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Piled foundations generally fail due to excessive deformations causing damage to the supported structure. Historically codes of practice have relied upon large factors of safety to ensure pile plunging and/or excessive bending is sufficiently unlikely. However, in order to properly assess foundation performance, reliable methods to predict deformations are required. Therefore, simplified methods for static and dynamic analysis of piled foundations under axial and lateral loads are of particular interest to an engineer. To this end: (1) a number of methods to calibrate Winkler springs and dashpots are briefly reviewed alongside existing Winkler solutions for homogeneous soil. (2) new exact and approximate solutions for the static and dynamic stiffness of single piles in axial and lateral modes are derived for inhomogeneous soil profiles using the Winkler model. The approximate solutions are based on energy principles obtained by means of shape functions analogous to those used in finite-element formulations. (3) novel solutions for pile groups under static and dynamic loads are derived using the interaction factor approach. Exact and approximate (energy-based) solutions for the interaction factors in axial and lateral modes are derived for both homogeneous and inhomogeneous soil profiles using the three-step model. (4) exact and approximate approaches are derived for the nonlinear response of piles. The exact solutions are based on linear elastic-perfectly plastic soil response while 't-z', 'q-z' and 'p-y' curves are used to obtain the approximate solutions. (5) results are presented in the form of dimensionless graphs and charts that show the influence of key parameters on pile response. Detailed comparisons with more rigorous numerical continuum solutions are presented alongside illustrative application examples. (6) an open-access database of axial pile load tests in UK soils was utilised to evaluate the settlement prediction performance of the relevant solutions developed in this work.

This thesis and thesis portfolio analyse factors that enable family ministry in three Church of England congregations. Literature suggests that working with youth and children (Y&C) in the context of the church family and the biological-legal home has beneficial effects on the faith retention of Y&C but there is a dearth of research around what might enable churches to work more closely and constructively with those two contexts. A review of the relevant literature reveals the way in which writers on Y&C ministry can be placed into two broad categories: those promoting a segmented ministry along age lines and those looking to integrate ministry to Y&C into the church and the home; this latter group can be sub-divided into those who focus on the church family and those who focus on the biological-legal family. Two articles follow, the first evaluates the sociological drivers to the segmenting approach, arguing that its roots lie deep in the emergence of modernity's view of the self. The second article examines the way in which the doctrine of accommodation can be used as a resource for those wishing to integrate Y&C into the wider church. These articles provide general background to the research question and do suggest factors that might enable or work against family ministry, but they do not form an integral part of the thesis. Empirical data from the three congregations was gathered through a case study approach that placed significant emphasis on semi-structured interviews with a representative sample of people from each congregation; observations and documentation were used as supporting and validating methods. The focus of the methodology was to examine the 'relationally positioned practices' of the congregations and the causes and meaning of those practices with respect to the enabling of family ministry. Themes arising from the case studies were brought into conversation with literature to provide the theological reflection needed to draw conclusions around the way in which the themes arising enabled family ministry. This analysis suggests that theology associated with charismatic and open evangelicalism is likely to lend itself to a focus on the church as family rather than the biological-legal home as family, with theology underpinning conservative evangelicalism having the reverse focus. In addition to theology, the theology and person of the leader enables or disables family ministry. Leaders' views of ministry are found to be a nuanced combination of theology, background experience, stage of life and personality. Without consideration of the impact of their background and stage of life, church leaders that have little experience of family ministry are unlikely to enable it in their churches. Additionally, those exhibiting the Myers-Briggs personality types of introversion, sensing, thinking and judging appear less likely to be comfortable with aspects specifically related to family ministry in the sense of intergenerational church (IG). Leaders whose personality and background do not suit IG can still foster IG via delegation to others better suited to the task. This thesis invites churches to consider enabling family ministry within the contexts and constraints of their own theological commitments and the leadership that they have, including the theology of the leaders but also their personality, background and stage of life.

Since their discovery over 50 years ago, a vast amount of work has been done to understand the complex radio emission mechanisms of pulsars. While their properties are stable on long timescales spanning many thousands of rotations, an abundance of fascinating, dynamic phenomena have been discovered by studying emission on short timescales of single pulses, with polarisation information being key to understanding the physical processes involved. This thesis presents a series of studies of the radio emission of four different pulsars from different segments of the population, with particular focus on their single-pulse modulation and polarisation properties. PSR B0031-07 exhibits three states with drifting subpulses of different periodicities, and is one of several pulsars known to show orthogonal polarisation mode (OPM) transitions that are modulated together with the total intensity emission. To explain this, I propose a model based on pulse longitude-dependent magnetospheric mixing and attenuation of the two linear OPMs. By exploring an atlas of possible geometries, the asymmetry in polarisation and total intensity is qualitatively reproduced by an axisymmetric carousel of sub-beams, while asymmetries occur due to propagation through the magnetosphere. This demonstrated that the carousel model is still a viable explanation for drifting subpulses. Secondly, the properties of PSR J1926-0652 are studied. This pulsar was discovered with the Five-hundred-metre Aperture Spherical radio Telescope (FAST) during commissioning, and was observed with the Parkes telescope as well. The single pulses of PSR J1926-0652 detected with FAST reveal somewhat unstable drifting subpulses and a moderate nulling fraction. The twin-peaked profile of this pulsar is shown to be significantly different to the average profile in the last active pulses immediately prior to a null. This suggests that drifting subpulses and nulling are associated processes, which would not be a natural consequence of existing models. Thirdly, the millisecond pulsar PSR J1518+4904 is studied with FAST, which is sensitive enough to clearly detect its single pulses and also to discover two new profile components at 1250 MHz. Fourier analysis of the single-pulse data shows that multiple periodicities are present in different profile components, including one associated with the main profile that has a pulse longitude-dependent fluctuation frequency. Such behaviour has never been observed in any pulsar before. No evidence is found for mode changing, leading to the conclusion that these single pulse periodicities occur simultaneously. Finally the multi-frequency observations of the slow pulsar PSR J0250+5854 are presented, which were performed simultaneously with FAST, two LOFAR international stations, and NenuFAR. The spectral coverage of this object is extended by a factor of ~5, revealing a steep radio spectrum with a low-frequency turnover. The profile is shown to broaden at higher frequencies, counter to the expectation of radius-to-frequency mapping. Polarisation data help to confirm that this is because only a small fraction of the open field lines produce radio emission at the lowest frequencies.

