VictorJuiz/thesis huggingface dataset:
Investigating the role of Viperin in beta-cell function and inflammation

Background:
In type 1 diabetes, insulin-producing pancreatic beta-cells are destroyed by an autoimmune response. There are various cellular mechanisms, genes and environmental factors that may influence the autoimmune destruction of beta-cells. Previous studies have shown high induction of Viperin (a viral-response protein of the innate immune system) in isolated human islets exposed to inflammatory cytokines and viruses. Viperin has also been shown to be present in the blood cells of pre-type 1 diabetic subjects. Based on this knowledge, we hypothesised on a possible role of Viperin in beta-cell apoptosis and dysfunction in the development and progression of type 1 diabetes.
Methods:
This research aimed to investigate the role of Viperin in immune-mediated beta-cell apoptosis by using a combination of both in vitro and ex vivo models of beta-cell inflammation. In the INS1-rat beta-cell line, induction of Viperin mRNA expression levels was assessed, and apoptosis was determined after establishing siRNA knock-down of Viperin. Beta-cell apoptosis was also studied in isolated mouse islets of Viperin knock-out mice. RT-qPCR and mRNA sequencing were applied to investigate the influence of Viperin on mechanisms controlling beta-cell function and survival
Results:
The research findings show that in the INS1 beta-cell line and isolated mouse pancreatic islets, Viperin mRNA expression is highly induced within a few hours of exposure to inflammatory cytokines, and expression levels start to decrease over time. Viperin expression was also induced in mouse islets after systemic infection with a chimpanzee adenovirus. Interestingly, apoptosis starts to peak when Viperin levels are decreasing, suggesting that the two events may be linked. In the absence of Viperin, cytokine-induced beta-cell apoptosis is increased, implying that Viperin expression plays a protective role in beta-cells. To investigate this further, RT-qPCR was used to quantify downstream markers of cytokine signalling in the presence and absence of Viperin and results showed that Viperin influenced the expression pattern of these markers under normal and cytokine-stimulated conditions.
As part of these studies, we opted to run total mRNA sequencing to take an unbiased approach to identify both individual genes, along with gene networks and pathways, that are influenced by viperin. These results indicated that Viperin seems to affect a wide array of genes involved in various cellular pathways such as cell development, immune response and homeostatic regulation.
Conclusion:
Viperin expression plays a protective role against cytokine-mediated beta-cell apoptosis. Viperin also influences the expression pattern of numerous genes and key regulatory markers that mediates various cellular functions in beta-cells.

Keywords: cytokine-induced apoptosis
beta-cells
Type 1 diabetes
Viperin
Advisor: Christian, H
Cantley, J
The role of oxygen and nitrogen in titanium alloys for aerospace applications

This thesis aims to improve the fundamental understanding of the mechanisms and effects underpinning oxygen embrittlement and high-temperature oxidation of titanium alloys. This has been accomplished by using Atom Probe Tomography (APT) and Electron Probe Microanalysis (EPMA) to quantify oxygen segregation on the micro and nanoscale, linking changes in composition, crystal orientation and microstructure to the local mechanical properties using nanoindentation.
The current literature reports that oxygen can embrittle titanium alloys by encouraging the formation of the intermetallic α2 phase, but the formation mechanism is not known. In this work, APT has mapped the interaction of oxygen and nitrogen with the α2 precipitates formed in both Ti-7Al model alloys and Ti-64, resulting in the proposal of an α2 precipitate formation mechanism. The interstitial elements are also mapped in detail within these microstructures to answer the question of where oxygen and nitrogen reside. Nanoindentation studies have determined that α2 precipitates are not the dominant hardening mechanism upon ageing, but suggest that oxygen ordering can cause significant hardening, highlighting the importance of controlling the cooling rate during alloy processing.
Current models for α case depth prediction often do not incorporate the effect of microstructure. In this thesis, oxygen ingress on an in-service TIMETAL 834 compressor disc has been shown to be affected by microstructure on both the micron and nanoscale, and reinforces the importance of orientation of α/ β interfaces on oxygen diffusion. The relative contributions of oxygen concentration, crystal orientation and microstructure to the hardness of the oxygen-rich surface layer have been measured using a novel analysis protocol. It has been found that the hardening effects of microstructure and crystal orientation are only significant at very low oxygen concentrations, whereas interstitial solid solution hardening dominates by order of magnitude for higher oxygen concentrations.
In this thesis, a deeper understanding of the processes of oxygen embrittlement and high-temperature oxidation has been developed through careful mapping and quantification of oxygen and nitrogen and their effect on mechanical properties. This will enable these processes to be better accounted for in decisions about material processing and aeroengine component life predictions.

