VictorJuiz/thesis huggingface dataset:
Mechanisms of genome regulation in human islets and their role in the pathogenesis of type 2 diabetes

Genome-wide association studies (GWAS) have made substantial progress in implicating genomic regions in type 2 diabetes (T2D) susceptibility. Whilst attributing causal mechanisms to loci has proved non trivial, these studies have provided insights into the genetic architecture underlying the disease. GWAS findings indicate a causal role for gene regulatory processes, and suggest that pancreatic beta-cells play a pivotal role in mediating common T2D association. Work presented in this thesis therefore sought to generate novel regulatory annotations from human islets, and to assess whether T2D-associated loci can be accurately fine-mapped using statistical approaches, with the aim of improving understanding of causal mechanisms underlying these associations through integration of the two approaches.
Using small RNA sequencing in human islets and enriched beta-cell populations (both n=3) and mRNA sequencing in a large number of human islets (n=130), I increased the number of available human islet annotations. These studies identified high or islet-specific expression in many micro RNAs (miRNAs) without previously known roles in human islets. It also provided the largest study of quantitative trait loci (eQTLs) and allele-specific expression (ASE) in human islets to date, identifying significant eQTLs for 1,636 genes and significant ASE at 8,754 genes. There was enrichment of active islet chromatin, compared to other tissues, at the best eQTL variant for each gene, but also substantial sharing of significant eQTLs between islets and other tissues.
Simulations were used to assess the utility of fine-mapping approaches for refining common disease-associated loci to smaller intervals or sets of variants likely to include the causal variant. The results demonstrated that fine-mapping can indeed refine these loci to sets or intervals of a size more amenable to functional follow-up or focussed intersection with high quality annotations. Furthermore, using an approximated Bayesian approach, I was able to refine twenty-one of the known common T2D-associated loci.
Finally, using the newly generated annotations, I demonstrated enrichment of T2D association signal for regulatory RNA annotations (islet lncRNAs and miRNA target gene sets). I also identified examples in which these types of annotation overlap common and rare variation suggestive of a role in T2D pathogenesis. Using further islet annotations, I also uncovered potential causal mechanisms at four of the twentyone fine-mapped common T2D loci.
These data therefore provide many novel islet regulatory annotations that can be intersected with T2D genetics, and provide a first example of how such an approach can lead to novel potential causal mechanisms underlying association loci.

Keywords: genetics &amp; genomics
type 2 diabetes
islet of langerhans
Advisor: McCarthy, M
Gloyn, A
Microwave studies of Van der Waals complexes

This thesis describes the commissioning and development of a pulsed supersonic nozzle, Fourier-transform microwave spectrometer and its application to the study of several weakly bound van der Waals complexes.
A pulsed supersonic expansion, Fourier-transform microwave spectrometer based on the Flygare design with a number of modifications has been constructed with an operating range of 6-18 GHz. A homodyne detection circuit mixing signals to modulus values between dc and 1 MHz is used, requiring two measurements to determine absolute transition frequencies. Transition frequencies are measured from the power spectrum by determining the first derivative zero crossing point in a least squares fitting procedure. Semiautomation of many of the spectrometer operations has been achieved allowing unattended data collection over scans of up to 300 MHz.
The microwave spectrum of Ar2-OCS and Ar2-OC34S has been observed and analysed using conventional Watson S reduction hamiltonian parameters. Effective structural parameters are derived and used in a harmonic force field analysis, based on the centrifugal distortion constants, to compare the trimer interations with a model based on the sum of dimer interactions.
A series of complexes containing the nitrogen molecule undergoing tunnelling motions have been studied. Hyperfine matrix elements for the first order nuclear quadrupole interaction are derived for the coupled identical nuclei case appropriate to the rapid tunnelling motions observed.
The microwave spectrum of N2-OCS is described. Tunnelling and nuclear spin statistical effects for two symmetry states are observed arising from the interchange of nitrogen nuclei. Rotational and quadrupole constants are derived; an accidental near degeneracy of two rotational levels allows the off-diagonal quadrupole coupling constant to be determined from second order effects. A tunnelling hamiltonian fitting the quadrupole coupling constants to an angular potential has been used to calculate the tunnelling frequency and barrier to N2 rotation.
The microwave spectrum of N2-O3 and a preliminary spectrum of N2-SO3 have been observed. Rotation-inversion motions of the O3 and SO2 moieties must be considered in addition to the N2 tunnelling to fit the spectrum. Tunnelling frequencies for the O3/SO2 and geared motions with the N2 are derived as well as structural parameters.
Modifications for production of refractory molecules and complexes by laser ablation have been made. A modified nozzle employing rods of material is used with the ablation process taking place in the nozzle throat. Modifications to obtain an expansion along the axis of the microwave cavity employ a hemispherical Fabry-Perot cavity configuration. The system has been tested on a number of diatomic molecules including PbS and CuCl.