Galaxy clusters are the largest gravitationally bound structures in our Universe, and hence can be used to constrain the physical laws that govern cosmic evolution. In order to use clusters as cosmological probes, large samples of bona-fide clusters are needed, in addition to a method with which to estimate cluster masses accurately. Additionally, clusters can be studied to understand the physical processes within the clusters themselves. As clusters form via hierarchical growth, growing ever larger through mergers with smaller systems and accretion of matter from the surrounding environment, understanding the physical processes in the outer regions of a cluster can tell us more about how they grow. The first project in my PhD tackled the issue of constructing reliable samples of clusters for cosmology, specifically analysing Chandra observations of high redshift cluster candidates detected in the XXL survey, to probe not only their AGN contamination, but also to ensure that they were indeed genuine clusters. The second project in my PhD focussed on the calibration of the X-ray hydrostatic cluster mass estimation method, by comparing the X-ray hydrostatic masses of a sample of 44 clusters with masses for the same sample of clusters measured with an entirely independent method based on information on galaxy dynamics obtained from optical observations. The final project in my PhD used the same sample of clusters as the mass calibration work to study the outer regions of clusters, specifically calculating the gas fraction at large radii of these clusters, to gain insight into the state of the cluster gas in the cluster outskirts.

Response to treatment for some cancers may result in a proportion of the patients being permanently cured of the disease, while the rest remain at risk of a relapse or progression. Standard survival analysis approaches assume that all patients will eventually experience the event of interest and so are not appropriate in these situations. The residual disease and tumour re-growth rate following treatment are two of the important predictors of outcomes among cancer patients following treatment. However, in most cases, data on these measures is not always available. Using data from multiple myeloma and chronic lymphocytic leukaemia trials conducted at the Leeds Institute of Clinical Trials Research, we investigated the role of the residual disease and other important factors associated with time to relapse and overall survival, as well as the probability of being cured of the malignancy following treatment. As the multiple myeloma trial also collected data on bio-markers for tumour growth rate, we used the structural equation modelling approach to investigate the role of growth rate on the survival outcomes using available statistical software. We then extended these models to also investigate the association of growth and the probability of being cured after treatment in a Bayesian framework including in situations where not all patients will relapse or die after treatment. This work demonstrates that it is feasible to use structural equation modelling within survival analysis to investigate the role of latent variables on time to event outcomes even in situations where not all patients will relapse or die after treatment.

Heterotopic ossification (HO) is the formation of new extra-skeletal osseous tissue. It is a common outcome following trauma, affecting up to 91% of blast-related amputees. However, the pathogenesis of HO remains poorly understood and there has been little investigation of the heterotopic bone which develops. The main objective of this thesis was to perform a multiscale characterisation of the structure of human heterotopic bone formed following trauma, for systematic and quantitative comparison with orthotopic bone. This was achieved using several analytical techniques. At microscale, μCT imaging was employed for 3-D visualisation and to perform digital histomorphometry and topological analysis on trabecular structure and osteocyte lacunae. At nanoscale, scanning wide- and small-angle X-ray scattering techniques using a synchrotron source were used to measure and map variations in the structural organisation of collagen fibrils and mineral crystals, supplemented by microscopic methods permitting direct visualisation of the collagen fibrillar organisation and mineral crystals. The data collected reveal that at microscale, heterotopic bone broadly resembles orthotopic bone tissue. At nanoscale, it undergoes a maturation process similar to that of fracture callus; and by around 50 – 100 weeks after injury it structurally resembles adult orthotopic bone. These similarities extend from the size and organisation of the nanoscale components including mineral crystals and collagen fibrils, to a common topological organisation of the trabecular bone, and the presence of a cortical shell. However, greater nanostructural heterogeneity was also observed. These observations provide support for the interpretation that heterotopic bone is essentially normal osseous tissue, where the structural abnormalities observed relate to the abnormal tissue environment rather than intrinsic structural differences relative to orthotopic bone. These findings extend prior understanding of heterotopic bone structure and have a range of implications which include providing indirect support for attempts to model HO in silico.

Introduction: Liver resection is increasingly being carried out via the laparoscopic approach (keyhole surgery) because there is mounting evidence that it benefits patients by reducing pain and length of hospitalisation. There are however ongoing concerns about oncological radicality (i.e. ability to completely remove cancer) and an inability to control massive haemorrhage. These issues can partially be attributed to a loss of sensation such as depth perception, tactile feedback and a reduced field of view. Utilisation of optical imaging and computer vision may be able to compensate for some of the lost sensory input because these modalities can facilitate visualisation of liver tissue and structural anatomy. Their use in laparoscopy is attractive because it is easy to adapt or integrate with existing technology. The aim of this thesis is to explore to what extent this technology can aid in the detection of normal and abnormal liver tissue and structures. / Methods: The current state of the art for optical imaging and computer vision in laparoscopic liver surgery is assessed in a systematic review. Evaluation of confocal laser endomicroscopy is carried out on a murine and porcine model of liver disease. Multispectral near infrared imaging is evaluated on ex-vivo liver specimen. Video magnification is assessed on a mechanical flow phantom and a porcine model of liver disease. The latter model was also employed to develop a computer vision based image guidance system for laparoscopic liver surgery. This image guidance system is further evaluated in a clinical feasibility study. Where appropriate, experimental findings are substantiated with statistical analysis. / Results: Use of confocal laser endomicroscopy enabled discrimination between cancer and normal liver tissue with a sub-millimetre precision. This technology also made it possible to verify the adequacy of thermal liver ablation. Multispectral imaging, at specific wavelengths was shown to have the potential to highlight the presence of colorectal and hepatocellular cancer. An image reprocessing algorithm is proposed to simplify visual interpretation of the resulting images. It is shown that video magnification can determine the presence of pulsatile motion but that it cannot reliably determine the extent of motion. Development and performance metrics of an image guidance system for laparoscopic liver surgery are outlined. The system was found to improve intraoperative orientation more development work is however required to enable reliable prediction of oncological margins. / Discussion: The results in this thesis indicate that confocal laser endomicroscopy and image guidance systems have reached a development stage where their intraoperative use may benefit surgeons by visualising features of liver anatomy and tissue characteristics. Video magnification and multispectral imaging require more development and suggestions are made to direct this work. It is also highlighted that it is crucial to standardise assessment methods for these technologies which will allow a more direct comparison between the outcomes of different groups. Limited imaging depth is a major restriction of these technologies but this may be overcome by combining them with preoperatively obtained imaging data. Just like laparoscopy, optical imaging and computer vision use functions of light, a shared characteristic that makes their combined use complementary.

