Search

Maintaining replicative immortality is a crucial step in the development of cancers and is achieved by activating a telomere lengthening mechanism. While the majority of cancers rely on upregulation of telomerase, approximately 10-15% of cancers achieve telomere length maintenance through a telomerase-independent mechanism referred to as the Alternative Lengthening of Telomeres (ALT) pathway. ALT cancers exhibit a number of characteristic markers and recent work has sought to understand the mechanisms that underly the generation of these markers and of ALT telomere maintenance. Previous work has also highlighted the striking loss of the chromatin remodelling protein ATRX and its histone chaperon partner DAXX in ALT cancers, and the ability of ATRX and DAXX to suppress the ALT pathway. Until now, however, it has remained unclear as to the mechanisms by which ATRX loss drives ALT development given that ATRX loss alone is generally insufficient to generate the ALT phenotype. In this thesis a novel marker of ALT, the presence of Replication Protein A coincident with telomeric sequences, is shown. This marker is dependent on the presence of the endonuclease Mus81, which is known to cleave stalled replication forks. In conjunction, evidence is presented showing that the telomeric replication stress or lesions on telomeric DNA when combined with loss of ATRX or DAXX are able to trigger ALT pathway induction. This induction can be triggered both through artificial means with genotoxic agents, but also through loss of the histone lysine methyltransferase SETD2, which is responsible for the methylation of Histone H3.3 at lysine 36. Together these observations provide critical understanding of a possible route of ALT development, given the frequent co-occurrence of histone H3.3 G34R/V mutations, which are known to be detrimental to SETD2 activity, and ATRX/DAXX mutations in ALT cancers.

The dynamics of the atmosphere span a tremendous range of spatial and temporal scales which presents a great challenge to those who seek to forecast the weather. To aid understanding of and facilitate research into such complex physical systems, `idealised' models can be developed that embody essential characteristics of these systems. This thesis concerns the development of an idealised fluid model of convective-scale Numerical Weather Prediction (NWP) and its use in inexpensive data assimilation (DA) experiments. The model modifies the rotating shallow water equations to include some simplified dynamics of cumulus convection and associated precipitation, extending the model of Wuersch and Craig (2014). Despite the non-trivial modifications to the parent equations, it is shown that the model remains hyperbolic in character and can be integrated accordingly using a discontinuous Galerkin finite element method for nonconservative hyperbolic systems of partial differential equations. Combined with methods to ensure well-balancedness and non-negativity, the resulting numerical solver is novel, efficient, and robust. Classical numerical experiments in shallow water theory, based on the Rossby geostrophic adjustment problem and non-rotating flow over topography, elucidate the model's distinctive dynamics, including the disruption of large-scale balanced flows and other features of convecting and precipitating weather systems. When using such intermediate-complexity models for DA research, it is important to justify their relevance in the context of NWP. A well-tuned observing system and filter configuration is achieved using the ensemble Kalman filter that adequately estimates the forecast error and has an average observational influence similar to NWP. Furthermore, the resulting error-doubling time statistics reflect those of convection-permitting models in a cycled forecast-assimilation system, further demonstrating the model's suitability for conducting DA experiments in the presence of convection and precipitation. In particular, the numerical solver arising from this research provides a useful tool to the community and facilitates other studies in the field of convective-scale DA research.

This thesis investigates the notion of fuel-reduction through formation flight for commercial aircraft, addressing the problems of global routing and assignment. A two stage centralised approach is presented, firstly, assuming a reduction in observed cost by flying in formation the routes, including rendezvous and break points, are calculated to minimise a total cost. The interconnected assignment problem then takes a set of flights, their possible formations and corresponding costs and optimally allocates them into a cost-minimising formation fleet. An analytic geometric approach is used to develop a scalable methodology for the formation routing problem enabling the quick calculation of costs. The rapid evaluation allows the large scale fleet assignment problem to be solved via a Mixed Integer Linear Program in reasonable time. A Transatlantic case study shows possible formation fuel savings against solo flight of around 8.7% and 13.1 % for formations up to size two and three respectively. Further case studies of three distinct sets of flights show that encouraging levels of saving can still be achieved by flights with varied distances , geographical locations and formation drag-reduction levels. For the more complex task of routing through wind, results show that the analytic approach can act as a reasonable estimate to the assignment problem, allowing higherfidelity and computationally more intensive routing methods to be introduced via a post-process, significantly reducing solve time. Methods for mitigating the impact of uncertainty in aircraft take-off times are explored, where a state-space approach, solved using value iteration, can provide optimal speed-policies for aircraft to follow for any possible realisation of delay. Additionally portfolio optimisation provides a method for formations to be assigned to simultaneously maximise reward and minimise the associated risk. Finally the calculation of efficient frontiers allows matching of reward to desired levels of risk-aversion.