Advisor: Howard, B
Confronting crisis 

The purpose of this thesis is theory development. It begins by evaluating existing explanations of why states undertake humanitarian intervention. Realists argue that states only intervene when their national interests are at stake. Normative scholars argue that states are at times motivated to save foreign citizens. Neither approach adequately accounts for the pattern of post-Cold War state practice. Building from this conclusion, the thesis conducts research based on two propositions derived from an analysis of existing debates: that examining state motive holds promise for elucidating the weaknesses in current approaches and that studying state argumentation can provide insight into state motives. To better investigate state motives, a theoretical framework is developed to explain how motives translate into state decision-making and manifest themselves in state argumentation.
By employing process tracing, argumentation analysis, and elite interviews, this framework is applied to three cases: Northern Iraq in 1991, Rwanda in 1994, and East Timor in 1999. Each case study constructs a theoretically informed narrative, assesses debates between states at the United Nations Security Council, and evaluates the consistency between state discourse and state practice. The cases are then used heuristically to identify opportunities for improving existing theory and developing new theory. This yields several conclusions. First, not only do states often possess mixed motives, but the humanitarian impulse also appears in some cases to have been a necessary condition for humanitarian intervention. Second, the norm of humanitarian intervention does not function as a general rule. Rather, it is a cluster of principles derived from just war theory and international law, but also connected to related norms about sovereignty, human rights, and self-determination. Third, state decision-making is a collective process structured by the prevailing post-Cold War institutional and normative context. The thesis concludes by outlining promising avenues of research for better understanding why states respond to some occurrences of mass atrocities and not others.

Keywords: argumentation
foreign policy
International Normative Theory
international relations
humanitarian intervention
International Relations Theory
Advisor: Welsh, J
The edifying and the polemical in Kierkegaard's religious writings

This thesis provides a theoretical framework that brings the unity of Kierkegaard’s ‘middle period’ into relief. I will analyse Kierkegaard’s writings between 1846 and 1852 when, I argue, the socially constructive dimension of his thought comes to prominence, involving two dialectical aspects of religiousness identified by Kierkegaard: the edifying and the polemical. How these two aspects come together and get worked out in the lives of individuals form the basis of what can be called a Kierkegaardian ‘social praxis’. I conclude that the tension between the edifying and the polemical can be coherently maintained in a communicative life that is also characteristic of a militant faith. This militant faith and life is presented as a critical guard against absolutisms, fundamentalisms, and intellectual aloofness; but the ‘militant’ individual is also utterly dependent, in need of edification and critique, and therefore chooses the risk of encountering others, seeking relationships out of a commitment to the development of persons and communities in co-operation. Therefore, not only does this dialectic provide readers with an important theoretical framework for understanding Kierkegaard’s ‘middle period’, but it is also a valuable resource for a constructive analysis of active social living suitable for theology in the twenty-first century.

Keywords: self and society
Kierkegaard
social theology
Advisor: Pattison, G
Protection of debtors on assignment under English and French law and the principles of European Contract Law

In an economy where the importance of receivables is continually increasing, the legalrules governing assignment can no longer be confined within national boundaries. Recently, several international texts with provisions on assignment have been adopted,including the Principles of European Contract Law (PECL) and their heir presumptive,the Draft Common Frame of Reference (DCFR). These texts can be seen as intending to facilitate assignment and therefore to favour indirectly assignees, whereas traditionally English and French law seek to ensure an effective protection of debtors, though in different ways and to different extents. As the Principles of European Contract Law or the Draft Common Frame of Reference may in the future have a direct impact on English and French private law, including the law of assignment, it is important to assess their impact on the protection of debtors as compared to these two existing national laws. Three levels of protection of debtors can be distinguished: the legal and contractual restrictions on assignment, the determination of the quantum of the right assigned and the determination of the person entitled to performance. This tripartite comparative analysis reveals several remarkable common points between English and French law, most notably in the area of the defences available to debtors on assignment. The PECL replicate these convergences and generally do not bring any major innovations on the protection of debtors. By setting clear and detailed rules for aspects of assignment still unsettled in national laws, the PECL contribute to the increase of legal security and indirectly improve the debtors’ situation. However, the inherent limited scope of international academic texts and the complexity of assignment prevent the PECL from having an even more considerable impact on the progress of the protection of debtors in English and French law.
Topics in price cap regulation

