VictorJuiz/thesis huggingface dataset:
Regulation of E2F1 by PAD4 mediated citrullination

Peptidyl arginine deiminase (PAD) 4 is a nuclear enzyme that converts arginine residues to citrulline. PAD4 activity has been implicated in inflammatory disease and cancer, although its mechanism of action, particularly the identity of functionally relevant targets, remains unclear. Moreover, there are no known reader domains specifically recognising citrulline modifications. E2F transcription factors play a central role in regulating gene expression during cellular proliferation but in addition participate in diverse biological processes. Furthermore, it is known that arginine methylation provides an important level of control in dictating the biological consequence of E2F1 activity. Here, we show that E2F1 is citrullinated by PAD4 on functionally important arginine residues. Citrullination of E2F1 assists its chromatin association, specifically to cytokine genes in granulocyte cells, and regulates binding of the bromodomain reader BRD4 to an acetylated domain inE2F1. Accordingly, the combined inhibition of PAD4 and BRD4 impedes the chromatin association of E2F1 and the activation of cytokine gene expression. When administered as a combination therapy in the murine collagen-induced arthritis model, small molecule inhibitors of PAD4 and BRD4 provide an effective approach for preventing collagen-induced arthritis. Our results shed light on a new E2F-dependent pathway that mediates the inflammatory effect of PAD4 and, for the first time, establish the interplay between citrullination and acetylation as a regulatory interface for driving inflammatory gene expression. Moreover, the results highlight a novel therapeutic approach for treating chronic inflammatory diseases.

Advisor: La Thangue, N
Pinchbeck regulars? The role and organisation of the Territorial Army, 1919-1940.

This thesis examines how Britain’s government and military establishment conceptualised the role of the voluntary Territorial Army (TA) between the World Wars, and explores the relationship with British defence policy during the period. It also evaluates whether or not the TA was capable of carrying out its ascribed role, through a balanced assessment of its organisation, training and military efficiency. It posits that the TA was integral to British defence planning and played a key part in the Army’s mobilisation plans, although the priority given to its role shifted throughout the period in accordance with the direction of Britain’s strategic focus. Additionally, this thesis will emphasise that the Territorial Army had not one purpose but several. Alongside its central function as the framework for a conscript National Army it held key responsibilities for both home and imperial defence.
This thesis examines the TA’s role and organisation in a thematic and broadly chronological manner. Part I deals with the TA’s expeditionary role and its function as the framework for all future military expansion, as well as its role as a voluntary imperial reserve for any medium scale wars conducted without resorting to conscription. Part II focuses on the Territorial Army’s home defence responsibilities, in particular its domestic role in aiding the civil power and its contribution to Britain’s increasingly important air defence capabilities.

Keywords: Territorial Army
Reserve Forces
Defence Policy
1919-1940
Interwar
Advisor: Johnson, R
The emergence of interbank exposure networks: an empirical analysis and game theoretical models

This thesis studies the emergence of financial exposures between banks and introduces a novel game of financial network formation. It shows empirically that governance structures influence how banks use the interbank market to manage liquidity and that strategic factors are additional drivers of interbank lending for private banks (Ch. 2). It further develops a model of optimal bank behaviour in the absence of liquidity shocks considering the effect of an exogenous bailout probability (Ch. 3), and introduces a model of endogenous liquidity co-insurance formation (Ch. 4).
The first chapter, The Purpose of Interbank Markets, tests competing theories of interbank lending using 43 quarters (2002-2012) of confidential data on the German banking sector and interbank market. It shows that banks use the interbank market for liquidity co-insurance as traditionally assumed. However, the importance of the liquidity management function is higher for regionally-focused credit cooperatives and savings banks than for private commercial banks. A distinct effect for private banks is identified; for private banks, increases in interbank liabilities are shown to correlate with a proxy for the bailout probability of banks. The chapter thus offers empirical support for an emerging literature on strategic behaviour in interbank markets and highlights the need to extend the traditional model of liquidity co-insurance.
The second chapter, The Emergence of Interbank Exposures, develops a model showing that, even in the hypothetical absence of liquidity shocks, under some conditions the presence of conditional liability guarantees can lead to interbank exposures as an equilibrium outcome. It shows that such an equilibrium is characterised by banks of different sizes and asymmetric bank behaviour. Some banks are active only as lenders with others investing in a productive technology while borrowing in the interbank market. An equilibrium interbank rate is derived which depends on parameters characterising the bailout probability, including different parameters of government behaviour.
The third chapter, Coordination and Competition in the Formation of Financial Networks, introduces a generalisation and extension of the seminal work of Allen and Gale (2000). It studies liquidity co-insurance between deposit-taking banks in an n-region economy. Both a static and a dynamic model of the endogenous formation of interbank liquidity co-insurance links are examined. Using a novel approach to model liquidity co-insurance, it is shown that contrary to previous findings it is not possible for banks with limited information to insure optimally against liquidity shocks. However, in a dynamic formulation of the model with best-response dynamics and learning, socially optimal insurance is an evolutionary stable equilibrium. The chapter also studies an extension to the model that introduces non-zero bailout probabilities, which endogenously leads to interbank networks consistent with the structure of interbank exposure networks documented empirically.