This thesis will address the question 'how has the concept of national security changed in 21st century Spain?' It will account for the shifts in modern Spain's approach to security policy and is based on an analysis of three recent administrations and their decisions, such as to support the US invasion of Iraq, as well as the responses to the economic crisis of 2008, and changes heralded in a process of national security strategies. To date, Spain's security in a broader sense has been little researched and this thesis examines a number of themes including securitisation, the indignados movement and the role of ministries in national security strategy. Case studies are used alongside Katzenstein's constructivist approach to analyse the evolution of security policy. The thesis synthesises the Copenhagen School's 'sectors' approach with a constructivist model to develop a concept of a culture of security in Spain supported by Clausewitz's 'remarkable trinity' to address the role of Spanish Prime Ministers. This approach has not been developed with regard to Spain before and, in conjunction with an analysis of the National Security Strategies of 2011 and 2013, it is argued that Spain's executive, the Prime Minister, still exerts an excessive influence on national policy and institutions. Interviews with key stakeholders and policy-makers underpin the argument that security in Spain remains contested and that recent initiatives to promote a broader security agenda are not supported in organisational structure or policy.

I hypothesise that cancer cells with high aldehyde dehydrogenase (ALDHhigh) activity present a new therapeutic target and will be selectively sensitive to 5-nitrofuran pro-drugs. Cancers are heterogeneous and contain subpopulations of ALDHhigh cells with tumour initiating potential. ALDH enzymes metabolize toxic aldehydes, and are highly expressed in somatic and cancer stem cells (CSCs), although their function in CSCs is not fully understood. In a small molecule screen coupled with target ID, Zhou et al. (2012) recently discovered that clinically active 5-nitrofurans (5-NFNs) are substrates of ALDH2. 5-NFNs are a class of pro-drug widely used to treat bacterial and parasitic infections, where their relative specificity is driven by nitroreductases, but little is known about the enzymes that bio-activate 5-NFNs in humans. Recent clinical cancer research has found that the 5-NFN, nifurtimox, has anti-cancer properties and it is currently in Phase 2 clinical trials for neuroblastoma and medulloblastoma (ClinicalTrials.gov Identifier: NCT00601003), however the mechanism underlying this anti-cancer activity is unknown. In melanoma and other cancers, ALDH1A1 and ALDH1A3 are highly expressed in CSCs. I demonstrate the anti-cancer activity of 5-NFNs in cancer cell lines, where they express high sensitivity to 5-NFNs in cell viability assays (A375 melanoma cells EC50 = 867nM). To test if ALDH1 enzymes are substrates of 5-NFNs, I performed in vitro activity assays by monitoring NADH production (λ = 340nm). I found that the clinically available 5-NFNs, nifuroxazide and nifurtimox, in addition to our own newly synthesised 5-NFNs, are competitive substrates for human ALDH1A3 activity in vitro (P < 0.05). Notably, nifuroxazide is not a substrate for ALDH2, suggesting that nifuroxazide may show selectivity toward ALDH1. Enzymatic assays with purified human ALDH2, demonstrate that ALDH2 requires NAD+ for bio-activation of 5-NFNs. Consistent with these assays, I found that 5-NFNs are competitive substrates for ALDH activity in melanoma cells by Aldefluor™, with 5-NFNs displaying a prolonged competitive inhibition of ALDH activity compared with the known inhibitor, DEAB. Importantly, no-nitro control compounds show no activity toward ALDH enzymes in vitro or in culture. Kinetic living-cell imaging (IncuCyte ZOOM®) reveals that a subpopulation of ALDH1A3 siRNA transfected A375 cells are protected from 5-NFN toxicity (P > 0.05) and cell death (DRAQ7™: P < 0.0001), demonstrating a functional role for ALDH1A3 in mediating 5-NFN activity in cancer cells. In contrast, A375 cells overexpressing ALDH1A3 by cDNA transient transfection were hypersensitive to 5-NFNs (P < 0.001), determined by Muse™ cell viability. Computational docking studies reveal that 5-NFNs have the potential to fit within the interior of the ALDH enzymatic cavity and interact with the catalytic cysteine, thereby offering a potential mechanism for 5-NFN bio-activation. Finally, in collaboration, we show a unique interaction between 5-NFNs and ALDH using mass spectrometry and have initiated protein crystallography trials. My work demonstrates a novel and biologically relevant 5-NFN-ALDH interaction in cancer cells. I propose 5-NFNs have the potential to target ALDHhigh CSCs within a tumour and advance the repurposing of clinical 5-NFN pro-drug antibiotics as anti-cancer therapeutics.

