VictorJuiz/thesis huggingface dataset:
The use of biomedical big data for economic analyses of genome sequencing in rare genetic diseases: a case study from the 100,000 Genomes Project
Keywords: health economics
genomics
rare diseases
big data

Countries around the world are increasingly translating next-generation sequencing diagnostics from research into clinical practice, especially for rare genetic diseases, but with limited health economic evidence. In the absence of data from clinical trials, the use of linked observational real-world patient-level genomic and clinical data, defined as biomedical big data (BBD), could improve the health economic evidence base. This thesis explores the use of BBD for economic analyses of genomic diagnostics in rare genetic diseases in the context of the Genomics England 100,000 Genomes Project (100KGP) and the National Health Service (NHS) in England.
The practical and methodological challenges of using BBD for health economic analyses in the context of genomic sequencing are summarised and described by the results of a literature review. These challenges are initially explored via an analysis of the healthcare resource use of patients suspected of having a rare genetic condition, using data from the 100KGP. The health economic value of using diagnostic genome sequencing for the diagnosis is then considered by conducting economic evaluations for two disorders: hereditary ataxia and craniosynostosis. For hereditary ataxia, a cohort-based analysis is presented that uses diagnostic yield as the outcome measure. For craniosynostosis, a model-based analysis is presented that uses quality-adjusted life years (QALYs) as the outcome measure. In each case, the choice of methodological approach is supported by evidence from a literature review that summarises economic evaluations that have compared genomic and traditional diagnostic pathways.
The results of the costing analysis indicate that patients with suspected rare genetic diseases consume considerably more healthcare resources than the general population in England. The results of the economic evaluations indicate that genome sequencing is a cost-effective use of scarce healthcare resources in the English NHS. However, these results are characterised by considerable uncertainty, so should only be considered as an early assessment of the likely cost-effectiveness of genome sequencing in this context. The thesis concludes that the use of BBD for economic analyses presents many challenges that may not be easily overcome, and which may require an evolution in health technology assessment and policy-making in this context.
Bayesian verification of stochastic models in systems biology
Keywords: machine learning
Bayesian inference
stochastic modelling
systems biology
formal verification

The accurate construction and verification of mathematical models from data in biology are paramount to the success of the fields of systems and synthetic biology. For systems biology, mathematical models are required to accurately model and provide further understanding of biological phenomena of interest, while for synthetic biology, such models are required for the efficient design and development of novel biological devices. In this thesis we integrate techniques from Bayesian methods, formal verification and machine learning to provide a framework that allows one to formally verify a property of interest on an underlying stochastic system with limited observed data. First we introduce this framework, titled Bayesian verification, which integrates likelihood-free inference techniques and probabilistic model checking to construct and verify mathematical models with accurate results, using sparse and noisy experimental data. Secondly, we then extend the generality and thus applicability of this framework by utilising statistical model checking and supervised machine learning, resulting in the Approximate Bayesian Computation - sequential Monte Carlo with Statistical model Checking (ABC-(SMC)2) framework. With this extended Bayesian verification framework, with noisy and sparsely observed data, we can simultaneously learn and verify a model of interest, the only requirement being that we are able to generate simulations from a proposed model. Although this extension greatly extends the generality of the Bayesian verification framework, the number of simulations required to perform Bayesian verification becomes restrictive. Thirdly, because of the aforementioned, we present a multifidelity Bayesian verification framework. This multifidelity Bayesian verification framework reduces the computational cost of the simulations required to perform data-driven verification, and here we also seek to further reduce the number of simulations required by exploring when and how to perform statistical model checking. We conclude the thesis with a summary of our results and discuss directions for future work.
Quintiliane, vagae moderator summe iuventae (Martial 2.90.1): The Didactic Conception of Quintilian’s Institutio oratoria
Keywords: Didactic prose
Flavian literature
Reception of Cicero
Rhetorical theory
Quintilian
Reception of Seneca the Younger
Latin prose
Institutio oratoria