Advisor: Reed-Tsochas, F
Young, H
Genetic and molecular technologies to optimise novel vaccines for Hepatitis C virus infection

Analysis of the immune response during spontaneous clearance and protection upon reinfection with hepatitis C (HCV) has highlighted the importance of T-cells in the control of HCV infection. An effective T-cell vaccine for HCV would have a significant effective on the global burden of disease associated with HCV. No clear immune correlates of protection exists for HCV and we lack immunological competent animal models in which to assess candidate HCV vaccines. I have performed in-depth characterisation of the T-cell response to candidate virally vectored HCV vaccines with regard to the T-cell parameters most likely to impact on their efficacy in a prophylactic and therapeutic setting.
I describe here a heterologous prime/boost vaccine regimen of a simian adenoviral vector (ChAd3), boosted with a modified vaccinia Ankara (MVA) encoding the non-structural (NS) proteins of HCV. This regimen elicits an unprecedented magnitude of HCV-specific CD8+ and CD4+ T-cells; which are broadly targeted, durable, and highly functional. ChAd3-NS/MVA-NS vaccination induces a population of persistent effector memory CD8+ T-cells (Tem) similar in phenotype to those induced by infection with CMV. I show that in these diverse settings the functional and phenotypic characteristics of the CD8+ T-cells are highly conserved and are controlled at the level of gene expression. Vaccination of HCV+ patients induced T-cell response that were significantly lower in magnitude, and viral sequencing at key epitopes demonstrates that the T-cells induced by vaccination show weak cross-recognition of the patients circulating virus.
While working with an industrial collaborator, I have developed our understanding of the mechanism of action of the enhancer element, MHC class II invariant chain. I show that tethering antigen to Ii within virally vectored vaccines targets it for rapid degradation by the proteasome, enhancing its presentation on MHC class I molecules and the concomitant CD8+ T-cell response to vaccination.
The work described here is relevant to T-cell vaccine development, in particular for Ad and MVA constructs, and to our understanding of antigen processing and heterogeneity within the CD8+ T-cell compartment.

Keywords: Immunology
T-cells
Vaccines
Hepatitis C
Adenovirus
Antigen presentation
modified vaccinia Ankara
Advisor: Barnes, E
Klenerman, P
Folgori, A
Epigenetic regulation of chronological and replicative longevity in Saccharomyces cerevisiae

Ageing and senescence remain among the most intriguing questions in biology. Saccharomyces cerevisiae has become well established as a fertile model system for the investigation of ageing. Remarkable conservation has been found to exist between interventions extending lifespan in higher animals and yeast – genetic, chemical, and nutritional – suggesting a network of common regulatory pathways controlling large-scale shifts in gene expression involved in senescence. While it has been proposed that epigenetic regulation controls these shifts, evidence remains incomplete. To address this question, novel longevity mutants were isolated in S. cerevisiae using a purpose-designed high-precision screen based on ageing culture outgrowth. A novel long-lived mutant in uncharacterised gene YDR026C was discovered and found to participate in a pathway distinct from TOR signalling, but share epistasis with the histone deacetylase SIR2Δ, a well established regulator of replicative longevity and rDNA maintenance. Through equilibrium density centrifugal separation of culture subpopulations, SIR2Δ and Ydr026cΔ cultures were found to demonstrate reduced and improved maintenance of post-diauxic quiescence respectively, previously shown to underlie chronological survival in strains including snf1Δ. Development of a quantified TUNEL-based assay for genome fragmentation indicated early apoptotic-like behaviour in the SIR2Δ strain. Microdissection experiments and sectored-colony assays of strains containing an rDNA-embedded ADE2 reporter determined that Ydr026cΔ cells also exhibit extended replicative lifespan, and reduced recombination at the rDNA spacer region hotspot, abrogated in SIR2Δ strains. SIR2Δ is well established to repress RNA polymerase II-derived transcripts in the rDNA spacer region, including IGS1-R. Northern analysis determined Ydr026c also silences transcription in the spacer, possibly through preventing termination of the main rRNA transcript, interfering with IGS1-R expression. By transformation with a vector overexpressing IGS1-R, partial reconstitution of the SIR2Δ phenotype was observed, including rDNA hyperrecombination, shortened replicative longevity, and higher-order chromatin structure restoration. These data suggests a model whereby non-coding rDNA spacer transcripts epigenetically determine rDNA maintenance through recombination, leading to physiological phenotypes of replicative and chronological ageing.

