VictorJuiz/thesis huggingface dataset:
ATP delivery rates in myocardial hypertrophy

This thesis aims to better understand the metabolic dimension of cardiac adaptation to increased work by studying the creatine kinase (CK) system in participants with pathological hypertrophy secondary to severe aortic stenosis with preserved ejection fraction (SevAS-pEF) or secondary to severe primary mitral regurgitation (MR), participants with hearts adapted to exercise training, and participants with no hypertrophy (NH). It also aims to understand why some hearts transition to failure in the presence of pressure overload, by studying a group with severe aortic stenosis with reduced ejection fraction (SevAS-rEF).
Broadly speaking there are two pathways for ATP delivery from sites of production in mitochrondria to sites of use at the myofibrils: facilitated diffusion by the CK system and simple diffusion. This thesis aims to investigate both. Closely related to this, CK also has roles in the temporal buffering of adenine nucleotides and the control of respiratory flux over varying work rates, so more broadly represents a kind of metabolic reserve. CK activity can be assessed on freeze-and-extract biochemical assay.
Using 31phosphorus-magnetic resonance spectroscopy (MRS) saturation transfer to estimate the CK rate constant (kf) is the first step toward estimates of in vivo flux. Over 60 intra-operative left ventricular (LV) biopsies in participants with pre-operative 31P-MRS are collected to validate the novel TRiST sequence against biochemically-assessed maximum CK rate. Ch. 3 describes non-invasive and invasive predictors of CK total activity and derives a three-variable linear regression model in 37 triplicate datasets to predict CK total activity from total creatine, kf and LV end-systolic volume index.
Ch. 4 studies invasive and non-invasive measures of the CK system in participants with sevAS-pEF, sevAS-rEF, and NH. The chapter argues for the assessment of metabolic reserve as a way of identifying – and explaining – the recently described subset of patients whose ventricles deteriorate sooner in the face of pressure overload. A stepwise fall in median CK total activity is found when arranging groups in order of increasing LV mass index. Non-invasive measures are also assessed in participants with moderate AS, healthy volunteers, and sevAS-pEF participants late post-operatively.
The CK system is then studied in participants with severe primary MR and preserved systolic function pre- and post-operatively (Ch. 5), and in participants with physiological hypertrophy or normal, non-trained, hearts at rest and during dobutamine stress (Ch. 6). Ch. 7 relates CK activity with ATP diffusion distance using 3D models built from tomographic stacks of electron microscopy images in a subset of LV biopsies.

Keywords: mitral regurgitation
saturation transfer
creatine kinase
aortic stenosis
phosphotransfer
cardiac metabolism
Advisor: Rider, O
Rodgers, C
Neubauer, S
Patterns of genetic diversity in clonally evolving bacteria

All bacteria reproduce asexually, and most rely on the transfer of genetic material by parasexual means to adapt through the acquisition of novel genotypes and to remove deleterious mutations. A handful of bacterial species do not undergo any such horizontal gene transfer (HGT), and evolve in a fully clonal manner. They gain novel genotypes solely through the accumulation of de novo mutations, and can only remove deleterious mutations by genome-wide selective sweeps. These clonally evolving bacteria include some of the most pathogenic species known to humans.
As a consequence of their restricted means of increasing diversity and frequent purges of variation due to genome-wide sweeps, these species have very limited genetic diversity. The low resolution of the earliest molecular typing methods led to the members of these clonal species being considered identical clones, whose genetic diversity was negligible. The advent of whole genome sequencing (WGS) has revealed this assumption to be incorrect, by providing high-resolution characterisation of their genomes and revealing their existing diversity. The detailed data provided by WGS has so far been used primarily for tracking transmission and detecting drug resistance mutations, but it has potential as the basis for an exploration of population-level patterns in diversity and evolutionary selection.
In this thesis, I develop a method of rapid and scalable analysis of these patterns that is suitable to large datasets, with thousands of genomes and thousands of genes. This allows for the full diversity of the population to be considered at once. I apply this method extensively to Mycobacterium tuberculosis, the best-studied clonal bacterial species and a widespread human pathogen. Lastly I compare the patterns in M. tuberculosis to three bacterial species which do undertake HGT, Campylobacter jejuni, Staphylococcus aureus and Neisseria meningitidis, to elucidate the patterns specific to clonally evolving bacteria.

