VictorJuiz/thesis huggingface dataset:
Mathematical modelling of drug-ion channel interactions for cardiac safety assessment

Unintended drug interactions with ion channels in cardiac cells can alter normal electrical activity in the heart. This can lead to the onset of cardiac arrhythmias which can be potentially fatal. Such arrhythmias are a leading cause of market withdrawal of pharmaceutical compounds. It is therefore important for pharmaceutical companies to identify drugs which may cause adverse changes to cardiac electrical activity as early as possible in the drug development process.
Computational approaches provide great potential for assessing cardiac safety at low cost and high-throughput. Regulatory guidelines for the assessment of cardiac safety are being revised and computational approaches are envisaged to form an integral part of future guidelines. It is therefore important that computational methods proposed for use are both accurate and well validated.
This thesis is focused around the use of mathematical models for cardiac safety assessment. We evaluate an approach which uses information on the extent of drug block of cardiac ion channels to predict changes in cardiac electrical activity in a rabbit-based safety test. A possible limitation of this approach is the representation of drug-ion channel interactions within the mathematical model. We go on to explore the representation of the kinetics of the cardiac potassium channel encoded by hERG (human-Ether-a-go-go Related Gene) within mathematical cardiac electrophysiology models.
We demonstrate how existing mathematical models of hERG channel kinetics can behave very differently when used to simulate the same voltage protocol. We also show the impact that the choice of hERG channel representation used within an action potential model can have on the prediction of drug effects on cardiac activity. We design and perform novel experiments to allow us to construct and validate mathematical models describing hERG channel kinetics.
We demonstrate the potential for the use of computational approaches in cardiac safety assessment. However, at the same time we indicate that models used for this purpose must be carefully constructed and thoroughly validated, as well as illustrating ways this may be achieved. Such considerations are a prerequisite for more predictive computational assessment of cardiac safety.

Keywords: Ion channel kinetics
Model selection
Mathematical modelling
Experimental design
Cardiac safety assessment
Model validation
human Ether-a-go-go Related Gene
Patch clamp
Parameter inference
Cardiac electrophysiology
Advisor: Mirams, G
Gavaghan, D
Louttit, J
New transformations of azacycles

The work presented in this thesis involves new transformations of azacycles, focusing on the introduction of functionality α-to N. α-C-H functionalisation on an azetidine has been a long-standing challenge, with N-protecting/activating groups that work well in the higher and lower azacyclic systems not viable. A recent breakthrough in the Hodgson group showed the rarely used N-thiopivaloyl group was effective for α-deprotonation– electrophile trapping on azetidines, but was not without limitations concerning harsh removal conditions and scope for further substitutions. This thesis describes efforts to overcome these issues by development of a new protecting/activating group for N, t-butoxythiocarbonyl (Botc).

Keywords: organic chemistry
azetidine
azacycles
asymmetric synthesis
heterocycles
organolithium
Advisor: Hodgson, D
Electrophysiological responses to noxious stimuli in the anaesthetised child

In the UK, more than 235,000 children admitted to hospital each year receive an operation or investigation under general anaesthesia. It is not known whether nociceptive stimulation evokes a change in cortical brain activity in the anaesthetised child. The aim of this thesis is to determine whether noxious stimulation administered to anaesthetised children results in a measurable change in brain activity and whether this evoked activity is altered in children who have been born prematurely and experienced a high level of pain in early life.
Changing patterns of neuronal activity evoked by noxious and non-noxious stimuli were 'time locked' to electrophysiological recordings by means of a novel high-speed camera and an event detection interface developed during this thesis. Changes in band power were examined pre- and post-stimuli and across the different stimulus modalities.
In all children, background EEG activity was dominated by delta (&LT;3 Hz) and alpha (8-12 Hz) band frequencies, consistent with previously reported anaesthetic literature. Clinical and experimental noxious stimulation, and tactile stimulation evoked a significant increase in delta activity (p&LT;0.05) with no changes in average heart rate or ipsilateral EMG activity observed between pre- and post-stimulus. The application of local anaesthetic to the stimulation site diminished the evoked increase in delta activity. The response to noxious stimulation in the children born prematurely was not significantly different from the age-matched control group (p&GT;0.05) but they had striking differences in their background EEG activity. Prematurely born children had significantly lower alpha and beta band activity.
The electrophysiological recordings we have obtained show that it is possible to measure evoked brain activity following a variety of noxious and non-noxious stimuli to investigate how the paediatric human brain processes sensory information under anaesthesia. The EEG measures were more sensitive to nociception than changes in autonomic activity and reflex withdrawal activity. Noxious stimulation caused a significant increase in delta activity, representing an increase in cortical synchronisation. While the children who were born prematurely did not respond differently to the noxious stimulation they had dramatically different background activity, which could have clinical relevance when using brain-derived patterns of EEG activity to help establish anaesthetic depth.

