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Luminal breast cancer remains a major clinical challenge with over 2 million cases diagnosed annually. While prognosis is favourable in these patients, roughly 40% will relapse over the course of the next 20 years. Understanding the evolution of disseminated tumour cells at distal sites is critical to effectively treating these patients. While metastatic driver mutations, such as those in the Oestrogen Receptor (ESR1) gene, can be identified in many cases for a significant proportion of patients, clear drivers remain elusive. A limitation of previous genomics studies in metastatic breast cancer is their focus on the coding genome. Advances in our understanding have revealed the critical role of regulatory elements such as enhancers and promoters in transcriptional regulation. This effect is mediated through the functional and hierarchical organisation of chromatin within the nucleus, the key unit of chromatin organisation is the Topologically Associating Domains (TADs). TAD organisation is, in part, mediated by the CCCTC-Binding Factor (CTCF) protein which physically binds to DNA mediating the formation of loops and domains. Together promoters, enhancers, and CTCF-bound regions provide potential as sites for non-coding mutations to occur, drastically impacting gene regulation and tumour evolution. In this work we interrogate the contribution of regulatory element mutations in the evolution of metastatic breast cancer. This is done through two projects. First, a proof of principle study functionally characterising a clinically relevant CTCF binding site mutation. Second, through the design of an informed panel of regulatory regions utilised in a longitudinal targeted sequencing study in patient samples and a CRISPRi perturbation study in cell lines. Through these studies we provide evidence that the mutation of TAD boundary associated CTCF binding sites is unlikely to contribute to tumour evolution. We also fail to identify recurrence of non-coding drivers, though more patient specific mutations may contribute to metastatic evolution. Results obtained from the CRISPRi screen illustrate the functionality of the regulatory regions in the panel, identifying regulatory elements that confer fitness or vulnerabilities when specifically repressed. This study identifies that repression of several members of the NF-κB signalling pathway provides MCF7 cells with an advantage in adapting to oestrogen deprivation. This data underlines the importance of regulatory regions in the evolution of luminal breast cancers and indicates that non-genetic mechanisms may play a key role.

Our unquenchable thirst for knowledge is one of the few things that really defines our humanity. Yet the Information Age, which we have created, has left us floating aimlessly in a vast ocean of unintelligible data. Hidden Web databases are one massive source of structured data. The contents of these databases are, however, often only accessible through a query proposed by a user. The data returned in these Query Result Pages is intended for human consumption and, as such, has nothing more than an implicit semantic structure which can be understood visually by a human reader, but not by a computer. This thesis presents an investigation into the processes of extraction and semantic understanding of data from Query Result Pages. The work is multi-faceted and includes at the outset, the development of a vision-based data extraction tool. This work is followed by the development of a number of algorithms which make use of machine learning-based techniques first to align the data extracted into semantically similar groups and then to assign a meaningful label to each group. Part of the work undertaken in fulfilment of this thesis has also addressed the lack of large, modern datasets containing a wide range of result pages representing of those typically found online today. In particular, a new innovative crowdsourced dataset is presented. Finally, the work concludes by examining techniques from the complementary research field of Information Extraction. An initial, critical assessment of how these mature techniques could be applied to this research area is provided.

Background Pulmonary arterial hypertension (PAH) is a rare progressive disease with no known cure. Of various aetiologies, PAH in association with connective tissue disease (PAH-CTD) is the most rapidly progressive and difficult to treat. Management of PAH has evolved significantly in the past ten years since the introduction of oral therapies. Evidence for the efficacy of these agents outside randomised controlled trials is limited, but guidelines exist. Aim To measure the impact of first-line monotherapy with bosentan or sildenafil and the introduction of prescribing guidelines on outcomes in PAH-CTD. Methods Following a retrospective analysis of consecutive, incident, treatment-naive PAH-CTD cases identified by the ASPIRE registry, influences on outcome measures have been compared. First-line monotherapy episodes for 247 patients was analysed against four distinct endpoints: change in exercise capacity, WHO functional class, time on monotherapy and all-cause mortality. Results Treatment with bosentan or sildenafil resulted in clinical stability at 2 years for nearly 1/4 patients. No difference was identified between the groups in terms of either exercise capacity or WHO functional class. Sildenafil patients were found to remain on monotherapy longer than those prescribed bosentan. Patients prescribed sildenafil have improved survival over those treated with bosentan. Unexpected baseline differences in between groups may confound the results as the haemodynamics of the bosentan patients were more severe. Conclusions A significant number of patients with PAH-CTD remain clinically stable on monotherapy at 2 years. Both agents seem equally effective in this aggressive form of PAH. A novel endpoint “TOM” may be of value in future research assessing response to treatment.

