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The proliferation of smart devices and sensors known as the Internet of Things (IoT), along with the transformation of mobile phones into powerful handheld computers as well as the continuing advancement in high-speed communication technologies, introduces new possibilities for collaborative distributed computing and collaborative workflows along with a new set of problems to be solved. However, traditional service-based applications, in fixed networks, are typically constructed and managed centrally and assume stable service endpoints and adequate network connectivity. Constructing and maintaining such applications in dynamic heterogeneous wireless networked environments, where limited bandwidth and transient connectivity are commonplace, presents significant challenges and makes centralized application construction and management impossible. The key objective for this thesis can be summarised as follows: a means is required to discover and orchestrate sequences of micro-services, i.e., workflows, on-demand, using currently available distributed resources (compute devices, functional services, data and sensors) in spite of a poor quality (fragmented, low bandwidth) network infrastructure and without central control. It is desirable to be able to compose such workflows on-the-fly in order to fulfil an 'intent'. The research undertaken investigates how service definition, service matching and decentralised service composition and orchestration can be achieved without centralised control using an approach based on a Binary Spatter Code Vector Symbolic Architec-ture and shows that the approach offers significant advantages in environments where communication networks are unreliable. The outcomes demonstrate a new cognitive workflow model that uses one-to-many communications to enable intelligent cooperation between self-describing service entities that can self-organise to complete a workflow task. Workflow orchestration overhead was minimised using two innovations, a local arbitration mechanism that uses a delayed response mechanism to suppress responses that are not an ideal match and the holographic nature of VSA descriptions enables messages to be truncated without loss of meaning. A new hierarchical VSA encoding scheme was created that is scaleable to any number of vector embeddings including workflow steps. The encoding can also facilitate learning since it provides unique contexts for each step in a workflow. The encoding also enables service pre-provisioning because individual workflow steps can be decoded easily by any service receiving a multicast workflow vector. This thesis brings the state-of-the-art closer to the ability to discover distributed services on-the-fly to fulfil an intent and without the need for centralised management or the imperative definition of all service steps, including locations. The use of a mathematically deterministic distributed vector representation in the form of BSC vectors for both service objects and workflows enables a common language for all elements required to discover and execute workflows in decentralised transient environments and opens up the possibilities of employing learning algorithms that can advance the state-of-the-art in distributed workflows towards a true cognitive distributed network architecture.

While in office from 1997 to 2010 the Labour government incorporated the US's ballistic missile defence (BMD) system into the UK's defence policy. Based on an upgrade of the radar systems at RAF Fylingdales and RAF Menwith Hill, this experimental technology was intended to detect and track incoming Intercontinental Ballistic Missiles (ICBM) and launch US interceptor missiles to destroy them. What is unusual about these developments is that they took place during the administration of a Labour government initially committed to the maintenance of the Anti-Ballistic Missile Treaty (ABM) Treaty, and emerged from a party with a history of antimilitarism. These events cannot be explained without referring to two themes running within and above British domestic politics. First of these is the skill of the Conservative Party in appealing to voters on defence issues. New Labour's promilitarism, including support for BMD, was an attempt to counter the Conservatives' dominance in this field. The second and perhaps overriding factor was the UK's Special Relationship with the United States. The UK relies on the US in order to augment its power internationally, and missile defence is part of this. Due to these constraints on the Labour government's defence policy, this research draws on the theoretical concepts of structure and agency, specifically the strategic-relational approach (SRA), to explain the UK's support for BMD. Labour's involvement with BMD during this time should be an area of substantial research. Yet it has been almost totally eclipsed by the UK's involvement in the invasions of Iraq and Afghanistan. This thesis deepens understanding of this under-explored subject and seeks to explain this research puzzle with reference to the structural factors relevant to Labour's policy towards BMD.