Among current techniques, used to assist the modelling of atmospheric processes, is an approach involving the balloon or aircraft launching of radiosondes, which travel along uncontrolled trajectories dependent on wind speed. Radiosondes are launched daily from numerous worldwide locations and the data collected is integral to numerical weather prediction. This thesis proposes an unmanned air system for atmospheric research, consisting of multiple, balloon-launched, autonomous gliders. The trajectories of the gliders are optimised for the uniform sampling of a volume of airspace and the efficient mapping of a particular physical or chemical measure. To accomplish this we have developed a series of algorithms for path planning, driven by the dual objectives of uncertainty and information gain. Algorithms for centralised, discrete path planning, a centralised, continuous planner and finally a decentralised, real-time, asynchronous planner are presented. The continuous heuristics search a look-up table of plausible manoeuvres generated by way of an offline flight dynamics model, ensuring that the optimised trajectories are flyable. Further to this, a greedy heuristic for path growth is introduced alongside a control for search coarseness, establishing a sliding control for the level of allowed global exploration, local exploitation and computational complexity. The algorithm is also integrated with a flight dynamics model, and communications and flight systems hardware, enabling software and hardware-in-the-loop simulations. The algorithm outperforms random search in two and three dimensions. We also assess the applicability of the unmanned air system in ‘real’ environments, accounting for the presence of complicated flow fields and boundaries. A case study based on the island South Georgia is presented and indicates good algorithm performance in strong, variable winds. We also examine the impact of co-operation within this multi-agent system of decentralised, unmanned gliders, investigating the threshold for communication range, which allows for optimal search whilst reducing both the cost of individual communication devices and the computational resources associated with the processing of data received by each aircraft. Reductions in communication radius are found to have a significant, negative impact upon the resulting efficiency of the system. To somewhat recover these losses, we utilise a sorting algorithm, determining information priority between any two aircraft in range. Furthermore, negotiation between aircraft is introduced, allowing aircraft to resolve any possible conflicts between selected paths, which helps to counteractany latency in the search heuristic.

The Large Hadron Collider at CERN completed its first data-taking phase in 2013, after three years of remarkable performance. The high-energy proton-proton collisions recorded by the ATLAS experiment provide a gateway to the world of subatomic particles. This thesis presents two analyses of the full 8 TeV dataset taken by ATLAS, inspired by two of the major physics goals of the experiment. The first analysis is a search for new phenomena that could explain the nature of Dark Matter and solve the hierarchy problem. In particular, the search is optimised to look for heavy supersymmetric particles decaying to large numbers (7 to ≥10) of jets. The events are further classified according to the number of jets identified as originating from a b quark. No evidence is found for physics beyond the Standard Model, so the results are interpreted in terms of exclusion limits on various simplified supersymmetry-inspired models where gluinos are pair produced, as well as a mSUGRA/CMSSM model. The main background to the search is due to multi-jet production via the strong force. This motivates the second analysis presented in this thesis, which is a measurement of the cross section of four-jet events. The measurement is performed differentially in a series of variables which describe the kinematics and spatial configuration of the events. The results are compared to existing theoretical predictions.

Deletions of the short arm of chromosome 12 (12p) are found in around 6% of acute myeloid leukaemia (AML). Particularly in paediatric AML they often occur as the sole cytogenetic change and are associated with a poor prognosis. Amplifications of the long arm of chromosome 11 (11q) are rarer, found in around 1% of AML, but are particularly prevalent in the poor prognosis complex karyotype group. Despite multiple deletion mapping studies, single genes have not been identified from these regions that are responsible for driving leukaemic progression, thus it is clear that a functional approach is required. This study aimed to functionally implicate significant genes through the use of competitive selection assays. Publicly available array data from eight studies were used to determine copy number from AML patient samples to define minimal regions of copy number alteration. Data were obtained from 866 samples which had been analysed on Affymetrix SNP array platforms. In total 58 samples (6.7%) were found to have deletions of 12p and were used to determine a minimally deleted region (MDR), whilst five samples (0.6%) were identified with amplifications of 11q and used to define a minimally amplified region (MAR). AML cell lines with deletions of 12p (NKM-1 and GDM-1) and amplification of 11q (UoC-M1) were selected to investigate the functional relevance of the genes within the regions of interest. Cell lines were used in vitro and in immunocompromised mouse models, where leukaemia was established by intrafemoral injection and monitored by luminescent imaging of luciferase expression constructs. Taking a pooled approach, 11 genes within the 12p MDR were overexpressed and 30 genes from the 11q MAR were knocked down using integrated lentiviral vectors. To evaluate effects of expression on leukaemia growth or survival, changes in construct copy number after cell line expansion in vitro and in vivo were determined by targeted high throughput sequencing on the Illumina MiSeq platform. Demonstrating a strong anti leukaemic effect for expression of this gene, a construct for cyclin dependent kinase inhibitor 1B (CDKN1B) was rapidly selected against in the 12p assay, whilst knockdown of MPZL3 and UBE4A from 11q were selected against in the 11q assay. Functional follow up work mainly focussed on CDKN1B, where its expression was measured in a range of a cell lines and patient samples, its effects on the cell cycle assessed and correlation of CDKN1B expression and treatment with a cyclin dependent kinase inhibitor (Flavopiridol) was established.

Over recent years there have been significant changes in both the diagnosis and management of palpable swellings of the parotid and submandibular major salivary glands. There is a requirement and an expectation from both clinicians and patients that a pre-operative diagnosis is available and that it is accurate and obtained in a manner which is safe and timely, this is of particular importance with the advent of minimally invasive surgical techniques. There is also increasing recognition that the principal current salivary gland biopsy technique, fine needle aspiration cytology (FNAC), is associated with significant drawbacks and is not performing reliably across a network of institutions.