This is a study about the didactic conception of Quintilian’s Institutio oratoria. Building on recent scholarship on ancient didactic prose and poetry and focusing particularly on Quintilian’s construction of an authoritative didactic persona, his self-profiling against other writers and didactic figures, and ‘proleptic’ strategies through which he deflects responsibility for the potential lack of success of students who follow his advice, I examine how throughout the Institutio, Quintilian persuades readers of the validity of the educational programme he presents.
Chapter one analyses how Quintilian introduces himself and his didactic project at the start of the Institutio and considers the overall conception of the work. I show how the impression of a gradually progressing didactic journey is conveyed and argue that the criteria that Katharina Volk identifies for didactic poetry can be fruitfully applied to the Institutio.
Chapter two reconsiders Quintilian’s relationship to Cicero. I argue that he acknowledges Cicero’s authority on rhetorical theory but strives to assert his own independence as a writer. I suggest that Quintilian celebrates Cicero’s oratory but denies that he was the ideal orator, maintaining that ‘now’ is the best moment to reach the ideal. This balancing act is key for the didactic framework of the Institutio, which would be undermined if the ideal orator had already existed or could not possibly exist.
Chapter three highlights the main differences between Quintilian’s and Cicero’s conceptions of the ideal orator, presents the key characteristics of his conception in the Institutio, and suggests that there are significant, if polemical, elements of a reception of Seneca the Younger.
Chapter four discusses how Quintilian contrasts ‘good’ style with two currents of stylistic corruption, ‘archaism’ and ‘modernism’, borrowing Senecan vocabulary to describe the latter but simultaneously using it to describe Seneca’s own writing. This chapter raises a central question: how can Quintilian’s criticism of contemporary oratory coexist with his predictions of its bright future? The answer I propose is that by linking modernism, the predominant current of corruption, to Seneca, Quintilian can present it as an anachronistic remnant of the Neronian past, which must be replaced by his own Flavian project.
In a nutshell, this thesis aims to analyse the didactic conception of the Institutio, setting these techniques against the background of the work’s overall construction, goal, and models.
Pluralist justice and protecting peoples
Keywords: Justice
Refugees
English School
Pluralism
Minorities

This thesis engages with recent work within the pluralist tradition of the English School which has sought to reinvigorate pluralist thought through the development of a ‘new’ or ‘revised’ pluralism predicated upon the moral value of communities and the ethical desirability of diversity in international society. This represents, in effect, an attempt to bring questions of justice, rather than simply order, to the core of pluralist thinking in the way that it has long been the core of solidarist thinking within the English School. At present, pluralist thinking on justice rests upon under-theorised ideas of the relationship between the notional moral worth of existing political communities and the historical development and contemporary functioning of international society. This thesis seeks to bridge the gap between ‘new pluralism’ and the new history of international society through an examination of the institutions of international society which work towards the achievement of pluralist justice. The question asked by this thesis, therefore, is: ‘how does international society protect communities and defend diversity in practice?’ It finds that there are three institutions that have been developed by international society to protect political communities – the primary institution of the State and the secondary institutions of ‘Shielding’ and ‘Recourse’. This thesis analyses the historical development and contemporary functioning of these institutions, uncovering dynamics of hierarchy and homogeneity that are anathema to the pluralist agenda. It also reveals possible avenues for enhancing pluralist justice within the contemporary global order, including strengthening the secondary pluralist institutions, increasing the agency of subaltern communities within international society, and rethinking current attitudes towards territorial borders and migration.
Limiting behaviour of combinatorial Markov chains
Keywords: trees with edge-weights
Intertwining
Aldous diffusion
Markov chains on multifurcating trees
Down-up chain
Rémy tree growth
Planar trees
Tree growth processes

In this dissertation, we propose to study a general notion of a down-up Markov chain for multifurcating trees with n labelled leaves. We study in detail down-up chains associated with the (α, γ)-growth process of Chen et al. (2009), in several different ways. Firstly, in the special case of γ = 1 − α, the stable tree growth process, we generalize a Markov chain by Aldous on binary trees, and show that an unrooted version of the chain has relaxation time of exactly order n2 , whilst the relaxation time for a rooted version is at least of order n2 and at most of order n3−α . Secondly, for general choice of γ, we generalise and further develop previous work by Forman et al. (2018, 2020) in the binary special cases to construct a Markov chain on multifurcating trees with stationary distribution induced by the (α, γ)-growth process. The technique we deploy utilizes the construction of a growth process and a down-up Markov chain on trees with planar structure. Our construction ensures that natural projections of the down-up chain are Markov chains in their own right. We establish label dynamics that at the same time preserve the labelled (α, γ) distribution and keep the branch points between the k smallest labels for order n2 time steps for all k ≥ 2. We conjecture the existence of diffusive scaling limits generalising the “Aldous diffusion” by Forman et al. (2018+) as a continuum-tree-valued process and the “algebraic α-Ford tree evolution” by Löhr et al. (2018+) and by Nussbaumer and Winter (2020) as a process in a space of algebraic trees.
Physical regulation of cell behaviors: multifrequency AFM measurement of mechanoelectric, mechanochemical, and hydration shell effects on ECM and cell substrate viscoelasticity
Keywords: Atomic Force Microscopy (AFM)
Extracellular Matrix (ECM)
Amplitude Modulation-Frequency Modulation Atomic Force Microscopy (AM-FM AFM)
Cell-Derived ECM
Viscoelasticity
Time Responses
Poly(2-hydroxyethyl methacrylate)   (poly(HEMA))
Nanoscale Dynamic Mechanical Analysis (DMA)
Mechanochemical Coupling
Mechanoelectric Coupling
Hydration Shells
Collagen