Perceived procedural justice in the implementation process of wind energy projects has been shown to be an important factor in shaping local acceptance of such schemes. However, thus far most research on this topic has focussed on large scale or private-developer led projects, with little research into how procedural justice might be important in "community" owned or led wind energy projects. The thesis addresses this gap by examining how local residents and project leaders perceive the implementation process of two community wind energy projects. It uses in-depth qualitative methods, with fifty-three interviews supplemented by participant observation in each community and a content analysis of key documents. The findings show that the implementation of community wind energy projects may be perceived as "procedurally just" by some local residents if the process generates a sense of community efficacy or "control" over the project. However, such perceptions are not guaranteed or necessarily consensual and very strong feelings of injustice can still exist with those who believe there to be unfair exclusions from the process or that community efficacy is more rhetoric than reality. One reason for this potential range of viewpoints is that claims and interpretations of procedural justice involve multiple "dimensions" of procedure, termed in this thesis: the extent of authority, the sharing of authority, inclusiveness, information provision, and communication & decision mode. These are interlinked and mutually reinforcing, with the perceived fairness of one dimension impacting on the perceived fairness of another. As such, creating perceived fairness in the implementation of community wind energy projects is not straightforward and attention must be to achieving justice in each dimension of procedure. A more explicitly "spatial" element to procedural justice, in terms of "where" decisions are taken, is also shown to be an important part of the justice interpretations and claims made by various stakeholders. In both case studies, the relatively local control of each community wind energy project was generally supported as a matte!; of justice, but defining exactly what the "fair" spatial boundaries of each "local community" ought to encompass was much more problematic and the subject of arguments over justice. The thesis concludes by stating that community control and ownership of wind projects does represent a significant opportunity to implement wind energy in a more just manner, and thus to potentially help reduce the extent and strength, of local opposition toward specific projects. However, community-ownership is not a "silver bullet". Instead, careful attention must be paid into how such projects are implemented and the justness of their implementation processes if greater local support and a more just mode of deploying wind power are to be achieved.

Tetraspanins are a superfamily of glycoproteins that function as ‘organisers’ of membranes by clustering with each other to form tetraspanin-enriched microdomains, into which certain other receptors and signalling proteins are recruited and regulated. Tetraspanin microdomains have been implicated in a range of biological processes including cell signalling, adhesion, intracellular trafficking, cell-cell fusion and viral entry. The tetraspanin CD37 was recently shown to negatively regulate the C-type lectin-like receptor dectin-1, which is essential for innate immune responses to fungal pathogens. The aim of this thesis was to firstly develop a cell line model system to investigate the mechanism by which tetraspanins inhibit dectin-1, and to secondly extend this work to the dectin-1-related CLEC-2, which is essential for platelet thrombus formation and stability. Using a nuclear factor of activated T-cells (NFAT) transcriptional reporter assay in the Jurkat T-cell line, transient over-expression of CD37 was found to powerfully inhibit dectin-1 signalling following stimulation with its ligand, β-glucan. Over-expression of other tetraspanins also inhibited dectin-1 signalling, but did not globally inhibit receptor signalling because the platelet collagen receptor, GPVI, was unaffected. Similar to dectin-1, CLEC-2 signalling in response to its ligand, the snake venom toxin rhodocytin, was also abrogated following tetraspanin over-expression. However, stable tetraspanin over-expression only partially reduced signalling. Moreover, knockdown of the major Jurkat cell tetraspanin, CD81, and deletion of the major platelet tetraspanin, CD9, did not affect dectin-1 and CLEC-2 signalling, respectively. In summary, the importance of transient tetraspanin over-expression for dectin-1 and CLEC-2 inhibition, and the fact that any tetraspanin can inhibit, suggests that tetraspanin microdomains are disrupted by the presence of one over-expressed tetraspanin. This leads to a failure of dectin-1 and CLEC-2 signalling by a mechanism that is not clear, but suggests that tetraspanin microdomains are important for signalling by these C-type lectin-like receptors.