Advisor: Maiden, M
Who will govern artificial intelligence? Learning from the history of strategic politics in emerging technologies

Artificial intelligence (AI) is a strategic general purpose technology (GPT) with the potential to deliver vast economic value and substantially affect national security. The central claim motivating this work is that the development of a strategic GPT follows a distinct pattern of politics. By modelling this pattern, we can make predictions about how the politics of AI will unfold.
The proposed model follows a life cycle of a strategic GPT. It focuses on three actors – the state, firms, and researchers. Each actor is defined by their goals, resources and constraints. The model analyses the relationships between these actors – specifically, the synergies and conflicts that emerge between them as their goals, resources, and constraints interact.
Case studies of strategic GPTs developed in the U.S. – specifically aerospace technology, biotechnology, and cryptography – show that the model captures much of history accurately. When applied to AI, the model also does well to capture political dynamics to date and motivates predictions about how we could expect the politics of AI to unfold. For example, I predict that AI firms will be increasingly constrained by the legislative environment, and more pressured to serve national defense and security interests. Some will be caught in the cross-hairs of public critique and researcher push back; some, however, will willingly sell AI technologies to the state with little friction. Further, I predict that the political influence of researchers will shrink, going against what some may view as a rise in researcher influence given recent events of employee backlash in AI firms. In turn, the inclination and capacity for the state to exert control over AI’s development and proliferation will likely grow, exercised via tools such as export controls.
Artificial intelligence is going to matter greatly, and indeed, already does. It matters, then, that we understand the politics that surrounds it, and that we ultimately lay the groundwork for the governance of a technology that is poised to be transformative.

Keywords: Strategic technologies
General purpose technologies
Technology governance
Advisor: Snidal, D
Enhancing the investigation of malware-related crimes using semantic technologies

The expansion of technology connectivity and the pervasiveness of data in our society pose both challenges and opportunities for the government and the private sector. Big companies like Google and Facebook are in the forefront of successfully tackling the challenge of extracting meaning from this data deluge: building rich profiles of people and networks enable them to monetise and make profits by selling such profiles for targeted marketing purposes. For most organisations, though, the challenge of generating actionable intelligence from the available data sources is still daunting.
In the government sector, one of the sectors that could benefit significantly from data-driven intelligence is that of Law Enforcement. However, the deficit of specialized personnel and tools which extract meaningful information from data (as Chapter~\ ef{sec:intro} shows) is directly linked to weak investigation capabilities, ultimately hampering catching serious organised organisations.
As the literature review shows, the available forensic tools are just starting to change the focus from improving processing performance to facilitating investigation and exploration. One example is the increasing adoption of domain taxonomies to describe data.
This thesis addresses the capability gaps by demonstrating that analysts working in law enforcement would benefit from an data exploration tool leveraging specific semantic features. In addition to semantic search and integration of data (features already provided by many semantic data exploration tools), allowing the investigators to materialise classes, object properties and datatype properties could help them shaping their knowledge during the course of an investigation. Moreover, the ability of expressing knowledge in terms of semantic queries and rules could enhance information exchange between analysts.
A prototype was developed to assess the feasibility of the idea and validate it with actual investigators. Their feedback after testing the prototype indicated that such computer-provided features could indeed support the reasoning of the human analyst, making cybercrime investigation more efficient.

Keywords: IOC
Threat intelligence
Intelligence
Investigation
Semantic
Malware
Cybercrime
Advisor: Goldsmith, M
Creese, S
Improving the specification of the target difference in the sample size calculation of a randomised trial of treatments for osteoarthritis

The sample size of a clinical trial is the number of participants the trial aims to recruit. Sample size is a critical aspect of clinical trial design and has ethical and financial implications. The sample size depends on the target difference, the difference in outcome that the trial is powered to detect. This thesis aims to improve methods for specifying the target difference in randomised trials of osteoarthritis.
I conducted a systematic review of sample size calculations in hip and knee osteoarthritis trials published in 2016. It found that most sample size calculations were poorly reported and could not be reproduced. The target difference in the sample size calculation was commonly justified by a published minimum clinically important difference (MCID).
Several versions of the WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) were commonly used in hip and knee osteoarthritis trials. It was often unclear which version was used, hindering interpretation of trial results.
I conducted a discrete choice experiment examining patient preferences when choosing between osteoarthritis medications. Duration of treatment effect was shown to be important to participants, viewed with similar importance to the amount of symptom relief provided and risks of the treatment.
I analysed a cohort of people with osteoarthritis and showed that MCID estimates for the WOMAC varied across different follow-up time points. However, there was no visual trend in the change in MCID estimates over time. Longitudinal methods were feasible to calculate MCID estimates, but did not improve precision.
A simulation study that I conducted found that the pattern of the treatment effect (its duration and consistency) affected the optimal statistical method of analysis for a randomised trial using the WOMAC as the primary outcome.
Future research is needed to examine whether the findings are generalisable to different datasets, outcome measures and health conditions.

