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The mass of the interstellar medium (ISM) consists of 99% molecular gas and 1% dust grain particles. At the low temperatures and pressures of the ISM, molecules condense onto dust grains to form ice. Interstellar ices are most commonly processed via thermal radiation from nearby stars leading to the desorption of molecules into the gas phase and subsequent rich chemistry of space. This work uses surface science techniques such as temperature programmed desorption (TPD) and reflection absorption infrared spectroscopy (RAIRS) to characterise the adsorption and desorption behaviour of astrophysically relevant organic molecules including acetonitrile, acetaldehyde and acetone. Interstellar ices are multi-component in nature, primarily consisting of water in its amorphous and crystalline phases. Water is known to trap and subsequently affect the desorption of other species; therefore, the interactions between organic molecules and water have been investigated in order to provide a detailed overview of the desorption of astrophysically relevant ices. In addition to water, interstellar ices are comprised of methanol. Previous studies have demonstrated that the desorption kinetics of water are significantly altered due to the presence of methanol. Consequently, an investigation into the modified desorption of water in the presence of methanol was carried out. To provide a detailed insight into the desorption of astrochemically relevant ices, the impact of this modified behaviour on the trapping and subsequent desorption of more complex molecules such as acetone was also investigated. Although thermal processing is most common in interstellar environments, non-thermal desorption of ice has also been observed due to processing via charged particle interactions in the ISM with substantial experimental work also carried out to investigate the photodesorption of molecules due to vacuum ultraviolet (VUV) irradiation. Infrared (IR) light is also present in similar environments; however, it is often omitted from astrochemical models. This work aims to provide a deeper insight into the non-thermally induced diffusion and desorption of small species in order to tackle the current lack of understanding of non-thermal desorption in astrophysical environments. Ices consisting of CO and H2O were irradiated with infrared light using the free electron laser (FEL) at the FELIX Laboratory, Nijmegen. RAIRS and mass spectrometry were used to monitor the infrared-induced photodesorption. The laser-fluence dependence was investigated and desorption cross-sections were obtained in order to propose a detailed mechanism of the photodesorption taking place.

This thesis aims to explore the politics of contemporary media production from the viewpoint of the ordinary people it represents. In an era of accelerated digitalisation, commercialisation, and deregulation, scholars have focused on the everyday realities of the creative labourers who work behind the scenes in the cultural industries, but little attention has been paid to the experiences of the participants who appear in front of the cameras. In the academic scholarship and public discourse alike, media contributors are frequently depicted as 'vulnerable victims' or exploited subjects of capitalist forms of media production, which prioritise profits above people. However, we have insufficient knowledge about the complexities of their motivations, the values they ascribe to participation, and whether they ultimately get from it what they desire. Drawing upon in-depth interviews conducted over the last four years, and informed by my own professional experiences of working as a television producer/ director for the preceding sixteen, this research project examines how documentary contributors feel about participating in the media and the ways they're portrayed, considering how their experiences take shape within the structural context of the media industries. Through an examination of a diverse range of topics - such as the casting and editing processes, the nature of relationships between documentary-makers and their subjects, issues of consent, and duty of care - I argue that the wellbeing of contributors, creative workers, and the production environment are all intrinsically connected, and as a result, ordinary participants have been profoundly affected by the changing values of the media.

Rheumatoid arthritis (RA) is an autoimmune disorder of the joint characterised by immune cell infiltration, synovial hyperplasia and neovascularisation, leading to cartilage and bone degradation. Current treatments risk severe immunosuppression and full disease remission is rare. Local gene therapy promises to overcome this, providing high therapeutic concentrations at the disease site with lower systemic concentrations. Optimal vectors should be delivered systemically to target all affected joints simultaneously, but should be specific to the inflamed joint. Our approach optimised receptor targeted nanoparticles (RTN) for plasmid DNA delivery to fibroblast-like synoviocytes (FLS), particularly aggressive cells in RA pathogenesis. Inclusion of an integrin targeting peptide achieved optimal transfection efficiency in cultured FLS and the PEGylated cationic lipid, ME42, stabilised RTN formulations in solutions without compromising transfection efficiency. However, delivery in vivo did not result in transfection and further optimisation is necessary. Additionally, mini-intronic plasmids (MIPs) were investigated for their ability to provide high and sustained transgene expression. When delivered with RTNs, these vectors transfected FLS as or more efficiently than conventional plasmid DNA (pDNA), dependent on cell type and promoter. Further, MIPs encoding a luciferase transgene driven by an NF-kB responsive promoter could upregulate luciferase expression in response to inflammatory cues in vitro, which may increase the specificity of the therapy. This system could drive expression of the therapeutic dimeric TNF receptor in primary human FLS, highlighting its potential as a human gene therapy. Interestingly, RTN transfection in FLS activated inflammatory signalling, as measured by transgene expression from the NF-kB promoter and IL-6 expression. Both liposomes and pDNA were required to drive this response, but delivering either alone had no effect. Further characterisation of this response is required. Taken together, this work provides the basis for a targeted gene therapy for RA.