In recent decades, reflective practice has taken a more central role in the construction of teachers’ knowledge and practice (Elliot, 1991; Roberts, 1998). Within reflective practice, action research has developed as an approach within which teachers can systematically question, challenge and improve their teaching and recently been introduced into teacher education programmes with the rationale of encouraging student teachers to critically engage with curriculum and practice (Mills, 2003). Recent years have additionally seen interest in how teachers’ knowledge is sociodiscursively constructed with a concomitant focus on the link between teacher identity and practice (e.g. Danielewicz, 2001; Miller Marsh, 2003; Norton 2000). However, few studies have attempted to explore the influence action research may have on the construction of student teacher practice and identity (Trent, 2010). This study explores the role of an undergraduate action research project in terms of the extent of its influence on the development of student practice in English Language classes and the trajectory of their emergent teacher identities. Informed by new theoretical directions in ethnography (Denzin, 1997), data was collected using naturally occurring texts integral to the student teachers’ studies, including weekly lesson observations, post-observation feedback discussions and three focus group discussions over the course of the research project. Analysis indicates that the undergraduate action research project differentially affects students’ practice and emergent identities, but that this relationship may be tangential and students’ agency may be overshadowed by methodological preoccupations and constraints of institutions. Both global and local discursive formations combine and interact to influence this process which occurs in a theoretical ‘interzone’ a third space, sociodiscursively constructed between institutions.

Impact ejecta material is produced during every significant impact event in our Solar System. Bodies that possess an atmosphere and sub‐surface volatiles produce unique morphologies of ejecta that are not observed on bodies that are devoid of these properties. Recent advancements in planetary exploration have lead to an explosion in research of cratering processes on Mars and other planets. However, the enthusiasm to interpret distant worlds has led many to neglect the areas of impact processes that are still to be fully understood on Earth. In doing so, interpretations of impact ejecta processes on other planets have been based on untested models. I present here extensive research that has set out to test the validity of published models of impact ejecta processes (both distal and proximal) by critically comparing them to actual geological observations. To achieve this I have developed new techniques, conducted various detailed laboratory and field investigations, and report for the first time the discovery of 2 new layered ejecta deposits. The results of this study have shown that published models for the genesis of proximal layered ejecta deposits are flawed. I suggest an alternative model based on geological observations showing that the morphologies of proximal layered ejecta deposits are controlled by identical processes (although on a larger scale) that occur in the volcaniclastic environment. I also state that both sub‐surface volatiles (in the form of water) and atmospheric interaction play vital roles in their development. Through the analysis of the Manicouagan impact crater and its associated distal ejecta deposit I have been able to prove, for the first time, the spatial origins of distal impact ejecta showing that it is derived from the top 1/3 of the target sequence. In doing so, the research presented also quantifies the actual amount of erosion that has occurred since the formation of the Manicouagan impact structure (>3.5 km) and that distal impact ejecta without a preserved melt component can still be successfully correlated to a crater through heavy mineral correlation techniques.