This thesis examines the theoretical properties of different price cap schemes that have been applied in the UK and the USA. The objective is to assess the consequences for price structures and welfare of different ways of defining the regulated price index. Chapter 2 surveys the literature on regulation under asymmetric information that is related to price caps. Chapter 3 presents a general analysis of five main types of price cap when the regulated firm sets linear tariffs. The schemes are the Tariff Basket (TB) scheme, the Fixed Weights (F) scheme, the Average Revenue (AR) scheme, the Average Revenue (Lagged) scheme, and the Paasche Price Index (PPI) scheme. The TB and PPI schemes generate efficient price structures in the long run, whereas prices are inefficient under the other schemes. In Chapter 4 the consequences of allowing freedom to set different prices, relative to the case of uniform prices, are analyzed. The conditions for price freedom to be desirable are derived for the case where the price level is not regulated. When the price level is regulated it is shown that AR regulation can cause welfare to be below the level that obtains without any regulation. Chapter 5 contains an analysis of the five price caps examined in Chapter 3 for the case where the firm sets a two-part tariff. The AR and PPI schemes are dominated, and the conditions under which TB, F and ARL are optimal are established. Chapter 6 explores some issues in the regulation of nonlinear tariffs by AR and TB price caps. Chapter 7 considers some extensions of the analysis. It is shown that when quality is a choice variable, the regulator is concerned about income distribution and there is demand growth the TB scheme can be adapted and retains its desirable properties. Chapter 8 contains conclusions and suggestions for future work.
Mathematical models of the retina in health and disease

The retina is the ocular tissue responsible for the detection of light. Its extensive demand for oxygen, coupled with a concomitant elevated supply, renders this tissue prone to both hypoxia and hyperoxia. In this thesis, we construct mathematical models of the retina, formulated as systems of reaction-diffusion equations, investigating its oxygen-related dynamics in healthy and diseased states.
In the healthy state, we model the oxygen distribution across the human retina, examining the efficacy of the protein neuroglobin in the prevention of hypoxia. It has been suggested that neuroglobin could prevent hypoxia, either by transporting oxygen from regions where it is rich to those where it is poor, or by storing oxygen during periods of diminished supply or increased uptake. Numerical solutions demonstrate that neuroglobin may be effective in preventing or alleviating hypoxia via oxygen transport, but that its capacity for oxygen storage is essentially negligible, whilst asymptotic analysis reveals that, contrary to the prevailing assumption, neuroglobin's oxygen affinity is near optimal for oxygen transport. A further asymptotic analysis justifies the common approximation of a piecewise constant oxygen uptake across the retina, placing existing models upon a stronger theoretical foundation.
In the diseased state, we explore the effect of hyperoxia upon the progression of the inherited retinal diseases, known collectively as retinitis pigmentosa. Both numerical solutions and asymptotic analyses show that this mechanism may replicate many of the patterns of retinal degeneration seen in vivo, but that others are inaccessible to it, demonstrating both the strengths and weaknesses of the oxygen toxicity hypothesis. It is shown that the wave speed of hyperoxic degeneration is negatively correlated with the local photoreceptor density, high density regions acting as a barrier to the spread of photoreceptor loss. The effects of capillary degeneration and treatment with antioxidants or trophic factors are also investigated, demonstrating that each has the potential to delay, halt or partially reverse photoreceptor loss.
In addition to answering questions that are not accessible to experimental investigation, these models generate a number of experimentally testable predictions, forming the first loop in what has the potential to be a fruitful experimental/modelling cycle.

Keywords: Retina
Eye
Hypoxia
Reaction-diffusion Equations
Photoreceptors
Ordinary Differential Equations
Hyperoxia
Asymptotic Analysis
Partial Differential Equations
Neuroglobin
Retinitis Pigmentosa
Advisor: Byrne, H
Gaffney, E
Novel adenovirus vaccine vectors