Keywords: Nociception
Preterm
Anaesthesia
EEG
Paediatrics
Children
Advisor: Slater, R
Synthesis and reactivity of the 2-phosphaethynolate anion and phosphinecarboxamide

This thesis describes a novel synthesis of the 2-phosphaethynolate anion, [PCO]–, via reaction of the [P7]3– Zintl cluster with carbon monoxide. The ligand properties of this fundamental molecule have been probed and compared to common isoelectronic pseudohalides: cyanate and isocyanate. The first ambient-temperature synthesis of the heavier congener, [PCS]–, is also reported, and studies show that this anion can act as an ambidentate ligand.
The cycloaddition chemistry of [PCO]– with heteroallenes afforded a range of novel anionic phosphorus-containing heterocycles. A collaborative study has shown that [PCO]– can act as a catalyst for the trimerisation of isocyanates, and potential intermediates in this catalytic cycle have been isolated.
By analogy with Wöhler's historic synthesis of urea, the reaction of [PCO]– with ammonium salts yields phosphinecarboxamide. This unprecedented molecule is a rare example of an air-stable "user-friendly" primary phosphine, and its structure and ability to coordinate to metal centres were explored. It was found that this species has similar σ donor and π acceptor properties to phosphine, PH3.
This reactivity has been extended to incorporate N-functionalised phosphinecarboxamides with a range of different functional groups. The Brønsted acidity, P-functionalisation and oxidation chemistry of these species was subsequently investigated to afford a diverse family of carbamoyl-bearing phosphides, phosphines and phosphine oxides. Some of these species have great potential to become industrially relevant molecules in the future. Preliminary results showing the generality of the reaction of [PCO]– with other protic nucleophiles are additionally presented.

Advisor: Goicoechea, J
Officially autonomous: anglophone literary cultures and the state since 1945

This thesis examines the role of the modern democratic state as a sponsor of literature in the English-speaking world between 1945 and 2000. Working with, and modifying, Bourdieu's conception of the literary field, it considers the often paradoxical consequences of the state's shift from censor to guarantor in this period. Granting 'official autonomy' in this way had numerous unexpected and often fraught effects on the writers, readers and institutions that shaped the literary field. To keep this large subject firmly based on available historical evidence, this thesis considers a series of distinct 'moments' of state intervention through detailed case studies of three specific institutions: the international Congress for Cultural Freedom (1960-1968), the Arts Council of Great Britain (1960-1990), and the private examination boards that implemented the National Curriculum in the UK (1989-2000). In each case, it shows how these different but related moments, and the larger diachronic narrative of which they form a part, take place against a backdrop of interlinking historical and socio-political transformations, including the Cold War, decolonisation and multiculturalism.
Drawing on evidence in literary and other public archives, the thesis not only brings into view questions about the public status of literature in recent history, it shows how an understanding of the state’s role enables us to think differently about the cultural consequences of modern democratic liberalism. The methodological emphasis it places on institutions challenges critical and popular orthodoxies, associated chiefly with the liberal tradition, which conventionally set the overbearingly powerful and monolithic state against the inescapably vulnerable but also courageous individual. The alternative picture that emerges reveals a world in which the actions of various individuals can be understood partly via the institutional roles they perform, and institutions operate as sites that negotiate competing ideas of literature and literariness, and implement state power in variegated, diffuse and contested ways. Each of the case studies provides a different, though comparable, perspective on this larger picture. As such, the thesis opens up a nuanced way of analysing the interventions of writers, critics and reading communities, while also offering a differentiated approach to understanding the state and its evolution.

