VictorJuiz/thesis huggingface dataset:
Human translational studies investigating the neurocognitive effects of 5-HT4 receptor agonism

Major depression is common, costly, and a global cause of significant morbidity. First-line antidepressant medication has a clinically problematic delay before therapeutic efficacy and is ineffective for a subset of those affected. In addition, many patients with depression, as well as other mental illnesses, find that cognitive impairment has a substantial impact on their quality of life and functioning. Cognitive impairment is poorly treated with medication such as antidepressants, and can persist after remission. Based on animal behavioural studies, as well as molecular and neurochemical evidence, 5-HT4 receptor agonism has been suggested to have putative antidepressant effects and to improve cognition. However, there is relatively little evidence in humans demonstrating such effects.
The aim of this thesis is to investigate whether it is possible to translate the pre-clinical neurocognitive effects of 5-HT4 agonism into humans. This would help to elucidate whether 5-HT4 receptor agonism may have therapeutic potential within psychiatry as an antidepressant and / or a pro-cognitive treatment.
A series of experimental medicine fMRI studies were conducted using the 5-HT4 receptor agonist, prucalopride, in healthy volunteers. Low dose prucalopride led to improved behavioural cognition on a memory encoding and implicit faces task, and increased neural activation in memory processing regions including the hippocampus. Resting-state fMRI provided further mechanistic support for prucalopride as a pro-cognitive agent. The latter findings were partially confirmed in a clinical population of unmedicated depressed patients treated with a novel 5-HT4 agonist, PF-04995274. Here, 5-HT4 agonism with PF-04995274 increased activation in another memory processing region and modulated activity within the hippocampus; however, the behavioural pro-cognitive behavioural effect seen with prucalopride was absent. Although there was no evidence of an antidepressant-like effect in experimental medicine studies, a pharmaco-epidemiological study suggested that one year of standard dose prucalopride for the treatment of gastrointestinal disorders was associated with reduced risk of depression.
Overall, this thesis identifies that 5-HT4 receptor agonism has neurocognitive effects consistent with other pro-cognitive medications in healthy participants and depressed patients. Data using electronic health records indicates that it may also reduce incidence of future depressive episodes. Future studies should consider confirming the correct dose of individual agonists to ensure optimised central receptor binding in clinical populations, using larger sample sizes to allow for variability inherent in clinical populations, and / or to assess the effect of medication over a longer time period.

Keywords: pharmacoepidemiology
experimental medicine
depression
5-HT4 receptor
cognition
serotonin
functional neuroimaging
5-HT4R
resting state fMRI
neurocognition
emotional processing
fMRI
Advisor: Harmer, C
Cowen, P
Murphy, S
Poetic revision in the long nineteenth century

This thesis argues that the making of poems is entwined with their meaning. I suggest that revision offered poets in the long nineteenth century an imaginative resource that was far more than a process of verbal fine tuning. More specifically, I examine how the process of composition in Wordsworth, Tennyson, Dickinson, and Hopkins is intimately tangled up with a broader set of questions each poet is working through, which range from philosophical enquiries into the continuity of the self to the practical matter of how poems work on the page. If revision is often characterised as a process of gradual improvement between drafts of a work, or a preparation for public consumption, this thesis suggests that revision can be a far more private dynamic that we should be alert to within drafts. Each writer studied in this thesis reflects something of Forster’s conviction ‘How can I tell what I think till I see what I say?’, as they continue to discover new ways of working through uncertainties in their compositions. Throughout this thesis, I connect textual theories with a close study of finer textual details, in order to shed light on the writing of these particular poets and to show how revision offers a mode of thinking that is built into the composition of a poem, and also remains detectable in the ‘finished’ work.
My introductory section suggests that Romantic notions of organic form do not wholly account for the labour detectable in a poet’s manuscripts, and that these theories are in fact at odds with the cognitive importance of revision. Chapter One then examines Wordsworth’s revisions as a process of self-division, arguing that a more fragmentary form of revision might vouch for the self’s amplitudes. My second chapter explores how revision in Tennyson is capable of effecting the continuity-through-change his poetry is often drawn to. Paying attention to his manuscript drafts, I suggest, helps us to see how this ongoing process of change registers at the level of his technique. In Chapter Three, I turn to the shorter forms of Dickinson, whose compositional process investigates various kinds of in-betweenness. My final chapter considers Hopkins’s revisions as a form of forward thinking, revealing an in-the-moment futurity and waywardness that runs parallel to the role of telos in his writing.