Since the collapse of communism in 1989-91, scholars have offered a number of conceptual paradigms to encapsulate the mnemonic entanglement of the Holocaust with painful gentile experiences of Soviet terror and the Second World War in Central and Eastern Europe. These entanglements have typically been fraught and competitive, involving appropriations of Jewish Holocaust memory as a means of legitimising gentile victimhood on the one hand, and the importation of Western, Jewish-centred narratives on the other - often as a pathway to EU accession. They have also been highly public, and continue to play out in political debates, education, scholarship, the arts, and even legal spheres, often with polarising effects. The construction of representational narratives of the Holocaust in formerly communist nations thus tend to be characterised by the binary doubles to which Eastern and Western memory cultures have typically been seen to pertain: namely, concentrationary/extra-concentrationary sites; neat/primitive killing; Nazi/Soviet regimes; Jewish/gentile victimhood and democratic/nationalistic as well as civilised/uncivilised societies. 'Postcommunist constellations' is the term used in this thesis to designate the dialogic, supranational canon of cultural texts from formerly communist nations on the axes of conventionally 'Western' and 'Eastern' European Holocaust remembrance. Finding expression in art, literature, film, memorials and museums, these constellations simultaneously resist the view of Eastern European memorial practices as out of sync with those of the West, and fill in the memorial gaps created by structural forgetting and revisionist configurations of the past in Central-Eastern Europe. Focusing on twenty-first century memory cultures that have surfaced in the last decade or so in particular, the present thesis connects the historical, geopolitical and representational coordinates of extra-concentrationary killing during the Holocaust years in an attempt to draw Western attention to these historical episodes and build a decolonial picture of marginalised victim narratives. The decolonial lens developed throughout the thesis figures both explicitly, via a critical engagement with the historical racialisation of Jews, Roma and Bosnian Muslims, and implicitly, by analysing non-hierarchical literary and artistic representations of genocide and extreme violence in the region. In so doing, it affords a theoretical Western perspective of specific case studies or micro histories of Holocaust killing that draw upon Ukraine, Poland, Romania and Romanian-administered territories and the former Yugoslavia. While interrogating the continued prevalence of Holocaust relativism in Central-Eastern Europe, the thesis shows how artists, activists and specific institutions are coming to terms with the past in new and productive localised ways.

This thesis provides a meaningful intervention in the history of African American women photographers in the long Civil Rights Movement. These women were "agents of change," who cultivated "spaces of agency" in their lives and in their images. This highlights the importance of everyday activism within the movement; through acts of spatio-symbolic reclamation, these women were able to both occupy space as photographers and document the community-orientated activism around them. The photographers, and their photography, claimed both physical space and symbolic space in the long Civil Rights Movement. As photographers, they occupied physical space by creating "spaces of agency" wherein they empowered people in their communities to have their photographs taken, and the photographers symbolically claimed space in the photographic canon of the Civil Rights Movement as artists and businesswomen. With their photography, they also operated within physical and symbolic "spaces of agency": physically their photographs occupied space - as the images were displayed in homes or in publications - and symbolically their work documented acts of spatio-symbolic reclamation, as African Americans challenged segregation by occupying and integrating public space. As such, this thesis intervenes in scholarship of both the long Civil Rights Movement and the spatial turn, whilst centring the activism and agency of African American women. Navigating the often conflicting societal pressures of the politics of respectability, these women worked within a long Civil Rights Movement to achieve a literal and metaphorical reclamation of space through their photography.

