Search

Continuous improvements in high-throughput genomic sequencing over the past two decades have made it exponentially faster and cheaper, enabling its routine use in the clinic and scientific research. Genomic prognostic tools make use of personalised genomic data to aid clinical decision making and inform patients of disease outcomes, allowing enhanced tailoring of treatment beyond traditional prognostic tools, which are insufficient for understanding the nuances of individual complex disease cases. This relies upon accurate sequencing data and effective quality control. We have developed improved genomic prognostic tools for use in the clinic and demonstrate a novel method for quality control of genomic sequencing data with broad applicability. Non-small-cell lung cancer (NSCLC) is the second most common cancer type in both males and females globally. Previous attempts to predict survival time for cancer patients have used genomic prognostic tools based on the burden of tumour mutations and neoantigens, but with limited success. We developed greatly improved classifiers of tumour mutation and neoantigenic burden showing strong 5-year survival differences between early-stage NSCLC patients. By using these together, we showed additional increases in prognostic efficacy, with the best survival group displaying a ~92% decreased risk of death in a 5-year period compared to the worst survival group. To improve the accuracy of sequencing data for uses such as this, we developed the first tool for automatically cataloguing systematic sequencing biases for a sequencing pipeline, and we demonstrated its value in human and SARS-CoV-2 sequencing quality control with Illumina and Oxford Nanopore sequencing. We discovered and blacklisted a range of false positive variants, and investigated the causes of these. Identifying these errors contributed to multiple studies, altering research conclusions. We share these tools to provide continued improvements to genomic prognostics and sequencing accuracy affecting a wide range of fields.

Ancient deep-water syn-rift systems provide a record of complicated interactions between changing sediment supply from multiple input points, relative base level changes, and evolving fault-related topography. Existing conceptual models have struggled to address stratigraphic variability at fine spatiotemporal scales. Outcrop investigations can address this scale gap, although exhumed systems are rare or often complicated by structural inversion. Here, the stratigraphic architecture of the Early-Mid Pleistocene West Xylokastro Fault Block (Corinth Rift, Greece) is documented using mapping, photogrammetric models, and an onshore research borehole to establish an integrated palaeoenvironmental and tectonostratigraphic evolution in a rare example of an exhumed deep-water syn-rift system. The results highlight substantial heterogeneity across a range of scales. Coeval transverse mass-wasting deposits impact the evolution of axial depositional systems through topographic forcing not captured in existing models. Structurally-induced bathymetry drives development of transient sediment bypass-dominated zones over ramps, and sediment accumulation in intra-basinal lows. Spatially, fan-apron systems pass into laterally confined channel systems over short distances (1–2km). The steep, short nature of onshore catchments and shelves makes this syn-rift system sensitive to changes in sediment supply from onshore catchments. Vegetation changes, recorded from palynological analysis of the research borehole, are integrated with magnetostratigraphic chronology and may be coherent with climate variability dictating sediment supply changes, including the development of laterally extensive mudstones. Basin physiography also permitted substantial quantities of coarse-grained material to be delivered, generating a spectrum of coarse-grained gravity flow deposits. The study provides rare examples of bed- to meso-scale architectures preserved by these flows within a constrained palaeogeographic context. The study updates existing conceptual models for the physiographic, climatic, depositional, and structural evolution of deep-water syn-rift systems. The thesis also highlights the challenges in characterising syn-rift deposits and provides quantitative data to aid understanding of tectono-stratigraphic controls and reduce uncertainty in other syn-rift systems.

Ultra-cold atoms have small kinetic energy and are therefore very sensitive to external fields that act on the atoms. By having fine control over the positioning of the ultra-cold atom cloud we can use the atom cloud as a sensor for magnetic fields. By imaging these atom clouds we can infer a spatial map of the magnetic field. This spatial map will have a resolution proportional to the distance between the source of the magnetic field and the atom cloud which can be on the order of 0:1 μm. In the first half of the thesis, we investigate the two colour magneto-optical trap. This is a simple technique that can lead to a multiplicative increase in the number of atoms in a magneto-optical trap with a simple change to the optical setup. Using the two colour magneto-optical trap we have observed an increase of 5 times in the number of trapped atoms. An increase in the number of atoms in a magneto-optical helps with later cooling processes that are not lossless such as evaporative cooling which in turn helps the realisation of the ultra-cold atom microscope. In the second half of the thesis, we demonstrate how a 2d current density can be recovered from a 2d magnetic field map generated by the ultra-cold atom microscope. We then go on to show the sensitivity and responsivity of a cold atom cloud and a Bose-Einstein condensate. We then use the results of the previous section to simulate the measurement of currents in a silver nanowire network. Properties of the silver nanowire network can be simulated and aid in showing the abilities and limitations of the ultra-cold atom microscope. We found that the ultra-cold atom microscope can directly measure currents in low-density silver nanowire networks. In a high-density silver nanowire network, the average distance between the wires becomes too small to resolve. Hot-spots, areas of high current density can still be identified using the ultra-cold atom microscope. The ultracold atom microscope could then be used as a tool to aid the research look to use silver nanowires in many industrial applications such as touch screens.