Burnout constitutes a significant challenge for healthcare organisations not only in respect to individual wellbeing but also in terms of the catastrophic downstream implications to patient safety, patient satisfaction, and quality of care. This DPhil, divided into three parts, aims to explore burnout in healthcare professionals, an accelerating phenomenon that is hotly discussed but minimally understood, with a focus on the impact uncertainty has and an exploration into the novel use of neurohormones as potential biomarkers of wellbeing. Part I: Exploration of concepts: burnout and uncertainty. Chapter 1 presents a selective overview of the broad context of burnout in healthcare, reporting existing literature on the impact of burnout—to physicians, to patients, and to healthcare organisations—and considering the challenges that pertain to burnout research, particularly relating to challenges in measurement. Chapter 2 explores the presence of uncertainty in the healthcare environment looking at what impacts an individual’s tolerance of uncertainty and how the reaction affects provider- and patient-centred outcomes. Chapters 3 and 4 present two observational studies exploring drivers of satisfaction at work for faculty in an academic medical centre, with an analysis of the interplay between burnout and uncertainty in the clinical environment. Chapter 5 presents a study that looks at how language used in clinical hand-over affects sense of uncertainty in the receiving clinician, demonstrating how language variation can influence emotional perception of uncertainty. Part II: Exploration of biology: exploration into use of biomarkers to measure burnout. Chapters 6 and 7 explore the novel use of cortisol and oxytocin levels as potential biomarkers of stress and burnout in clinical faculty at a large teaching hospital. Part III: Exploration of interventions to reduce burnout and strategies to embrace uncertainty. Chapter 8 presents an interprofessional intervention study looking to reduce burnout through self-facilitated groups meeting monthly for three months. This study re-affirms the importance of the findings presented in this thesis and points to the need for more interventions aimed at enhancing trainee and faculty wellbeing. Chapter 9 synthesises current literature on tolerance of uncertainty alongside findings of the thesis, self-experience, and experience of colleagues and students in a narrative review to identify strategies to help clinicians thrive in the face of clinical uncertainty. Finally, Chapter 10 presents an overview of the key findings from each study, their methodological strengths and limitations, directions for future research, and implications for clinical training, the measurement of wellbeing initiatives, and patient care.

Molecular replacement (MR) is the most popular technique to solve the phase problem in macromolecular crystallography. The conventional approach to finding search models for MR is to use the sequence of the target structure to identify a suitable homologue. This approach is based on the assumption that sequence similarity is a useful guide to structural similarity. Whilst largely true, this strategy is not always effective. For example, when a contaminant protein has been crystallised or when the most similar matches sequentially are not the most similar structurally. This thesis describes the development of SIMBAD, a three-step pipeline to perform sequence-independent MR. The first step performs a lattice-parameter search against the entire Protein Data Bank (PDB), rapidly determining whether the protein or a close homologue has been solved in the same crystal form. The second step is designed to screen the data against a database of known contaminants; thus determining if a contaminant protein has been crystallised. The final step is a brute-force search of a non-redundant derivative of the PDB provided by the MoRDa software package. In Chapter 3 the initial implementation of SIMBAD using AMoRe’s fast rotation function is presented, with encouraging results. Testing on a set of structures that covered a wide range of resolution limits, copies in the asymmetric unit, space groups, monomer sizes and secondary-structure types, gave a 40% success-rate with the full MoRDa database search and increased to 52% when combined with the lattice-parameter search. Further validation has come in the form of nine structures deposited to the PDB which used SIMBAD for structure solution. Leading on from the work in Chapter 3, research was carried out on whether the maximum-likelihood enhanced rotation function in Phaser would improve the sensitivity of the full MoRDa database search. Results presented in Chapter 4 show that the use of Phaser yielded a 60% success-rate on the test cases, a marked improvement on the previous iteration of SIMBAD. Combining this method with ensemble search models improved this further to 68%. Lastly, Chapter 5 explores the use of anomalous Fourier maps (AFMs) to validate partial MR solutions obtained from SIMBAD. This was necessary as the absence of sequence information meant that automated model building could not be included in the pipeline as a means to test the correctness of a potential solution. The findings in Chapter 5 demonstrate that when anomalous signal was available, the maximum peak height obtained in AFMs could be combined with R-free to train a classifier with 99% precision and recall.