Keywords: British state
Arts Council
The state
multiculturalism
Advisor: McDonald, PD
Role of histones in DNA double-strand break repair in Dictyostelium

Correct repair of DNA double-strand breaks is crucial for maintenance of genome integrity. Despite data showing the importance of histones variants and histone post-translational modifications in the cellular response to DNA damage, there is still a lack of knowledge concerning the role of histone H3 and its variants as well as histone ADP-ribosylation in such processes. In this work Dictyostelium discoideum was employed as genetically tractable model organism to address the role of histone H3 variants and histone ADP-ribosylation in DNA double-strand break (DSB) repair. Vegetative cells lacking two out of three histone H3 variants – H3b and H3c, were shown not to be sensitive to DNA DSB. No evidence for altered DSB repair was found as phosphorylation of histone H2AX (a marker of DSB) and one of the pathways of DSB repair, non-homologous end joining, were not altered. Altogether, this work demonstrates that H3b and c variants are not required for overall DNA DSB repair in Dictyostelium. Among the core histones histone H2B was discovered to be the major acceptor of ADP-ribosylation by major ADP-ribosyl transferase involved in DSB repair, Adprt1a, in vitro. ADP-ribosylation in vitro was shown to occur on glutamate E18 with E19 being a potential regulator of this modification. Using an epitope-tagged overexpressed H2B, in vivo H2B ADP-ribosylation in response to DSBs was observed in Dictyostelium for the first time. Decreased ADP-ribosylation of epitope-tagged H2B mutated in both E18 and E19 residues was demonstrated. Overall, this work demonstrates the presence of the ADP-ribosylation of H2B in Dictyostelium in response to DSBs and identifies the major site of this modification.

Advisor: Pears, C
Lakin, N
Risk factors for anogenital cancers in postmenopausal women: the Million Women Study

Background: Anal, vulval and vaginal cancers predominantly affect postmenopausal women. Over 85% of registrations occur after the age of 50. Risk factors for these cancers, other than high-risk human papillomaviruses, are not well defined.
Methods: 1.3 million UK women, mostly aged 50-65 at recruitment, were followed for incident anogenital cancer. Cox regression models with age as the underlying time variable were used to calculate adjusted relative risks associated with various lifetime exposures.
Results: 570 anal, 898 vulval, and 170 vaginal cancers were registered over an average 13.8 years of follow-up. History of cervical intraepithelial neoplasia grade 3 (CIN 3) prior to recruitment was associated with a 4-fold increase in risk of anal cancer, a doubling of risk of vulval cancer, and a 7-fold increase in risk of vaginal cancer. Significant associations were also seen for past cervical cytological abnormalities, with an increase in risk of anal cancer for low-grade, and an increase in risk of all three cancers associated with high-grade abnormalities.
Anal cancer risk was also associated with smoking, prior use of oral contraceptives, nulliparity, tubal ligation, and not living with a husband/partner. Risk of vulval cancer was increased in overweight, obese women, and those with a menopause prior to age 50. Risk of vaginal cancer was increased amongst women who were nulliparous, overweight or obese, who had a hysterectomy prior to recruitment, or who were not married or living with a partner.
Conclusions: Despite anatomical proximity and histological similarities of the anogenital tissues, anal, vulval and vaginal cancers have heterogeneous associations with many lifetime exposures, suggesting differences in aetiology. Past high-grade cervical abnormalities are a marker of increased risk of subsequent anogenital cancer, but only a small proportion of women with such a history go on to develop anal, vulval or vaginal cancer later in life.

Advisor: Beral, V
Barnes, I
Genetic and genomic analysis of Arabidopsis thaliana with low-coverage next-generation sequencing data

Next-generation sequencing technologies have transformed our understanding of genetic variation segregating in populations and its relationship with phenotypic traits. Sequencing large populations at low coverage, thus sampling only a fraction of the genome of each individual, may increase statistical power in genetic mapping [Pasaniuc,2012] compared to genotyping arrays. This thesis explores several novel applications of low-coverage population-based sequencing, using data from 488 recombinant inbred lines from the MAGIC population of Arabidopsis thaliana, descended from 19 inbred founder accessions. Based on the full catalogue of genetic variation that is available in the 19 founders [Gan, 2011], I describe every MAGIC genome as a mosaic of founder haplotypes and analyse the accuracy of the mosaics by simulation. I then use the mosaics in three ways. First, I investigate structural variation using a novel method that treats anomalies in the alignment of sequencing reads, potentially representing signatures of structural variants (SVs), as quantitative traits. These can be mapped genetically to identify loci in which genetic variation correlates with signatures of SVs. The method can distinguish short- (e.g. indels) and long-range (e.g. translocations) SVs and has led to the discovery of a large number of SVs segregating in the MAGIC population, including thousands of long-range SVs. I show that SVs have a significant impact on silencing gene expression and that they explain a large fraction of the phenotypic variation in several physiological traits. Second, I use the mosaic structure of the MAGIC lines to map recombination events and analyse lineage-specific recombination in MAGIC. I infer recombination hotspots and compared recombination in the MAGIC lines to the Arabidopsis genetic map. Finally, I detect bacterial endosymbionts hosted in MAGIC genomes from unmapped reads that have high sequence similarity with bacterial DNA and examine whether variation in the presence of endosymbionts can be explained by host genetic variation.