The extracellular matrix (ECM) is a scaffold of molecules, constructed and maintained by cells, that determines tissue structure. Cell-ECM interactions are crucial for maintaining healthy tissues. Understanding these interactions could provide insight into regenerative medicine and help develop new disease treatments. The mechanical properties of cells and the ECM are crucial in this interaction. Biological systems are viscoelastic (viscous and elastic), meaning they respond to applied forces with characteristic time delays known as time responses. For models of viscoelasticity that describe biological structures, time responses are the ratio of viscosity to elasticity. Furthermore, viscoelastic, electrical, and chemical properties of biological systems are coupled.
In this thesis, I applied advanced dynamic atomic force microscopy (AFM) to quantify effects of electrical and chemical stimuli on ECM viscoelasticity at cellular length scales. Mechanoelectric coupling in the ECM was studied by measuring how ions altered collagen (the most prevalent component of the ECM) mechanics. Increased ion concentration increased collagen elasticity and viscosity, maintaining constant time responses. Ion flow decreased collagen time responses. Additionally, these experiments demonstrated that collagen hydration shells are viscoelastic, suggesting fluid within tissues contributes directly to tissue viscoelasticity. Next, mechanochemical coupling in the ECM was studied by measuring viscoelasticity of ECMs produced by cells in response to growth factors and mutation. Cells deposited more ECM in the presence of growth factors, increasing ECM viscosity and elasticity, yet maintaining constant time responses. Mutants exhibited reduced ability to produce ECM, modify viscoelasticity, and less control over time responses. The final set of experiments measured viscoelasticity of substrates known to alter cell behaviors, demonstrating a potential relationship between substrate time responses and cell behaviors. Together, my findings suggest that ECM time responses remain constant in many environmental conditions. Alteration of time responses may be a physiological mechanism of regulating cell activities and tissue health.
African cosmopolitanism and the Atlantic: trade, imperial contact and relating to the past in the Niger Delta (nineteenth to twenty-first centuries)
Keywords: material culture
religious contact
postcolonial theory
collaborative research
historical anthropology
trade
Nigeria
museums
collecting histories
transculturation
memory
Atlantic
Niger Delta
colonial contact
gift

This thesis analyses the role of material culture in shaping imperial contact in the Niger Delta, a centuries-long hub for transatlantic trade, and examines the ways in which people use the remnants of this material culture to relate to the past in Nigeria’s petro-state today. Based on sixteen months of fieldwork in Nigeria and London, it gives a nuanced account of the politicisation of transatlantic encounters in the current political economy of oil. Drawing on Mikhael Bakhtin’s (1981) notion of ‘chronotope’ and Kristina Wirtz’s (2014) concept of ‘temporality-emplacement’, it moves beyond the often-contested concepts of ‘history’ and ‘memory’ and looks at the performative modes with which people use material culture to relate to the past, stake claims in the present and envision possible futures. The concept of chronotopes allows for a better understanding of how people perform time and space with help of ‘things’, including images, artefacts, bodies and the environment, and thus create worlds which allow particular subjectivities to emerge. In the Niger Delta, where African merchant elites have been ‘seeing and acting beyond local environments’ (Prestholdt 2008) for centuries, these subjectivities are predominantly cosmopolitan. Gifts from transatlantic trade and international commodities fostered cosmopolitan lifestyles and identities. Today, it is this cosmopolitan reach that makes the remnants of transatlantic encounters particularly valuable for the formation of heritage and the contestation of land and, thus, mineral rights. Taking a crisis of leadership in the Kingdom of Warri and a film made by expatriate Nigerians in London as starting points, the thesis compares the competing chronotopes of Pentecostalism, sacred kingship, ancestral worship, theatre and museums in Nigeria’s postcolony and highlights their entanglements with intra- and interethnic as well as national-regional and transnational politics. It gives insights into the interdependencies of cultural practices and shifting political economies and contributes to a better understanding of Africa’s relationship with the Atlantic world.
Energy sustainability and the water sector: systems modelling approaches for decision-making
Keywords: water resources planning and management
Demand-side response
water-energy nexus
systems analysis
optimisation