This thesis examines the 're-nationalization' and retrenchment of traditional forms of identity in the context of football in England and Scotland by: first, charting the economic and cultural history of football in both countries, illustrating the centrality in each nation's history of defining itself in binary opposition to the other; and, second, by focusing on the discourses of football culture as they are elaborated across a range of contemporary media, including both 'tabloid' and 'broadsheet' newspapers, television and radio commentaries, advertising, popular books on football history, and other cultural products (including, in Chapter Six, a discussion of the style of England national team's current football strip): a process which, I argue, sees the elaboration of traditional national identities intensify especially in the era since 1990, when football's traditional bureaucracy was replaced by a system underpinned by free market economics (which, after Richard Sennett, I term 'new capitalism'). While the term 'football culture' comprises many different constituent parts - professional players, coaches, managers, physiotherapists, and different groups of fans, among others -the main focus of this thesis is the discourse within forms of media outlined above; that is to say, professional commentators on football: journalists, writers, and other 'opinion formers'. As Crolley, Hand, and Jeutter (2000) illustrate through a discursive analysis of tabloid football journalism across four European nations (England, Spain, France, and Germany), this type of writing consistently evoke references to warfare, politics, history, economics, and popular culture that serve to reinforce stereotypes and myths of national difference. And, as Jon Garland (2004) has suggested, using a qualitative discourse analysis approach to the study of British tabloid newspapers, while a 'new, more inclusive Englishness was evolving amongst England supporters' during the 2002 World Cup finals tournament (moving away from the largely homogenous, white, male-dominated England support of the recent past), tabloid coverage of England's matches tended to be 'flavoured with the kinds of military metaphors and xenophobic cliche evident in previous reporting of football tournaments ... [which constituted] a narrower and more nostalgic Englishness was commonly observed'. Bearing this in mind, it is another contention of this thesis that, although generally expressed in less overt terms, the language of football discourse (including the more upmarket 'broadsheet' or'quality' press) continues to reinforce difference along national lines, necessarily covering up and muting internal cultural variations. As I seek to illustrate, the extensive breakdown in the 1990s of football's bureaucracy-the set of rules governing the finances of clubs, and the restrictions of movements of players (among other things), which I take to have begun in the late nineteenth century and which underwent a slow dissolution throughout the second half of the twentieth century - led to a ubiquitous sense in the discourse of football outlined above of loss and nostalgia for the apparent stability (financial, structural, cultural - especially in terms of notions of identity) of the recent bureaucratic past. As regards this sense of loss, in the second half of my thesis I evoke Paul Gilroy's concept of 'melancholia' as a means through which we might begin to tackle this defining feature of football discourse In the era of new capitalism. In After Empire: Melancholia or Convivial Culture? (2004), Gilroy suggests that in post-War British culture there is 'an obsessive repetition of key themes - invasion, war, contamination, loss of identity-and the resulting mixture suggests that an anxious, melancholic mood has become part of the cultural infrastructure of the place, an immovable ontological counterpart to the nation-defining ramparts of the white cliffs of Dover' (Gilroy 2004: 15). He argues that while, 'technology, deindustrialization, consumerism, loneliness, and the fracturing of family forms have changed the character and content of those ethnic and national cultures as much or even more than immigration ever did', immigration has become a pathological focus in the British imagination as a means to explain the feelings of a lack of national unity in post- War Britain (2004: 27)"' As part of this'mood'. Gilroy suggests that the 'anti-Nazi war' has become a touchstone for the perceived decline of Britishness and the certainty that identity provided as an ideal in the imperial period. While I have much sympathy for this reading of contemporary British culture, and while I think the concept of melancholia is useful when addressing the discourse of football in this thesis, it does not provide sufficient scope to take into account the feelings, sensations, and notions (experienced by fans at matches, television viewers of sport, and, indeed, writers on football) of joy, excitement, and euphoria, that football still engenders in the contemporary era. " (In my conclusion I attempt to describe my own ambivalent feelings in this regard). Thus, the concept of melancholia with regard to football discourse is but one part of a more generalized sense of nostalgia which idealizes the past, criticizes the present, and fears for the future. As such, 'melancholia' is useful for a macro view of the current discourses of football culture that constantly reiterate the lack of the present compared to the idealized view of the past; while 'nostalgia' is more able to take into account specific moments where a longing for the past can structure present experiences of joy and euphoria, however limited those experiences may be. An example of this may arise, for instance, during a season when the team one supports is enduring a string of desperately bad results. Within that context of defeat and sadness, a surprising, unexpected, or comprehensive victory over a rival inevitably creates a euphoria and joy that engenders, however briefly, feelings of joyous community with your team's other fans (in an imagined community) that bring to mind memories of previous victories, and participates in a nostalgic lineage with past victories and glory. These feelings, therefore, have the potential to momentarily cover over the flux of the modern world, the disappointments of the season up until then, and the fissures of identity and melancholia created by the effects of global capitalism on the cultures of football. Of course, a danger in the contemporary, postmodern world is that to talk about nostalgic feelings is, in itself, to perform a nostalgic act: that is to say that unless one completely rejects the possibility of nostalgia being anything other than 'irrational', 'bad', or regressive, one risks appearing totally at the behest of the heart rather than the head. (To which I would, again, point to my conclusion as evidence of my belief not in the 'good' or 'bad' of nostalgia, but that it is an ambivalent phenomenon which needs to be addressed as such). In this sense, then, nostalgia is perhaps a more prescient or useful concept than melancholia in a thesis that seeks to hold the joys and despairs that football engenders in a state of constant tension.