Aim: This study explores what type of information patients and nurses share with, or provide to, each other, and whether or not the information received was relevant and sufficient for their needs. Background: Information exchange, as part of shared decision-making, is advocated in policy and practice throughout the healthcare sector. Much of the literature on information exchange relates to one-to-one consultations with consultants or GPs. To date, no studies have explored information exchange between patients and nurses in ward settings. Nursing literature on patients’ information needs focuses on one-way information provision from nurses to patients, rather than on two-way information exchange between patients and nurses. Methods: Interactions between patients and nurses were observed and audio-recorded using a remotely controlled audio-recording system. Semi-structured individual face-to-face interviews were then conducted to clarify and add to the observation data. A multiple case study design was used for this study: each case comprised one patient, the nurses caring for that patient, and the interactions between them. A pilot study was undertaken to inform the methods for recruitment and data collection for the main study. Results: The pilot study comprised five cases (patients n=5, nurses n=3). Changes to the recruitment strategy for the main study included surgical patients being invited to participate in the same way as medical patients. There were no difficulties with the data collection methods. The main study comprised nineteen cases (patients n=19, nurses n=22). Information exchange seemed unfamiliar to ward-based nurses. The findings show that information exchange may not be a one-off event but a complex series of interactions. Patients did not distinguish between clinical and non-clinical information in the same way as nurses. Primary reasons for patients’ hospital admission were not discussed and nurses did not share information about nursing interventions. The relevance for patients and nurses differed; patients generally wanted information for reducing anxiety and socialization; nurses wanted information for assessment and care planning. In terms of sufficiency, observation sessions highlighted that insufficient information was provided, often due to lost opportunities and paternalistic practice. However, the majority of patients and nurses perceived that they had exchanged sufficient information. Conclusion: This multiple case study provides insights into the type, relevance and sufficiency of information for patients and nurses in ward settings. In ward settings, information exchange as conceptualised by Charles et al. (1997 and 1999) may be difficult to achieve due to the complexity of patient/nurse interactions. Therefore, there are implications for policy makers as policies are not context specific. However, information exchange may be helpful for reducing patients’ anxieties. The concepts of shared decision-making and information exchange are not part of ward-based cultures and philosophies, which suggests implications for patient and nurse education. Research on information exchange between patients and nurses in other ward contexts may contribute to further understanding of information exchange in ward settings.

The writings of Georges Bataille (1897- 1962), Maurice Blanchot (1907-2003) and Michel Serres (1930- ) all encompass critical theory and literary narrative. The theoretical and literary strands of these writers' works allude frequently to instances of perception which involve sight and touch. The approaches to questions of corporeal sensation favoured by Bataille, Blanchot and Serres differ appreciably, however. For this reason, analyses of any common literary or theoretical ground that may exist between these authors are relatively scarce. In fact, there are currently no other in-depth analyses which compare the writings of Bataille, Blanchot and Serres. In this thesis, I take " the further unprecedented step of comparing these three writers' theoretical and literary output by examining the manner in which they approach the sensory possibilities of haptic perception. The term 'haptic' (or haptisch) is often associated with aesthetic theories posited by Alols Riegl (1858- 1905). Broadly speaking, Riegl's model of haptic perception describes a synergy between touch and vision that is inspired by artworks, examples of handicraft or built structures. Following an introductory analysis of Riegl's theorisation of haptic sensation, I examine three recent reformulations of his concept which are provided by Laura U. Marks (1963-), Mark Paterson (1972-) and Jean-Luc Nancy (1940-). These understandings of haptic perception have been chosen because they capture the sheer diversity of haptic sensory experiences portrayed in the writings of Bataille, Blanchot and Serres. My subsequent close readings of Bataille, Blanchot and Serres's works show that the three writers' theoretical and literary texts eventually shun allusions to haptic perception to varying degrees. In spite of these apparent rejections, I conclude that for Bataille, Blanchot and Serres, portrayals of haptic perception play an enduring role in reconciling the abstractive tendencies of philosophical writing with the empirical demands of literary narrative.

The thesis presents and inquires into a first person research story about the development of a ‘Community of Practice’ for asset-based rural development practitioners from across the UK and Republic of Ireland. It includes an account of how geographically remote members of the CoP were supported to come together over eighteen months to co-produce an online handbook called ‘Exploring Community Resilience’ (included as Appendix 1). Findings include: - Social networking and social media technologies can be powerful enablers of third and second person inquiry; - A compass tool (included here) can help hosts and curators make good design and facilitation choices as they host the emergence of complex, large scale social learning architectures (which this thesis calls ‘Digital Forests’); - Action researchers can benefit from developing skills as digital curators, producers of social media, and hosts of transformative learning processes; - Future generations of social media are likely to challenge the assumptions, methods and findings of this thesis. As we navigate our way into this fast changing future, it will be helpful to inquire into their impacts of new generations of digital technologies on our personal and collective psychological, cultural and social wellbeing.

Flexible plastic liners are sometimes installed into new and existing oil and gas pipelines to prevent corrosion of the pipe wall. A practical difficulty of this method is that the plastic liners are permeable to gases, which can collect and form an annular space between the liner and the pipe. If the operating pressure in the pipe decreases then the collected gas can cause the liner to collapse and block the pipe. One method for overcoming this problem is to insert vents at intervals along the liner to allow the gas to escape into the pipe during depressurisation. However, there is concern that this arrangement might lead to excessive corrosion beneath the vent where the pipe wall is exposed. The rate of corrosion is expected to be controlled by the vent size but this principle needs to be confirmed by experiment. The work described in this thesis is aimed at investigating this corrosion by experiment for a range of conditions typical of oil and gas production. A novel crevice corrosion cell was designed, consisting of an X100 carbon steel plate and a sheet of transparent Perspex, separated by a thin gasket. A small hole in the Perspex simulated a liner vent and allowed carbon dioxide to reach the steel surface. Tests were carried out in 3.5% NaCl solutions saturated with carbon dioxide at 1 bar partial pressure. Corrosion rates along the length of the annular space were measured using the Linear Polarisation Resistance (LPR) technique on pairs of insulated X100 electrodes set into the plate. The corrosion rates within the annular space have been shown to be small compared to those in the bulk solution and to diminish rapidly with distance from the vent. Mathematical modelling, based on the transport of carbon dioxide, is described to explain these findings and support the experimental work. The effectiveness of the LinerVentTM, installed over the vent, in a turbulence pipeline was demonstrated. The benefit of applying cathodic protection within the annular space was also demonstrated. The results are discussed in terms of the fundamental corrosion principles and their practical implications