Water managers face enormous challenges in securing future supplies of water under the uncertainty of climate change and population growth. Energy sustainability is an increasingly important factor in the planning and management of water resources. Electricity use in the water and wastewater sectors has been growing at unprecedented rates. Left unchecked, this could compromise both the affordability and sustainability of the sector. At the same time, a number of promising options exist to the industry to enhance its energy efficiency and also reduce its reliance on the energy grid, though there are few analyses of the costs and risks associated with these opportunities at the moment. Water managers need reliable decision-making frameworks and tools to understand the complex interactions between water and energy systems. Such methodological advances will be important for the sustainable planning and development of the water industry.
The aim of this thesis is to introduce novel modelling techniques and frameworks that can capture the linkages between water and energy systems, for the purpose of facilitating transitions toward a more reliable, resilient, and energy sustainable water industry. Specifically, this thesis presents analytical approaches to: (1) understand the temporal evolution and drivers of electricity consumption in water-related systems; (2) model integrated water, wastewater, and energy networks; (3) model and study the costs, risks, and benefits of operational changes at high temporal resolution; and (4) map pathways to energy sustainability in the water sector under deeply uncertain futures.
The tools and frameworks developed in this thesis are applied to study the water system in the Thames basin, a region considered to be `seriously water stressed' and encompassing the mega-city of London. Results from the case-study demonstrate that water-related energy use has been rising sharply in the region (10.8% per year) and this is driven by expansions in operational capacity for larger populations, as well as local climate mitigation efforts. Yet, a number of opportunities to curtail rising energy costs are also available to the local utility. Results from this thesis demonstrate that participation in energy demand-response programmes has the potential to substantially lower energy costs by up to £5.2 million per year. Further, the utility can also expand on its energy self-generation capacity using a combination of biogas, solar, and wind generation, to decrease their reliance on the local energy system and realise net-zero carbon targets.
Aerodynamic performance of turbine rim sealing flows
Keywords: Rim seal flows
Rim sealing
Aerodynamics
Turbine rim seal

An investigation of the hot gas ingestion phenomenon in the Oxford Rotor Facility ex- amined rotor disc rotation, mainstream pressure asymmetries and unsteady structures in the cavity as main drivers. The facility underwent major modifications to allow different annulus flow configurations, higher resolution in the low and high bandwidth pressure instrumentation and the installation of a new system to quantify the sealing effective- ness using the tracer gas technique (±0.0068 uncertainty). Rotationally-driven ingestion was simulated with a bladeless annulus and conditions of pressure-driven ingestion with nozzle guide vanes. By decoupling each contribution, the fundamentals of hot gas ingestion are addressed. A chute rim seal arrangement has been studied with two gap sizes. The influence of non-dimensional purge flow, Cw, rotational Reynolds number, Reφ, axial Reynolds number, Reax, and seal clearance, sc, has been examined through the mean cavity pressure coefficient, Cp, sealing effectiveness, ε, and frequency spectra of the unsteady pressure signals. The maximum Reφ was 3.3 × 106 with a flow coefficient of 0.45 with NGVs. The mean pressure field in the cavity revealed the existence of two vortices. Values of sealing effectiveness showed good agreement with the disc pumping orifice model at low flow coefficients, suggesting operation in the rotationally-induced regime. This finding challenges the extended assumption that pressure-driven ingestion dominates when asymmetries exist in the annulus. However, this hypothesis matched the experimental data at high flow coefficients. The frequency spectra of the high bandwidth pressure signals revealed two sources of unsteadiness in the rim seal region: the large-scale flow features due to rotation of the disc and the interaction between the annulus and purge flows.
Structural analysis of Wnt signalling pathways
Keywords: Wnt
Norrin
Notum
Frizzled

Wnt signalling through its principal receptor Frizzled (Fzd) is one of the key determinants of metazoan development. Fzd is a member protein of the G-protein coupled receptor family, yet despite a wealth of functional information available on various aspects of its role within cells and during development, the molecular mechanism for Wnt-activated Fzd signalling has remained unknown. To shed light on this question, this project pursued a cryo-EM approach to obtain structures of different Fzd signalling complexes. To facilitate the assembly of complexes containing transmembrane regions of several proteins, as well as their subsequent examination by cryo-EM, I also explored the reconstitution of Fzd within two detergent-free systems, nanodiscs and SMALPs. Both systems posed unique challenges for obtaining well-behaved samples, ultimately proving to be unsuitable for sample examination by cryo-EM. I then returned to detergent systems, focusing on the assembly of Fzd4 in complex with an atypical ligand Norrin and bound Fab fragments, which, after an extensive sample optimization strategy, appeared to be too flexible for structure determination. This may support the theory that instead of functioning as a classic GPCR with defined intrahelical movements and a rigid structure upon activation, Fzd acts as a passive scaffold that brings different intra- and extra-cellular components together to result in signalling.
In parallel to this project, I successfully determined the structures of several small molecule inhibitors in complex with the Wnt deacetylase Notum via X-ray crystallography. This led to the identification of several key determinants controlling the affinity of molecules binding to the Notum catalytic site, thus aiding further drug development targeting this protein.