Resource patchiness results in spatially fluctuating population densities and thus variable levels of competition. If different traits are favoured in different population densities, individuals should adjust their physiology and behaviour in response, to maximise their fitness. In this thesis I manipulate resource distributions to investigate the implications this has on the social environment, and the sex differences in subsequent reproductive responses. Under high levels of perceived sperm competition, male Drosophila melanogaster will lengthen copulation durations. Despite this being a well established responses, little is known about the biological mechanism that facilitates this behaviour, as most of the studies that have demonstrated it have done so by comparing solitary males to paired (or grouped) males - social environments unlikely to be experienced by wild living males. Given that resource patchiness affects encounter rates, I predicted that this ecological variability might be one of the natural stimuli affecting plasticity in mating-related traits in the wild. Here I demonstrate that these sperm competition linked responses respond to spatial heterogeneity: males on clustered food resources were found in closer proximity to rivals, and consequently had longer copulation durations (Chapter 3). I then expand on this work by matching individual movement patterns in a variably patchy environment with individual-level mating behaviour and fitness (Chapter 4). I show that clustered food resources not only result in increased encounter rates, but also reduced home range size. Surprisingly, however, I find no evidence of fitness impacts associated with these responses. Alongside increased copulation duration, males also increase sperm transfer, improve sperm quality and alter seminal fluid composition after exposure to rivals - and intriguingly have longer lifespans, although it is not understood how or why. To attempt to better understand this unexpected result, I compare survival impacts in males exposed to direct rival interactions (exposed to likely injurious aggression) and males only exposed to rivals via a barrier (Chapter 2). It appears that indirect exposure is beneficial for starvation resistance, but direct interactions result in longer lifespans. In addition, I discover that these survival benefits are only activated by male and not female presence. Comparatively little is known about female responses to environmental variability and conspecific presence. This is surprising given that females have greater control over progeny investment due to their role in oviposition. I address this knowledge gap by exploring the impact of resource patchiness and competition on oviposition decisions. I demonstrate that females show a preference for clustered resources (with a higher number of females choosing to lay on clustered patches, and also then laying on a higher number of patches), likely due to the benefit of cooperative foraging in larvae. Interestingly, the impacts of competition differed when exposure to rivals was experienced prior to, rather than during, oviposition. After prior exposure to competition, females laid fewer eggs (Chapter 5) whereas this effect disappeared when females were laying in the presence of another female (Chapter 6). This suggests that those females were copying conspecific oviposition decisions, minimising exploration costs and enabling them to lay a higher number of eggs.

Evidence increasingly suggests that the movement behaviours of potamodromous fishes can be highly diverse in well-connected systems. Intra-population divergence in spatial and temporal resource-use is an important component of fish distribution patterns and population structure, which can affect population viability and adaptive potential. The common bream Abramis brama (µbUHaP¶) is a potentially strong model species for testing the importance of habitat connectivity and examining variation in movement patterns in lowland rivers. Concurrently, the Broads National Park (µBURadV¶), eastern England, provides a large network of interconnected rivers, lakes and dykes in which to examine unconstrained fish movement. Thus, biotelemetry was applied to investigating the movement ecology of bream in the northern Broads wetland system. Acoustic telemetry is a central tool for fish movement ecology, but robust data interpretation requires detailed knowledge of its efficiency and the fate of tagged individuals. Here, variation in acoustic receiver performance was quantified, along with the post-tagging survival rates of bream and Northern pike Esox lucius. The results demonstrated that acoustic detection range and efficiency were highly variable temporally, being negatively impacted by increased water temperature and precipitation, or reduced transparency (a surrogate measure of algal density). For both bream and pike, post-tagging survival rates were lowest in the reproductive periods of both species, but in bream, fish tagged just prior to spawning actually had the highest subsequent survival rates. Acoustic signal loss, potentially due to tag expulsion, also accounted for the loss of some bream from the study. These results emphasise the need for long-term receiver monitoring and consideration of the relative effects of tagging to be incorporated into telemetry study design. Geostatistical models of stable isotope landscapes (µLVRVcaSHV¶) provide a complementary tool to telemetry for assessing and predicting animal movements. The efficacy of single versus dual-isotope isoscapes in predicting the foraging locations of roach Rutilus rutilus was compared, with the dual-isoscape approach emerging as the most efficient. Dual-isoscapes were then applied to predicting the movement distances of individual bream in comparison to their movements recorded by acoustic telemetry. This revealed that isoscape-predicted movement was a significant predictor of the spatial extent of subsequent movements recorded by telemetry, suggesting repeatable individual activity levels between years. Dual- isotope isoscapes can thus provide a reliable alternative or complementary method to telemetry. Acoustic telemetry was then applied to investigating the diversity of bream migration behaviour throughout the northern Broads wetland system and examining more fine-scale spatial and social preferences during their reproductive period, with the aim to understand their spatial occupancy patterns and spatial population structure. Bream movements showed considerable diversity, with some individuals making repeatable spawning migrations of up to ~25 km, whereas others were relatively sedentary. Behavioural type (resident/ migrant) was highly consistent within individuals, although both phenotypes were detected mixing in space and time during the reproductive period. This suggests the Broads bream population is comprised of several distinct, semi-independent subpopulations that reside in spatially distinct areas throughout much of the year, but converge and potentially interbreed in their spawning period. Thus, this research explores the utility of acoustic telemetry and stable isotope tracking for documenting the movement ecology of lowland wetland fishes. The results emphasise the fundamental importance of connectivity in freshwater systems for enabling and maintaining high phenotypic diversity in the migration behaviours of potamodromous fishes.