Keywords: Victorian Poetry
Poetic form
Romantic Poetry
Revision
Literature and philosophy
Aesthetics
Advisor: Douglas-Fairhurst, R
Bevis, M
Romanness and Islam: collective Roman identity in Byzantium from the seventh to the tenth century

The thesis seeks to engage with ongoing historiographical debates over the nature of Roman identity in the Byzantine Empire. It aims to circumvent debates over the ethnic or national character of Romanness in Byzantium by focusing on the fluid nature of the boundaries of collective identities to isolate the core qualities that defined the group at its most expansive — which generally occurs in relation to an external ‘other’.
To that end, the thesis is divided into two broad sections. The first examines the underpinnings of Romanness in Byzantium in the late sixth and early seventh centuries, immediately prior to the emergence of Islam and the Arab conquests. It concludes that the defining features of Roman group identity, sine qua non, were adherence to Christianity and an acceptance of the legitimacy of Roman imperial power, vested in the person of the reigning emperor in Constantinople. In this regard, whilst there existed a normative discourse of Romanness in the form of the Chalcedonian Hellenophones that made up the majority of the empire’s elite group, this did not preclude non-Chalcedonians or non-Greek-speakers from considering themselves Roman or being considered as such by others.
The second section takes a diachronic view of how Romanness interacted with the rise of Islam from the middle of the seventh century to the middle of the tenth. Knowledge of Islamic theology spread to the empire gradually over the span of two centuries, resulting in the formation of a particular image of Islam and its practitioners within the empire’s discourse that served a particular socio-cultural function. In short, Islam in Byzantium was constructed in such a way to act as a mirror to Romanness to express the collective identity of the people in the empire and define those who were perceived as ‘non-Roman’.

Keywords: Byzantine studies
groupness
Byzantine history
cultural history
identity
Islamic history
Advisor: Frankopan, P
Assessing hypoxia in cancer: a data-driven approach

Low levels of cellular oxygen, also known as hypoxia, is a major characteristic of solid tumours. Cancer hypoxia is associated with poor prognosis, resulting in prometastatic and angiogenic effects as well as inducing resistance to both chemo- and radiotherapeutic treatments. Despite the critical role that low oxygen tensions play in cancer progression, the clinical use of hypoxia-targeting treatments is still extremely low due to the absence of both accurate and cost-effective methods available to measure hypoxia.
One promising technique to measure hypoxia are gene expression signatures. As opposed to other methods, usually more expensive or invasive, gene expression signatures can be used to measure hypoxia from cancer biopsies, and even in retrospective cohorts. During the last twenty years, more than fifty hypoxia gene expression signatures have been developed. These expression signatures were derived using a variety of computational methods and different experimental conditions. For example, some signatures have been derived in vitro, others in vivo only and others using both approaches including one or more cancer types. As a result, the scientific community has to decide which of the plethora of signatures to use in their experiments and clinical trials, but which signature and which way of summarising a signature into a “score” is most appropriate for which scenario is currently unknown.
This work is the largest and most comprehensive analysis and validation of the 53 published hypoxia gene expression signatures to date. Hypoxia gene expression scores were calculated on publicly available gene expression data from ~1,000 cell line samples (the Gene Expression Omnibus) and ~6,000 clinical samples (The Cancer Genome Atlas) and compared to the same score on normoxic samples. These hypoxia signature scores were compared to the scores derived from more than 7.5 million Random Gene Signatures (RGS) to determine whether they were truly able to measure hypoxia. The overall most effective signature and score combination on cell line samples was the Sorensen 2010 signature using the median score. This achieved an impressive 92.84% accuracy in identifying hypoxic samples in 98 cell lines. In clinical samples, the Buffa 2010 signature using the mean score appears most appropriate as it fulfils the three key criteria of a) being on average higher in tumour samples than in normal tissue samples, b) differing in performance compared to random gene signatures c) serving as a strong prognostic marker (using a number of different thresholds) across 10 important tumour types. However, large prospective clinical studies with multiple measures of hypoxia are urgently needed to affirm our recommendation. This work lays down a new benchmark in how to measure hypoxia and the novel method used may transform how gene expression signatures in multiple fields might be evaluated in years to come.

Keywords: hypoxia
gene expression signatures
random gene signatures
cancer hypoxia
Advisor: Buffa, F
O'Neill, E
Harris, B
Fundamental physics with black holes and scalar fields

