VictorJuiz/thesis huggingface dataset:
Genomic variation in human health and disease

Understanding the structure and function of genomic variation within and be- tween individuals will be crucial for the translation of genomics into improved health and clinical outcomes. This thesis addresses current issues around the study of genomic variation in that context.
Variant annotation is a vital step in the analysis of whole-genome and whole- exome sequence data. I compared variant annotations for 80 million variants from a clinically-focused whole-genome sequencing study, obtaining annotations with two different sets of transcripts and two different software tools. I found that choice of transcripts and choice of software both have a large effect on variant annotation. The extent of discrepancy in annotations has implications for all research that relies on variant annotation, especially as we try to use whole-genome sequencing in the clinic.
Type 2 diabetes (T2D) is a common, complex genetic disease imposing a large global health burden. Although over 80 genomic loci have been associated with increased risk for T2D, many questions remain about the genomic architecture of the disease. I used 11 million rare, low-frequency and common single-nucleotide variants obtained from whole-genome sequence data from 2,657 individuals with and without T2D to assess the contributions of different classes of genomic variation to T2D susceptibility. Using linear mixed model methods and variance partitioning approaches I characterised contributions from variants in different allele frequency classes. Partitioning variance into different functional classes revealed significant four-fold enrichment (P &LT; 0.01) for variants in enhancer regions identified in pancreatic islet cells and significant depletion for variants without any functional annotation (P &LT; 0.01).
Single-cell RNA-sequencing (scRNA-seq) technologies are rapidly gaining traction to interrogate transcriptomic heterogeneity across individual cells. How- ever, raw scRNA-seq data require a large amount of processing to obtain a clean, tidy dataset ready for statistical modeling. I have developed a new, self- contained R software package, SCATER, to fill the niche between raw scRNA-seq data and downstream analysis. The package streamlines the pre-processing, quality control and data normalisation procedures while enabling flexible ways to visualise data and integration with other scRNA-seq analysis tools.

Keywords: quality control
RNA-seq
heritability
linear mixed models
single-cell
software
variance partitioning
genomic variation
enhancers
variant annotation
type 2 diabetes
Advisor: Donnelly, P
After the new failure of nerve: Charles Olson and American modernism, 1946-1951

One medium has dominated accounts of American art in the years following the Second World War. The period witnessed, in the words of one critic, a 'Triumph of American Painting', with advances in the easel picture far surpassing those in other media. Whilst more recent accounts have nuanced this view, drawing attention to developments in music and sculpture, literary contributions to the new American modernism have gone almost without assessment. Were there advances in literature comparable to those of Mark Rothko and Barnett Newman, David Smith and John Cage?
Drawing extensively on his unpublished writings, After the New Failure of Nerve reveals the poet Charles Olson to have been the keenest literary advocate of the new American avant-garde and one of the most astute observers of its conditions and possibilities. Paying special attention to unpublished notes, lectures, and correspondence, the thesis utilises Olson’s early writings in order to examine the momentum given early postwar modernism by a potent contemporary reaction against abstract rationality, a reaction identified at the time as a 'New Failure of Nerve'.
Born of recent disillusionment with 'scientific' Marxism and New Deal progressivism, the thesis demonstrates the several ways in which this 'New Failure of Nerve' fuelled vanguard American art from the middle of the Second World War to the end of the decade. It argues that the new critique of abstract rationality—which was also reflected in the contemporary American work of the Frankfurt School—defined the way American artists understood the function of postwar modernism, the posture of the postwar modernist artist, and the status of the postwar modernist artwork. This pivotal moment in the history of modernism was shaped, I contend, by a philosophical critique explored most ambitiously by an American poet.

Advisor: Bate, J
Stake and stage: judicial burning and Elizabethan theatre, 1587-1592

This thesis is the first sustained analysis of the relationship between Elizabethan theatre and the judicial practice of burning at the stake. Focusing on a five-year window of theatrical output (1587-1592), it argues that polemical literary presentations of burning are the key to understanding the stage's negotiation of this most particular form of judicial violence.
Unlike other forms of penal violence, burning at the stake was not staged, and only fourteen incidences of the punishment are recorded in Elizabethan England. Its strong literary presence in Protestant historiography is therefore central to this study. Part I explores the tragic and overtly theatrical rhetoric that the widely available Acts and Monuments built around the burning of heretics in the reformation, and argues that the narrative of this drama of injustice intervened in the development of judicial semiotics over the late-sixteenth century. By the time that Tamburlaine was first performed, burning at the stake was a pressing polemical issue, and it haunts early commercial theatre.
Elizabethan historiography of the stake was deeply influential in Elizabethan theatre. In Part II, I argue that Marlovian fire spectacles evoke tableaux from the Acts and Monuments to encourage partisan spectatorship, informed by the rhetoric of martyrdom. Dido's self-immolation courts this rhetoric by dismissing the sword from her death, while Tamburlaine’s book burning is condemned through its emphatically papist undertones. These plays court the stake through spectacles utilizing its rhetoric. In Part III, I show that characters historically destined to face the stake required thorough criminalization to justify their sentence. Alice Arden is distinguished from female martyrs celebrated for their domestic defiance, while Jeanne d'Arc's historical heresy is forcefully rewritten as witchcraft and whoredom to condemn 1 Henry VI's Joan la Pucelle. Both women are punished offstage, and the plays focus instead on the necessary task of justifying the sentence of burning.
Though rare in practice, burning at the stake was a polemical issue in Elizabethan England. Despite the stake’s lack of imitation in the theatre, I argue that widely available Protestant historiography—propaganda at the heart of debates about burning and religious violence—affected both how plays were written, and how they could be viewed.