Vaccinia virus is a 250-300nm enveloped DNA virus from the poxvirus family and is used as a vector for oncolytic viral gene therapy. No unique cell surface receptor has been identified for Vaccinia virus and the reasons for its tropism for cancer cells are unclear. Pancreatic adenocarcinoma (PDAC) is resistant to conventional chemotherapy and typically contains areas that are profoundly hypoxic. We have investigated the utility of Vaccinia virus as a vector for targeting hypoxic regions in pancreatic adenocarcinoma, as other viral vectors have been found to replicate poorly in hypoxia. We found that cytotoxicity was equivalent in normoxia and hypoxia in some PDAC cell lines but in others cytotoxicity was enhanced in hypoxia. This increase in cytotoxicity was only seen in cell lines where there was hypoxic induction of vascular endothelial growth factor (VEGF). Functional studies using over-expression and knockdown of VEGF in pancreatic cancer cell models showed that VEGF can augment viral transgene expression, cytotoxicity and replication in vitro and in vivo. We found that VEGF facilitates the internalisation of Vaccinia virus. These results show that VEGF is an additional factor involved in the tropism and pathogenesis of Vaccinia virus. We then constructed an oncolytic Vaccinia virus to target hypoxic cancer cells using the HIF-1α oxygen degradation domain, encephalomyocarditis virus internal ribosomal entry site and the VEGF 3‟ un-translated region to regulate luciferase expression in hypoxia. We have shown a dose-, time- and oxygen-dependent effect using this construct and propose this may be adapted to regulate therapeutic genes, or produce a conditionally replicating Vaccinia virus, in hypoxic conditions.

The technique of medium energy ion scattering (MEIS) can be used to elucidate the structural details of surfaces, both in general terms and in a more qualitative manner, in order to help solve a number of outstanding uncertainties relating to the structures of a number of surface systems. MEIS, involving the back-scattering of light ions from a material of interest, in this case 100 keV H+ ions from adsorbate covered single crystal metal surfaces, can potentially be a powerful tool for obtaining either depth-dependent compositional information or quantitative structural details. MEIS has been used to study the surface relaxations at the Cu(410)-O stepped surface. The results have been compared to a number of models favoured by previous studies, and an optimisation of the structural parameters associated with the outermost Cu atoms was undertaken so as to determine the positions of these atoms to a reasonable degree of precision. In this thesis, MEIS has also been used to probe the surface reconstructions triggered by the adsorption of the methylthiolate species on the Cu(100), Au(111) and Pd(111) surfaces. Methylthiolate is derived from the n-alkylthiol molecule methylth- iol, the simplest molecule of a species which ubiquitously form so called self-assembled monolayers (SAMs) on single crystal metal surfaces. In the case of Cu(100), our study confirms the existence of a radial lateral distortion of the outermost Cu layer, and we quantify this distortion. For Au(111), two competing structural models for the methylth- iolate overlayer have been proposed, namely the Au-adatom-monothiolate (AAM) and Au-adatom-dithiolate (AAD). MEIS has been used to compare these two models, and we find in favour of the AAD model. Additionally, evidence has been found for a significant reconstruction of the Pd(111) surface triggered by adsorption of methylthiolate. We have carried out a MEIS investigation of the (3×2)-alaninate phase formed by adsorption of the chiral molecule alanine on Cu(110). Evidence is found for a small degree of lateral surface distortion.

The nature of learning and teaching in higher education has changed significantly in recent years. The emergence of social media and technologies has had a profound impact upon learner engagement and tutors have had to adapt their learning and teaching strategies accordingly. The thesis discusses the author’s published body of research and presents a pedagogical framework for engaging the networked learner. The framework is based upon three perspectives that have emerged from the author’s research. Firstly, different learning paradigms should be acknowledged when developing pedagogical approaches to using learning technologies. Secondly, the thesis discusses how the author’s research on learning technologies, including VLEs and iPod technologies, should embrace networked communities and learner empowerment. Thirdly, the research on learning approaches is discussed which acknowledges different learning behaviours and the adoption of differentiated methods in learning and teaching. Whilst discussing the evolving nature of the learning environment, the pedagogical framework draws together each of the aforementioned perspectives. The framework raises a number of factors for engaging the networked learner. A set of practical guidelines based around institutional, tutor and learner perspectives are discussed and underpin the application of the framework. The thesis concludes with theoretical observations on learning and learning theory and presents limitations and areas for further research.

This thesis describes a combined exploratory analysis, on a fine spatial scale, of (i) England and Wales house prices, between the years 2000 and 2006; (ii) aggregate statistics taken from the UK census of 2001; and (iii) interaction statistics also taken from that census. The house price data is derived from individual transactions and analysed mainly in the form of ward level indices with a time resolution of 100 days. The study has twin aims: firstly, to improve understanding of the data set - which is large in nature - particularly with respect to exploring the interaction statistics; secondly, to improve the methods of exploratory analysis themselves. With respect to the aim of understanding the data, both migration and house price changes are visualised in a novel way, and regression is used to determine indicators of likely house price cross-correlations between different market areas. Ripple type effects are shown to be related both to reactive mechanisms, and to the composition of migration flows. Further visualisation shows that the market may be understood in terms of clusters with similar behaviour, or alternatively, in terms of market-driving and market-driven regions. Variables which can be used to define these clusters and regions are identified via further regression. With respect to improving the techniques of analysis, existing methods of visualising interaction data - based on clustering and linear ordering of points in geographic space - are extended to larger, hierarchical data sets and evaluated in this context. Novel approaches are presented for (i) construction of relative house price indices with minimal hedonic data, (ii) enhancement of time series predictions using cross-correlation data, and (iii) comparison of heterogeneous data sets via unification of all relevant information in the interaction domain, making it susceptible to analysis by regression aided with principal component based dimensionality reduction.

