VictorJuiz/thesis huggingface dataset:
Multi-omics analysis and modelling of T cell immunity and interferon signalling pathways for engineered T cell therapy

This thesis examines the nature of T cells through the lens of genomics. It delves into type I interferon (IFN)-mediated signalling in the tumour microenvironment (TME), focusing on the GMP-AMP synthase (cGAS)-stimulator of IFN genes (STING) pathway, and explores novel strategies to optimise T cell-based immunotherapy for triple-negative breast cancer (TNBC). In the first chapter, gene expression patterns of distinct T cell subtypes are studied to gain insight into the diverse T cell landscape. Cell type annotation methods are evaluated for their ability to identify closely-related T cell populations in single-cell RNA sequencing (scRNA-seq) data. In the following chapter, single-cell and spatial transcriptomics methods, mainly scRNA-seq, single-cell immune profiling, Slide-seq, in situ sequencing and Molecular Cartography enable the comprehensive analysis of immune infiltrates in tissue biopsies from patients with TNBC. The advantages and limitations of emerging spatial transcriptomics technologies are put into context. Tumour-infiltrating T cells were characterised at varying levels of resolution and cGAS was found to be most highly expressed in proliferating T cells. Tissue-wide spatial patterns revealed a strong relationship between programmed cell death-1/programmed cell death ligand-1 and cGAS but not STING. In addition, gene transcripts encoding the downstream protein kinase TANK-binding kinase 1 were found to spatially associate with hypoxia markers. Finally, T cells genetically engineered to express chimeric antigen receptors (CARs) are investigated using a systems biology approach. An agent-based model is developed to explore the effect of CAR tuning on on-target off-tumour toxicity and therapy efficacy. Gene regulatory networks are used to present readily testable hypotheses for combination strategies using immune checkpoint inhibitors, oncolytic viruses, and cGAS-STING-targeting treatments to potentiate anti-tumour responses. The work presented therein will feed into a novel computational framework to enable the modelling of patient-specific responses to T cell-based immunotherapy and synergistic combinations.

Keywords: Breast Cancer
Spatial Transcriptomics
Immunotherapy
Multi-Omics
CAR T Cells
T Cells
Clinical Samples
scRNA-Seq
Interferons
Tumour Immunology
cGAS–STING
Advisor: Fulga, T
Buffa, F
Klenerman, P
Structural and behavioural signatures of enhanced plasticity resulting from a single dose of the psychedelic drug DOI

Psychedelic drugs can aid fast and lasting remission from various neuropsychiatric disorders, presumably by increasing neuroplasticity. Growing evidence shows enhanced neuronal plasticity in the first week post-treatment, but it is unclear if these changes are integrated across higher levels of analysis to explain the long-term shifts in behaviour. We searched for signatures of enhanced plasticity at behavioural, cognitive, and structural levels to determine if a single dose of the psychedelic drug DOI induces a comprehensive and lasting high-plasticity state in young adult C57BL/6 male mice.
On a behavioural level, high-plasticity states are environmentally sensitive, so we tested whether the acute psychedelic state in mice is context-dependent. We compared DOI’s dose-response curves in a familiar and novel context and found that novelty modulated the frequency of psychedelic-like behaviours without modulating the drug’s effects on exploration.
On a cognitive level, high plasticity implies better cognitive flexibility, so we tested reversal learning in a two-step decision-making task in the weeks after a single moderate dose of DOI. Adaptability to a novel reversal one day after DOI was comparable to the controls. But when we initiated a novel reversal one week after treatment, allowing for consolidation of putative neuronal plasticity, DO-Itreated mice adapted faster and developed a richer choice strategy.
On a structural level, high and extensive neuronal plasticity would lead to regional changes in grey matter volume. Using ex vivo magnetic resonance imaging, we showed increased volumes of several sensory and association cortices 24h, but not three weeks, after one moderate dose of DOI.
In conclusion, we found signs of DOI-induced higher brain plasticity at several levels of analysis that are correlated but not necessarily coincidental with known neuronal plasticity. We suggest that while DOI’s neuronal plasticity can initiate higher-level plasticity, its consolidation might be required for any enduring cognitive and behavioural change.

Advisor: Walton, M
Bannerman, D
Lerch, J
Vyazovskiy, V
Economics and writing in Jeremiah 32

In Jeremiah 32, the portrayal of economic writing creates conditions suitable for reading Jer 32 as a creative and productive analogy for prophetic writing. The composite nature of the text allows it to be read as a microcosm of the growth of the Book of Jeremiah.
Just as economic writing secures testimony to a transaction, conveys ownership through time, and offers the possibility of economic renewal after exile, prophetic writing secures testimony to the divine message, conveys divine speech through time, and offers the possibility of covenant renewal after exile. What is more, Jer 32 presents economic writing as the prophet's initiative, and the expansion of the historical sign-act into the wider narrative of the chapter presents a sophisticated evocation of the potential of prophetic writing to address circumstances in other times and places.
The transformation of the sign-act of Jer 32.6–15 into a written prophetic text, and the growth of the text over time, allows Jer 32 to be read as a microcosm of the development of the Book of Jeremiah. The realism of the material details enhances the persuasive effect of the analogy between economic and prophetic writing, rather than providing a precise basis for identifying the origins of elements of the composite text of Jer 32.
Jer 32 does not offer a presentation of ethical norms for the economic practice of redemption of land. Redemption of land and economic hope are, of course, central to the narrative of Jer 32 as a whole. Jer 32 does not, however, offer a clear prospective ethic for economic practices. Instead, the economic practice of redemption, with all its details, provides narrative realism for the text, and the economic practice of writing provides a narrative analogue for the idea of prophetic writing.

