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Characterisation of a novel hydroxylase complex and its role in replication fidelity
Get PDFProtein hydroxylation is an emerging and poorly characterised post-translational modification that is generally catalysed by enzymes called ‘2-oxoglutarate-dependent oxygenases’. JMJD5 is an ‘orphan’ hydroxylase, which has likely contributed to a relatively poor understanding of its cellular role. In this thesis we have attempted to further our understanding of JMJD5 by focusing on an activity-independent interaction between JMJD5 and the Regulator of Chromosome Condensation Domain containing protein 1 (RCCD1). We begin by identifying the specific amino acids in RCCD1 and the JMJD5 N-terminus required for this interaction. We subsequently show that RCCD1 knockdown causes replication stress and that this phenotype is epistatic with respect to JMJD5. Importantly, we demonstrate the importance of the JMJD5:RCCD1 interaction for DNA replication fidelity through reconstitution of the corresponding binding mutants into knockdown cells. We additionally demonstrate that JMJD5:RCCD1 form a stoichiometric 1:1 heterodimeric complex and develop a co-overexpression system for structural characterisation and interactome analysis. Through subsequent proteomic screens we identify a possible activity dependent interaction of the JMJD5:RCCD1 with the CX3 complex of RAD51 paralogs that prescribe the JMJD5:RCCD1 complex with a role in replication fork restart. Overall, our work identifies a novel heterodimeric complex with an important role in faithful DNA replication and genome stability. With genome instability being regarded as a key hallmark of cancer and both JMJD5/RCCD1 being implicated in cancer, our work is helping to understand a potential novel pathway that may contribute to tumorigenesis
Extended producer responsibility and its role in facilitating a circular economy in the European Union: an analysis of four directives
Get PDFMost economies are built on the linear 'take-make-use-throw' model of consumption, which has led to rising rates of production, consumption and waste. If not managed appropriately, high levels of waste represent both an environmental hazard and a loss of resources. Given this, the European Union (EU) has targeted the most ubiquitous and environmentally hazardous waste by Directives. Spanning waste batteries, vehicles, electrical and electronic equipment, and packaging, each of the Directives contain notions of Extended Producer Responsibility (EPR). This requires producers to maintain physical or financial responsibility over products throughout their life-cycle, although in practice, is often only implemented at a products end-of-life. In recent years however, impetus has been placed on the transition from a linear consumption model to one which is circular by design, termed the Circular Economy. This aims to prevent waste, keep products, components and materials at their highest utility value at all times and protect the environment. This study assesses whether existing EPR regulatory frameworks within the EU support circularity and found that the current regime does not do so
High data rate atom interferometric gravimetry for inertial navigation applications
Get PDFThis thesis details the development of a high-data rate absolute gravimeter targeting future applications in inertial navigation. The technology is underpinned by performing atom interferometry with stimulated Raman transitions with laser-cooled Rb. A key highlight of this work is validating a optical single sideband laser system based on fibre-Bragg grating filters which offers a promising pathway toward portable quantum sensing. Another highlight is validating a simple MOT dynamics model in the relatively unexplored high-data rate operation mode. Typically, the system operates with 30 Hz bandwidth by launching 1×10 atoms at 0.25 ms downwards at a temperature of 20 μK. Atom interferometry is performed with a T time of 2.5 ms giving a preliminary accuracy of 10 μg and a sensitivity of 20 \(\frac{μg}{\sqrt Hz}\
Local functions on blocks and automorphisms of partial groups
Get PDFIn the first chapter of this thesis we define a block-by-block version of Isaacs and Navarro’s chain local condition and then prove that the Alperin–McKay conjecture is equivalent to a certain function on groups having this property. We then go on to prove several other block-by-block versions of results from Isaacs and Navarro’s paper. The results in this chapter have also been published in [35].