This study seeks to address the fact that dramatic change in the way companies perform their accountability to all their stakeholders cannot be expected to happen suddenly, dramatically or, in any sense, mutationally. Change in corporate affairs does not have that nature. However, stakeholders, including faith communities, make justifiable demands of those who manage corporate affairs that they perform their business in a manner which can be seen to be accountable to those who are affected by it - their neighbours, the global community (especially in the case of transnational corporations), the succeeding generations, their employees and customers, and the environment which we all share. The project's methodology is to use the scientific discoveries of palaeontology to parallel corporate accountability by the evidence of human evolution and to use that model to expose the underlying theological principles which can be said to apply to corporate business and the journey towards appropriate corporate social responsibility. The methodology is described in the first chapter and the existing literature of corporate social responsibility and of the address to evolutionary principles together with the critiques of them and the ideas of scientific and theological analysis are explored in the second chapter. There follow four chapters in which case studies are used to draw out specific issues of corporate social responsibility arising from the concerns of faith communities in various locations. The first (Chapter Three) raises the deep-felt concerns of indigenous communities confronting the extractive industries - mining and forestry - based on researches conducted in face-to-face discussions with Aboriginal people in Australia. Secondly (Chapter Four) there is an exploration of the implications for corporate business of the pandemic of HIV / AIDS especially in Southern Africa based around experience and personal contacts in South Africa and on other researches gathered from journalistic sources in Malawi. The third study (Chapter Five) looks at the corporate outrage which was Enron and its deliberate application of human greed to corporate affairs. The study does not hesitate to define this as being a ramification of 'corporate sin'. The final case study seeks to explore the way in which faith communities can collaborate together on a global basis to work for 'a better way of doing things'. This study uses the activities of one mining company, BHP Billiton, to explore these processes. The final chapter (Chapter Seven) seeks to bring these researches together in a theological analysis of the issues and principles of concern and to discover a way in which faith communities can use these researches in their own analysis of corporate social responsibility as a means by which they can seek appropriate corporate accountability from the corporations in which they are stakeholders. This study is unique in that it brings together the analysis of corporate social responsibility with a tool for its measurement in the form of the study of principles of human evolution. The models of the way that the human species have evolved - achieving bipedalism, making tools, caring devotion for fellows, the development of brain power amongst them - are seen in the study as the guides to understanding the theological principles which must undergird a faith community's search for appropriate corporate performance and this is the contribution this study seeks to make to academic knowledge.

Neuropeptides native to parasitic flatworms, such as Neuropeptide F (NPF) and GNFFRFamide in Moniezia expansa, the sheep tapeworm, are believed to play vital survival roles in the parasites and therefore offer potential as anthelmintic drug targets based on knowledge of their primary structures. The gene sequence of GNFFRFamide is unknown, and doubts exist about whether only one primary structure of NPF exists. Both aspects have been investigated in this study. Vasoactive intestinal peptide (VIP) whose primary structure is highly conserved in mammals and to a lesser extent in non-mammalian vertebrates, has so far only been isolated and characterised in mammals and other vertebrates, in which it has been found to have a number of vital functions. Elucidation of the primary structure of VIP in a parasitic cestode is of interest both evolutionarily and because of the potential for its exploitation as an anthelmintic drug target. A previous study revealed the existence of molecules immunoreactive to mammalian VIP (VIP-IR) and peptide histidine isoleucine (PHI-IR) in M expansa whose chromatographic properties suggested that they may be identical to the mammalian orthologs - a surprising observation in view of the large phylogenetic difference between the species involved. Transfer of the PHI/VIP gene from the ovine host to the tapeworm parasite, previously suggested as a possible explanation for the observation, was investigated in the present study. Genomic methods failed to detect VIP cDNA in M expansa although NPF cDNA and sequences which may code for GNFFRFamide and for a number of other peptides which may be involved in important functions were amplified. Three different peptide extraction methods combined with mass spectrometry failed to detect VIP in homogenized M expansa tissue, possibly due to its low abundance. Other peptides, including putative neuropeptides, were detected in the extracts and analysed. Immunocytochemical analysis revealed VIP immunofluorescence apparently confined to the tegumental lining of M expansa tapeworm, a strikingly similar situation to the previously reported VIP-IR in Echinostoma liei, a parasitic cestode resident in the mouse small intestine. In mammals VIP is known to be expressed and secreted by enteric neurones and immune cells including Th2 lyrnphocytes, mast cells and oesinophils and as part of a response to antigenic and inflammatory stimulation. A Th2, mast and oesinophilic cell response is strongly characteristic of the mammalian immune response to enteric parasites. It is postulated that the VIP immunofluorescence observed on the M expansa tegumental surface in the present study may be due to VIP expressed and secreted by the host enteric neurones and / or immune cells. This possibility remains to be investigated further.

The thesis interprets a selection of phrases from the Wenxian covenant texts, using a methodological procedure presented and discussed prior to the analysis. This is the first detailed study of these texts and the first attempt to describe and demonstrate a procedural approach for the analysis of an excavated Chinese text. These covenant texts, excavated in their thousands in 1980 - 81 from sixteen pits in Wenxian, Henan, were written on stone tablets using ink and brush. They have been dated to the early fifth century BC. A single covenant is repeated on many tablets, each individualized with the name of a covenantor. The covenants, which are highly formulaic, call on spirits to sanction various stipulations, mainly concerned with loyalty in serving the covenant lord and prohibitions on dealings with various named and un-named enemies. They are significant for our understanding of many aspects of early China, from script development to religious belief and political organization. In form and period they are very similar to the Houma covenant texts, excavated in 1965 at Houma, Shanxi. Chapter Two of the thesis presents the methodological procedure I constructed to analyse the Wenxian texts. A number of key terms used in the palaeographic analysis and transcription of characters are first defined and discussed. The methodological procedure is then set out. In Chapter Three this procedure is applied to the analysis of eighteen characters and the seven phrases in which they are found in the Wenxian texts. In the final chapter I conclude that the methodological procedure facilitated this analysis and I discuss methodological issues raised by the study. I suggest that this procedure is transferable to the analysis of other Zhou-period texts and that an awareness of the steps of the process can aid the assessment of transcriptions and annotations of published excavated texts.