The epidemic of obesity has led to increased interest in its role in the pathogenesis of cardiometabolic disease. Adipose tissue, formerly regarded as purely an energy storage site, is now regarded as an important endocrine organ. It produces various peptide hormones, including the adipocytokines which are implicated in metabolic control and disease. Whilst some adipocytokines may contribute to the development of cardiovascular disease, others e.g. adiponectin, may protect against it. The recently identified ligand for the G protein coupled receptor APJ, apelin, is a unique vasoactive adipocytokine. Both apelin and APJ mRNA are highly expressed in the cardiovascular system. Apelin has been found to modulate cardiovascular function, fluid homeostasis and inflammation. To date, however, apelin has not been investigated in the context of ischemia-reperfusion and its benefits in this clinical setting are not yet established. APJ/apelin activates the cell survival cascades Akt/PKB and ERK-1/2 which are associated with the pro-survival Reperfusion Injury Salvage Kinase (RISK) pathway. Apelin also promotes mitogenesis, a feature commonly exhibited by cardioprotective agents. We, therefore, hypothesised that apelin may protect the heart via the RISK pathway in an ischemia/reperfusion (MR) model. We investigated if apelin has potential as a cardioprotective agent employing murine models of ischemia-reperfusion injury and rat cardiomyocytes, in which mitochondrial permeability transition pore (mPTP) opening was examined. Apelin- 13 was found to produce a concentration-dependent decrease in infarct size with a maximal effect being observed at 1000nM. The physiologically less active peptide, apelin-36, also reduced infarct size but to lesser extents than seen with the shorter isoform. LY294002 and U0126, inhibitors of the PI3K-Akt, p44/42, abolished the effects of apelin-13. Further evidence for the involvement of these pathways in the cardioprotective actions of apelin was obtained on Western blot analysis. Apelin-13 delayed mPTP opening which was blocked by LY294002 and MEK inhibitor 1, an alternative inhibitor of p44/42. This is the first study to demonstrate that apelin has a direct cardioprotective action involving the PI3K- Akt, and p44/42 signalling pathways.

In the closing decades of the thirteenth century, the king of England, Edward I, embarked upon a series of wars in Wales, France and Scotland that placed unprecedented demands on the community of the realm. Although the Crown's war aims varied depending on whether the campaigns were being fought within the British Isles or on the continent, one factor remained constant: the need to recruit hundreds and sometimes thousands of soldiers on an almost annual basis from among the landholding elites. It is the aim of this thesis to assess how the gentry and nobility responded to these demands; how they discharged their military obligations; and what their service patterns and military experiences can tell us about the strengths and weaknesses of the armies that were put into the field. By using an innovative methodological approach established in recent decades by historians such as Philip Morgan, Andrew Ayton and Anne Curry, the thesis seeks to gain insights into the characteristics of the military community in its entirety. The individual soldier forms the main focus of enquiry throughout much of the discussion; and the frequency with which he gave military service, his connections to other members of the military elite, and, in the case of the king's chief commanders, the leadership duties that he performed, are each considered in detail. Nevertheless, the experiences of medieval combatants are best understood in the context of the local communities from which they were recruited and the retinues in which they served. Consequently, an attempt is also made to reassess the subject of military organisation under the first two Edwards by examining the composition and structure of these armies from the perspective of the soldiers and small units that comprised them.

The prosthetic groups of the respiratory fumarate reductase from Escherichia coli have been studied by electron paramagnetic resonance. The iron-sulphur clusters of this enzyme were characterised in membranes from a strain of E. coli with amplified expression of the fumarate reductase. Two ferredoxin centres, paramagnetic in the reduced state (FR1 & FR2, Em -50mV & -280mV) were shown to be present at the same concentration as the flavin, together with a centre paramagnetic in the oxidised state (FR3, Em -30mV), present at the same concentration. Another ferredoxin signal was observed in reduced membranes at 1/10th the concentration of the other centres. The relaxation processes of the iron-sulphur centres were characterised and shown to be similar to those reported for other iron-sulphur centres. These relaxation processes changed when more than one centre was paramagnetic, indicating interaction between the centres, which were characterised between FR1 & FR2, and FR1 & FR3, by the observed changes in e.p.r. properties. Estimates of the distances between centres were made from these observed changes. The orientation of the g-tensors of the iron-sulphur centres was studied in membrane multilayers, both from a wild-type strain and a strain with amplified expression of the enzyme. The iron-sulphur clusters were shown to have distinct orientations in both cases, with the amplified strain producing crystalline multilayers. The interactions between the iron-sulphur centres were shown to have an angular dependence and thus to be magnetic dipole-dipole interactions. The location of the iron-sulphur centres was studied using the exogenous paramagnetic probe dysprosium(III), and they were all shown to be on the cytoplasmic aspect of the cell membrane. The catalytic site of fumarate reduction was also located as cytoplasmic, by the use of mutant strains of coli, and inhibitors of the dicarboxylic acid porter. The iron-sulphur centres were shown to be located deep within the catalytic subunits of the enzyme. The flavin moiety of fumarate reductase was characterised in the isolated enzyme by e. p. r. The semiquinone form of the flavin was shown to be stable in the physiological pH range and to have an Em7 of -12mV (n = 2). Interaction between the semiquinone and FR1 was shown and characterised.