The second part concerns automorphisms of partial groups, specifically which groups can arise as automorphisms of different types of partial group. We show that for any finite group one can construct a finite partial group that has this finite group as an automorphism group. We also prove an analogous result for groups and objective partial groups as well as a partial result for finite groups and finite objective partial groups. Lastly we show that there are no automorphism groups of localities that do not arise as automorphism groups of groups, a rephrasing of the same result for fusion systems.
This thesis is split into two entirely self-contained chapters
The development of an evidence base for assessing and managing the risk of terrorism in the UK
Get PDFThis thesis tracks my learning journey from a dedicated three-year project developing a professional risk assessment methodology for terrorist offenders in HMPPS, through advising Prevent, to academia where I have continued to contribute to a growing evidence base for understanding the psychology of terrorism. As a co-I for CREST, I compiled a Directory of extremism risk assessment frameworks and networked with subject matter experts in the USA, Canada and Australia. This led to invitations to contribute chapters to the second edition of the International Handbook for Threat Assessment, and to the NATO Science for Peace and Security Programme on Terrorism Risk Assessment Instruments. As an expert member of the European Radicalisation Awareness Network I contributed two papers on countering extremism, one advising on ethical practice for mental health practitioners and the other on the increasing challenge of detecting lone actor terrorists pre-crime. The as yet unpublished paper is informed largely by my work as an expert witness for those charged under counterterrorist legislation and completes my learning journey to date. It exposes a gap between legal and psychological approaches to assessing terrorist risk with the potential for miscarriages of justice where national security is prioritised over individual rights
‘Welcome to this countre, can you speke Italian’: encounters, books and practices for Italian language-learning in the Tudor period (1509–1558)
Get PDFThis thesis investigates Italian language-learning in the pre-Elizabethan Tudor period (1509–1558), despite the tendency in the literature to set the beginning of this phenomenon during Elizabeth I’s reign (1558–1603) with Thomas Hoby’s translation from Italian of The Courtier (1561) and the English-Italian manual First Fruits (1578) by the tutor John Florio. This project expands our knowledge of the history of the Italian and English languages, the history of language teaching, the history of linguistics, the history of education, Italian religious reformers and the English Reformation, and, more generally, Anglo–Italian cultural history.
The methodological challenge of this research concerns the scarcity of printed books specifically developed for English learners of Italian (with the exception of Principal Rules (1550) by William Thomas), curricula, manuals for language tutors, and lesson reports. Investigating English students of Italian and deducing their motivations allows me to propose and discuss a collection of personal and textual encounters that favoured learning practices in a multilingual and highly mobile Europe. Chapters in this thesis consider in their inquiry books printed in London, Venice, Rome, and Antwerp of different genres, such as treatises on spelling and pronunciation, a treatise on the Italian questione della lingua (Chapter II), a manuscript Tuscan grammar written in England (Chapter II), polyglot dictionaries (Chapter III), a polyglot religious text (Chapter IV), and an Italian vocabulary (Chapter V).
The results show that English students of the Italian language in the pre-Elizabethan Tudor period had various backgrounds, including women and non-aristocratic individuals. In the absence of formal curricula, individuals relied on self-study and peer-learning that was functional to their professional, social, and private aspirations. Language tutors were both Italians and non-Italians, and sometimes unofficially appointed for this role. Learning practices stemmed from comparative and contrastive approaches coherent with the presence of a prevalent multilingualism in Europe and from the necessity of using the language for effective communication
A prospective study of the effects of renal transplantation on uraemic cardiomyopathy using cardiac magnetic resonance imaging: the RETRACT study
Get PDFBackground: There is an inverse graded relationship between cardiovascular risk and renal function, with the greatest risk observed in those with end-stage kidney disease. This relationship is attributed to the development of uraemic cardiomyopathy which is characterised by the development of myocardial fibrosis, left ventricular hypertrophy and both diastolic and systolic dysfunction. Following renal transplantation this risk reduces dramatically a finding which is often attributed to positive cardiovascular remodelling. At present, however, this has not been demonstrated in a prospective adequately powered study employing cardiac magnetic resonance imaging.
