VictorJuiz/thesis huggingface dataset:
Genome-wide association of statin-induced myopathy

Lowering LDL-cholesterol with statin therapy produces substantial reductions in cardiovascular events, and larger cholesterol reductions may produce larger benefits. Rarely, myopathy occurs with statins, especially at higher doses and in combination with certain medications. Similarly strong associations might exist between myopathy with high-dose statin regimens and genetic variants, especially those affecting blood statin levels. This study aimed to find genetic variants associated with statin-induced myopathy.
A feasibility study was completed to assess whether plausible effect sizes of 5 to10-fold higher risks per genetic variants could be detected among 50-100 cases with statin-induced myopathy and to consider the best study design. A genome-wide association study was then carried out using approximately 300,000 genetic markers (and additional fine-mapping) in 85 people with definite or incipient myopathy and 90 controls, who were all taking 80mg simvastatin daily in a 12,000 participant trial of 80mg vs 20mg simvastatin daily. The cases were also compared to 2,300 additional controls who had not been exposed to intensive-dose statin therapy. Replication of the myopathy result and lipid-lowering associations were tested in a 20,000 participant trial of 40mg simvastatin daily versus placebo.
The genome-wide scan yielded a single strong association (p = 4x10-9) of myopathy with the rs4363657 single nucleotide polymorphism (SNP) located within the SLCO1B1 gene on chromosome 12. This non-coding SNP was in nearly complete linkage disequilibrium (r2=0.97) with the non-synonymous rs4149056 SNP. The population prevalence of the rs4149056 C allele was 15%, and the odds ratio for myopathy was 4.5 (95% confidence interval 2.6 to 7.7) for each copy of the C allele and 16.9 (4.7 to 61.1) for CC vs TT homozygotes. Over 60% of these myopathy cases could be attributed to the C variant.
The SLCO1B1 gene encodes the organic anion transport polypeptide OATP1B1, which has been shown to regulate hepatic uptake of statins. In literature reports, rs4149056 reduced statin transport and was associated with 37% (31% to 44%) higher systemic statin acid levels per C allele. The association of rs4149056 with myopathy was replicated in the trial of 40mg simvastatin daily, which also showed that it was associated with the cholesterol-lowering effects of simvastatin. No SNPs in any other region were clearly associated with myopathy (although comparison of the myopathy cases with the 2,300 controls identified a region of chromosome 1p12 that warrants further study).
This study identified common variants in SLCO1B1 that influence the risks of statin-induced myopathy substantially. Genotyping these variants may be useful for tailoring both the statin dose and safety monitoring. More generally, such studies of the genetic determinants of serious adverse reactions with other drug classes may help to improve the balance between treatment efficacy and safety.

Keywords: rhabdomyolysis
statin
myopathy
genome-wide association study
candidate gene study
Advisor: Parish, S
Rory, C
Electricity distribution in Italy