Neutrophils are essential for effective innate immunity. Conversely, inappropriate or excessive neutrophil activation can result in damaging inflammation. This damage is implicated in the pathogenesis of a number of respiratory diseases including acute respiratory distress syndrome (ARDS) and chronic obstructive pulmonary disease (COPD) which are also both frequently complicated by hypoxia. Cells sense and respond to hypoxia through the activity of the transcription factor HIF (hypoxia inducible factor) and its regulatory hydroxylases, the prolyl hydroxylase domain enzymes (PHDs) 1- 3. In the presence of oxygen, PHDs hydroxylate HIF, preventing the HIF mediated transcriptional response. Close links exist between the pathways which regulate hypoxic and inflammatory responses. Our group has previously found that in mouse models of infection, acute hypoxia leads to increased sickness and that this is driven by neutrophilic inflammation. I have used a murine model of Lipopolysaccharide (LPS) -induced acute lung injury, characterised by neutrophil influx, to investigate how exposure to hypoxia alters lung inflammation. Using high-resolution mass spectrometry, I have defined the proteome of the inflammatory lung neutrophil. I have shown that hypoxia results in a distinct proteomic signature in inflammatory neutrophils. Hypoxia drives lung neutrophilic inflammation through increased neutrophil degranulation and upregulation of inflammatory receptors. I have also identified key metabolic alterations in hypoxic neutrophils. The hypoxic lung represents a low glucose, high protein environment and neutrophils adapt to exploit this. I have shown that neutrophils can scavenge proteins from their extracellular environment, catabolise these proteins in the lysosome and utilise the breakdown products for metabolism. These processes are upregulated in hypoxic lung neutrophils which show increased lysosomal protein expression, increased protein uptake and increased glutaminolysis. Utilising heavy labelled protein extracts, I have traced breakdown products from scavenged proteins into central carbon metabolism, demonstrating that extracellular protein can fuel neutrophilic inflammation. Finally, I have investigated the role of the prolyl hydroxylase PHD1 in regulating neutrophilic inflammation. Using a neutrophil specific PHD1 knockout mouse line, I have identified a specific role for PHD1 in regulating neutrophil metabolism and survival. I have found that the micro-environment, particularly oxygen availability, determines the impact of PHD1 loss with consequences for inflammation resolution in vivo. In summary, hypoxia is a key regulator of neutrophil function and is associated with increased neutrophilic inflammation. Utilising a proteomic approach, I have identified the mechanisms which drive the hyperinflammatory phenotype including the ability of neutrophils to scavenge proteins from the environment to fuel inflammation. I have also shown that PHD1, a key component of the hypoxic signalling pathway, may regulate these functions. A more complete understanding of these mechanisms will help to identify therapeutic targets for treatment of neutrophilic inflammation in the lung.

Drosophila Protein Inhibitor of Activated STAT (PIAS) is required for chromatin organisation. PIAS proteins are SUMO E3 ligases that provide target specificity for the addition of small ubiquitin like modifiers (SUMO) to proteins to alter their function. Previous experiments in the Heun laboratory, which used a PIAS overexpression system, identified a relationship between PIAS and XNP (X-linked nuclear protein). Both proteins play a role in silencing transposable elements and likely interact. XNP and ADD1 (ADD (ATRX-DNMT3-DNMT3L) domain-containing protein 1) together make up the two halves of their mammalian homologue, the chromatin remodeller ATRX. XNP and ADD1 have been shown by us and others to be SUMOylated. We hypothesise that the SUMOylation of XNP by PIAS could be essential for its role in chromatin organisation and aimed to study this interaction within a Drosophila model using S2 tissue culture cells and embryos. In this thesis, I defined the interactomes of PIAS, ADD1 and XNP using immunoprecipitation-mass spectrometry (IP-MS) in the presence and absence of SUMOylation. Using CRISPR/Cas9 epitope tagged PIAS in S2 cell lines and primary antibodies against endogenous PIAS, I could confirm an interaction between PIAS and XNP in a SUMO dependent manner. Interestingly, I found PIAS interacts with ADD1 and heterochromatin protein 1 (HP1) in a SUMO independent manner. These interactomes support the hypothesis that SUMOylation of XNP by PIAS is involved in the association of XNP with ADD1 to promote heterochromatin organisation.