Objectives: To establish if the features of uraemic cardiomyopathy are reversible following renal transplantation.
Participants: 50 renal transplant recipients recruited from local transplant waiting list. 20 transplant-listed control participants with end stage kidney disease not scheduled for live donor transplantation.
Methods: Participants had demographic and CMR parameters recorded at baseline and follow-up at 12- 24 months. Renal transplant recipients were studied within a one-month period prior to transplantation. Measures of left ventricular mass, volume, systolic and diastolic function, myocardial fibrosis and biochemical parameters were all recorded both before and after transplantation.
Results: There were significant reductions in LVM observed in transplant recipients compared to control patients (between group mean difference -18.76g 95%CI [-30.46 - -7.05] P=0.002). There was also a significant reduction in LVMI in the transplant group compared to controls (between group mean difference -11.37g/m2 95%CI [-18.49 - -4.25] P=0.002). There were no significant differences observed in measures of either systolic or diastolic function. In terms of native T1 mapping times, there were significant reductions observed in transplant recipients compared to controls, in the global average of all segments in the mid ventricular slice (between group difference -34.37ms 95%CI [-61.01 - -7.74] P=0.01. There were no significant changes in T2 times between groups. Analysis of biochemical parameters indicated significant differences in multiple parameters including haemoglobin (18.39 g/l 95%CI[7.12- 29.66]P<0.001), NTproBNP (x0.10[0.05-0.22]P<0.001), and marker of chronic kidney disease – mineral bone disorder; parathyroid hormone (x0.40 95%CI[0.17 – 0.93]p+0.035, phosphate (-0.28 mmol/L [-0.41 - -0.16]P<0.001) and Vitamin D (31.54 nmol/L 95%CI(16.03 -47.05)P<0.001).
Conclusion: The RETRACT study has shown that the features of uraemic cardiomyopathy are reversible following renal transplantation. This works adds to the current understanding of uraemic cardiomyopathy and provides a rationale for the development of targeted therapies aimed at reversing cardiovascular remodelling in those in whom transplantation is not a treatment option
Electrophysiological differences in atria and ventricles
Get PDFAtrial fibrillation (AF) is the most common arrhythmia, affecting over 1% of the population. Sodium channel blockers are commonly used to treat AF by restoring sinus rhythm. Current anti-arrhythmic drugs such as flecainide, do not specifically target atrial sodium channels, and information on electrophysiological differences between atria and ventricles is limited. Furthermore, flecainide is contraindicated in ischaemic heart disease (IHD) patients due to increased mortality. The mechanisms are unknown, necessitating further study. Understanding electrical differences and drug sensitivities is vital for effective treatment and improved patient outcomes.
The project aimed to characterise electrophysiological properties in left atria (LA) and left ventricles (LV), distinguish the differential effects of flecainide, in LA and LV, and investigate interaction of flecainide and ischaemia. Electrical activity from ex vivo hearts were measured using optical mapping from healthy wildtype (WT) mice aged 10 to 15 weeks. Global ischaemia was triggered using low perfusion pressure method, and regional ischaemia was triggered by ligating left anterior descending artery (LAD) ex vivo.