This thesis analyses technical efficiency of local electricity distribution in Italy (1994, 1996) by using both econometric (deterministic frontier, stochastic frontier) and linear programming (Data Envelopment Analysis) tools. Cross-sectional data was examined with respect to
(a) ENEL - the Italian electricity monopolist whose restructuring and privatisation is now under way - and its local distribution branches (Chapters 2, 3, and 5); (b) municipal authorities (MUNIs), i.e. town-based electric utilities which sometimes hold franchises for electricity distribution within city limits (Chapters 4 and 5).
Estimation results from Chapters 2 and 3 highlighted non-exhaustion of scale economies at sample-mean values. Scope economies between medium and low-voltage distribution were also detected (Ch. 2). Efficiency score series stemming from both econometric and linear programming techniques in Chapters 3 and 5 showed that Southern distributors were relatively under-represented among top units even after allowing for several exogenous environmental variables. The external effects which proved to influence technical efficiency in electricity distribution were consumer density, the percentage of industrial customers, the geographical nature of areas served (metropolitan areas, mountains, etc.), and the interaction between ENEL's units and municipal utilities in those towns featuring ENEL and MUNIs bordering each other.
Pooled ENEL-MUNI analysis from Chapter 4 failed to spot any systematic superiority of ENEL's units over municipalities. Generalisation on the ENEL-MUNI efficiency dispute was then discarded, in favour of case-by-case comparison. Paired-samples statistical testing (both parametric and non-parametric) from Chapter 5 showed limited agreement between Stochastic Frontier Estimation (SFE) and Data Envelopment Analysis (DEA) efficiency outcomes. Statistical concordance was more often found when comparing SFE and DEA models sharing the same input-output specification. Again, no apparent superiority of ENEL over MUNIs was found out by DEA linear programs. One-to-one comparisons confirmed that the outcomes were mixed, with ENEL's local branches outperforming MUNIs in metropolitan and (sometimes) rural areas, and MUNIs faring better in medium-sized, Po Valley towns (Northern Italy). Results were not clear-cut for Alpine and rural distributors. The latter however - should be considered on a separate basis in that they will probably need permanent subsidies to meet universal service obligations, irrespective of the future structure of electricity distribution in Italy. Comparable (e.g., urban) units might - on the other hand - be subject to yardstick regulation based upon DEA's 'efficient peer' outcomes.
Apart from the main empirical work, this thesis also features institutional and theoretical overviews (Chapters 2 to 5) with relevant literature surveys, a DEA Numerical Appendix (Chapter 5), and a regional map of the Italian territory (end of thesis).
Rethinking Article 6: the criminal fair trial rights case law of the European Court of Human Rights

This thesis is a critique of the European Court of Human Rights’ case law on the right to a fair trial in criminal cases. It is the result of a focussed and extensive survey of Article 6 case law, and, unlike other work on Article6, does not analyse each component right of Article 6 one-by-one. Instead, the thesis considers ‘cross-cutting’ themes common to all, or many, of the Article 6 component rights: how the Court interprets Article 6, how the Court sees its role in Article 6 cases, how the Court approaches Article 6’s internal structure, the Court’s implied rights jurisprudence, and how the Court assesses alleged Article 6 violations. In considering how the Court assesses alleged violations of Article 6, the thesis charts the Court’s attempts to solve ‘the puzzle of Article 6’: how should violations of Article 6 be assessed in the absence of an express metaprinciple? In this regard the thesis examines notions such as the proceedings as a whole test, counterbalancing and defect-curing, the ‘never fair’ jurisprudence, and the extent to which the public interest may justify restrictions on Article 6. The thesis uses a rule of law framework to test the Article 6 case law for its ability to provide guidance to citizens, lawyers and officials. It argues that the case law is marked by considerable uncertainty, inconsistency, and incoherence, with the result that the ability of that case law to provide guidance is significantly undermined. Indeed, the thesis establishes that there is inconsistency and uncertainty within the various tools and approaches used by the Court, and that there is significant incoherence between those approaches. To the extent the thesis makes a normative argument, it constitutes a robust and targeted call for the Court to adopt in this area of law a renewed, rejuvenated approach that is more consistent, more coherent, and better explained.