Aims: To investigate the clinical feasibility of performing magnetic resonance imaging (MRI)-only radiotherapy planning for patients undergoing treatment for brain tumours. Method: A systematic review was performed of methods which convert MRI scans into synthetic computed tomography (sCT) scans for the purposes of MRI-only radiotherapy planning. The feasibility of using two methods which had been developed at different centres for different anatomical sites, for the production of brain sCTs was assessed. The quality of automatically segmented brain structures generated using one of these techniques was determined. The temporal stability of geometric distortions of four MRI scanners over a year was investigated. A prototype of an MRI and CT compatible anthropomorphic head and neck phantom was developed for the purpose of quality assurance (QA). Results: The review demonstrated that atlas-based and voxel-based techniques were clinically useful methods for sCT generation, with machine learning techniques beginning to develop. An atlas-based technique (previously developed for prostates) and a neural network technique (not previously tested for brains) were found to produce sCTs of acceptable quality for the majority of metrics, after modifications to the clinical MRI scanning protocol were introduced. Dosimetric deviations meant that further optimisation would be required. Larger brain structures were generally well segmented automatically, whilst smaller structures were segmented erratically. The stability of MRI geometric distortions varied between scanners and sequences. A prototype anthropomorphic head and neck phantom was designed and constructed, with future modifications needed in certain areas. Conclusions: The feasibility of producing clinically acceptable brain sCTs along with automatically segmented structures, using models developed at different centres for different anatomical sites, has been shown. The variation in temporal stability of MRI geometric distortions means that careful consideration should be paid to the frequency of distortion QA. An MRI and CT compatible head and neck phantom prototype has been developed.

Neuroblastoma (NB) is one of the most common childhood cancers, constituting 8% of paediatric cancers, and 15% of paediatric cancer deaths. The majority of patients have high risk disease, with poor outcome despite intensive treatment regimens. Current therapies, which include chemotherapy and radiotherapy, are highly toxic, with significant treatment related mortality, and there is little scope for further intensification. Alternatives strategies, such as immunotherapy are a priority for improving patient outcomes. A number of different immunotherapies, such as antiGD2 antibody therapy, have shown promise in NB, but combining these with conventional chemotherapy regimens is challenging. Classically, chemotherapy has been regarded as immunosuppressive but recent work has highlighted that this may not entirely be accurate for certain immunogenic chemotherapies. Furthermore, immunomodulatory antibodies such as checkpoint inhibitors have shown efficacy in adult cancers such as melanoma, with little investigation into their potency in paediatric tumours. Although NB tumours are not particularly inherently immunogenic, the application of an 'immunogenic' chemotherapy may render them susceptible to further immunomodulatory immunotherapy. Firstly this study aimed to identify the immunomodulating effects of cyclophosphamide (CPM) treatment on immune cells, within murine NB models. To achieve this, CPM's ability to induce 'immunogenic cell death' (ICD) markers both in vitro and in vivo was investigated. Induction of ectoCRT, Hsp-70 and HMGB1 expression was observed. Secondly, effects of different doses of CPM on the immune cell infiltrates in the tumour microenvironment were studied in vivo using syngeneic murine NB models. It was demonstrated that low dose CPM was able to selectively deplete and possibly reduce the suppressive activity tumour infiltrating Treg cells in both NXS2 and 9464D NB models, alongside maintaining and activating CD8+ and CD4+ T cells. Additionally, using an apoptosis resistant NB cell line and mouse strain, investigation into whether ICD induction or Treg depletion is most critical aspect of CPM immunomodulation was conducted. It was observed that overexpression of BCL-2 either in the tumour cell line in vitro or Treg cells in vivo, prevented apoptosis and CPM dependent depletion. Finally, it was assessed whether immunogenic CPM could be efficiently combined with immunomodulatory antibody therapy to slow tumour growth, utilising a combination of syngeneic and spontaneous transgenic NB models. Experiments utilising the three in vivo models demonstrated that combination of CPM with anti-PD-1 antibody led to an increase in survival over monotherapies alone, which was further enhanced by a metronomic weekly dosing strategy. Ongoing work is exploring this approach, to refine and establish the most effective chemotherapy and antibody combination in NB preclinical models, along with defining the mechanisms behind combination efficacy.