Frankliniella occidentalis (pergande) is a serious pest of protected crops within the UK because it damages crops and is a vector of tospoviruses. It is resistant to a wide range of insecticides and exhibits thigmokinetic behaviour, making contact between pest and treatment difficult. Applying control procedures to correspond with the diel behaviour patterns of F. occidentalis could enhance control ofthrips. Studies of glasshouse crops showed that the abundance of adults on leaves and flowers increased in ~he afternoon compared to the morning. This could not be accounted for by movements within or between plants, but could be from sites off the plant. This hypothesis deserves further investigation. Infrared videography in the glasshouse generally showed little difference In abundance on plant parts between scotophase and photoppase. In addition, observations made at the time suggested that there was little difference in locomotory activity between the light phases. Contrastingly, laboratory locomotory activity patterns showed an increase in the early morning and late afternoon. A light burst during the scotophase, devised in the lliboratory to enhance locomotory activity, had little effect on thrips in a cucumber glasshouse. These two findings cast doubt on the applicability of laboratory studies to the glasshouse. Flight could be predicted well using ambient light and temperature and showed a clear diel pattern. There was a diel pattern of larval dropping to the ground to pupate, with the majority of larvae falling between late afternoon and midnight. Further sampling within a ,?ucumber glasshouse showed that on any particular day most larvae dropped within a two-hour window. Flight activity, and larvae falling from the crop showed clear' diel patterns. Locomotory activity on the crop djd not show a clear diel pattern. Interpretation and use of these findings would depend upon the type of control procedure applied to a crop.

Flavonols are polyphenolic plant secondary metabolites found in high concentrations in fruits, vegetables and beverages such as tea and red wine. Many possess antioxidant and free radical scavenging activity and epidemiological studies indicate that consumption of flavonols is associated with a reduced risk of coronary heart disease. (+)-Catechin is one such compound found in red wine and green tea. The absorption and metabolism of (+)-catechin is poorly understood and radiolabelled material is required to determine its bioavailability and role as an in vivo antioxidant. We envisaged two main approaches in our retrosynthesis of labelled (+)-catechin from aryllithium and radiolabelled carbon dioxide. The first involved flavene as a key intermediate whilst the second relied on the preparation of 1,3-diarylpropene. A number of routes to model flavenes v were attempted. A range of potential synthetic intermediates were prepared, but all failed to give the cyclised product. Various routes to synthetic intermediates corresponding to the 1,3-diarylpropene synthon were then investigated. The most successful approach proved to be crossmetathesis. Thus, phloroglucinol was protected as its tris-THP ether, lithiated and allylated to give a mixture of diastereomeric compounds. Cross-metathesis then gave 1,3-diarylpropene and dihydroxylation provided the racemic syn diol. Other potential substrates for alkenation reactions were prepared including phosphonium salt and sulfone and a range of novel benzothiazole chemistry is discussed.