Keywords: Atom Probe Tomography
Aerospace materials
Oxidation
Nanoindentation
Titanium alloys
EPMA
Advisor: Armstrong, D
Bagot, P
Moody, M
Kinetic resolution in rhodium-catalyzed [5+2] cycloisomerization

This thesis demonstrates the ability of a rhodium(I)-phosphoramidite catalyst to effect the first examples of kinetic resolution in [5+2] cycloisomerization (Scheme i). This methodology was applied to a range of diversely substituted enyne substrates, including a novel chiral silane tether. Depending on the substrate, either a classical resolution, or a diastereodivergent resolution was achieved, both with exceptional selectivity.
Furthermore, this methodology was applied to the asymmetric synthesis of the natural product (+)- dictamnol, a trinorguaiane sesquiterpene isolated from the roots of Dictamnus dascarpus TURCZ, with diastereodivergent resolution of an allene vinylcyclopropane as the key step.

Advisor: Anderson, E
What can we learn about plant evolution from a robust phylogenetic framework?

A robust molecular phylogeny provides insights into evolutionary history because it illustrates the order that different taxa have diverged from each other, and the changes that have accumulated between different taxa over evolutionary history. However, a molecular phylogeny does not provide information about a range of other fundamental parameters in macroevolutionary research. This includes the absolute time-scale over which a clade has evolved, and the rate that different clades have diversified. In order to estimate absolute time-scales (referred to as divergence time estimation), and infer net diversification rates, speciation rates, and extinction rates (referred to as diversification parameter estimation), additional analyses are therefore required. As robust phylogenies are inferred for an increasing number of groups, and complex analyses are performed to infer macroevolutionary parameters in a greater variety of contexts, evaluating the robustness of methods for inferring divergence times and diversification parameters is more important than ever. Here, I evaluate the robustness of methods for inferring divergence times and diversification parameters. I show that even in the context of genomic scale datasets, among-branch-substitution-rate-variation that acts consistently across entire genomes causes considerable error in divergence time estimates, regardless of the quantity of molecular sequence data that is sampled. I then show that methods that implement multiple fossil calibrations with relaxed clock methods, which are designed to account for among-branch-substitution-rate-variation, make unrealistic assumptions about the fossil record. I show that these unrealistic assumptions are likely to be a further source of error in divergence time estimates. I then characterise the implications of these problems for estimating divergence times and diversification parameters within Ipomoea, and show that they can lead to very uncertain inferences. However, I show that if questions are carefully framed, and the assumptions of different methods fully accounted for, robust inferences can be made. This includes the inference that the storage root of the Sweet Potato (Ipomoea batatas) evolved in pre-human times, challenging the existing paradigm that it evolved relatively recently as a result of human domestication. It also includes the inference that there is a significant increase in net diversification rates for a clade of Neotropical Ipomoea that is of a scale equivalent to some of the most iconic radiations in the plant kingdom. Taken together, this thesis illustrates fundamental problems that underlie methods in macroevolutionary research, but highlights that when methods are used in the right context, they can serve as a basis for making novel and robust inferences about the natural world.