Keywords: non-coding RNA
Replicative longevity
Saccharomyces cerevisiae
rDNA
Chronological longevity
Advisor: Mellor, E
Investigating the in vivo functions of non-coding RNAs in Drosophila melanogaster

The number of annotated non-protein coding genes has increased dramatically in recent years, but the functions of very few are well understood. In this thesis, I study the functions of two classes of non-coding RNA in Drosophila melanogaster. Firstly, through characterisation of six putative long non-coding RNA loci containing transposon insertions, I identified a long non-coding RNA, lnc703, suitable for in depth characterisation. Using a GAL4/UAS fluorescent reporter I found lnc703 to be expressed in the larval fat body and confirmed this using qRT-PCR. Transcriptome profiling identified ribosomal genes as upregulated in two independent lnc703 mutant strains. Additionally, I have identified decreased lifespan in some lnc703gal4 strains and it will be interesting to determine whether there is a relationship between increased ribosomal protein gene expression and reduced lifespan. I also used transcriptome profiling of the musculature and CNS of miR-8 null larvae to determine tissue specific targets of miR-8. Many indirect effects of miR-8 were detected but using MRE prediction algorithms a number of potentially direct targets of miR-8 were identified. One of these, ilp5, which is upregulated in the CNS, was identified as a non-cell autonomous effect of loss of miR-8 in the fat body. Together this work highlights the importance of using multiple, complementary techniques to study the function of non-coding RNAs in vivo.

Keywords: long non-coding RNA
Drosophila
Advisor: Ponting, C
Liu, J
The Late Anglo-Saxon Royal Agent

This thesis examines the identities and functions of late Anglo-Saxon royal agents (c. 950-1066), focusing on bishops and ealdormen. To establish who royal agents were, the thesis explores the family relationships among the leading men in the ecclesiastical and secular spheres, especially those linking men administering ealdordoms to the senior clergy. It also examines the offices of royal agents in late Anglo-Saxon England and argues that the duties of ecclesiastical and secular officials were not fundamentally different.
While traceable kin networks appear among senior clerics and among high secular officials, few familial links connect the senior clergy to ealdormen. Thus, this thesis divides these kin-groups into those who gained secular offices, ‘lay families’, and those who sought power through the ecclesiastical positions, ‘church families’. The analysis of the strategies adopted by ‘lay families’ and ‘church families’ to secure and maintain political power indicates how the aristocracy served both the king and their own ambitions in the governance of late Anglo-Saxon England. Although these royal agents came from different family groups, their obligations as royal agents appear remarkably similar with the exception of their military functions. This information provides a better understanding of the pool of men from whom English kings generally chose their officials, how rulers may have kept this group from becoming too small, and what was expected of these royal agents.
The lack of (recorded) nepotism across episcopal and secular lines provides a more nuanced understanding of the aristocracy in Anglo-Saxon England. Furthermore, by offering an examination of both the identities and the functions of royal agents, this thesis provides a better understanding of the late Anglo-Saxon kingdom and its administration. In addition it creates a clearer picture of the aristocracy, the king, and the Church as well as the relationships between all three.

Advisor: Foot, S
Diplomacy and foreign policy in the personal reign of Constantine VII Porphyrogennetos (945-959)

This thesis examines Byzantine diplomacy and foreign policy in the round in the personal reign of Constantine VII Porphyrogennetos (945-959). This particular period has been singled out for investigation because Constantine had a keen personal interest in foreign affairs and two treatises from his reign, the De administrando imperio and the De cerimoniis aulae byzantinae, shed light upon the Byzantine view of the outside world and the workings of imperial bureaux charged with diplomatic affairs and the administration of military campaigns. After introducing the subject and the key sources, the thesis makes a clockwise circuit of all of the theatres in which Byzantine foreign policy was active. The first chapter looks at worldviews as documented in sources from Byzantium, Ottonian Saxony, and the Islamic Near East in order to determine how these key players saw their place in the world and systematised their relationships with each other. The second chapter discusses relations with the Islamic Near East and Transcaucasia and provides a survey of sources, historical reconstruction, and analysis of goals and processes. Chapter three examines relations with the Islamic caliphates of the central and western Mediterranean, and assigns them greater importance than generally acknowledged. Chapter four chronicles the nascent relations with Ottonian Saxony and Byzantium’s re-engagement with the Transalpine Franks. Chapter five deals with the peoples of the Eurasian steppe and homes in on Byzantium’s attempts to diffuse threats from this volatile world. Chapter six focuses on Italy as the region in which three strands of Byzantine foreign policy met and evaluates the empire’s response to wholesale changes in power relations in the peninsula in the early years of Constantine’s personal reign. The conclusion to the thesis interrogates whether Constantine’s foreign policy kept the empire safe, enhanced its prestige, managed the military elites, and had an enduring legacy.