Advisor: Ashworth, A
Transfer learning for object category detection

Object category detection, the task of determining if one or more instances of a category are present in an image with their corresponding locations, is one of the fundamental problems of computer vision. The task is very challenging because of the large variations in imaged object appearance, particularly due to the changes in viewpoint, illumination and intra-class variance. Although successful solutions exist for learning object category detectors, they require massive amounts of training data.
Transfer learning builds upon previously acquired knowledge and thus reduces training requirements. The objective of this work is to develop and apply novel transfer learning techniques specific to the object category detection problem. This thesis proposes methods which not only address the challenges of performing transfer learning for object category detection such as finding relevant sources for transfer, handling aspect ratio mismatches and considering the geometric relations between the features; but also enable large scale object category detection by quickly learning from considerably fewer training samples and immediate evaluation of models on web scale data with the help of part-based indexing. Several novel transfer models are introduced such as: (a) rigid transfer for transferring knowledge between similar classes, (b) deformable transfer which tolerates small structural changes by deforming the source detector while performing the transfer, and (c) part level transfer particularly for the cases where full template transfer is not possible due to aspect ratio mismatches or not having adequately similar sources. Building upon the idea of using part-level transfer, instead of performing an exhaustive sliding window search, part-based indexing is proposed for efficient evaluation of templates enabling us to obtain immediate detection results in large scale image collections. Furthermore, easier and more robust optimization methods are developed with the help of feature maps defined between proposed transfer learning formulations and the “classical” SVM formulation.

Keywords: Object Detection
Transfer Learning
Computer Vision
Advisor: Zisserman, A
The role of international law in establishing corporate accountability through codes of conduct

The thesis answers the following research question: what is the extent of the influence of international law on the construction and application of corporate codes of conduct, what factors determine this influence and through which processes does it occur?
The thesis uses a mix of methods: a content analysis study, used to measure the extent to which codes of conduct incorporate international labour standards and the degree to which they have changed over time in this respect; legal research on whether corporations can be liable for violating their codes and how this risk factors in the drafting of codes; and case studies of fifteen retailer corporations, which examine how their codes were created and how they are being applied.
The study's findings show there is an influence of international law on the construction and, to a far smaller degree, on the application of codes. The creation and application of codes is a politicised and contested process and codes are based on international law principally due to the pressure exerted by trade unions and NGOs, but also due to reputational risk, commercial pressure and mimicry by corporations. This influence has been selective, with corporations applying provisions in their codes that protect the rights carrying the biggest reputational risks.
These findings show the flaws in the current international framework for corporate accountability, which is based on self-regulation through codes and audits. They also raise issue of whether changes, such as a binding international treaty or the creation of more collaborative and inclusive programmes to oversee the application of codes, may be required in order to ensure wider respect for labour rights of workers.

Keywords: human rights
Corporate accountability
labour rights
governance
Advisor: Kurkchiyan, M
Davies, A
Studies towards the synthesis of complex amino acids derived from microsclerodermins

This thesis describes the studies towards the synthesis of β-amino acids found in the microsclerodermins, a family of complex macrocyclic hexapeptides. These β-amino acids have four or five contiguous stereocentres and an aliphatic side-chain. The synthetic route utilised an aminohydroxylation reaction to install the most challenging moiety in the structure - the 1,2- amino alcohol. The work aimed to construct the core structure (five contiguous stereocentres) of the β-amino acids and install the side-chain later to enable the synthesis of multiple members (A, B, F, G, H and I) of the microsclerodermin family.
The synthesis started with Roche ester, which contained the first methyl stereocentre. It was converted to the diene precursor in four high yielding steps. The next two stereocentres were installed via a Sharpless asymmetric dihydroxylation. With the appropriate protecting groups in place, the remaining two stereocentres were to be installed via a Sharpless asymmetric aminohydroxylation. Various reported reagents and conditions were used to effect the transformation, but the attempts were unsuccessful. This forced us to alter our synthetic plans, and the revised synthetic route involved the use of the tethered aminohydroxylation (TA) reaction developed by the Donohoe group. After the development of an efficient protocol to prepare the TA-precursor, the alkene, with three stereocentres already in place, was successfully converted to the desired stereopentad via the TA-reaction (10 steps, 11% overall yield).
With the stereopentad in hand, installation of the side-chain of the β-amino acids through an alkenyl or alkyl linkage was investigated. For alkenyl-linked side-chains, the appropriate aldehyde was synthesised, but attempts to effect the transformation via a Horner-Wadsworth- Emmons reaction or a Witting reaction failed. With lessons learnt from those, we then focused our efforts on installing an alkyl-linked side-chain. In this case, we were able to install a side- chain via a copper-mediated displacement reaction, which gave us a protected form of the precursor of the β-amino acid of microsclerodermin B. Finally, various efforts to study the reactivity of the stereopentad and the investigations into finding the most effective set of protecting groups have been used to propose a synthetic route for the incorporation of the β- amino acid into the macrocycle.