Our data showed a significantly slower conduction and shorter action potential duration (APD) in the LA compared to LV. Flecainide showed inhibition of the sodium current and slowed conduction to a greater degree in the LA compared to LV. CV was further slowed in ischaemic hearts in the presence of flecainide. Ischaemia prolonged the APD when compared to baseline APD. Further investigation of molecular drivers of the atrial and ventricular resting membrane potential (RMP) and the molecular interaction partners of flecainide may help to identify new targets for early rhythm control therapy in patients with AF
Ethnomusicological research on intangible cultural heritage preservation in Oman
Get PDFCultural heritage (CH) is considered a precious gift of humankind that nations and communities strive to safeguard for future generations. A recent turn in CH perception from tangible objects and property to the intangible cultural artifacts and knowledge has caused the need to develop new tools for adequate capturing, evaluation and preservation of such CH elements. One of the most efficient and commonly used methods of ICH safeguarding used worldwide, and in Oman in particular, is archivisation. However, musical ICH is one of the most ephemeral and subjective living forms of human culture that escapes precise capturing without the consideration of context of its production; the process is also incomplete without participation of the bearers of living tradition. How a government arranges ICH archiving efforts often determines the inclusivity, fairness and comprehensiveness of ICH safeguarding measures. Therefore, this ethnomusicological study focuses on the archivisation efforts in Oman – a country with a rich, diverse and turbulent geopolitical past and vibrant cultural heritage unifying many intertwining and overlapping traditions.
My broad ethnomusicological inquiry touches upon the current state of musical ICH safeguarding through archivisation in the state of Oman, as seen from the competing perspectives of institutional and grassroots archivists, as well as the Omani community members and musicians who operate as living tradition’s bearers and promoters. The most significant player is the government, which sets the ICH safeguarding agenda, allocates budgets to organisations concerned with archiving and determines the archive-worthy elements of the country’s musical heritage. My primary area of interest was how governmental officials envision the process of ICH safeguarding, what measures they put in place to conduct ICH safeguarding activities and what ICH elements they cover in their efforts. The research also examined how these initiatives align with or are complemented by grassroots activists’ efforts to create a comprehensive, representative complex of musical archives.
Another significant and presently understudied force contributing to ICH archiving and fair representation of all cultures living in Oman are grassroots archivists. These are amateurs and enthusiasts who select heritage to archive in their immediate surroundings, travel to musical festivals or compile social media archives and collections. My study uncovered a unique complementary dimension that grassroots archivists add to the process of Omani musical ICH archivisation along with the centralised and well-funded governmental initiatives. The findings suggest that the Omani work on musical heritage collection, archivisation and promotion to national and international audiences is well-established, consistent and organised, with many notable gains in this area that showcase unique Omani legacy and contribute to modern Omani identity and nation-building efforts. At the same time, grassroots archivists fill the gaps in outreach and bottom-up perspective on musical ICH evaluation that limit governmental initiatives. This way, grassroots and governmental musical ICH archiving processes work in tandem to create a strong musical legacy of old musical traditions, revived and rethought by the modern generations, conserved for successive generations and archived for international tourists and broader intercultural exchanges.
The central part of my research examined the process of ICH archiving and the challenges that numerous participants encounter. The interviewed archivists revealed numerous bottlenecks in the ICH archivisation process, from technical equipment to access to rural communities with unique musical traditions. A separate concern was the problem of music decontextualization during archiving and the potential issue of old records’ vulnerability. My interviewees also repeatedly noted the modernisation and globalisation pressures that pose additional threats to traditional music.
My findings point to the complex landscape of musical ICH determination and its varied roles for different actors. The meanings associated with traditional Omani music are diverse, ranging from instrumental ones of an economic asset and a tourist attraction to living experience-embedded, part of the Omani identity and family ties
Tayloring a postsecular theology?: postsecular interpretations of Charles Taylor
Get PDFThis thesis constructively interprets the work of Charles Taylor and appraises how it offers resources for addressing the problematic secular assumptions of a double dualism between both the sacred/religious and the secular as well as between transcendence and immanence. It addresses the first dualism by contextualizing the sociological contributions of Charles Taylor into postsecular discourses by constructing a postsecular critique of the secular. It addresses the second dualism by utilizing Taylor’s philosophical contributions as a catalyst for constructing a postsecular incarnational theology of presence. It constructs both a postsecular critique of the secular and a postsecular incarnational theology of presence to provoke new ways of understanding what it means to retrieve transcendence as a viable option of believing and being human in the cross-pressures of a secular, immanent frame
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