Corneal dystrophies are a clinically heterogeneous group of rare inherited ocular disorders that often result in a reduction in visual acuity. These dystrophies can be inherited as either an autosomal dominant or autosomal recessive trait, which can affect one or more layers of the cornea. Autosomal dominant congenital hereditary endothelial dystrophy (CHED1) is a severe disease, which affects the corneal endothelium. The largest reported family with CHED1 was used to identify the locus for the disease on chromosome 20 using linkage analysis. The CHED1 disease interval was refined to 2.7 cM on chromosome 20p11.2 flanked by the markers D20S48 and D20S471. A physical map was created using a YAC and PAC contig to anchor sequence tagged sites (STSs) and expressed tagged sites (ESTs) to the CHED1 interval. The genes, destrin, VSX1 and the cystatin gene cluster were excluded as candidates for CHED1 (Chapter 3). The autosomal recessive form of congenital hereditary endothelial dystrophy (CHED2) was previously localised to an 8 cM region on chromosome 20p13. A positional candidate gene approach was adopted to identify the causative gene for CHED2. In collaboration with the Chromosome 20 group at the Sanger Institute, a PAC and BAC contig was created spanning the 3.7 Mb disease interval. Analysis of the genomic sequence predicted 62 genes or transcripts within this region. A small Pakistani family, which had previously been linked to the locus on 20p13, was used to screen CDS2 for mutations (Chapter 4). Granular corneal dystrophy (CDGG1) is an autosomal dominant disease characterised by non amyloid deposits in the stroma. A British CDGG1 pedigree was linked to chromosome 5q31-33 flanked by the markers D5S421 and D5S399. YACs from the CEPH YAC library were used to create a physical map of the disease interval. [beta]ig-H3, previously identified as the causative gene for a number of stromal dystrophies, was screened in this pedigree and a mutation in exon 12 was identified (Chapter 5). Cornea plana is characterised by a flattened corneal surface and can be inherited as a mild autosomal dominant disease (CNA1) or a more severe autosomal recessive form (CNA2). A small Hispanic family with CNA2 was ascertained and screened for mutations in the keratocan gene. A homozygous mutation in exon 2 was identified (Chapter 6). This molecular genetic study of both recessive and dominant disease has contributed to our knowledge of corneal dystrophies.

Collision avoidance systems offer the possibility of significantly reducing the costs of road and specifically motorway driving, in terms of both accidents and their associated effects. Additionally, similar schemes such as autonomous intelligent cruise control (AICC) also offer the possibility of increased road capacity. Accidents at night are relatively more frequent and severe, and thus this work initially concentrates on the development of techniques and algorithms to automatically detect potential night-time collisions. Hence, this thesis considers the design and development of a complete processing chain, from initial image acquisition, through the recovery of trajectory measures describing the threat or otherwise posed by other road vehicles. Since lights are the dominant features in night imagery, a feature extraction algorithm has been developed to locate and extract vehicle tail-lights from input imagery. Trajectories are extracted by tracking such vehicle cues temporally, which may then be passed to a set of trajectory analysis processes. The trajectory analysis initially considers area-based recession rates recovered from single regions. However, due to the low signal to noise ratio in the recovered areas and recession areas, a novel pairing technique is developed enabling a subsequent pair-wise trajectory analysis to be performed, which allows significantly improved recession rates to be recovered. A additional clustering technique is also developed which allows pairings consistent with individual vehicles to be aggregated, substantially reducing the number of recovered targets. These techniques developed for night driving are further developed and extended to daylight scenarios, by the application of a novel combined vehicle detection and classification system.

The thesis seeks to contribute to the study of the urban economies of the small, slow growing towns of the late Georgian and early Victorian period. This is undertaken at two levels. First, consideration is given to sources. A number of mainly quantitative sources became available from the later 18th century. Four principal ones are identified. Each of the main chapters deals with one of these; evaluating the information contained and considering methods by which this can be used to assess the character and prosperity of the small town urban economy. At the second level the thesis applies these methodologies to a case study of three north Essex cloth towns. Despite experiencing the transition to factory-based production, these towns did not witness the associated urban expansion. A two-part hypothesis is advanced to explain this phenomenon. The first suggests that differences in economic orientation existed between the case study towns and their rapidly growing counterparts in the north; the second, that the dominance of these non-industrial activities restrained the extent to which industry in the Essex towns grew. Results gained from application of the sources to the case study are shown to support the hypothesis. First, in contrast to towns such as Halifax and Macclesfield, marketing and thoroughfare functions formed the staple economic activities of the Essex towns. Second, the Essex silk manufacturers pursued a low wage policy requiring expansion of production through the establishment of additional mills in other settlements. This policy is shown to have been a rational response to local labour markets created by the operation of the towns as agricultural marketing and thoroughfare centres. In concluding similar observations are made for other towns in southern England.