Advisor: Moore, H
McCullough, P
The expression patterns of non-classical and classical forms of HLA-B27 in spondyloarthritis

The strong association of the human leukocyte antigen HLA-B27 (B27), with spondyloarthropathies (SpA), was discovered more than four decades ago, yet the role B27 plays in disease pathogenesis remains unclear. It has been demonstrated that HLA-B27 can form non-classical FHC forms, including B27 FHC homodimers (B272) and misfolded FHCs. Two leading theories of SpA pathogenesis proposed that both cell surface NC-B27 (the B27 homodimer theory) and intracellular (the B27 misfolding and UPR theory) can drive immune responses in SpA. Several studies demonstrated that cell surface NC-B27 binds to immune receptors and suggested that these interactions can activate Th17 immunity. My DPhil project focuses on the investigation of the cell surface expression of NC-B27 molecules in cells and tissues obtained from AS patients and B27 TG2 rats. I used both existing reagents and a novel HD6 antibody, generated against B272, to examine the expression of HLA-B27 by flow cytometry, confocal microscopy and immunoprecipitation. This thesis provides evidence that the expression of HD6- and HC10-reactive molecules in AS patients is rather restricted to specific cell types (e.g. osteoclasts) and possibly particular environmental factors and tissue types (e.g. synovial fluid and joint tissue). My data using B27 TG2 rats demonstrated that resident joint cells express HD6- and HC10-reactive molecules before the onset of clinical manifestations. Furthermore, I showed increased expression of NC-B27 on antigen presenting cells (APCs), and CD161+ and CD8+ cell populations in blood and secondary lymphoid organs. Based on these findings I hypothesized that cell surface expression of NC-B27 may not only be crucial for activation of Th17-driven immune responses, but may also shift the balance between immune tolerance and activation. Importantly, the expression of potentially pathogenic HD6-reactive molecules is restricted to specific cell and tissue types hence HD6 antibody may be a potential future therapeutic agent in SpA.

Keywords: non-classical HLA-B27
Ankylosing Spondylitis
B27 transgenic rat model
Advisor: Bowness, P
Kollnberger, S
3D printing in the commons: knowledge and the nature of digital and physical resources

3D printers are a type of digital fabrication tool being used by communities committed to shared software, hardware, and digital designs. This shared digital knowledge can be understood as an emerging common resource for the fabrication of physical goods and services. Yet the knowledge associated with physical resources used in 3D printing is less understood. This thesis explores what factors enable or prevent knowledge about physical materials entering the commons.
3D printing, with its particular configuration of digital and physical goods, offers a unique angle to advance the field of commons scholarship. This thesis elaborates the use of commons theory for traversing the boundary between knowledge associated with physical materials and digital content from the perspective of 3D printer users. Particular contributions are made to the branch of knowledge commons theory: notably, how design rules in technological systems can be used to theorise boundaries; how differentiating between the nature of underlying resources can help explain the inclusion of knowledge in the commons; and, how patterns of user engagement with types of knowledge in the commons can be studied over time.
To develop these contributions I employ theory on the design rules of technological architecture, and use insights from the study of peer production in online communities. Empirical data comes from a qualitative study of users of Fab Labs, community workshops for digital fabrication, as well as from a quantitative study of the online user forum for the Ultimaker 3D printer.