One well-motivated proposal to address the limitations of the Standard Model and General Relativity (GR) is the addition of one or more novel scalar fields. In this thesis we will study the interaction of scalar field dark matter (DM) with black holes (BHs), and scalar fields in theories of modified gravity.
The Nobel-Prize-winning detection of gravitational waves (GWs) has opened up a new area of astrophysics. Scalar fields can form dense clouds around BHs, so as most GWs are produced from BH binary mergers, one might be able to detect scalar DM with GW astronomy. We will start by exploring the formation of such clouds, conducting novel simulations of scalar DM accretion onto a spinning Kerr BH, characterising the growth, and estimating the potential for GW signals.
A binary BH merger can be divided into the early inspiral, the highly relativistic merger, and the post-merger “ringdown”. First we will examine the ringdown, deriving a novel analytic perturbative formula to estimate the shift in the GW quasi-normal mode frequencies due to an accreting cloud. We will show that the contribution from the accretion rate, previously neglected, can dominate the shift.
For the early inspiral we will simulate the accretion of scalar DM around BHs on fixed orbits, finding that there is a preferred, quasi-stationary scalar field profile. For the highly relativistic regime we use full Numerical Relativity. We will examine the impact of different initial scalar distributions, showing that the quasi-stationary profile is an attractor solution, and that naively superimposing matter onto a quasi-circular binary can produce unphysical eccentricity.
Lastly, we will explore scalar fields beyond GR. Scalar-tensor theories are a popular modified-gravity model, yet they often predict “fifth forces” which are tightly constrained. It has been shown that for scale-invariant gravity the fifth force is highly suppressed. However, this result was obtained in a particular frame, and quantum effects make the choice of frame highly non-trivial. We will discuss how one can apply a covariant formalism to extend the result to all frames, and show that the usual dichotomy of “Jordan” versus “Einstein” frame can be better understood as a geometric continuum.

Keywords: dark matter
numerical relativity
general relativity
black holes
gravitational waves
scalar fields
fifth forces
Advisor: Ferreira, P
Clough, K
The paladins of Punjab: a history of the Board of Administration, 1849-1853

This thesis is a study of the Board of Administration and its government of Punjab between 1849 and 1853, primarily from the perspective of its British officials. The Board’s administration reflected the conjunction of several interrelated strands. Above all, there was the felt imperative of maximizing the authority of the Company-State in the conditions of Punjabi society, whilst operating in a context of constrained resources. This endeavour was both determined and complicated by British cultural ideals, pre-conceptions, and misperceptions. It was also informed by the specific interests, ambitions, and self-image of individual officials, as well as the institutions and groups of which they were a part. But they were not operating in a vacuum. Pre-existing conditions in Punjab were absolutely critical; so too, the activities of Punjabis themselves. The Board’s administration was susceptible to pushback, subversion, and modification from those it purported to govern. In fact, British-Punjabi collaboration was decisive to the Board’s work. Policies of co-optation were essential to the viability of the Company-State, which was far too weak to impose an entirely autonomous or unilateral will. Equally, coercion was a necessary condition for the Company-State’s authority throughout; and the tactics, strategy, and theory behind the violence inflicted by the Board and its subordinates were fundamental attributes of its rule. But, crucially, much of this coercion depended on the collaboration of certain Punjabi groups. Other core features of the Board’s administration were the gaps between ideals and practice, intentions and outcomes, and the degree to which a lack of accurate information shaped the policies and practices of imperial rule.

Keywords: violence
state formation
imperialism
underdevelopment
Advisor: Morrison, A
Anomalous symmetries of classifiable C*-algebras

This thesis studies the existence and uniqueness of G
-kernels on those C∗
-algebras classified by the Elliott programme. We develop two obstructions to the possible H3
invariants of a G
-kernel. These obstructions arise from studying the unitary algebraic K1
group and the topological K0
group of a C∗
-algebra. As a consequence of these obstructions, we show that any G
-kernel on the Jiang-Su algebra has trivial H3
invariant. Similarly, for finite groups G
, any G
-kernel on the Cuntz algebra O∞
must have trivial H3
invariant.
We construct multiple examples of G
-kernels with non-trivial H3
invariant and, under a UHF-absorption condition, we classify those G
-kernels that have the Rokhlin property on both Kirchberg algebras satisfying the UCT and unital, separable, simple, nuclear, tracially AF C∗
-algebras that satisfy the UCT. As a follow up to this classification, we study the structure of G
-kernels with the Rokhlin property.

Keywords: group actions
classification
G-kernels
actions of tensor categories
Advisor: White, S
Evington, S
The impact of material deprivation and socioeconomic inequalities on the mental health outcomes of children and adolescents

