VictorJuiz/thesis huggingface dataset:
Screening and the association between cervical cancer and known reproductive and hormonal factors
Keywords: Reproductive risk factors
Cervical screening
Hormonal risk factors
Cohort study
Cervical cancer
Histological type
Epidemiology

Epidemiological studies have shown associations between reproductive and hormonal factors and cervical carcinogenesis, but have had limited information on previous cervical screening. Screening is known to reduce the incidence of invasive cervical cancer (ICC) and there is some evidence that reproductive and hormonal factors affect screening uptake. The main aim of this thesis was to examine the risk of cervical neoplasia i.e., pre-invasive cervical intraepithelial neoplasia grade 3 (CIN3) and ICC, associated with reproductive factors, namely parity and age at first birth, and hormonal factors, namely use of oral contraceptives (OC) and menopausal hormone therapy (MHT), taking into account confounding by screening history.
Analyses involved over 800,000 women in the Million Women Study with linked NHS Cervical Screening Programme records, including over 1400 cases of CIN3 and 1000 cases of ICC. Using logistic regression, non-attendance for cervical screening was found to vary considerably according to reproductive and hormonal factors. Using Cox regression to estimate relative risks of cervical neoplasia, I found that early childbearing was associated with increased risks of CIN3 and ICC after adjustment for multiparity. For hormonal factors, while use of OCs was not associated with overall ICC, there were heterogenous associations by histo-type. In particular, among users of OCs risks were increased for squamous cell carcinoma (SCC) but reduced for adenocarcinoma (AC). The increased risk of SCC with increasing duration of use of OCs persisted for up to 30 years after cessation of use. Use of MHT was associated with a reduction in risk of ICC which was also heterogenous by histo-type; for SCC there was a significant reduction in risk with MHT use, but no significant association with AC.
This large prospective analysis confirms that early childbearing contributes to cervical neoplasia risk and suggests that long duration use of OCs confers a persistent risk of invasive SCC. This study also provides new evidence that hormonal risk factors for cervical cancer may vary between the two major histo-types, SCC and AC, highlighting the need for further research on these cancers.
Desperate remedies and vital lies: art, literature, and escapism, 1840-1914
Keywords: evasion
Bion
Winnicott
art
Edmund Gosse
psychoanalysis
Victorian
ambivalence
narcosis
therapuetic
escapism
illusion
Thomas Hardy
tragedy
poetics
literature
John Ruskin
Klein
bibliotherapy
catharsis
nineteenth century
Freud

In response to a pervasive pessimism that saw little ‘help for pain’ in facing reality, writers of the late nineteenth century recuperated escapism, the use of art to avoid reality for the sake of relief, as a viable remedy for discontent. This thesis uncovers a specifically ambivalent escapist tradition across genres in the writing of the art and social critic John Ruskin (1819-1900), the novelist and poet Thomas Hardy (1840-1928), and the memoirist and man of letters Edmund Gosse (1849-1928). Their ambivalent rehabilitation of avoidance provides a necessary corrective to dominant trends in Victorian studies, which instrumentalise literature as an aid to cognitive clarification, ethical commitment, and emotional containment. Ruskin, Hardy, and Gosse envisage ambivalently escapist conceptions of art that paradoxically retain the disquietude they ostensibly seek to elude. The pleasures their texts offer are distinctly guilty pleasures, and this cultivation of ambivalence allows them to fundamentally challenge the escapist predicament even as they appear to accept its terms. In their writing, simplistic dichotomies, such as confrontation and evasion, or contentment and discontentment, give way to more nuanced negotiations of the uses of disillusionment and reillusionment, and the place of ambivalence as both an obstructive and motivational force in psychological development. While Ruskin finds in diminished consciousness a space for dreaming new political and psychological realities into being, Hardy conceptualises cathartic relief as uncontainment to explore the embodied nature of the ethical problem of tragic pleasure in a way that overcomes narrow moralistic didacticism, and Gosse finds in escapism a way of exploring homoerotic and sadomasochistic desire, as well as a method of detaching himself from the circumstances of his upbringing. Engaging critically with insights from psychoanalysis, the eudaimonic tradition in ethics, and queer theory, this thesis proposes new accounts of the function of art in Victorian and Edwardian self-culture, the utopian character of Ruskin’s moralism, Hardy’s satirical engagements with the Aristotelian tradition in his tragic fiction, and Gosse’s initiation of the modern memoir as an essentially escapist fiction.
Development of culture and imaging techniques to investigate human follicle development
Keywords: tissue clearing
follicle
tissue culture
ovary
fertility preservation