Advisor: Scotland, R
Electrochemical anion sensing in solution and at receptive interfaces

This thesis describes the investigation of halogen bonding and hydrogen bonding anion receptors for the electrochemical sensing of anions in solution and at receptor-modified electrodes.
Chapter 1 introduces the general concepts of supramolecular host-guest chemistry and electrochemical anion sensing. A range of voltammetric, impedimetric and potentiometric anion sensors and their basic operational principles are discussed.
Chapter 2 describes redox-active ferrocene- or osmium (II) bipyridyl-containing anion receptors for the voltammetric detection of anions in aqueous-organic solvent systems. This includes detailed studies and comparisons of voltammetric sensing under diffusive as well as surface-confined conditions.
Chapter 3 explores the unprecedented use of non-Faradaic capacitance spectroscopy for the sensing of anions in pure water. This is demonstrated at surface-immobilised foldamer receptors enabling the selective sensing of perrhenate, thiocyanate and iodide.
Chapter 4 expands on the use of the capacitive methodology developed in Chapter 3 for the enantioselective detection of anions at chiral molecular films.
Chapter 5 investigates the sensing of ion-pairs via non-Faradaic capacitance spectroscopy at surface-confined heteroditopic receptors.

Keywords: Anion binding
Host-guest chemistry
Molecular recognition
Voltammetry
Impedance spectroscopy
Electrochemistry
Sensors
Halogen bonding
Supramolecular chemistry
Anion sensing
Capacitance spectroscopy
Surface modification
Advisor: Davis, J
Beer, P
Essays on technology, trade and labour markets

This thesis consists of three standalone chapters. Chapter 1 investigates how automation in high-income countries affects trade and multinational activity involving less developed ones. This chapter studies Spain's manufacturing sector from 1990 to 2016 and exploits advances in the capabilities of robots over time, finding that the use of robots in Spanish firms actually had a positive impact on their imports from, and number of affiliates in, less developed countries. We provide a modelling framework and empirical analysis on why this has been the case. Chapter 2 explores how trade policy uncertainty and the threat of a reversal of deep integration affects labour demand. This chapter studies how the the threat of trade barriers caused by the Brexit referendum affected the posting of online job adverts between 2015 and 2019, finding that local labour markets that were more exposed to the threat of services trade barriers experienced a relative decline in online job adverts after the referendum, particularly in months when there was heightened uncertainty about trade policy, but the threat of tariffs on goods had little impact. Chapter 3 is on a similar theme to Chapter 1 and explores how the use of Artificial Intelligence (AI) in high income countries affects services offshoring to less developed countries. I construct new measures of the demand for Machine Learning (ML) skills in the UK based upon the text of online job adverts. Using these measures and instrumenting for ML demand using advances in task-specific capabilities of AI over time, I show that the deployment of ML in the UK has had a positive impact on services offshoring, particularly to low and middle income countries.

Keywords: economics
development
automation
trade
technology
Advisor: Javorcik, B
Woodruff, C
Age-period-cohort models for individual-level data: An acceleration-based regression framework

I develop a framework to analyse the relationship between an outcome of interest and an individual's age, period of observation, or birth cohort, using individual-level data. The framework is suitable for any continuous or binary outcome. I have created a package for the statistical software R which implements this framework.
It is well-known that linear relationships between age, period, or cohort and an outcome of interest are not separately identified. My framework instead focuses on non-linear relationships, described by age, period, and cohort (APC) accelerations.
My framework embeds the age, period, and cohort (APC) accelerations as parameters in a regression model. The regression approach makes it easy to include covariates and to test restrictions on the model. I develop a regression-based test of the APC acceleration model against a more general model, the time-saturated model.
My APC acceleration framework is suitable for repeated cross section and panel data. For repeated cross section data, a generalized linear modelling strategy is used which accommodates continuous and binary outcomes. For panel data, a generalized least squares strategy is used which accommodates continuous outcomes. I consider three panel settings: pooled ordinary least squares, random effects, and fixed effects.
I give three examples of applying the APC acceleration framework. First, I identify a new stylized fact about the role of birth cohort in obesity among English men. Second, I use the framework as a diagnostic tool to evaluate control variables in a model linking commute time and hospital in-patient stays. Third, I show that the framework can detect well-known relationships between wages and age and period.