Keywords: Open source
Resources
Advisor: Reed-Tsochas, F
Rayner, S
Advance relief in aircraft finance and the Cape Town Convention

The Cape Town Convention came into force on the 1st April 2004 and the Aircraft Protocol came into force on 1st March 2006. To date, the Convention has sixty-six States Parties, the Aircraft Protocol fifty-eight States Parties, and together they can be regarded as one of the most successful recent commercial law treaties. The Convention's overriding object is to offer creditors the highest possible protection in the form of an effective, speedy and strong legal remedial framework for the international enforcement of creditors rights in the event of the debtor's default or insolvency. The underlying rationale is that this will lead to significant reductions in borrowings costs for lenders to the advantage of all interested stakeholders in the aircraft sector. However, without effective implementation of the remedial system of the Convention and the Aircraft Protocol, it is difficult for financiers to have confidence that they are able to defend their legal rights effectively.
First, this thesis examines the legal nature and purpose of Article 13 ("Relief Pending Final Determination") of the Cape Town Convention, since it does not fit any traditional remedy under domestic law. Secondly, this thesis answers the crucial questions whether, and to what extent, elements of national procedural law in a Contracting State are relevant to the application of advance relief under the Convention. Further, to the extent that domestic procedural law may be applicable, the thesis examines if the relevant domestic rules of procedure are in conformity with the fundamental principles of the Cape Town Convention and the legal nature of advance relief. Ultimately, it thereby clarifies the relationship between the Convention and national procedural law in the context of Article 13.

Keywords: Aircraft Protocol
Cape Town Convention
Relief Pending Final Determination
Advisor: Gullifer, L
Goode, R
Past, present and future volcanic activity at restless calderas in the Main Ethiopian Rift

There is growing recognition that magma plays a key role in the extension and eventual break-up of the continental lithosphere. One of the most intriguing aspects of magmatism during the transition from continental rifting to sea-floor spreading is that large silicic magmatic systems develop within the rift zone. However, the processes by which these silicic magmatic centres develop as well as their larger role in rift development remains poorly understood.
This thesis focuses on silicic volcanism in the Main Ethiopian Rift; the most extensive active continental volcanic field in the world, and home to over 10 million people. I use a variety of geological, geochemical, geophysical and geochronological techniques to explore spatial and temporal variability in volcanism in this active rift segment. In particular I focus on Aluto volcano, a restless caldera volcano just &Tilde; 200 km south of Addis Ababa, but by extension I make inferences about what this means for past, present and future volcanism at other caldera systems in East Africa.
Aluto has been active for over 300,000 years, and has overwhelming erupted chemically-evolved peralkaline rhyolites that are derived through protracted (>80%) fractional crystallisation. Tectonic faults dissect the volcanic complex, and along with an underlying caldera ring fault provide key pathways for fluid release. Episodic ground deformation events occur at Aluto, and are characteristic of a coupled magmatic-hydrothermal system, where faults networks connecting the surface and deep reservoirs play an important role in the deflation. Finally, new 40Ar/39Ar geochronology suggest that silicic volcanism in this segment of the rift is pulsed, not steady, on human evolutionary timescales.

Keywords: Volcanology
Advisor: Pyle, D
Mather, T
Biggs, J
Carbon dioxide and coccolithophore physiology in ancient oceans

Coccolithophores form an important and dynamically evolving component of the carbon cycle. These ubiquitous single-celled marine calcifying phytoplankton are re- sponsible for half of the calcium carbonate production in the modern surface ocean, and their adorning calcite plates (coccoliths), produced intracellularly, have con- tributed to sedimentary carbonate for over 200 million years. They constitute a significant control on the partitioning of carbon between the atmosphere, ocean and sedimentary reservoirs on timescales from the instantaneous to the geological. Coc- colithophores are also uniquely placed to record aspects of the carbonate chemistry of the surface ocean, because the carbon isotopic composition of the organic matter (δ13Corg) and calcite (δ13Ccal) that they produce is a function of many parameters, including ambient aqueous carbon dioxide concentration [CO2].
This thesis addresses the bidirectional interaction between coccolithophores and the carbon cycle in the geological past, by asking how cellular carbon fluxes relate to physical evidence that is preserved throughout geological time. First, I present and calibrate a novel rationale for size-normalising coccolith mass, and show that over two glacial-interglacial cycles, coccolithophores appear to calcify more under high [CO2] conditions; a result that is manifest on evolutionary timescales, and is necessarily elusive to experiments. Second, I investigate the parameters controlling δ13Ccal and δ13Corg in coccolithophores through in vivo experimentation, and devel- opment of a model of cellular isotopic fluxes. I show that so called "vital effects" in coccolithophores arise as a result of differences in calcification to photosynthesis ratios. Third, using a combination of novel and established protocols for extraction and isotopic analysis of specific organic molecules from fossils taxonomically separated by size, I show the very first size-specific geologic time series of coccolith-associated δ13Corg, and the first time-series of size-separated coccolith δ13Ccal over a glacial cycle. A novel means of inferring past carbon dioxide concentrations, based on an iterative inverse modelling approach, is presented and tested.