The number of young cancer survivors is growing, as both the incidence and survival rates for cancer increases. Cancer treatment can cause damage to the ovaries, which can cause infertility. Although there are ways of preserving the fertility of girls and women undergoing cancer treatment, these methods are invasive and some do not restore ovarian function. In recent years, there has been growing interest in developing non-invasive pharmacological methods of fertility preservation, including administrating drugs to protect the ovaries from the damaging effects of chemotherapy. However, the mechanisms of chemotherapy-induced follicle loss remain poorly understood, hampering progress in the field. The aim of this thesis was to address the knowledge gaps by developing culture and imaging techniques to investigate human follicle development in vitro. The effect of different culture conditions on follicle health and development in cryopreserved human ovarian tissue was investigated, revealing that culture in a low volume of αMEM medium improved follicle health. Experiments investigating different thawing protocols on ovarian stromal health highlighted that cryopreservation causes damage to both follicles and stroma and therefore fresh ovarian tissue was used in the remaining experiments. A technique to allow three-dimensional visualisation of follicles was developed using whole-mount immunolabelling and tissue clearing and was used to investigate follicle activation of fresh ovarian tissue in vitro. This study revealed that three-dimensional analysis was necessary to accurately distinguish between primordial and transitional follicles and that a large proportion of follicles were disc-shaped rather than spherical. No apparent increase in follicle activation was observed within 48 h of culture, however low sample numbers limited this study. A final set of experiments was planned, investigating the effects of chemotherapy drugs on human primordial follicles in vitro, however this could not be performed due to the coronavirus disease of 2019 (COVID-19) pandemic. The work presented in this thesis highlights the need to consider the heterogeneity and the three-dimensional structure of follicles within the human ovary.
Investigation of neuronal dysfunction in Parkinson's disease using advanced physiological induced pluripotent stem cells
Keywords: Parkinson's disease
microcircuit
induced pluripotent stem cells
medium spiny neuron
microfluidics
organoid

The study of Parkinson’s Disease (PD) pathogenesis has been greatly facilitated by the revolutionary induced pluripotent stem cells (iPSC) technology which permits modelling of PD using human neurons and with human-specific genetics. However, current iPSC-derived models are still largely dependent on adherent monoculture of a single cell type with limited capacity to capture the complex neuronal microenvironment and the resulting plethora of cell-cell interactions evident in vivo. Here, I described attempts at establishing three different strategies of advanced culturing of iPSC-derived neurons, namely i) the striatal presynaptic microcircuit consisting of iPSC-derived medium spiny neurons (MSN), cortical and dopaminergic neurons , ii) human midbrain-like organoids (hMLO) and iii) the fluid-walled microfluidic-based corticostriatal pathway. The striatal microcircuit recapitulated the directed connectivity of the presynaptic landscape of MSN wherein both cortical and dopaminergic axons converged on the MSN. Electrophysiological recordings of the MSN of the striatal presynaptic microcircuit delineated the pro-maturational roles of cortical and dopaminergic inputs on MSN physiology, as well as the pathological effect of DaN harbouring PD-related GBA N370S mutation on inducing early and transient immature and hyperexcitable-like phenotype of the connected healthy MSNs. On the other hand, characterisation of the hMLO suggested expression of DaN of floor-plate origin surrounded by diverse subsets of neuronal and neural cells. However, hMLO derived from PD patients carrying the triplication of SNCA or the N370S GBA mutation lacked phenotypic DaN degeneration or synucleinopathy. Lastly, I recreated the corticostriatal pathway on the novel fluid-walled microfluidic platform. This provided the proof-of-concept of the possibility to recapitulating any neuronal circuits of interest in an open-access fashion free of the obstructive barrier apparent in conventional microfluidic approach, rendering it suitable for direct physical manipulation such as directed axotomy. Live monitoring of axon growth post directed axotomy suggested the positive effect of permissive environment such as that induced by exogenously supplied brain-derived trophic factor (BDNF) or endogenous post-synaptic target (i.e. MSN) on cortical axon regeneration. Taken together, this work offers frameworks of novel advanced culture strategies that could be employed to improve neuronal maturation in in vitro modelling as well as to facilitate studies of network-dependent biological phenomena.
Combined optogenetic and pharmacological analysis of 5-HT control of cortical microcircuitry
Keywords: PVIN
Optogenetics
DOI
Psilocin
DRN
mPFC
5-HT
Optotagging
5-HT2A
Silicon probe recording