Keywords: natural product synthesis
biologically active products
synthesis
Advisor: Donohoe, T
Factor market disequilibrium in neoclassical and neo-Keynsian models

This thesis explores two different approaches to the study of simple general equilibrium models in situations where "full" or "long-run" equilibrium does not prevail.
The first part of the thesis examines the consequences of dynamizing the two-sector model of competitive equilibrium, in the sense of making explicit the process whereby momentary equilibrium (i.e., full equilibrium with a given factor endowment) is attained. A number of plausible adjustment mechanisms are proposed, of which the "short-run capital specificity" hypothesis is an interesting special case. The implications of these adjustment mechanisms for international trade theory, for the theory of proportional factor market distortions in both open and closed economies, for the behaviour of the Harris-Todaro model when capital is intersectorally mobile, and for the dynamic response of the trade balance to a devaluation in a small open economy are then examined.
The second part of the thesis studies the properties of a neo-Keynesian temporary equilibrium, by which is meant a shortperiod equilibrium where agents base their behaviour on their expectations about the future and where prices and wages do not move to clear markets in the short run. It is shown that the closed economy model of Malinvaud and the open economy model of Dixit are both special cases of a more general model which incorporates a non-traded good whose price is sticky in the short run, and a traded good, whose price is determined on world markets. While the long-run properties of this model are shown to be fully consistent with the monetary approach to the balance of payments (so, for example, a devaluation has no real long-run effects), its short-run comparative statics properties are shown to provide, in some circumstances, considerable support for discretionary policy.
Synthetic and mechanistic studies of arylsilane oxidation 

In this thesis, we study arylsilane oxidation from both a synthetic and a mechanistic perspective. Building upon previous work within our group, we demonstrate in an early chapter that arylhydrosilanes are surprisingly reactive to oxidation. This disproves the previous assumptions of the Tamao oxidation and provides new insights into the mechanism of the reaction. Furthermore, we find that the best substrates for oxidation are arylmethoxysilanes, and we describe rapid and efficient syntheses for these compounds. A further chapter addresses applications of arylsilane oxidation to natural product synthesis, protecting group chemistry and cycloadditions. By collecting concentration profiles of the oxidation of various arylsilanes, we reveal a rapid equilibration between arylmethoxysilanes and arylsilanols. By comparison, phenol formation (especially from silanol) is often slow. The rate of oxidation turns out to be highly sensitive to both the concentration of the oxidising agent and the substituents of the aromatic ring. In the final chapter we discuss in detail the consequences of these observations for the mechanism of arylsilane oxidation.

Keywords: arylsilane
oxidation
phenol
Advisor: Anderson, E
Simulations and modelling of bacterial flagellar propulsion

Motility of flagellated bacteria has been a topic of increasing scientific interest over the past decades, attracting the attention of mathematicians, physicists, biologists and engineers alike. Bacteria and other micro-organisms cause substantial damage through biofilm growth on submerged interfaces in water cooling systems, ship hulls and medical implants. This gives social and economic motivations for learning about how micro-organisms swim and behave in different environments. Fluid flows on such small scales are dominated by viscosity and therefore behave differently from the inertia-dominated flows that we are more familiar with, making bacterial motility a physically intriguing phenomenon to study as well.
We use the boundary element method (BEM) to simulate the motion of singly flagellated bacteria in a viscous, Newtonian fluid. One of our main objectives is to investigate the influence of external surfaces on swimming behaviour. We show that the precise shape of the cell body and flagellum can be important for determining boundary behaviour, in particular, whether bacteria are attracted or repelled from surfaces. Furthermore, we investigate the types of motion that may arise between two parallel plates and in rectangular channels of fluid and show how these relate to the plane boundary interactions.
As an extension to original models of flagellar propulsion in bacteria that assume a rotation of the rigid helical flagellum about an axis fixed relative to the cell body, we consider flexibility of the bacterial hook connecting the aforementioned parts of the swimmer. This is motivated by evidence that the hook is much more flexible than the rest of the flagellum, which we therefore treat as a rigid structure. Elastic dynamics of the hook are modelled using the equations for a Kirchhoff rod. In some regimes, the dynamics are well described by a rigid hook model but we find the possibility of additional modes of behaviour.