Keywords: target difference
simulation
systematic review
discrete choice experiment
minimum clinical important difference
MCID
Advisor: Cook, J
Buchanan, J
Fitzpatrick, R
Dutton, S
Lamb, S
The genetic architecture of carpal tunnel syndrome

Carpal tunnel syndrome (CTS) is a debilitating disease of the hand caused by compression of the median nerve within an anatomical tunnel in the wrist. It is a common disease with an estimated population prevalence of 5–10%. Symptoms include pain, paraesthesia, and numbness of the hand, and thenar weakness that ultimately leads to functional impairment. Many patients require surgery to relieve the pressure on the median nerve; although surgery is successful in the majority of patients, a significant sub-group experiences persistent or recurrent symptoms.
Despite being such a common disease, the pathophysiology of CTS is poorly understood, and even less is known about the genetic contribution to the disease. The heritability of CTS is estimated at 0.46, and approximately one-third of patients report a family history. CTS is a complex disease, where genetic and non-genetic factors interact to affect overall phenotypic expression. The current best method for interrogating a complex disease is with a genome-wide association study (GWAS).
I present the findings from the first ever genome-wide association of CTS, undertaken in over 12,000 CTS cases and nearly 400,000 controls from UK Biobank. The GWAS uncovered 16 genomic loci significantly associated with CTS. In silico analyses of the GWAS data using an array of bioinformatic tools discovered genetic variants at the GWAS-associated loci with strong evidence of functionality, and implicated several biologically plausible genes in CTS pathogenesis, including EFEMP1, ADAMTS17 and ADAMTS10. These genes were strongly enriched for biological pathways and gene ontologies pertaining to the extracellular matrix.
These analyses were followed by epidemiological investigations in UK Biobank, including Mendelian randomisation to assess the causal role of various putative risk factors on CTS aetiology. These studies identified a causal role for shorter height, greater BMI, and younger age at menarche in the development of CTS.
In the final results chapter, a polygenic risk score was constructed to validate the genetic variants discovered in the GWAS in a small cohort of deeply phenotyped CTS patients. RNA- sequencing performed in tenosynovial tissues collected from these patients demonstrated high expression of the candidate genes that were identified in the GWAS. Several GWAS loci demonstrated genotype-specific expression of these genes, providing evidence of functionality.
This work represents the first use of big data and computational genetics to delineate the genetic basis of CTS. I have provided evidence for a robust genetic architecture underlying CTS and have identified several biologically plausible candidate genes that contribute to its pathophysiology. The insights into the aetiology of CTS have revealed testable functional hypotheses and potential therapeutic avenues for further research.

Advisor: Furniss, D
Bennett, D
Structural studies of the type three secretion system export apparatus

One of the most widespread bacterial secretion systems is the type three secretion system (T3SS), which is critical for the virulence of many pathogens and responsible for assembly of the bacterial flagellum. The virulence-associated T3SS is a molecular syringe that uses a highly conserved export apparatus (EA) to secrete effector proteins through a needle directly into the host cell cytoplasm. The flagellar T3SS secretes flagellar subunits through the EA which then self-assemble into a filament. Despite recent progress in the structural biology of T3SS, the highly conserved membrane domains of the five inner membrane proteins of the EA have evaded structural characterisation.
Here, multiple cryo-EM structures of complexes of the three core EA proteins from both flagella (FliPQR) and injectisomes (SctRST) are presented, revealing a pseudohexameric, helical complex. Remarkably, the complex is made up of a series of long, highly kinked helical hairpins rather than the predicted canonical transmembrane helices. Many of the hydrophobic residues predicted to lie in transmembrane helices are instead buried at the interfaces between subunits, leaving only a small membrane domain. In the assembled T3SS this complex is encased in the basal body, above the plane of the inner membrane, and connects to the helical filament, whose helical parameters it matches. The membrane domain of the fourth export apparatus protein, FlhB/SctU, is shown to form a complex with FliPQR, and the complex structure suggests a mechanism of how interactions between FlhB and FliPQR could lead to opening of the complex. Finally, stable rings of full-length FlhA/SctV, the last EA protein, were prepared and cryo-EM confirmed the structure of the nonameric cytoplasmic domain. While little high-resolution information of the membrane domain was obtained, these studies provide a framework for future studies.
Together these results reveal the structure of part of the secretion pathway and suggest that the core of the export apparatus templates the assembly of the helical filament.

Keywords: T3SS
flagella
protein secretion
cryo-EM
Advisor: Lea, S
Robinson, C
A transcriptomics-based investigation of the landscape and mechanisms of self-antigen splicing in thymic epithelial cells