Keywords: time
R
age
identification
cohort
period
econometrics
fixed effects
Advisor: Nielsen, B
Exploration of rare-missense variant clustering in Mendelian disease-genes

Decades of medical genetics research have yielded great insight into clinically relevant genetic variation. Despite this, the overwhelming complexity of the human genome means much still remains unknown. In this thesis, it is hypothesised that our understanding can be further enhanced by investigating the phenomenon of missense-variant clustering in disease-genes.
Missense-variants clustering is the key concept uniting this thesis. A clustering-detection method (BIN-test), a rare-variant association method (ClusterBurden), models of mutational hotspots (hotspot models), and pathogenicity prediction models (hotspot+ models), comprise the bulk of research reported here. Existing statistical methods are adapted to incorporate the clustering signal, solving either gene-discovery or rare-variant interpretation, and their performance is evaluated from multiple angles. The final chapters report auxiliary analyses including investigation into the prevalence of clustering and potential biases impacting rare-variant analyses.
The developed association methods had superior power to published alternatives when missense variants clustered. In a large inherited-heart-disease gene-panel dataset, BIN-test confirmed the existence of clustering in many definite positive-control genes and ClusterBurden gave theoretical power boosts in all of these. Hotspot models then inferred the locations of mutational hotspots in these clustered genes, enhancing variant interpretation. Extension to include pathogenicity scores in hotspot+ models, further improved interpretation. A large-scale scan in a database of clinical relevant variation yielded a huge number of significantly clustered genes and identified thousands of missense-variant clusters. Finally, supplementary analyses provide some insight into biases in rare-variant analyses of population controls.
Clustering observed in this thesis, and simultaneous publication of the opposite phenomenon regional constraint, indicate its widespread prevalence. This confirms the value of the statistical methods developed here and urges their continued development and application to increasingly large datasets. The deployment of methods developed here as an R package and web application, support their application by researchers of clinical genetics into the future.

Keywords: genetics
association-testing
rare-diseases
variant-interpretation
statistics
ACMG
Advisor: Farrall, M
Anchoritic prayer in time: enclosure and encounter, c. 1080-1350

This thesis argues that interpretation of medieval anchoritic literature requires a central analytic focus on prayer, as the primary activity and essential orientation of the recluse. It presents a theoretical framework for understanding prayer as encounter between the person and God, on a continuum with the subject position of the modern reader encountering the ‘other’ of the past author or text. Having introduced anchoritic prayer as a model for transhistorical reading, Chapter One argues that solitude and withdrawal form a crucial unifying discourse in the history of Christian prayer.
The following chapters identify and theorise the intersections of anchoritic identity and prayer practice in a series of textual groupings. Chapter Two discusses instructional texts for anchorites. It argues that, rather than directly theorising prayer, they assume it as the anchorite’s basic daily work, producing holiness from practice as the latter shapes the orant towards conformity to God’s purposes. Chapter Three considers how prayer functions in and through hagiographical texts for and about recluses, identifying a central concern with enclosure as the means to the reader’s desired prayerful encounter.
Chapter Four argues that the aspects of prayer prioritised in the routine found in Part I of Ancrene Wisse lay the foundation for the text’s delineation of anchoritic identity and practice. It similarly analyses the modelling and performance of prayer in the Wooing Group texts, in both cases asserting the inextricability of textual engagement from prayer. Chapter Five analyses Richard Rolle’s Form of Living and English Psalter as works associated with his instruction of another solitary religious, highlighting his emphasis on the full range of prayer, from practical to contemplative. Finally, a coda integrates the key themes of anchoritic prayer delineated in the preceding chapters with an experimental reading of T.S. Eliot’s poetry and drama, reflecting the transtemporal orientation of anchoritic prayer-texts and the polytemporality of reading itself.