Replication defective adenoviruses have emerged as promising vectors for delivery of vaccine antigens. The development of new vaccine vectors has recently focused on serotypes to which the human population is less exposed in order to circumvent pre-existing anti vector immunity. This thesis describes the construction and optimisation of ChAdOX1, a new vector based on chimpanzee adenovirus Y25, which has recently been manufactured to clinical grade for a Phase I human trial.
Comparative immunogenicity studies between vectors of different serotype were performed in mice, with careful consideration of the infectious titer of vector preparations, since this parameter can confound studies based solely on viral particle estimation. After intramuscular administration, HAdV-5 (Human adenovirus C) based vectors elicited superior transgene product specific T cell and antibody responses compared to a selection of chimpanzee adenovirus vectors (from Human adenovirus E) including ChAdOX1.
The construction of ChAdOX1 in a bacterial artificial chromosome (BAC), enabled precise and flexible modification of the genome by recombination mediated genetic engineering (recombineering). Reverse genetics was performed to identify vector determinants of immunogenicity. Chimeric ChAdOX1 vectors were created by replacement of native virus associated RNA (VA-RNA) and fiber sequences with the corresponding sequences from HAdV-5. Using these chimeric vectors, the importance of innate immunity and vector transduction in determining vector immunogenicity was investigated. Though the mechanisms responsible ultimately remain unclear, superior transgene product specific immune responses with HAdV-5 correlated with higher levels of transgene expression in vivo after vector administration. The current study has conclusively demonstrated that neither VA-RNA sequences, nor the fiber protein, are responsible for differences in immunogenicity between vectors, contrary to hypotheses based on previous studies.

Keywords: vaccines
adenovirus
Viral vectors
Advisor: Hill, A
Gilbert, S
Spencer, A
Cottingham, M
New insights into Cenozoic Silicon cycling in the Southern Ocean: refined application of silicon isotope ratios in biogenic opal

The marine silicon and carbon cycles are intrinsically linked by a unique group of primary producers; the diatoms. These siliceous-walled phytoplankton play a significant role in carbon export, making them a critical component of the global biological carbon pump with the power to affect climatic change. In this thesis, the silicon isotope composition (δ30Si) preserved in diatom opal is used together with the δ30Si of sponge opal, a powerful new proxy for deepwater silicic acid concentration, to document the Cenozoic Silicon cycle, shedding light on its role in carbon cycling and global climatic change. This study has developed a novel size-separation methodology to produce the first core top calibration of diatom δ30Si. The calibration demonstrates that diatom δ30Si exhibits a strong negative correlation with surface water silicic acid concentration, supportive of its application as a proxy for silicic acid utilisation. The refined method is used to produce a diatom δ30Si record, for the first time combined with sponge δ30Si, to gain insight into the Southern Ocean silicon cycle over one of the largest Cenozoic climatic shifts; the onset of Antarctic glaciation (~33.7 Ma). The two δ30Si records yield the first geochemical footprint to demonstrate that diatom proliferation, coincident with the onset of Antarctic circumpolar current flow, was a precursor event to the Eocene-Oligocene Transition. Diatoms are shown to have played a role in climate cooling through enhanced export and burial of organic carbon on the seafloor. The first long term reconstruction of silicic acid concentration in subsurface waters of the Southern Ocean, which spans the Late Eocene to the earliest Pliocene, provides new evidence that oceanic vertical mixing rates, coupled with the efficient removal of silicon from the surface by the diatoms, have been the most important factor in controlling the silicon chemistry of the ocean over the Cenozoic.

Keywords: Eocene
Diatom
Silicon Isotope
Oligocene
Advisor: Rickaby, R
Halliday, A
Augustan accounts of the regal period

This thesis examines accounts of the regal period in Cicero's de republica, Varro, Dionysius of Halicarnassus and Livy, as well as references to the period in Propertius IV and Ovid's Fasti. Cicero, Varro and Dionysius all present idealized accounts of the period, responding to the aetiological traditions concerning it, and making Rome's founders represent ideal originators, in different ways depending on the nature of their interests. Cicero acknowledges the problems of idealizing history, pointing to the influence of historical context on views of history. Dionysius' historiographical theories are examined, revealing a coherent theory in the light of which Dionysius' idealization can be seen as an informed attempt at an historical reconstruction. Livy too gives the regal period an originative function, to display in microcosm many themes important in later history. His interest in the origin of Rome's problems prevents him from idealizing the period. Instead he demonstrates political and social development under the kings which leads to a republic where the tensions of Rome's later history can be foreseen. Elegy had traditionally rejected history, but in Propertius IV history is included, much of it regal. Propertius establishes a particular relationship between the regal period and the elegist which is continued in Ovid's Fasti. Both poets reinterpret history, applying the self-conscious skill which had hitherto rejected historical material, and subverting expectations of the relationship of past to present. Ovid also displays kinship to themes of the Augustan revival, celebrating the present as the culmination of the past. The main unifying feature of all accounts is the dominance of the author's view of the present in shaping his version of history, stemming from the importance of the regal period as the period of Rome's origins. In the conclusion, these writings are placed within their Augustan context.