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Bromodomains (BRDs) are protein modules which bind to acetylated lysines on histones and transcriptional regulating proteins. BRD-containing proteins are involved in a large variety of critical cellular processes and their misregulation, or mutation of the genes encoding for them, has been linked to pathogenesis in humans. The generation of chemical probes (potent, selective and cell permeable small molecules) in cellular experiments to investigate the biological role of the BRDs is thus desirable. A chemical probe for the CREB (cyclic-AMP response element binding protein) binding-protein (CBP) and E1A binding protein (p300) BRDs was developed, starting from a low molecular weight, weak and non-selective dimethylisoxazole benzimidazole compound. Parallel synthesis was used to optimise the initial hit into a weak, but selective CBP inhibitor. Further modification of the two N-1 and C-2 moieties of the benzimidazole scaffold, led to highly potent and selective CBP inhibitors. Structure-guided design was then applied to optimise the selectivity of the series for CBP over the first domain of bromodomain-containing protein 4 BRD4(1). A strategy to reduce the flexibility of the N-1 and C-2 ethylene linker groups through the incorporation of conformational constraints led to inhibitors with increased selectivity. The optimal compound was highly potent for the CBP and p300 BRDs (Kd 21 nM and 32 nM, respectively) and selective over BRD4(1) (40-fold and 27-fold, respectively). On-target cellular activity was observed in a fluorescence recovery after photobleaching (FRAP) assay (0.1 μM), a p53 reporter gene assay (IC50 1.5 μM) and a Förster resonance energy transfer (FRET) assay (5 μM). A weak indolizine bromodomain-containing protein 9 (BRD9) inhibitor was used as the starting point for the development of a BRD9/BRD7 chemical probe. Analogues were synthesised via [3+2] cycloadditions. An optimised compound was found to be highly potent (68 nM) and selective over BRD4(1) (34-fold). On-target cellular activity was observed in a FRAP assay (5 μM). Efforts were made to improve the cellular activity through the introduction of an ionisable centre to aid solubility. A selection of piperazine analogues were shown to be potent and selective, and these compounds warrant further investigation of their selectivity and cellular activity. Overall, the work has led to the first potent and selective inhibitors of the CBP/p300 and BRD9 BRDs. It also highlights the role of structural analysis in the development of inhibitors that modulate protein-protein interactions.

The body of poetry and prose produced by Iain Sinclair between 1975 and 2002 represents a sustained engagement with the question of the role of art and literature in the representation and comprehension of the city. This thesis reads Sinclair's work as a political intervention in the relationship between literature, urban space, and history, and takes its theoretical stance from the body of critical approaches to the city first articulated in Walter Benjamin's Arcades Project. The thesis proceeds on a broadly temporal and geographical basis from the East End of the author's 1975 poetic work Lud Heat to the suburbs of the capital in 2002's London Orbital, and is split into three sections of two chapters each, entitled 'Form', 'Place', and 'Memory' respectively. This structure periodises the author's oeuvre, demonstrating the ways in which his work responds to a series of historically specific cultural and political constellations; the titles name the perennial themes and critical concerns of Sinclair's writing, and allow the investigation of the ways in which these are instantiated and elaborated in his texts. Sinclair's earliest work builds upon the formal innovations and ambition of modernist poetics. Through an analysis of his first major collection of poetry, Lud Heat (1975), and his first novel, White Chappell, Scarlet Tracings (1987), the first part of the thesis - 'Form' - argues that these texts constitute an interrogation of the institutions of literature in postwar Britain in the wake of what Peter Burger identifies as the failure of the historic avant-gardes. These opening two chapters contextualise Sinclair's work so as to reveal its anti-establishment, oppositional character; the second section of the thesis - 'Place' - moves on to examine how these concerns are expressed in relation to urban space. Chapter 3 turns to the figure of the flaneur in his second novel, Downriver(1991), and demonstrates how this work at once radically decentres this subjectivity and is conditioned by his limitations. Downriver marks a moment of political nihilism in Sinclair's work, neither able to bring to representation Fredric Jameson's aesthetic of 'cognitive mapping', nor the emancipatory potential of postmodernism. His later 'psychogeographic' writing articulates a response to this impasse: chapter 4 demonstrates the ways in which Sinclair's use of this term at once divests it of the utopian character of its Situationist origins and transforms it into a dissenting, heterogeneous, literary mode. The final two chapters - 'Memory' - investigate the political potentialities of the models of history expressed in Sinclair's work. Chapter 5 turns to the author's use of the Gothic in relation to Benjamin's 'messianic' notion of 'the what has been', and argues that whilst such strategies can be of great critical potential, they at once risk collusion with that which they attack. Chapter 6 then analyses 2002's London Orbital, and argues that this work's ironic, tentative nostalgia for both the author's anti-establishment past and for the utopian character of former socio-political projects represents an attempt to find a way beyond the political malaise that Sinclair's London corpus identifies.