Keywords: Microfluidics
Bacterial locomotion
Boundary element method
Flagellar propulsion
Advisor: Gaffney, E
A sociological study of the Church Army

The thesis examines aspects of the organisational adjustment of the Church of England in the nineteenth century which occurred following the recognition that the working classes were so little reached by the Church's ministrations. Church leaders, increasingly aware that the Church no longer enjoyed a monopoly position in religion, came increasingly to accept the need for home missionary work as a way of competing with other religious organisations, and the Church Army was one significant response to this situation. The thesis examines the origins of the Church Army in 1883 and its development up to 1914. The problems of accommodating Church Army techniques within the structure and activities of the Church of England is examined, together with the reactions to this type of new enter prise, by local clergy and by the Church authorities.
An appraisal of the appeal and effectiveness of the Church Army, and of the influences affecting the style of organisation and its doctrinal orientation is made, and the organisation is examined for its quasi-sectarian potentialities. Attention is given to the processes of internal change within the Church Army, both in response to problems encountered in missioning and with respect to its acceptability to the Anglican clergy. The accretion of new goals, particularly in the development of social work, and the gradual domestication of the organisation are the subject of analysis in which the transformation of a quasi-sect into an agency of the Church is documented.
The role of homeobox gene NKX3.1 in prostate cancer

NKX3.1, a prostate specific homeobox gene is a known marker of prostate epithelium during embryogenesis and is also expressed subsequently through different stages of prostate differentiation. However, all studies on NKX3.1 are focused on its regulation by androgen receptor (AR). The aim of this project is to establish the role of NKX3.1 in differentiation in prostate cancer, independent of AR regulation. In this thesis, I characterize the cell lines in terms of their differentiation capabilities in 3D, expression levels of NKX3.1 and the mismatch repair status. The genes potentially involved in differentiation and regulators of NKX3.1 are also identified using microarray data of the cell lines (Chapter 3). Although NKX3.1 plays a key role in prostate development no studies have been conducted on the effect of NKX3.1 expression on differentiation capabilities of prostate cell lines. In Chapter 4, this was investigated by siRNA mediated knockdown of NKX3.1 in 22Rv1 cell line and overexpression of NKX3.1 in PC3 (designated PC3-Nkx3.1) and PNT1a cells followed by growth in 3D. These functional studies show that the expression of NKX3.1 is vital for lumen formation in 3D, which is used as a measure of differentiation. The microarray data and overexpression of NKX3.1 studies suggest that this gene may also be involved in inhibiting epithelial to mesenchymal transition (EMT). Homeobox B13 (HOXB13) was identified as one of the downstream targets of NKX3.1. NKX3.1 and HOXB13 expression levels are positively correlated not only in the panel of prostate cell lines but also in the NKX3.1 overexpression and knockdown studies (Chapter 5). The results of the work presented in this thesis demonstrate that there is a striking parallel between the function of NKX3.1 in prostate and Caudal-type homeobox 1 (CDX1) in the colon and rectum. In conclusion, NKX3.1 plays a key role as a tumour suppressor in prostate cancer by controlling differentiation of prostate cancer cells.

Keywords: cancer stem cells
NKX3.1
prostate cancer
Advisor: Bodmer, W
Hamdy, F