Poverty and inequality are well-evidenced risk factors for mental health, though most of what we know is based on adults in high-income settings. This thesis contributes to efforts to better understand these risks for children and adolescents globally, for whom early intervention might be particularly important. Through a series of mixed-method studies in diverse datasets, the work in this thesis advances our understanding of how poverty and inequality are conceptualized, how they may impact mental health, and what potential interventions may be suitable to address both problems simultaneously. First, Chapter 1 provides a theoretical overview of the concepts of poverty and inequality and the potential mechanisms through which they may affect mental health, with a particular focus on children and adolescents. Second, Chapter 2 charts how the concept of socioeconomic status is defined and operationalized in a critical literature review, arguing that the wide heterogeneity of specific measures used poses important challenges for transparency, understanding of mechanisms, and ultimately appropriate intervention selection. Next, in a large cross-national survey, Chapter 3 zooms in on hunger as a measure for individual-level deprivation and investigates its relationship with mental health, providing evidence for the negative associations between hunger and worrying and suicidality, in addition to stable gender differences, with girls reporting more mental health problems. Then, Chapter 4 broadens out beyond the individual level and examines how country-level indexes for inequality and poverty relate to children and adolescents’ mental health through a multiverse analysis, further corroborating the negative associations between hunger and mental health, and higher frequencies of reporting mental health problems for girls. Finally, Chapter 5 explores one candidate intervention to improve mental health: cash transfers and monetary programs. A systematic review and metaanalysis support small but positive and significant effects of these programs on child and adolescent mental health. Overall, I argue that poverty and inequality can be captured via different specific measures, though relationships may differ in magnitude and significance; that consideration of sub-group effects, such as by gender, is important; that children and adolescents’ own perspectives are often critically left out from informing such choices and their further inclusion should be a priority. Across my work, I find that poverty and inequality are neither unmeasurable, nor unmodifiable. There are effective interventions, such as cash transfers, that can not only improve the material circumstances of young people, but also improve their mental health. As such, I hope my work can contribute to broader efforts that bring us closer to a world without childhood poverty and with better mental health for all.

Keywords: socioeconomic status
global mental health
children and adolescents
inequality
mental health
poverty
Advisor: Bowes, L
Reeves, A
Essays on the relation between higher education and the labour market

An important theme in the economic analysis of education is the relation between students’ decisions to invest in education and the implication of these investments for their wages and productivity on the labour market. Despite being an area of very active research, there is much that remains unknown about why and how students make education decisions, whether these decisions are optimal, and what the effect of these investments are. This thesis contributes to the literature by exploring three questions directly or indirectly relating to these open issues. In the first essay, “Individual and Aggregate Mismatch in Higher Education”, I study the broad public concern that there are too many students who choose to go to university. I produce a model that combines endogenous education choice with heterogeneity and uncertainty in returns, with a labour market framework based on matching that creates supply and demand-like wage responses. In this setting, uncertainty about returns generates individual education mismatch, while endogenous education choice in a matching market generates aggregate inefficiency in education choice. In the second essay, “The Butcher, the Brewer, or the Baker: The Role of Occupations in Explaining Wage Inequality”, we study the importance of the occupational structure in wage determination. We introduce a model that nests Abowd et al. (1999), and estimate it on British data. We find that even if workers and firms were identical, 25% of current log-wage variance would remain, due solely to heterogeneity between occupations. Thus, occupational pay-premia are important sources of wage heterogeneity in the economy. In the third essay, “Determinants of University Subject Choice in the UK”, I study the elasticity of students’ demand for university courses in particular subjects with respect to their expected earnings in that subject. I find that earnings, defined as earnings at age 25 or as lifetime earnings, are positively associated with choice probability, although the quantitative impact of expected earnings on subject choice is not large. I document substantial differences in choice probability between students of different sexes, ethnicities and to a lesser extent, socio-economic classes.

Keywords: wage inequality
higher education
subject choice
occupations
labour market
overeducation
Advisor: Stevens, M
Adams-Prassl, A
Synthesis and application of light-activated DNA

This thesis describes the synthesis and application of UV- and blue light-activatable oligonucleotides for use in cell-free expression systems. A blue light-activatable photocage was developed for control of linear DNA templates, which has shown excellent caging ability and rapid uncaging with blue light. Due to its orthogonality to UV light, a two wavelength-controlled logic gate was developed, and spatiotemporal control of gene expression using these linear templates was demonstrated with one and two wavelengths in synthetic cells. The developed photocaging approach could also be employed on antisense oligonucleotides, providing tight caging and photoactivation of gene knockdown in cell-free conditions. Employing this together with the blue light-activatable DNA templates developed previously allowed for two wavelength-controlled transcription and translation. Two orthogonally activatable light-controlled antisense oligonucleotides were also developed, allowing for the orthogonal control of gene knockdown of two different genes in cell-free conditions through choice of appropriate wavelength. The photocages could also be utilised to form constrained, macrocyclised antisense oligonucleotides by divalent binding of an oligonucleotide to wild-type streptavidin. The resulting handcuff structures showed minimal RNase H activity and were suitable for the control of gene knockdown in cell-free conditions. Lastly, an alternative caging approach was developed by chemoselectively attaching photocages to phosphorothioate linkages in an antisense oligonucleotide. The resulting oligonucleotides showed drastically reduced duplex formation ability and only minimal RNase H activity and enabled light-controlled gene knockdown in cell-free conditions.

Keywords: Control
Gene Expression
Synthetic Cells
Synthetic Biology
Synthetic Chemistry
DNA
Photocages
Advisor: Booth, M
Bayley, J