5-HT (5-hydroxytryptamine, serotonin) powerfully influences cognition and mood regulation. In the medial prefrontal cortex (mPFC), the intricate balance between excitation and inhibition in celluar microcircuits allow the generation of network oscillations that encode behaviour and cognition. In particular, parvalbumin expressing interneurons (PVINs) act as key regulators of the excitatory/inhibitory balance. The precise interactions between the 5-HT system and these PVINs, however, are little understood. Using an array of modern neuroscience tools, this thesis provides a comprehensive report of interactions between the 5-HT system and different neuron subtypes in the mPFC, including PVINs.
In slice electrophysiology experiments, local application of 5-HT greatly increased the intrinsic excitability of genetically labelled PVINs in the mPFC via the 5-HT2A receptor. Such 5-HT2A receptor-mediated activation of PVINs was then demonstrated in in vivo silicon probe multi-unit recordings following the systemic administration of the 5-HT2A receptor agonists DOI and psilocin. Pharmacological activation of the 5-HT2A receptor suppressed slow wave oscillations and elevated multi-unit activity in the mPFC, possibly via the excitation of putative PVINs and the disruption of their correlated activity with neighbouring neurons.
With an optogenetic approach, the effects of physiologically evoked 5-HT on neural activity in the mPFC were determined. This methodology was first verified with immunohistochemistry as well as in vitro and in vivo electrophysiology, which revealed diverse firing properties of optotagged 5-HT neurons. Specifically, optotagged regular-firing 5-HT neurons tended to fire action potentials following light stimuli up to 20 Hz, whereas optotagged irregular-firing 5-HT neurons were unlikely to sustain spiking at higher frequencies. Optogenetic activation of 5-HT neurons induced frequency-dependent suppression of slow wave oscillations and increase in UP state duration. Changes in the firing rate of individual neurons, including PVINs, were mainly inhibitory, although excitatory effects and non responders were also observed. Notably, optogenetic activation of 5-HT neurons at high frequencies disrupted the spiking correlation between putative PVINs and other neurons, once again providing a potential mechanism for 5-HT modulation of excitatory-inhibitory balance and local oscillations in the mPFC.
Collectively, this thesis presents concrete evidence for 5-HT modulation of microcircuit activity, including PVINs, in the mPFC. These findings highlight the importance of elucidating the actions of 5-HT on a cellular level in gaining a better understanding of how 5-HT shapes cortical network output and, ultimately, cognition.
Harmful grandiose delusions: developing a cognitive model
Keywords: psychosis
cognitive model
grandiose delusions

Background
Grandiose delusions are inaccurate beliefs about having special powers, wealth, mission, or identity. They are a common psychotic experience, but neglected as a specific focus of research. There is no evidence-based theoretically driven psychological intervention for harmful grandiose delusions.
Aims
The thesis aimed i) to determine the extent to which patients identify harmful consequences occurring as a result of grandiose delusions and whether they want help with these harms, and ii) to develop a theoretical causal model of grandiose delusions and conduct preliminary tests of the model.
Method
A qualitative study is reported in which fifteen patients with experiences of grandiose delusions were interviewed. Thematic analysis and grounded theory were used to analyse the data (Chapter 2). Analyses are also reported from cross-sectional questionnaire data collected from two non-clinical cohorts (n=13,323) and a clinical cohort of 798 patients with a psychosis diagnosis, 375 of whom had grandiose delusions (Chapters 3-5).
Results
More than three-quarters of patients with grandiose delusions identified grandiose-related harms occurring in the past six months. Over half of patients wanted help with these difficulties. Six putative maintenance factors for grandiose delusions were identified. Tests of association found that in the clinical group, the meaning of grandiose delusions, repetitive thinking about the grandiose belief, immersion behaviours, and daydreaming accounted for 53.5%, 20.4%, 39.5%, and 19.1% of the variance in grandiosity severity respectively.
Conclusions
Most patients with grandiose delusions identify difficulties arising from their grandiose delusions, which may provide a route for engagement in treatment. Potential maintenance mechanisms that may be suitable targets for intervention include the meaning of the grandiose delusions, immersion behaviours, perseverative thinking, and pleasant daydreams. If these findings are verified by further longitudinal and experimental research, this would enable the development of a specific cognitive-behavioural intervention for people with harmful grandiose beliefs.
Sound and control in Welsh poetry (c. 1300-c. 1600)
Keywords: early modern
iolo goch
studies
1300
cerddoriaeth
late
cynghanedd
middle ages
bilingualism
Lucier
David Willis
Dutch
sound
hearing
Llawysgrifau
performance
music
control
Harper
multilingualism
crwth
poetry
perfformio
Irish
gymreig
dafydd ap gwilym
manuscript
study
harp
1600
Dafydd Johnston
sensory
Corbin
1282
French
multilingual
Welsh
Robert ap Huw
lears
listening
Edwardian
cymraeg
cymreig
gymraeg
Celtic
Cornish
Conquest
manuscripts
English
Latin
barddoniaeth
bilingual
noise
Schafer
senses
medieval
literature
beirdd yr uchelwyr