The aim of this research is to develop a new policy framework for the use of Combined Heat & Power systems' (CHP) in Small and Medium Sized Enterprises2 (SMEs). This entailed an assessment of the extent to which the current national policy framework for the use of CHP is effective and from contemporary data obtained from CHP operators, policy makers, designers and regulators, subsequently to develop a new policy framework. The design of the research process combines the strengths of engineering, economic and social policy academic disciplines for an examination of the potential for the use of CHP in SMEs. The research methodology dictated the use of qualitative and quantitative methods for data collection. The analyses of the data collected formed the basis for proposing a new Governance policy framework designed to encourage the use of CHP in the SMEs. The new Governance framework is proposed as an amalgamation of Support Systems set on the macro and micro levels of SME governance. A Governance Support System (GSS) offers SMEs an integrated structure for regional sustainable development, including flexible decision support base. The Business Decision Support System (BDSS) is designed as a simple tool for use by SME managers' considering CHP as part of any proposal involving capacity constraints for heat or electricity in the business. The thesis concludes that proactive adoption of the new Governance framework would allow for easier access of SMEs to CHP systems as well as assisting the Government in meeting its climate change objectives. 1 A CHP system is one that simultaneously produces heat and electricity in a single process. 2 Enterprises that employ less than 250 staff, with an annual turnover no more than 40 million Euros andis less than 25% owned by s large enterprise.

My subject is Legitimism in the Third Republic, focusing on the period 1877- 93, namely the period which witnessed both the stabilisation of the Republic and the decline and ultimate failure of Legitimism as a political movement. Legitimism can be read as a local phenomenon, which makes studying it in the local context an obvious approach. I have opted for a comparative study, selecting two contrasting departements in the Midi-Pyrenees, the Haute-Garonne and A veyron. I approach Legitimism as a political culture, examining the ideas and ideology that underpinned Legitimist activity. In particular I investigate the role of myths of the Revolution of 1789 within this political culture, given the context of the 'republican Republic' that took shape 1877-79 and drew explicitly on the Revolution to legitimate itself. I suggest that previous research on Legitimism has seriously underestimated the importance of these myths within the Legitimist movement. My study is centred on an examination of the struggles initiated by the advent of the 'republican Republic': the struggle for republican education, the struggle for republican politics and the struggle for republican symbolism. At all these levels the Legitimist conceptions of society and of the nature of France were challenged. Legitimist mobilisation in the face of these challenges revealed not only their social and political conceptions, but also raised questions about the political strength of Legitimism in the novel context of mass politics. I show the successes and the failures that ensued, the importance of the local dimension and discuss Legitimist engagement in broader reactionary politics, suggesting that standard studies of the French right in this period have neglected nondynastic clerical conservative politics. I conclude by offering a new perspective on the nature of Legitimism.

This is a study ofWimbome Minster, one of 700 or so small market towns that existed in the early modern period. Urban historians have tended to concentrate on the larger towns and cities, due partly to the lack of archive material. The Wimborne sources allow for a number of themes to be discussed. The study of demography highlights the growth in the urban population between the 1640s and 1670s, whilst the rural population stagnated. In the rural area it was a period of change with enclosure, the development of new crops and the conversion of copyhold to leasehold tenure. The analysis of the urban economy shows that Wimborne had a relatively sophisticated occupational structure. It was also developing as a cultural centre. The administrative structure of a non-corporate town can be investigated, identifying a three-tier hierarchy dominated by kinship and occupational networks. There have been very few attempts to analyse law and order issues of a community 'in the round'; issues discussed are punishment, court jurisdiction, the perceptions of crime and the hierarchy's attitude to morality. The turbulent nature of seventeenth-century politics and religion is apparent in towns both large and small. The hostility between the Arminian and Puritan factions within the established church in the 1620s and 1630s, reactions to the Commonwealth and Restoration, and the persecution of the recusant and Protestant nonconformist communities are analysed to reveal a community in conflict with itself The research concludes by examining the urban/rural interface. It highlights the crucial role that the rural hinterland played in supplying food to the growing urban centre. It discusses the relationship between the rural and urban through occupational groups. Small towns such as Wimbome contained complex societal networks, through kinship, religion, politics and occupations. By studying these inter-relational networks a more complete and valid picture of these communities can be seen.

The factors that influence the ultimate level of success or failure of systems development projects have received considerable attention in the academic literature. Two particularly significant areas of interest have been the importance of applying best practice during systems development and the need to explicitly consider organisational issues to ensure a positive organisational impact. However, despite the existence of a well developed best practice literature and an emergent organisational issues literature, many projects still fail. The record of the NHS has been particularly poor in terms of the successful development and implementation of information systems and it was thought that this area would provide a fertile domain for information system research. Whilst the use of information systems in community healthcare has increased greatly over the last ten years the majority of existing research has been conducted in acute hospital environments with little attention devoted to the community sector. Consequently, this research project has two main aims: To identify the key best practice variables and areas of organisational impact associated with the development, implementation and use of a Community Information System (CIS) in National Health Service Trusts; and to examine the relationships between these two sets of variables and the system's resultant level of effectiveness. This research project has a number of positive methodological attributes in that it studies a homogenous organisational sector using a common type of information system and so minimises the potentially confounding influences of sector and system. In addition, the research design involves a three stage approach, combining both quantitative and qualitative research approaches. The research project has produced several key findings. A positive relationship was identified between the adoption of best practice and system effectiveness and similarly, there was a positive relationship between the level of organisational impact and system effectiveness. In order to ensure a positive organisational impact it was found that the successful treatment of key organisational issues is required. In addition, two new variables have been identified, user ownership and positive user attitudes, that play an important mediating role in ensuring system effectiveness. Finally, it was also recognised that the adoption of best practice variables had a dual role, directly influencing the level of perceived system effectiveness but also as a method of effectively managing organisational issues, user ownership and user attitudes. In summary, this study has emphasised the importance of adopting best practice and assessing and managing organisational impact during a community information system development project to ensure system success. These results will be of particular interest to practising IM&T Managers in the NHS and to the wider academic community. A series of practical recommendations are presented at the end of the thesis.