This thesis analyses the social life of British Indian picture postcards of Bengaluru from their initial production in the early 20th century into the postcolonial present. The research is based upon a mixed methodological approach of participant observation, and archival and digital research conducted over the course of 15 months in Bengaluru. Whilst the current body of literature on colonial picture postcards has been conducted solely from a historical perspective, my research shows that their biographies continue into the present as they act as material mediators in postcolonial experiences of history, locality, heritage and urban renewal. Discussions of Bengaluru, both in popular and academic discourse, often focus on its rise into the ‘IT capital of India’. In doing so, the identities and histories of the city that stretch back beyond the 1990s liberalisation of the Indian economy are often obscured. Within this context, this thesis proposes that postcolonial Bengalureans reflexively engage with the ephemeral debris of colonialism as an accessible archive of historical documents as they contend the forces of rapid urban development that are experienced as de-historicising the city. Situated between visual and historical anthropology, the project focuses on the multiple engagements of picture postcards as they are brought into new relationships, forms and contexts in their journey through time and space. Ultimately, I propose that acts of collecting, remediating and displaying picture postcards of Bengaluru are key referents that help citizens understand the city’s transformations and, at times, become enmeshed in wider discourses of its future.

When biological information about an individual is produced in healthcare or research settings, ethical questions may arise about whether the individual herself should be able to access it. This thesis argues that the individual’s identity-related interests warrant serious attention in framing and addressing these questions. Identity interests are largely neglected in bioethical, policy and legal debates about information access – except where information about genetic parentage is concerned. Even there, the relationship between information and identity, and the interests involved, remain unclear. This thesis seeks to fill this conceptual gap and challenge this exceptionalism. It does so by developing a normative account of the roles that a wide range of information about our health, bodies and biological relationships – ‘personal bioinformation’ – can play in the construction of our self-conceptions. This account is developed in two steps. First, building on existing philosophical theories of narrative self-constitution, this thesis proposes that personal bioinformation has a critical role to play in the construction of identity narratives that remain coherent and support us in navigating our embodied experiences. Secondly, drawing on empirical literature reporting individuals’ attitudes to receiving three categories of personal bioinformation (about donor conception, genetic disease susceptibility, and neuroimaging-based psychiatric diagnoses), the thesis seeks to illustrate, demonstrate the plausibility of, and to refine this theoretically-based proposition. From these foundations, it is argued that we can have strong identity-related interests in whether and how we are able to access bioinformation about ourselves. The practical implications of this conclusion are then explored. It is argued that identity interests are not reducible to other interests (for example, in health protection) commonly weighed in information disclosure decisions. They, therefore, warrant attention in their own right. An ethical framework is developed to guide delivery of this. This framework sets out the ethical responsibilities of those who hold bioinformation about us to respond to our identity interests in information disclosure practices and policies. The framework is informed by indications from the illustrative examples that our interests engaged as much by how bioinformation is communicated as whether it is disclosed. Moreover, these interests are not uniformly engaged by all bioinformation in all circumstances and there is potential for identity detriment as well as benefit. The ethical framework highlights the opportunities for and challenges of responding to identity interests and the scope and limits of potential disclosers’ responsibilities to do so. It also makes recommendations as to the principles and characteristics of identity-supporting disclosure practices.