Objective: To determine how stress from uncertainty is related to resilience among pediatric residents and whether these attributes are associated with depression and burnout. Study Design and Setting: Cross-sectional study of 50 residents in pediatric residency programs from four urban freestanding children’s hospitals in the United States and Canada. Main outcome measures: Stress from uncertainty using the Physicians’ Reaction to Uncertainty Scale, resilience using the 14-item Resilience Scale, depression using the Harvard national depression screening scale, and burnout using single item measures of emotional exhaustion and depersonalization from the Maslach Burnout Inventory. Results: There was a strong correlation between stress from uncertainty and resilience (r=-0.597; p<0.00001). 5 residents (10%) met the criteria for depression and 15 residents (31%) met the criteria for high burnout. Depressed residents were more likely to be stressed by uncertainty (mean 51.6; SD 9.07 vs. mean 38.7; SD 6.73; p=0.0003) and to lack resilience (mean 56.6; SD 10.7 vs. mean 85.4; SD 7.97; p<0.0001) compared to residents who were not depressed. Burnt out residents were also more likely to be stressed by uncertainty (mean 44; SD 8.46 vs. mean 38.3; SD 7.13; p=0.0186) and to lack resilience (mean 76.7; SD 14.8 vs. mean 85.0; SD 9,77; p=0.0242) compared to residents who were not burnt out. We were able to identify the scores at which stress from uncertainty best predicts depression and burnout. Conclusion: Depression and burnout are major problems among pediatric residents. We found strong correlations between stress from uncertainty, resilience, depression, and burnout. Efforts to enhance tolerance of uncertainty and resilience among residents may provide opportunities to mitigate resident depression and burnout.

The purpose of this study was to identify and describe the convictions about choral conducting is held and applied by Caro Carapetyan which may have contributed to his superior choral work. The primary source of information was a series of personal interviews with Carapetyan. The report was organized into five sections. The first part supplied background material. Subjects covered in the report include philosophy, the relationship between conductor and singers the conductor's knowledge of music history and literature, rehearsal planning, conducting technique the selection of singers, choral tone, blend and balance, diction, intonation, rhythm, and dynamics. Each of the chapters in Parts II, III and IV includes a summary and some comparisons with other choral music sources. The fifth part is a summary of the findings, conclusions, and recommendations. Recommendations for choral conductors and future researchers are included.

John Blow (1649-1708) was among the first group of boys pressed into the service of King Charles II, following the decade of Puritan rule. Blow would make compositional efforts as early as 1664 and, at the age of nineteen, began to assume professional positions within the London musical establishment, ultimately becoming, along with his pupil and colleague, Henry Purcell, London's foremost musician. Restoration sacred music is generally thought of in connection with the stile nuovo which, for the first time, came to be a fully accepted practice among English musicians for the church. But the English sacred polyphonic art, little threatened by England's largely political Reformation, embodied sufficient flexibility as to allow it to absorb new ideas, thereby remaining vital well into the seventeenth century. Preserved from decisive Italian influences by the Interregnum, the English sacred polyphonic tradition awoke at the Restoration full of potential for continuing creative activity. In addition to studying Blow's polyphonic compositions, including the transcription of several not available in modern edition, this paper seeks to address the unique nature of the English polyphonic tradition which allowed it to retain its vitality throughout the seventeenth century, while other polyphonic traditions were succumbing to the ossifying influences of the stile antico concept. Identification of the Continental stile antico through pertinent treatises and scores revealed a marked distinction between its application and the English polyphonic art as seen in the work of John Blow. In the end, the peculiar nature of Restoration polyphony is seen to be derived from a number of factors, among them, the continuation of liturgical ceremonial within the independent English church, the flexibility of the English polyphonic medium with regard to new musical developments, and the interruption of England's cathedral music tradition just as Italian influence was beginning to be felt in liturgical music. The sacred polyphony of John Blow represents the last great flowering of the English polyphonic tradition, with all of its idiosyncracies, in a lively, as yet unfettered style.