VictorJuiz/thesis huggingface dataset:
Investigation of neuronal dysfunction in Parkinson's disease using advanced physiological induced pluripotent stem cells

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.

Keywords: Parkinson's disease
microcircuit
induced pluripotent stem cells
medium spiny neuron
microfluidics
organoid
Advisor: Wade-Martins, R
Bengoa-Vergniory, N
Marquez Gomez, R
Combined optogenetic and pharmacological analysis of 5-HT control of cortical microcircuitry

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.

Keywords: PVIN
Optogenetics
DOI
Psilocin
DRN
mPFC
5-HT
Optotagging
5-HT2A
Silicon probe recording
Advisor: Sharp, T
Mann, E
Beyond action: applying consequentialism to decision making and motivation

It is often said that there are three great traditions of normative ethics: consequentialism, deontology, and virtue ethics. Each is based around a compelling intuition about the nature of ethics: that what is ultimately important is that we produce the best possible outcome, that ethics is a system of rules which govern our behaviour, and that ethics is about living a life that instantiates the virtues, such as honesty, compassion and loyalty. This essay is about how best to interpret consequentialism. I show that if we take consequentialism beyond the assessment of acts, using a consequentialist criterion to assess decision making, motivation, and character, then the resulting theory can also capture many of the intuitions about systems of moral rules and excellences of character that lead people to deontology and virtue ethics.
I begin by considering the argument that consequentialism is self-defeating because its adoption would produce bad outcomes. I take up the response offered by the classical utilitarians: when properly construed, consequentialism does not require us to make our decisions by a form of naïve calculation, or to be motivated purely by universal benevolence. Instead it requires us to use the decision procedure that will produce the best outcome and to have the motives that lead to the best outcome. I take this idea as my starting point, and spend the thesis developing it and considering its implications.
I demonstrate that neither act-consequentialism nor rule-consequentialism has the resources to adequately assess decision making and motivation. I therefore turn to the idea of global consequentialism, which assesses everything in terms of its consequences. I then spend the greater part of the essay exploring how best to set up such a theory and how best to apply it to decision making and motivation. I overcome some important objections to the approach, and conclude by showing how the resulting approach to consequentialism helps to bridge the divide between the three traditions.

Advisor: Broome, J
Parfit, D
Harmful grandiose delusions: developing a cognitive model

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.

Keywords: psychosis
cognitive model
grandiose delusions
Advisor: Freeman, D
Bentall, R
Sound and control in Welsh poetry (c. 1300-c. 1600)

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.

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
Advisor: Williams, M
Connectivity modelling for a species-driven nature recovery network in Oxfordshire

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.

Keywords: spatial prioritization
network modeling
nature recovery
conservation
species distribution model
connectivity
Advisor: Smith, A
Machine learning approaches for computer aided drug discovery

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.

Keywords: structure-based drug discovery
deep learning
drug discovery
cheminformatics
Bayesian optimization
machine learning
molecular docking
graph neural networks
Advisor: Morris, G
Integrative approaches in fragment-based drug discovery


This thesis combines experimental and computational methods to investigate aspects of fragment identification and elaboration in fragment-based ligand design, a promising approach for identifying small molecule drugs, to target the pharmacologically relevant bromodomain PHIP(2). The research covers various aspects of the process, from initial crystallographic fragment screening to validation of follow-up compounds.
Chapters 1 and 2 provide an overview of relevant perspectives and methodologies in fragment-based drug discovery. Chapter 3 reports a crystallographic fragment screening against PHIP(2), resolving 47 fragments at the acetylated-lysine binding site, and evaluates the abilities of crowdsourced computational methods to replicate fragment binding and crystallographic poses. This chapter highlights the challenges associated with using computational methods for reproducing crystallographic fragment screening results with submissions performing relatively weakly. Chapter 4 demonstrates the advantages of X-ray crystallographic screening of crude reaction mixtures generated robotically, showcasing reduced time, solvent, and hardware requirements. Soaking crude reaction mixtures maintains crystal integrity which led to the identification of 22 binders, 3 with an alternate pose caused by a single methyl addition to the core fragment and 1 hit in assays. It demonstrates how affordable methods can generate large amounts of crystallographic data of fragment elaborations. Chapter 5 develops an algorithmic approach to extract features associated with crystallographic binding, deriving simple binding scores using data from Chapter 4. The method identifies 26 false negatives with binding scores enriching binders over non-binders. Employing these scores prospectively in a virtual screening demonstrated how binding features can be exploited to select further follow-up compounds leading to low micromolar potencies. Chapter 6 attempts to integrate more computationally intensive methods to identify fragment follow-up compounds with increased potency through virtual screening enhanced with free energy calculations. Only two out of six synthesised follow-up compounds showed weak binding in assays, and none were resolved in crystal structures.
This thesis tackles critical challenges in follow-up design, synthesis, and dataset analysis, underlining the limitations of existing methods in advancing fragment-based drug discovery. It emphasises the necessity of integrative approaches for an optimised “design, make, test” cycle in fragment-based drug discovery.

Keywords: Structural Biology
Computational chemistry
Biophysics
Fragment-Based Drug Discovery
Pleckstrin-homology domain interacting protein
Advisor: Biggin, P
von Delft, F
Theoretical and practical continuity in the making of Ottoman/Turkish literary history: a metahistoriographical analysis

The practice of literary historiography in the Ottoman Empire and Turkey is considered to be a relatively recent phenomenon, the emergence of which is thought to take place in the early twentieth century. Mehmed Fuad Köprülü (1890-1966) is widely acknowledged as a pioneer of the discipline. Neither the period preceding Köprülü’s input, nor the aftermath of his impact have yet come under the spotlight of rigorous scholarly research. There have been no comprehensive analytical surveys of the corpus, with a comparative perspective that evaluates the works in and of themselves as well as their similarities and differences, which could reveal the evolution of the theoretical and practical aspects of the making of Ottoman/Turkish literary history.
The purpose of this study is to tell the untold story of the intellectual journey taken by the literary historians of the Ottoman Empire and Turkey employing a novel, analytical and systematic approach to the original texts. In this project, the focus is on the historiography of literary production in Turkish, both in Perso-Arabic script and Latin, and of the Ottoman Empire and of the Turkish Republic, although there might be historiographical practices carried out in other languages, by other peoples of the Empire. The study features an extensive analysis of the corpus, commencing with early forms of literary historiography seen in the second half of the nineteenth century and encompassing the forty-five works written in the following period until the present day. It continues with an argument that challenges the prevalent viewpoint posited by contemporary criticism, featuring the idea of an epistemological rupture attributed to the transformations in the late nineteenth and early twentieth century, and particularly to the formation of the Republic. Here is demonstrated that the idea of continuity dominates the course of historiographical practice, both in the theoretical and practical sense.

Keywords: metahistoriographical analysis
Ottoman/Turkish literary historiography
theoretical and practical continuity