The chirality of biological systems can be probed using highly emissive lanthanide complexes with the aid of circularly polarised luminescence and emission spectroscopy. Such chirality probes can be synthesised through the incorporation of a remote chiral centre within the ligand framework, which can preferentially stabilise a particular stereoisomer giving an enantiopure complex of well-defined helicity. Alternatively, lanthanide chirality probes can be derived from achiral or dynamically racemic ligands, where the selective induction of a CPL signal can be monitored as a function of the nature and concentration of a selected chiral analyte. A series of chiral lanthanide complexes has been synthesised. Each complex is based on an amide substituted 1,4,7-triazacyclononane system derived from either R-(+) or S-(-)-α-methylbenzyl amine. The stereochemistry of the amide moiety controls the helicity of the complex, and one major diastereoisomer is formed for each lanthanide metal. The absolute stereochemistry of the major diastereoisomer was determined by X-ray crystallography (S-Δ-λλλ and R-Λ-δδδ). Inclusion of an aryl-alkynyl chromophore generated complexes that exhibited large extinction coefficients (up to 55,000 M-1 cm-1) and high quantum yields (up to 37%) in water. A second set of bright Eu (III) complexes has been prepared based on an achiral heptadentate ligand system, which vary in the nature of the pyridyl donor (phosphinate, carboxylate and amide). The binding of a number of chiral acids including lactate, mandelate and cyclohexylhydroxyacetate was monitored by a change in the emission spectrum and the induction of strong CPL. Empirical analysis of the ΔJ = 4 region of each of the Eu (III) complexes allows an assignment of the complex-anion adducts as R-Δ and S-Λ. Furthermore, variations in the sign and magnitude of CPL allow the enantiomeric purity of samples with unknown enantiomeric composition to be assessed. Finally, several dynamically racemic lanthanide chirality probes have been synthesised and characterised. Induced CPL has been assessed, which arises as a result of the change in complex constitution upon binding to important chiral biomolecules such as, sialic acid, O-phosphono-amino acids and peptides and oleoyl-L-lysophosphatidic acid (LPA). This work presents the first example of induced CPL in the detection of cancer biomarkers, sialic acid and LPA, and demonstrates the utility of this class of dynamically racemic Eu (III) complexes as chirality probes.

This thesis concerns the study of chiral algebras over schemes of arbitrary dimension n. In Chapter I, we construct a chiral algebra over each smooth variety X of dimension n. We do this via the Hilbert scheme of points of X, which we use to build a factorisation space over X. Linearising this space produces a factorisation algebra over X, and hence, by Koszul duality, the desired chiral algebra. We begin the chapter with an overview of the theory of factorisation and chiral algebras, before introducing our main constructions. We compute the chiral homology of our factorisation algebra, and show that the D-modules underlying the corresponding chiral algebras form a universal D-module of dimension n. In Chapter II, we discuss the theory of universal D-modules and OO- modules more generally. We show that universal modules are equivalent to sheaves on certain stacks of étale germs of n-dimensional varieties. Furthermore, we identify these stacks with the classifying stacks of groups of automorphisms of the n-dimensional disc, and hence obtain an equivalence between the categories of universal modules and the representation categories of these groups. We also define categories of convergent universal modules and study them from the perspectives of the stacks of étale germs and the representation theory of the automorphism groups.

The Earthly Paradise was William Morris’s first real success, and it remained his best-known work even after his death. It has not fared as well since the mid-twentieth century, when it became overlooked and problematic, as the Morris of The Earthly Paradise years became coextensive with a portrait of Victorian middle-class myopia. This verdict has been brought to the doors of the poem’s first readers, who are imagined to have liked it for uncomplicated reasons of fashion and entertainment. I reconsider these assumptions by returning to the contemporary reception of the poem to ask what audiences thought about Morris as a public figure, what it was that they so responded to in his work, and what the poem itself says about reception—the relationship between story, audience, and speaker. I argue both within the text and in the reception of it, such relationships are nearly always understood as communal, as storytellers—Morris and those in his text—address audiences as collective publics, and speak on behalf of them. Moreover, this speech is always marked by a mutually inclusive relationship with text, so that stories are properly understood as arising from the discursive field established through the participation, both textual and vocal, of anyone who understands himself or herself addressed by the discourse.