Keywords: T.S. Eliot
prayer
medieval literature
anchorites
Ancrene Wisse
Advisor: Sutherland, A
Exploring interactions between the sleep homeostatic process and cortical neuronal dynamics

The need for sleep increases during wakefulness and decreases during sleep. This process, termed Process S, homeostatically regulates vigilance states, ensuring that individuals obtain a relatively constant daily quantity of sleep. Process S is thought to reflect the regulation of core functional properties of neurones, but many fundamental questions remain. In this thesis, a combination of electrophysiological, pharmacological and mathematical techniques are applied to better characterise interactions between the sleep homeostatic process and cortical neuronal dynamics. The local and activity-dependent origin of Process S was explored through novel computational models, demonstrating that variability in local neuronal firing rates in mouse motor cortex can predict the dynamics Process S measured both in the slow oscillation and also in population off periods. It was concluded that Process S at the local level reflects an integration of cortical activity over time, and at the global level reflects an integration over space. Multi-scale statistical properties of neuronal dynamics were then explored across the sleep-wake cycle, using the theory of criticality. It was found that neuronal avalanches indicative of criticality did not change as a function of Process S during wake, however, did so across vigilance states in association with slow wave activity. The results demonstrate one way in which the control of global brain dynamics might be intrinsically interlinked with the regulation of arousal and sleep. Neuronal dynamics in the waking brain state were then perturbed in mice using the serotonergic psychedelic, psilocin. Although the drug briefly disturbed sleep, no enduring changes were observed in sleep-wake architecture or in the dynamics of Process S, despite perturbation to ongoing neuronal dynamics. Finally, it is argued that these results support the possibility that sleep homeostasis does not serve the active homeostatic regulation of any one specific neuronal variable, but that Process S fundamentally corresponds to an intrinsic time-keeping mechanism, precisely tracking the passage of time in each state and thereby enabling only that a daily sleep quota is obtained. This perspective reconciles the global level of sleep need’s dissipation from the local level of its accumulation and offers new insights into understanding both why each individual sleeps every day and why sleep duration shows dramatic differences across the animal kingdom.

Keywords: Cortex
Sleep
Sleep homeostasis
Psychedelics
Criticality
Neural dynamics
Advisor: Vyazovskiy, V
Essays on money and financial frictions in finance and macroeconomics 

This thesis consists of four essays in the area of macro-finance and international finance in financial economics. The common thread linking the four essays is the interaction between money and endogenous default, as well as the scope for policy to improve social welfare. Chapter 1 introduces the novelty of inside money and banking to a New Keynesian model, with the policy focus on the real and nominal behaviours of the macro-economy. The model shows at the zero lower bound on deposit rates (ZLBD), further policy rate reductions reduce spreads, and thereby reduce bank profitability, deposit creation, and output. Moreover, at the ZLBD, Phillips curves are flatter because credit rationing is both contractionary and inflationary. Finally, alternative policy rules are proposed to alleviate the economic strain at the ZLBD. Chapter 2 develops a two-country general equilibrium model to examine the benefits of the bankruptcy code of a capital markets union - in the absence of a fiscal union - as an alternative mechanism to improve the financial stability and welfare of a currency union. I show when domestic credit risks are present, a lenient union-wide bankruptcy code that allows for default in the cross-border capital markets union removes the pecuniary externality of banking insolvency; therefore, it leads to a Pareto improvement within the currency union. The model provides the welfare and financial stability implications of bankruptcy within a capital markets union in the Eurozone. Chapter 3 develops a dynamic stochastic general equilibrium (DSGE) model featuring deposit issuance via bank credit and endogenous default to study the complex interactions between the real and nominal sectors of the economy, with policy implications provided. Chapter 4 builds a dynamic model with endogenous default and banks’ costly monitoring to assess the Basel III liquidity tool Net Stable Funding Ratio and its effect on bank credit quality and monetary policy transmission.

Keywords: bankruptcy codes
macro-finance
currency union
monetary policy
general equilibrium
financial stability
Money, equilibrium default
international finance
Advisor: Tsomocos, DP
Sussman, O