Thymic epithelial cells (TEC) are remarkable for their ability to promiscuously express virtually the entire protein-coding gene repertoire to generate a molecular library of self-antigens for T cell education and selection. This process is essential for the establishment of central T cell tolerance. While the functional relevance of alternative splicing in TEC has been demonstrated for specific genes, the extent and fidelity of peripheral isoform representations of tissue-restricted genes in TEC is only poorly understood. We therefore subjected TEC to deep, stranded, paired-end sequencing and compared their transcriptome to that of peripheral tissues, using matching data from the mouse ENCODE project. In line with previous reports of unusually high splicing entropy in mTEC, I first demonstrated that these cells utilize a broader array of splice junctions than was observed for any of the peripheral tissues examined. Medullary mTEC further transcribed and spliced the highest fraction of known protein-coding gene isoforms. At the same time mTEC do not splice unusually high numbers of novel transcripts identified in a transcriptome assembly of peripheral mouse tissues and mTEC. Using long-read sequencing data from the Oxford Nanopore Technology I confirmed 97 % of highly-expressed novel transcripts expressed in mature mTEC. In this study, I found a limited role for Aire in regulating alternative splicing, but observed a role in modulating transcript usage. Investigating tissue-restricted splicing factor expression in mTEC revealed that a subset of peripheral tissue-restricted splicing factors was present in TEC, which might be regulating the unusual splicing complexity in these cells. However, a set of neuronal splicing factors was not detected in mTEC, which was in line with the absence of a set of neuronal microexons in mTEC.

Advisor: Sansom, S
Holländer, G
Reduced-precision arithmetic in numerical weather prediction with an emphasis on data assimilation

The skill of weather forecasts has improved dramatically over the past 30 years. This improvement has depended to a large degree on developments in supercomputing, which have allowed models to increase in complexity and resolution with minimal technical effort. However, the nature of supercomputing is undergoing a significant change, with the advent of extremely parallel and heterogeneous architectures. This paradigm shift threatens the continual increase of forecast skill and prompts a reevaluation of how Earth-System models are developed. In this thesis we explore the notion of reduced-precision arithmetic to accelerate Earth-System models, specifically those used in data assimilation and in numerical weather prediction.
We first conduct data assimilation experiments with the Lorenz '96 toy atmospheric system, using the ensemble Kalman filter to perform assimilation. We reduce precision in the forecast and analysis steps of the ensemble Kalman filter and measure how this affects the quality of the data assimilation product, the analysis. We find that the optimal choice of precision is intimately linked with the degree of uncertainty from noisy observations and infrequent assimilation. We also find that precision can be traded for more ensemble members, and that this trade-off delivers a more accurate analysis than otherwise.
We then consider the SPEEDY intermediate complexity atmospheric general circulation model, again with the ensemble Kalman filter. In this case we find that, in a perfect model setting, reducing precision in the forecast model gives an unacceptable degradation in the data assimilation product. However, we then show that even a modest degree of model error can mask the errors introduced by reducing precision.
We consider also a precision reduction in the 4D-Var data assimilation scheme. We find that reducing precision increases the asymmetry between the tangent-linear and adjoint models, and that this retards the convergence of the minimisation scheme. However, with a standard reorthogonalisation procedure we are able to use single-precision, and even lower levels of precision, successfully.
Finally, we consider the use of reduced-precision arithmetic to accelerate the Legendre transforms of an operational global weather forecasting model. We find that, with a few considerations of the algorithmic structure of the transforms and the physical meaning of the different components, we are able to use even half-precision without affecting the forecast skill of the model.
In conclusion, we find that the errors introduced by reducing precision are negligible with respect to inherent errors in the forecasting system. In order to make optimal use of future supercomputers, reduced-precision arithmetic will be key.

Advisor: Palmer, T
Dueben, P
Visions of citizenship and state: debating Jews and Judaism in eighteenth-century Prussia

This dissertation explores debates about Jews and Judaism in eighteenth-century Prussia. Methodologically, it adopts the contextual approach associated with the Cambridge School of intellectual history, exploring the complex connection between attitudes towards Jews, and the intellectual influences of the eighteenth-century German Enlightenment. It builds upon recent scholarship which stresses the importance of seeing eighteenth- and nineteenth-century German Jewry in its own terms and not through the lens of the Holocaust. The primary aim of this dissertation is to show that the eighteenth century witnessed a remarkable transformation in perceptions of Jews and Judaism — a transformation which helped lay the groundwork for the Jewish entry into modernity. By treating the entire chronological span of the eighteenth century, this study not only sheds new light on familiar terrain, such as Christian Wilhelm von Dohm’s famous plea for emancipation; it also addresses themes which have largely been neglected. Chapter 1 investigates the origins of the eighteenth-century Jewish question, exploring early modern German responses to the experience of Jewish social mobility. Chapter 2 examines and conceptualises mid-eighteenth-century utilitarian arguments for toleration vis-à-vis Jews. Chapter 3 offers a reassessment of Dohm’s humanitarian arguments for emancipation. Chapter 4 treats the debate about Jewish military service. Chapter 5 studies Immanuel Kant’s influence on late eighteenth-century controversies about Jewish religious reform.

Keywords: Kant
Dohm
Enlightenment
Jews
Prussia
Jewish emancipation
Advisor: Robertson, R