This thesis connects the fields of sound studies and medieval Welsh history and literature. In doing so, it argues two related points. Firstly, by using the poetry of ‘Beirdd yr Uchelwyr’ (the Poets of the Nobility, c. 1300–c. 1600) as a case study, it demonstrates that much new and nuanced meaning can be unveiled by listening carefully to the sounds represented in a body of medieval literature. In this sense, it is the first attempt to apply the theories and methods of sound studies systematically to literature in a Celtic language.
Secondly, in assessing some of these new meanings, it shows the relevance of several aspects of medieval scientific thought concerning sound, especially the importance of controlling ‘sound’ lest it become ‘noise’; meaningful sound was controlled sound. It argues that Welsh poets’ concern with control was partly a reaction to social and environmental change. Poets felt threatened by aspects of colonisation, urbanisation, and mechanisation caused by the Edwardian Conquest, and wider European trends. Anxious that patrons were turning elsewhere, poets emphasised the exceptionalism of their controlled and refined Welsh, especially their strict-metre poetry. This anxiety was projected onto the wider auditory world. Acceptable sounds – holy bellringing, the Latin language, beautiful harps – were described in terms of control, while unacceptable noises – minstrels, foreign vernaculars, crwth music – were described in terms of disorder.
Overall, this thesis argues for the importance of listening to all aspects of premodern literature, particularly the highly aural poetry of medieval Wales. Before industrialised, mechanised, and electrified sounds, and before sight became the primary means to access truth and knowledge, hearing was just as important as seeing. An aural-sensitive reading reveals several new meanings in this body of poetry produced by anxious and conservative listeners attempting to control a changing world with a changing place for poets.
Connectivity modelling for a species-driven nature recovery network in Oxfordshire
Keywords: spatial prioritization
network modeling
nature recovery
conservation
species distribution model
connectivity

The development of England’s new Nature Recovery Network has been piloted in several counties in the country, but few have systematically mapped connectivity based on species dispersal. This study proposes and evaluates a novel modelling framework that integrates various layers of species information into a spatial conservation prioritization analysis. It aims to strategically identify optimal zones for nature recovery that can maximize species connectivity in Oxfordshire, using bats as a focal species. The framework was able to not only identify key landscape corridors but also stepping stone habitats for bats and emphasized how well-placed, small-scale green and blue infrastructure, such as hedgerows and ponds, can be just as effective as larger reserves. It also found that the current coverage of protected areas may not adequately be protecting woodland habitat needed for connectivity. Next steps for Oxfordshire’s NRN should scale up the application of this connectivity framework to address these areas of priority in the landscape.
Machine learning approaches for computer aided drug discovery
Keywords: structure-based drug discovery
deep learning
drug discovery
cheminformatics
Bayesian optimization
machine learning
molecular docking
graph neural networks

Pharmaceutical drug discovery is expensive, time consuming and scientifically challenging. In order to increase efficiency of the pre-clinical drug discovery pathway, computational drug discovery methods and most recently, machine learning-based methods are increasingly used as powerful tools to aid early stage drug discovery.
In this thesis, I present three complementary computer-aided drug discovery methods, with a focus on aiding hit discovery and hit-to-lead optimization. In addition, this thesis particularly focuses on exploring different molecular representations used to featurise machine learning models, in order explore how best to capture valuable information about protein, ligands and 3D protein-ligand complexes to build more robust, more interpretable and more accurate machine learning models.
First, I developed ligand-based models using a Gaussian Process (GP) as an easy-to-implement tool to guide exploration of chemical space for the optimization of protein-ligand binding affinity. I explored different topological fingerprint and autoencoder representations for Bayesian optimisation (BO) and showed that BO is a powerful tool to help medicinal chemists to prioritise which new compounds to make for single-target as well as multi-target optimisation. The algorithm achieved high enrichment of top compounds for both single target and multiobjective optimisation when tested on a well known benchmark dataset of the drug target matrix metalloproteinase-12 and a real, ongoing drug optimisation dataset targeting four bacterial metallo-β-lactamases.
Next, I present the development of a knowledge-based approach to drug design, combining new protein-ligand interaction fingerprints with a fragment-based drug discovery approach to understand SARS-CoV-2 Mpro-substrate specificity and to design novel small molecule inhibitors in silico. In combination with a fragment-based drug discovery approach, I show how this knowledge-based interaction fingerprint-driven approach can reveal fruitful fragment-growth design strategies.
Lastly, I expand on the knowledge-based contact fingerprints to create a ligand-shaped molecular graph representation (Protein Ligand Interaction Graphs, PLIGs) to develop novel graph-based deep learning protein-ligand binding affinity scoring functions. PLIGs encode all intermolecular interactions in a protein-ligand complex within the node features of the graph and are therefore simple and fully interpretable. I explore a variety of Graph Neural Network architectures in combination with PLIGs and found Graph Attention Networks to perform slightly better than other GNN architectures, performing amongst the best known protein-ligand binding affinity scoring functions.