This qualitative research informed by the interpretivist paradigm analyses how senior management team members in the Irish public and independent mental health sectors have influenced the evolution of clinical governance. A 54 item schedule (the Organisational Progress in Clinical Governance schedule) [OPCG] is utilised to inform a process of semi-structured interviews. A review of the-clinical governance and-other literature is undertaken to frame the research question, to highlight originality and position expectations. Newell and Burnard's 'Pragmatic Approach to Schematic Content Analysis' in conjunction with NVivo is used as the data analysis framework. A reference group is utilised in advance of the study and 25 executive and director level senior management team members are interviewed in their capacity as senior leaders and experts in the research area of clinical governance evolution. 5 separate healthcare organisations (3 public and 2 independent) were purposively selected. Participants completed the OPCG prior to participating in semi-structured interviews. The interview schedule was informed by the results of the OPCG and the literature review. Senior management team members were drawn from an interdisciplinary perspective. Processes to establish the rigour and plausibility of the study are outlined including the use of multiple coding, a reflexive diary and respondent validation. Following data analysis, findings are distilled and presented. Recommendations for education, practice, management and governance are expounded. These refer to strategies to enhance leadership capacity, commentary on the expanding role of regulation in healthcare, discussion of the differences apparent between HSE and independent sector mental health providers and the implementation of key national policies specifically ICT. Additionally, current issues in recruitment, staff and staff management processes, formal and informal power structures, in-service training and education, evaluation of health service re-structuring at national and regional levels and the re-imagining of strategic alliances with the higher education sector are explored.

The intent of this thesis and its attendant body of practical work was to examine and test ideas and practices that can inform and expand the artists' role in the post-industrial public realm and its environmental context. The general focus was on transformative approaches to contemporary public art. The specific interest (and area of practice) is defined by artwork that takes an interdisciplinary approach to new forms of social creativity in the context of post-industrial environmental change. This dissertation begins with a broad literature review to understand public art and its relationship to: the public realm, ecology, nature and the environment. The intent was to understand the theory and process that inform answers to questions regarding the artists' ability to affect public policy; the ability to expand the creative act beyond singular authorship and finally the question of can we verify the impact of art? The thesis closes with two chapters describing practical work on 'Nine Mile Run' a project that developed an ecolo nPical restoration approach to post-industrial public space; also'3 Rivers 2n Nature'which focused upon the emancipation of, and a means to advocate for post industrial nature. These projects were developed with the intention to test theory through application and value through outcome. The goal was to provide a better understand of ideas that define and enable collaborative or inter-relational approaches to transformative art practice. The intention was to make a small contribution to the theoretical framework that informs the conceptualization, experience and valuation of transformative public art practices that intend to affect the material and conceptual forms of the postindustrial public realm. It is through intellectual study and ongoing practice that the three original questions are addressed with a cautionary affirmative. Other specific findings include the following. " The ongoing tension between individual freedom and social interaction is best addressed through a moral commitment to creativity in relationship to the emancipation of people, places and things. " Visual evidence can not be the sole focal point of critical engagement with transformative practice. " Transformative practices that undertake an inter-relational methodology demand ethical, responsible and distributed outcomes.

The starting point of this thesis is the hitherto under-explored relationship between Russian apocalypticism and formal fragmentation in Russian literary modernism, both prominent in an early twentiem-century climate of heightened religiosity and aestheticism. The project borrows Joseph Frank's theory of 'spatial form', which demonstrates how a text's temporal coordinate is suppressed by disruption of order, and postulates that this technique stems from the modern mood of existential crisis, attracted to the otherworldly and timeless. This analysis encounters more concrete resonances when applied to the eschatological perceptions of time and aspirations for religious experience via art in contemporary Russia. The project focuses on post-Revolutionary prose, taking Babel"s Konarmiia, Platonov's Chevengur and Zoshchenko's Pered voskhodom solntsa as case studies. Given that the Revolution was widely depicted as an apocalyptic end, the subsequent 'post-apocalyptic' condition raises narratological and philosophical problems for texts, such as these, that engage with inherited, transformative models. Although the eschatological paradigm continues to play a crucial part in understanding the Revolution, it is inevitably affected by the passage of the purported End from future into past, as well as by the need to incorporate an atheistic twist into a myth deeply rooted in Orthodox Christian traditions. Such redefinitions of the apocalyptic paradigm can also be manifested in textual fragmentation. In this context the project draws on Frank Kermode's description of how increased non-linearity in narrative structures reflects a rise in the complexity of experience and scepticism toward the biblically-derived narrative, with an absolute beginning and end. Kermode thus offers an alternative to Frank's theory. Together, the two provide a framework for exploring the extents to which the collision of Russian messianism with the Revolution is experienced by modernist writers as a transcendent moment of timelessness, or a stimulus to deconstruct the paradigm.

