VictorJuiz/thesis huggingface dataset:
An evidence-based approach to the urgent referral of suspected oral cancer in England
Keywords: Oral cancer
Urgent cancer referral
English two-week rule for cancer

Background
Reports that UK outcomes for several cancers, including oral, were inferior to comparable European countries prompted the UK Government’s ‘NHS Cancer Plan’; a central aim was reduction of late presentation. One key policy was the English ‘two-week rule’ (TWR) system for suspected cancer, specifying a maximum of 14 days between referral and specialist consultation. For oral cancer, little research has been undertaken on several key areas including its influence on stage on presentation and how the system might be improved.
Aim
To conduct evidence-based evaluation of the policy for urgent referral of suspected oral cancer in England and conduct 4 studies in areas where important evidence is absent or sparse.
Methods
(1) A time-series study examining stage on diagnosis of oral cancer before and after the TWR (2) A qualitative study comparing the views of specialists in England and the Netherlands on their head and neck cancer referral systems (3) A systematic review comparing oral cancer referrals from doctors and dentists (4) A Delphi study of expert opinion on the priority of the methods of encouraging early oral cancer diagnosis.
Findings
English/UK outcomes for oral cancer are probably genuinely worse than the European best. The causes are multiple and complex, although late diagnosis is an important cause.
A time-series study of 1483 patients between 1992-2012 suggests the TWR system has not influenced the trend in late oral cancer presentation. Socio-economic differences in late presentation are reducing but persist and oral cancer presentation is increasing.
A qualitative study highlighted similarities between the English TWR system and the more flexible Dutch system but also differences. The Dutch system featured more direct professional communication, greater flexibility and more rapid referral of head and neck cancer.
A systematic review confirmed both GPs and dentists refer oral cancer. Overall, dentists may refer earlier stage disease and refer some cancers following routine inspections, in the absence of symptoms.
In a Delphi study experts consider rapid referral systems high priority for oral cancer but a range of measures were also considered useful.
Conclusions
The current TWR urgent referral system alone may be limited in reducing late oral cancer presentations. Earlier referral may be improved by more flexible referral systems with better communication and by improving access to regular dental inspections, particularly for those at high risk.
Allosteric contributions of muscle nicotinic acetylcholine receptor residues in small-molecule interactions, disease and subunit assembly
Keywords: nAChR
Bispyridinium
CMS
Electrophysiology
MD simulation

The nicotinic acetylcholine receptor (nAChR) is a member of the Cys-loop receptor superfamily of heteropentameric ligand-gated ion channels. The nAChR subfamily has 17 different possible subunits in vertebrates that are found in multiple stoichiometric combinations. Compared to other nAChRs, muscle type nAChRs possess a large subunit repertoire with respect to other nAChRs being comprised of four different subunits- namely alpha, beta, delta and either epsilon or gamma in adult or foetal varieties respectively.
The endogenous neurotransmitter of nAChRs, acetylcholine (ACh), binds at the interfaces of alpha(+)delta(-) and alpha(+)epsilon(-) or alpha(+) gamma(-) subunits. By controlling the safety margin of neuromuscular transmission, nAChRs maintain high-fidelity muscle contraction under a range of physiological conditions. The interference of this process as a result of organophosphorus nerve agent (OPNA) exposure or from genetic disorders such as congenital myasthenic syndrome (CMS) can therefore have deleterious consequences.
OPNAs work by covalent modification of acetylcholinesterase, preventing the breakdown of acetylcholine leading to desensitising block of nAChRs. No antidotes that interact with nAChRs currently exist, however a class of non-oxime bispyridinium compounds (BPDs) have been shown to be efficacious in this regard. In the first part of this project, we sought to rationalise the structure activity relationship data of a series of congeneric BPDs using molecular dynamics (MD) simulations, followed by mutagenesis and electrophysiology to elucidate molecular determinants for their interactions.
In part II of this thesis we identify a novel CMS mutation located at the muscle nAChR alpha subunit transmembrane domain and use enhanced sampling MD simulations and patch-clamp electrophysiology to reveal a new CMS pathomechanism caused by a swap in charge selectivity from cationic to anionic.
In the final part of this thesis, we sought to further explore observations from part I regarding functional differences between orthosteric interfaces as well as discern the structural correlates responsible for the fixed stoichiometric assembly of muscle nAChRs. In the first instance, by integrating MD simulation, evolutionary data and electrophysiology we determine the structural correlates for muscle nAChR subunit assembly and show functional differences between WT and ’double delta’ human muscle nAChR subtypes . Further to this, we explore the relative importance of individual domains of the nAChR delta subunit in contributing to this fixed stoichiometric assembly by generating a range of chimeric epsilon and delta subunits and assessing their cell-surface expression with I125-alpha-BuTx binding assays.
Investigating the role of Viperin in beta-cell function and inflammation
Keywords: cytokine-induced apoptosis
beta-cells
Type 1 diabetes
Viperin

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.
The role of oxygen and nitrogen in titanium alloys for aerospace applications
Keywords: Atom Probe Tomography
Aerospace materials
Oxidation
Nanoindentation
Titanium alloys
EPMA

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.
Electrochemical anion sensing in solution and at receptive interfaces
Keywords: Anion binding
Host-guest chemistry
Molecular recognition
Voltammetry
Impedance spectroscopy
Electrochemistry
Sensors
Halogen bonding
Supramolecular chemistry
Anion sensing
Capacitance spectroscopy
Surface modification

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.
Essays on technology, trade and labour markets
Keywords: economics
development
automation
trade
technology

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.
Age-period-cohort models for individual-level data: An acceleration-based regression framework
Keywords: time
R
age
identification
cohort
period
econometrics
fixed effects

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.
Exploration of rare-missense variant clustering in Mendelian disease-genes
Keywords: genetics
association-testing
rare-diseases
variant-interpretation
statistics
ACMG

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.
Anchoritic prayer in time: enclosure and encounter, c. 1080-1350
Keywords: T.S. Eliot
prayer
medieval literature
anchorites
Ancrene Wisse

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.
Exploring interactions between the sleep homeostatic process and cortical neuronal dynamics
Keywords: Cortex
Sleep
Sleep homeostasis
Psychedelics
Criticality
Neural 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.