Abstract Zircon in mudstones, sandstones and greenschist facies metasediments has been investigated using conventional SEM techniques (BSE, CL and SE imaging) and reveals highly variable microstructures and textures. In these rocks, zircon readily responds to low temperature events due to radiation damage in its crystal lattice while crystalline zircon remains unmodified. Zircon that alters as a result of metamictization has a low BSE intensity (dark BSE zircon) and electron microprobe measurements show an enrichment of Mg, Al, Ca, Fe, Y and a loss of Si and Zr, while Hf appears to remain relatively constant between the unmodified parent and the resulting modified phase. Dark BSE zircon forms via two main mechanisms. The dominant dark BSE zircon form (Group 1) has a microstructure containing an abundance of pores, cavities and inclusions forming as a result of a coupled dissolution-reprecipitation mechanism. Electron backscattered diffraction (EBSD) analyses suggests that the structure is composed of randomly orientated nanocrystalline zircon. The other form of dark BSE zircon (Group 2) is produced by a solid-state diffusion-driven cation-exchange process in which structural recovery occurs (as determined by EBSD) and where inclusions or pores are absent in the microstructure of the product phase. The different forms of altered zircon are chemically indistinct. Zircon outgrowths (c.1µm thick) on the margins of detrital unmodified zircon in clay-rich sandstones indicate Zr was transported from altered grains. These zircons crystallised below 100°C. The upper temperature at which metamict zircon may be dissolved is constrained by the annealing temperature of the zircon lattice whereby metamict areas are repaired above c.250°C. Zircon outgrowths are larger (c.3µm thick) and in much greater abundance in slates that have experienced deformation and temperatures c.350°C. They have a complex microstructure, partly as a result of interactions with xenotime that also forms outgrowths upto 12µm thick on zircon. Xenotime inclusions and zircon-xenotime complexes have been identified within zircon outgrowths using TEM and LV-STEM. Electron transparent foils of the outgrowth were prepared using the FIB microscope. Zircon outgrowths have similar chemical characteristics to dark BSE zircon but have distinctly different substitution relationships. There are also differences between the chemistry of dark BSE zircon from sedimentary and greenschist facies rocks where the latter is considerably more enriched in Al, Y and Ca. The implications of this are that zircon chemistry is strongly influenced by the local conditions in which in formed. Sedimentary processing causes considerable bias in the zircon population. Fine-grained sediment is a sink for high U and Th, heavily radiation damaged, old zircon in comparison to mature sediment that is likely to contain an abundance of low U and Th zircon or young zircon upon deposition. Small metamict zircon fragments are prone to dissolution and can be readily stripped from the matrix of fine-grained sediments. The concentration of zircon outgrowths in fine-grained sedimentary and metasedimentary rocks is primarily the result of sedimentological processes. The findings of this work illustrate the importance of studying minerals in-situ and within their petrological context. The wide-spread and abundant nature of low temperature zircon is a major consideration for geochronology, sedimentary provenance studies, the interpretation of zoning in zircon and has significant implications for the long-term storage of radioactive material.