This thesis presents a strategy for power-scaling diode-end-pumped solid-state lasers based on Nd:YLF operating on the 1.053μm line whilst retaining, efficient, single-frequency, diffraction limited output, the characteristics of low power operation. This strategy reduces the effects of energy transfer up-conversion (ETU), which can decrease the lifetime of the upper lasing level and increase the heat generated per unit volume within the laser rod, increasing the effects of detrimental thermally related problems such as thermal lensing, stress-induced birefringence and stress induced laser rod fracture. Also a passive technique for mode-hopping-suppression is described, allowing the oscillating frequency within the laser cavity to tune over many axial mode spacings before a mode-hop occurs. In order to de-couple the problems of laser resonator power scaling from the maintenance of robust and reliable single-frequency operation, the Nd:YLF laser oscillator output is amplified via Nd:YLF based amplifier stages. A model is presented of the effects of ETU on thermal lensing and small signal gain within the amplifiers along with projected results for further power-scaling prospects. In order to increase the frequency tuning capabilities of the master-oscillator-power-amplifier (MOPA), it was used to pump a series of cw singly-resonant optical parametric oscillators (SROs) based on periodically-poled lithium niobate. Although SROs are inherently single-frequency they suffer detrimentally from mode-hopping, therefore in the final stages of this thesis, we propose to utilise the novel passive technique for mode-hopping-suppression with the SRO cavities in order to achieve robust and reliable single-frequency output. Theoretical expressions and design strategy for low SRO threshold and efficient slope efficiency are expressed along with detailed analysis of the mode-hopping nature of their output. Preliminary results for cw SROs are presented and details of SRO mode-hopping-suppression are included

The work described in this thesis has focused on clarifying some of the important determinants and mechanisms of effective RIT of syngeneic B-cell lymphoma, both in vivo and in vitro. A successful animal model of RIT in B cell lymphomas was established by initially generating a panel of antibodies against mouse B cell antigens. The in vitro characteristics of these antibodies have been compared with their subsequent performance, in biodistribution studies and RIT in vivo. For the first time in an in vivo model the relative contributions of antibody and irradiation are described. Some antibodies including anti-MHC Class II were shown to be effective delivery vehicles of low doses of Iondine-131. These antibodies, which appear to be inactive delivery vehicles can cure animals with low burdens of tumour. However antibodies such as anti-idiotype and anti-CD40 which are active as "naked" antibodies are required to eradicate larger tumour burdens and to cure animals. For anti-idiotype antibodies the antibody and irradiation were shown to have an additive effect in vitro and in vivo in increasing the amount of tumour apoptosis. This increased therapeutic efficacy translated into animals with large tumour burdens being cured. These results strongly imply that RIT is much more than targeted irradiation and suggest potential mechanisms for the successes in the clinic. During the course of this work a new in vivo and in vitro variant of the BCL₁ tumour was isolated Π-BCL₁. In contrast to the BCL₁ tumour this variant establishes as a syngeneic nodular lymphoma in vivo and grows in free suspension in vitro. This tumour model has provided a useful tool to investigate the induction of apoptosis both in vitro and in vivo. Finally apoptosis induced by irradiation and antibody were investigated in murine and human lymphoma cells in vitro. The murine radiosensitive B- and T-cell lymphomas were demonstrated to induce large amounts of early apoptosis within 24 hours.

Sabkhat Matti forms a wide depression that extends from the coastline of western Abu Dhabi, in the north, approximately 125km south. The area has been studied with a view to investigating the impact that Quaternary climatic changes have had on the geology and geomorphology of modern desert sediments. The depression was formed by (?Pliocene) fluvial erosion followed by deflation which was localised in the region by the presence of underlying N-S fractures and lineaments. Sabkhat Matti and the deserts of the United Arab Emirates form the upwind, north-eastern margin of the interior desert of SE Arabia. The desert geomorphology of the Emirates is dominated by four main depositional processes: coastal accretion of marine carbonates, the formation of salt flats in low-lying areas, aeolian deflation and deposition to the south and alluvial deposition adjacent to the Oman Mountains in the west. Some of the desert landforms that are present in the U.A.E. were generated during earlier, glacially influenced climatic conditions. These landforms have been influential in affecting the subsequent geomorphological development of the deserts of the U.A.E. Two ancient desert sequences which form hydrocarbon reservoirs have been studied from NW Europe, the Lower Triassic, Ormskirk Sandstone of the Irish Sea Basin and the Lower Permian, Upper Slochteren Sandstone of the Southern North Sea (offshore Netherlands). The sedimentological interpretations of these ancient desert sequences has benefitted from a thorough understanding of the modern depositional processes. This knowledge has also assisted in the development of a method for modelling the theoretical accumulation of desert sediments. The idealised facies cycles that have been produced using this technique have closely resembled those observed in the ancient desert sequences from NW Europe.