Leukocyte extravasation is mediated in part by tissue specific chemotactic cytokines (chemokines) and specific chemokine receptors expressed on the surface of circulating cells. C-C chemokine ligand CCL25 is expressed exclusively in the intestine and thymus and mediates chemotaxis by cells expressing receptor CCR9. This chemokine and receptor pair may be relevant in the pathogenesis of intestinal inflammation, in diseases such as Crohn’s disease (CD) and coeliac disease. In this thesis I investigated CCR9 expression in situ, in tissues affected by intestinal inflammation, and also examined the effects of CCR9 antagonist treatment in patients. In vitro I investigated CCR9 function using human peripheral blood T cells enriched for CCR9 by cell sorting or all-trans retinoic acid treatment. Using tissues collected as part of a clinical trial in CD testing CCR9 antagonist, CCX282-B, I investigated ways of measuring if treatment reduced the number of CCR9 expressing cells in the intestinal mucosa. However, in situ staining for CCR9 by immunohistochemistry was unsuccessful, and in this thesis, I explored reasons why this might be the case. Treatment with CCX282-B did however, show a tendency to reduce T cell density in the intestinal mucosa, although results were highly variable between individuals. In an examination of human CCR9 function in vitro I demonstrate for the first time that CCL25 stimulates CCR9 surface internalization. These data clarify the observation that CCR9 staining by IHC produces poor results in tissues where ligand is abundant, such as the intestine and thymus. I describe a novel technique for measuring calcium flux in two populations simultaneously by flow cytometry, which confirmed that in a heterogeneous population of cells, only CCR9 expressing cells respond to CCL25 by calcium flux. Variability in clinical trials is partly created by the use of concomitant medications, and in CD, corticosteroids are widely used. For the first time I show that glucocorticoids (GC) impair CCR9 mediated chemotaxis, calcium flux and intracellular signalling without changes to CCR9 mRNA and surface protein expression. Reduced CCR9 mediated signalling was accompanied by an enhanced expression and function of co-expressed CXCR4, demonstrating that the effects of GC were receptor-specific and not mediated by non-specific toxicity or inhibition of cell signalling. In a second study CCX282-B was tested in patients with coeliac disease, and in this trial, there was no reported concomitant use of GCs. It was confirmed that dietary gluten stimulates significant T cell recruitment to the intestinal mucosa with a pronounced accumulation of intraepithelial lymphocytes (IEL) and a rise in the frequency of FoxP3 expressing cells. Patients on CCX282-B had lower IEL counts, and an equivalent proportion of FoxP3 expressing T cells, suggesting that CCR9 blockade restricted the recruitment of effector T cell subsets. This thesis confirms that the accumulation of T cells is central to inflammation in the intestine and that modulating chemokine receptor function may affect this. Furthermore, this thesis demonstrates that the function of CCR9 is suppressed by GCs, which are widely used therapeutically and therefore could identify a novel mechanistic basis for their activity in CD.

Background: Although research suggests that obese children and adolescents are stigmatised, experience victimisation, have poor body image, body dissatisfaction, depression and low self-esteem, these findings have been inconsistent. There is increasing evidence to suggest that body perception rather than actual body size leads to negative psychosocial outcomes with many obese people miss-rating themselves as being ‘normal’ weight; body perception is also the strongest predictor of weight change attempts. The majority of studies in this area have been quantitative; the few previous qualitative studies have either not fully utilised qualitative methods or not focused on adolescents. This study uses qualitative methods, and a unique sampling strategy, to improve understanding of obesity related experiences and reasons for weight change behaviours and success in adolescence. Methods: 35 semi-structured interviews were conducted between November 2007 and April 2008. Young adult (aged approximately 24) males (17) and females (18) were purposively sub-sampled from The West of Scotland 11 to 16/16+ Study cohort based on measured adolescent obese status (SDS > 1.65 at one or more of the 11 to 16/16+ study age 11, 13 or 15 measurement points). A picture task was used to stimulate discussion about perceptions of health and weight and the interviews continued with discussion of adolescent experiences, weight related behaviours (diet and exercise) and any weight change attempts. Framework analysis was used to organise data and facilitate analysis. Findings: Initial quantitative secondary analysis of the 11 to 16/16+ data demonstrated that the majority of participants had been worried about both their weight and putting on weight in the future, although this did not translate into slimming behaviour for all. This study found that body size awareness and related ‘botheredness’ varied greatly and were inconsistently related to each other or to weight. While none of the most obese were among the least aware, some were among the least bothered and vice versa. Botheredness related to body concerns, comparisons with others, clothing, romantic relationships, and for approximately half the sample, victimisation. Although the majority of participants reported using changes in diet or exercise behaviours in order to try to lose weight at some time, botheredness did not always translate into effective weight change attempts. Participants were categorised as effective slimmers (active and successful weight change attempt), failed slimmers (active but unsuccessful weight change attempt), passive slimmers (weight loss without active weight change attempt), and passive maintainers (had made no attempts to change weight and had no weight loss). As young adults, 14 were non obese, 14 were obese and 5 were morbidly obese. Those who made successful long lasting weight changes described determination, a greater degree of behaviour change and continued behaviour monitoring. There appeared to be no real pattern to when or why effective changes were made. Age related transitions were often described as being tipping points as well as ‘just being ready’ to change. Those who described sudden unplanned changes were among those who showed the most sustained improvement in weight Conclusions: Not all those who are obese as adolescents are aware or bothered. Most adolescents are aware of how to lose weight. Being bothered is not enough of a motivator to make long lasting changes – obese individuals need to be ‘ready’ to change regardless of knowledge of health behaviours. More needs to be done to assist individuals in being ready to change, this might include raising; body awareness through periodic body measurements at transition points. Further study of ‘tipping points’ in obese adolescents may aid intervention targeting and design.