The Mental Health Act 1983, amended in 2007, appears based on the assumption that an undisputed entity of “mental disorder” exists, that people who are designated mentally disordered should be treated, and if necessary, detained by doctors. This study aimed to examine how mental disorder was discursively constructed and how different institutional interventions and practices were justified and legitimised in the House of Commons’ debates regarding the Mental Health Act 2007. Verbatim transcripts from House of Commons debates on the Mental Health Act (conducted between 24th April and 15th May 2007) were studied through a discourse analysis. Seven primary discursive constructions were identified: “The Trusted and Medically Objective Expert,” “The Emergency,” “A Fair Process,” “Supporting Subjects,” “The Decision-Making Impaired and Vulnerably Ill Patient,” “The Lawyer’s Field Day,” and “Societal (Dis)Order.” The study concludes that mental disorder was represented in selective and systemic ways that can help justify and legitimise different interventions and practices, for example, enforced medication, making government legislation and psychiatric practices seem necessary. Consideration was given to how psychiatric practices could be problematic for some service users and how legislation could be based on political and public concerns about social disorder.

The concept of countertransference, which refers to the emotional response of the therapist to their client, has been at the heart of theoretical debates and clinical practice within both psychotherapy and psychology. Most of the literature on countertransference has either been written by experienced therapists, with the empirical literature focusing on trained therapists. There is a relative neglect of trainee psychologist and psychotherapist's experience of countertransference particular among trainee counselling psychologists. This study aims to address this gap by exploring the narratives around the area of countertransference as told by seven participants all of whom are trainee counselling psychologists based in the UK. Participants took part in semi-structured interviews, which were analysed using the Critical Narrative Approach (CNA). CNA brings together a focus on how people narrate their lives to form a meaningful whole and how in this process a narrative identity: a sense of self both for ourselves and others is constituted. CNA involves six stages of analysis beginning with the analysis of the preconceptions of the researcher with stage two identifying narratives and stage three exploring the narratives tone and rhetorical function. Stage four explores how identities are constructed or projected in the text and the fifth stage identifies important themes and relationships between these themes. Within the sixth stage, the narratives are subjected to critique, which in the case of this research is from a Foucauldian perspective on power relations as they operate in relation to therapeutic practice/action and Lacan's ethics of responsibility. Finally, the results of all previous stages were presented and discussed. The findings suggested that countertransference has a significant influence on trainee's personal and professional identity with trainees in their stories talking about their lack of awareness of countertransference and their often feeling powerless or angry and frustrated with clients. It was recommended that more reflective training may help trainee's navigate the difficulties in their experience and management of countertransference.

This research explores how the largely taken-for-granted concept of Personal & Professional Development (PPD) is constructed within the Counselling Psychology profession and asks what the effects of this might be for therapeutic training and practice. A discourse analytic approach inspired by Foucauldian theory was used to examine seven trainee Counselling Psychologist's talk of PPD, paying particular attention to the ways in which power might be reflected in the text. The analysis suggested that PPD discourse can result in a number of more disempowering positions for trainees and therapeutic clients, demonstrating how power struggles can be concealed by therapeutic discourse. It is argued that the prevailing constructions of PPD, as demonstrated within the research interviews, serve two key functions, most notably by legitimising institutionalised training practices as necessary to ensure the competence and ethical integrity of future therapists, whilst also increasing the credibility of therapeutic practitioners more broadly. This thesis therefore contends that practitioners and training institutions might become more sceptical of dominant PPD discourses, including the practices which are legitimised as a result. As such, Counselling Psychologists are invited to raise their awareness of the cultural, social and historical contexts which inform our understanding of 'the therapeutic self' and its 'development' more broadly, as well as remaining mindful of imbalances of power to ensure PPD practices seek to empower rather than control.