Keywords: Recombination
Genetic variation
Low-coverage sequencing
Structural variation
Genomic imputation
Next-generation sequencing
Advisor: Mott, R
Hein, J
A theory of communal reciprocity

This thesis sets out an interpretation of the value of community that I call communal reciprocity. It charts the history of that ideal, analyses its use in the work of an important academic proponent, G.A. Cohen, and develops a more comprehensive account of its main features. It also discusses the implications of communal reciprocity, including whether or not it conflicts with certain freedom-based concerns and its application, including in the assessment of market economies.

Advisor: Miller, D
Leopold, D
Swift, A
Keeping up with technologies: revisiting the meaning and role of internet access in digital inclusion

The ways people go online have been transformed by the emergence of new mobile Internet technologies. As modes of Internet access are becoming increasingly diverse, this thesis sets out to examine how various forms of access shape engagement with online resources. Inequalities in Internet access have been neglected in the "second-level digital divide" research, which has focused on differences in skills and usage. Thus, I argue that inequalities of access have to be revisited and their role in digital inclusion reassessed.
To study individuals' arrangements of Internet-enabled devices and locations holistically and as a dynamic entity, access is conceptualised as infrastructure. Theoretically, I distinguish between material dimensions of access and social practices shaping access, and draw on existing models of digital inclusion to examine the role of these dimensions and practices in online engagement. Empirically, a mixed methods research design is employed, complementing longitudinal analyses of survey data representative of the British population with 29 qualitative interviews with British Internet users.
This study contributes to our understanding of material and social dimensions of access and their impact on Internet use patterns. First, the conceptualisation of Internet access as infrastructure is empirically validated. Second, quality, locality and ubiquity are established as material dimensions of access, where offline social and economic resources most strongly affect inclusion in high-quality, multi-local and ubiquitous Internet access. Third, three specific practices encompassing how users develop and maintain their access infrastructures are identified: spotlighting, distributing and being stranded. They reflect differences in roles Internet technologies play in individuals' daily lives as well as differences in availability of offline resources. Fourth, the results show that, controlling for a range of digital inclusion factors, the access inequalities have significant effects on a range of online engagement types, but are most strongly related to commercial and communication uses of the Internet.
In sum, this study provides a nuanced understanding of how different mechanisms underlie the development, maintenance and engagement with Internet access, depending on whether access arrangements are shaped by digital exclusion or choice. Specifically, by outlining critical differences among all-round, mobile-mostly, mobile-only and home-only Internet users, broader policy and research implications are also discussed.

Keywords: digital divide
internet use
smartphones
mobile internet
new media
Advisor: Blank, G
Casing effusion cooling

The design, modelling and testing of a film cooling system intended for the casing of an unshrouded HP turbine rotor is described in this thesis. Due to the dense network of small film cooling holes employed in such a system, this is often referred to as a casing effusion cooling scheme. Though there are patent references to such systems, there is as yet very limited published material on the aero thermal performance of such film cooling schemes. The casing of an unshrouded HP rotor is an incredibly hostile environment, witnessing the periodic passing of the HP rotor tips within close proximity at a frequency of &Tilde;10 kHz. These blade passing events subject the casing to extremely large amplitude fluctuations of pressure and heat load, which may at first seem to preclude the use of a film cooling scheme.
This thesis details many theoretical, computational and experimental advancements related to the research topic. Highlights include:
The introduction of a new fundamental mechanism to the field of film cooling, the propagation and reflection of pressure waves within film cooling holes and the impact on film cooling performance.
The development of new miniature thin film heat flux gauges manufactured using a new process. Sensor resolution is improved by a factor of seven.
The first published computational model reporting heat transfer data on a film cooled rotor casing.
Improvements to heat transfer data processing techniques and theory. These are applied to experimental work to produce the highest resolution heat transfer data obtained on the casing of a scaled rotating transonic HP rotor for both uncooled and cooled geometries.
Computational models are used to demonstrate that coolant injection on the rotor casing reduces the over-tip leakage mass flow, offsetting the spoiling and mixing losses that film cooling schemes introduce.
Much of the work in this thesis is based on papers that have been submitted to or are pending submission. To date three papers have been presented at conference with two published in journals and the third recommended and pending journal publication. Two other papers are pending submission. A patent has also been filed with the European and American patent office regarding novel film cooling hole shapes designed to make use of acoustic effects.

Advisor: Povey, T