring PV output requires knowledge of the output of many PV systems embedded in the distribution network whose generation are not directly visible through existing transmission system metering. In this thesis a review of 27 national solar PV monitoring services which provide national PV output estimates for 20 different countries was performed showing that every service follows the same general approach. First, the PV yield is modelled using a set of data from reference PV systems providing data in real-time. Then the modelled PV yield is scaled by an estimate of the national solar PV capacity to estimate the national PV output. National PV output is then used, along with similar measurements for other embedded technologies such as wind, to train and validate electricity forecasts which ensure efficient electricity market operation. Using Great Britain as a case study, the total error and uncertainty associated with the estimates from a national PV monitoring service are analysed. There are three main sources of error which contribute to the overall error in the national PV output estimates; the sample bias error, the statistical error in the yield model, and the error in the national capacity estimate. For the GB PV monitoring service, the domestic sample was shown to be unbiased for estimating national PV output. However, at a regional level the domestic sample used in the GB service is biased for estimating commercial/utility PV systems. The statistical error in the yield model was shown to be ±1% providing that a sample size of at least 6000 was used. The error in the GB national capacity estimate was shown to be ±5%. I can conclude that, the capacity error, at ±5%, dominates the yield calculation error, at < ±1% and leads to an overall error in GB solar PV output estimates of ±5.1%. I also conclude that solar PV measurements, and consequently national electricity demand forecasts, are currently limited by the state of national PV capacity registers.