Advisor: Howard-Johnston, J
Rural change in north Wales during the period of the industrial revolution: Livelihoods, poverty and welfare in Nantconwy, 1750-1860.

This thesis explores how a typical area of rural Wales participated in and was shaped by social and economic change during the period of the Industrial Revolution. It investigates how increasing numbers of people made a livelihood in the Caernarvonshire hundred of Nantconwy over the period 1750-1860, including the role of women in the local economy. A wide range of record types are used to explore inter-relationships between population growth, agriculture, proto-industry, the organisation of farming households, and the livelihoods of the poor. The thesis covers a key gap in the historical literature, as most studies of agrarian change at this period concentrate on England, and there has been little investigation of the experience in rural Wales.
Unlike many parts of England where economic modernization was accompanied by growing inequality involving a transition from a household economy to a capitalist tripartite society of landowners, tenant farmers and landless wage labourers, Nantconwy experienced a growth of subsistence smallholding, as more people faced with a shortage of waged employment sought to make a livelihood from the land. Family by-employment and proto-industry also played a crucial role in the local economy. Bringing the commons and wastes into private ownership had relatively little impact on the poor, but smallholders’ livelihoods were adversely affected after 1815 by the mechanization of spinning and declining earnings from stocking knitting. Living standards began to improve after 1830 with the expansion of male employment in slate quarrying, while the role of women on family farms was enhanced. Parishes evolved a low-cost system of poor relief which supported mainly older residents who were no longer able to quite make ends meet from the traditional cottager economy, while encouraging the young to leave the land or migrate to local towns or quarrying areas with better employment prospects.

Keywords: livelihoods
Caernarfonshire
common land
charity
women farmers
Wales
farming
poor relief
poverty
proto-industry
demography
by-employment
Advisor: Tiller, K
Second order proximal methods applied to elastic net penalised vector generalised linear models

The Vector Generalised Linear Model (VGLM) framework extends Generalised Linear Models (GLMs) to a large number of univariate and multivariate statistical models. The object of this thesis is to study the estimation of the maximum elastic net penalised log-likelihood of VGLM models. As the elastic net penalty has a separable non-differentiable part, second-order proximal methods are considered. For VGLMs, depending on the model, it may be more convenient to use the Fisher information matrix instead of the Hessian. Hence, we propose a proximal Fisher scoring method. Two examples are then investigated. The first example is an application of an elastic net penalised ordinal probit model to the prediction of mid-market price changes for tick-by-tick Limit Order Book data. The second example is an application of an Expectation Maximisation (EM) proximal Newton/Fisher scoring algorithm to variable selection for a bivariate Poisson regression model applied to health care data.

Advisor: Doucet, A
Development of in-vitro models to study effects of compounds that modulate cellular functions in patients with mitochondrial disease

Background: Adverse drug reactions caused by off-target activity can limit the use or withdrawal of otherwise effective drugs. Mitochondria have been recognised as potential target for inadvertent drug activity thus causing toxicity. It is difficult to detect drug induced mitochondrial toxicity in pre-clinical animal models and in human trials. Drug trials are carried out in healthy humans and it is not until a large population has been exposed to the drug that adverse reactions leading to mitochondrial toxicity come to light. The development of pre-clinical in vitro assays to detect drug induced mitochondrial toxicity can help reduce adverse drug reactions and drug development costs. In this project, we used different in vitro cell models (with or without mitochondrial disease) to study the effect of the anticonvulsant drug, sodium valproate (VPA) on cellular functions such as mitochondrial respiration, under both normal conditions (glucose) and energetic stress (galactose). To investigate changes to the morphology of the mitochondrial network, we developed a novel high-throughput imaging method.
Results: The results presented in this thesis indicate that sodium valproate treatment did not have the same effect on cellular activity and mitochondrial network morphology in all the in vitro models used. VPA treatment inhibited mitochondrial respiration in the cell model without mitochondrial disease. However, in the models harbouring mitochondrial disease the effect was variable. Treatment under normal and energetic stress condition caused increased cell death and a reduction in cell number in all the cell models. We also evaluated a novel high-throughput imaging method and found that VPA treatment affects mitochondrial network morphology with fragmentation observed in two of cell models. It was found that not all cell models are suitable for this type of high-throughput imaging.
Conclusion: Our results suggest that the effect of VPA under normal and energetic stress condition varies according to the cell model used. The induction of energetic stress by galactose is possibly too acute for certain cell models leading to complications in data interpretation. Depending upon the model used, reducing the glucose concentration could potentially be sufficient to detect drug induced mitochondrial toxicity.

Advisor: Morten, K
Poulton, J