Keywords: Proxies
Coccolithophores
Coccoliths
Carbon Dioxide
CO2
Carbon isotopes
Fossils
Paleoclimate
Calcification
Advisor: Rickaby, REM
Hermoso, M
Venetian humanism in the Mediterranean world: writing empire from the margins

My dissertation examines the cultural history of the Renaissance Venetian maritime empire. In this project I bring into conversation two historiographical subfields, the intellectual history of Venetian Renaissance humanism and the colonial history of the early modern Mediterranean, which have previously developed separately. In doing so, I examine the relationship between power and knowledge as it unfolded in the early modern Mediterranean. The ways in which Venetian Renaissance intellectual culture was shaped by its imperial engagements - and, conversely, how Venetian approaches to governance were inflected by humanist practices - are the central axes of my dissertation.
In the first part of the dissertation, I examine the ways in which writing and textual collecting were used by elite Venetian readers to represent the geopolitical dimensions of their empire. I consider a group of manuscripts and printed books which contain technical, navigational, and cartographic writing and images about Venetian mercantile and imperial activity in the Mediterranean. In the second part, I undertake two case-studies of Venetian patrician governors who were trained in the humanist schools of Venice, before being posted to colonial offices in Dalmatia and the Aegean, respectively. I examine how their education in Venice as humanists influenced their experience and practice of governance in the stato da mar. Their personal texts offer an alternative intellectual history of empire, one which demonstrates the formation of political thought amongst the men actually practicing and experiencing imperial governance. Overall, I aim to build a picture of the ways in which literary culture, the physical world of the stato da mar, and political thought came to be entwined in the Venetian Renaissance; and then to describe how these dense relationships worked for the Venetian administrators who experienced them in the Mediterranean.

Advisor: Davidson, N
Holmes, C
The genomic epidemiology of hyperinvasive and carriage-associated lineages of Neisseria meningitidis

Neisseria meningitidis is the bacterial pathogen responsible for meningococcal disease: 10% of cases result in death. Endemic disease is sporadic, with fewer than three cases per 100,000 population, but elevated incidence also occurs during hyperendemic and epidemic periods. Successful control of meningococcal disease is achieved via immunisation against capsular polysaccharides, however, no vaccine exists against serogroup B polysaccharide due to poor immunogenicity and safety concerns.
Recently, 'serogroup B-substitute vaccines' containing sub-capsular antigens have been developed: one such vaccine is to be introduced to UK infant immunization schedules from September 2015. Meningococcal populations are genetically diverse and arranged into clonal complexes that fluctuate in geotemporal prevalence. It is therefore essential to survey meningococcal populations in given locations to understand molecular evolution following vaccine introduction.
The advent of whole-genome sequencing presents an opportunity to investigate meningococcal populations at high genetic resolution. This thesis introduces the MRF Meningococcus Genome Library, a comprehensive collection of WGS data from national surveillance of meningococcal disease in England and Wales between the 2010/11-2012/13 epidemiological years. The utility of WGS data in routine surveillance was investigated.
Structuring of genomic variation revealed population-level lineages analogous to clonal complexes. Prevalent hyperinvasive lineages were composed of immunologically distinct sub-lineages that, when linked with patient data, were age-group associated: vaccines may affect age-groups differently. Sub-lineage specific core-genome and epigenetic DNA methylation variation was primarily in metabolic loci. Finally, genomic variation of an epidemic clone, generated by recombination, was great, and epidemiological data remains indispensible for investigating transmission. These findings provide insight into meningococcal evolution and are of importance in understanding the effects of new vaccines.

Advisor: Maiden, M
Challenging the orthodox view of human rights

The concept of human rights holds a distinctive significance in political practice, yet philosophers remain divided over the nature of these rights. The Orthodox View defines human rights as moral rights possessed by all individuals simply in virtue of their humanity. Proponents of this view claim that the contemporary idea of human rights is a continuation of the natural rights project of the eighteenth century and shares many of its basic philosophical assumptions.
This thesis argues that the Orthodox View is no longer an appropriate characterisation of the concept of human rights we find in current domestic and international practice. It also rejects recent alternatives offered by supporters of the Political View, who define human rights by particular functions they serve, specifically their role(s) in acting as benchmarks for the legitimacy of states or triggers of international concern.
I propose instead a new 'Political Justification View' of human rights, which states that human rights are demands which challenge unjustifiable political-institutional orders, which are the concern of all people, and which protect the equal standing of individuals in political decisions that affect the collective or individual good. This view better captures the diversity of practices that employ the term 'human rights', whilst also explaining its innovative power as a moral language that enables individuals to challenge the official institutional order under whose authority they live.
Finally, I argue that within this broader view of human rights there are two distinct moral concepts which pertain to different parts of human rights practice: Domestic Human Rights and International Legitimacy Rights. Separating these two concepts is helpful in resolving long-standing debates about whether human rights are properly thought of as minimalist moral concerns of legitimacy or broader social goals to be achieved through political institutions.

Keywords: Human Rights
Political theory
Advisor: Stears, M
Tomalty, J