Advisor: Najman, H
Towards truly open-ended reinforcement learning

Deep reinforcement learning (RL) has achieved some remarkable successes in the past decade, from super human performance in games to real world problems such as robotics and even Nuclear Fusion. Indeed, given its generality, many prominent researchers in the field believe RL alone may be sufficient for producing Artificial General Intelligence (AGI). It is easy to see why, RL is in theory an open-ended process where an agent never stops learning from its own experiences, given a suitably complex environment. In this thesis we posit that the key factor limiting RL agents is the requirement for static, human designed configurations. On the agent side, we typically tune a single set of hyperparameters for a specific agent with a specific architecture, ignoring the fact these may need to adapt over time. At the same time, even if we did have a powerful RL agent, we lack a sufficiently complex environment that could facilitate the learning of general behaviors.
We hypothesize that the only way to get past this problem is to embrace open-endedness, by designing systems with infinite capacity to produce new, interesting things. In the first part we introduce new methods for adapting several important agent hyperparameters on the fly, using a population of agents. We show this makes it possible for agents to adapt several of their own hyperparameters over time. Next we introduce a new approach for automatically designing environments, evolving a curriculum that constantly proposes new challenges at the frontier of the student agent’s capabilities. Combining these two advances could produce an open-ended learning system where agents and environments co-adapt over time, producing increasingly complex problems and an agent that can solve them.
However, even this would not be truly open-ended, as it would eventually plateau once the agent can solve every task from a human-specified distribution. In the second part of the thesis we propose directions to make this system unbounded. First, we introduce two new approaches for encouraging the discovery of diverse solutions, which we show can help avoid deceptive local optima and discover a broader set of behaviors. Finally, we posit that one path towards a truly open-ended system is to remove the need for human-designed simulated environments altogether and instead train agents inside learned world models. We discuss several contributions in this area including active data acquisition to improve the world model, as well as an approach to produce synthetic experiences inside the world model that increase the robustness of our agents. We conclude with a proposal for a future system combining these insights, which we believe could be truly open-ended.

Advisor: Roberts, S
The evolutionary ecology of phage mediated horizontal gene transfer

The continuing rise of antibiotic resistance is threatening a return to a world where we are unable to treat the most minor of bacterial infections. Drug-resistant pathogenic bacteria are already killing hundreds of thousands of people and causing considerable economic damage around the world. These numbers will only increase unless steps are taken to curb the spread of resistance.
We need, therefore, to understand how resistance spreads and persists in populations of bacteria. One of the ways that resistance spreads is on plasmids, but it is not clear how these plasmids can persist in the absence of positive selection. It has been shown that conjugative plasmids can be maintained by experiencing episodes of horizontal gene transfer. However, numerous plasmids cannot transfer through conjugation, and how they persist is challenging to understand. Bacteriophages (which are the most numerous biological entity on the planet) could play a part in transferring plasmids horizontally.
My research aims to look at the transduction of an antibiotic resistance plasmid using both experimental and theoretical approaches. I start by looking at whether temperate or lytic phage could mobilize the plasmid and move it between bacteria. I then use a long term experiment to see whether phage can transfer and maintain a plasmid in a population of bacteria. I also examine modelling approaches to see the insights they can provide into how horizontal gene transfer and different aspects of transduction can allow plasmid persistence.
Bacteria-Bacteriophage interactions are complex and will be affected by several factors not considered here. However, my work shows that study of antibiotic resistance should significantly consider the effects of transduction, especially considering the large number of resistance genes that have already been found in the phageome.

Advisor: MacLean, C
Bonsall, M
'Literary studies must be a science' (Yury Lotman): representing and interpreting character relationships in Russian drama by means of quantitative methods

This thesis explores and demonstrates the possibility of using quantitative and digital methods to analyse Russian drama texts. The methodology under discussion lies within the fields of Digital Humanities and Digital Literary Studies, and includes Social Network Analysis (SNA) and Natural Language Processing (NLP) techniques. The project is structured as several independent case-studies that are united by a discussion of the advantages and limitations of the methodology.
The first chapter of this thesis introduces the reader to the encoding standards of the texts (TEI XML) necessary for carrying out the quantitative analysis of the plays, as well as the basics of the methodology, including definitions and formulas for calculations. These methods are then illustrated in detail by presenting a first case-study, showing how automatic methods can be used to establish the hierarchy of the protagonists in three 19th-century Russian plays.
This thesis aims to reflect the exploratory and innovative nature of the application of digital methods to literary data. Hence, each chapter introduces new methods in addition to the ones discussed in the Introduction. The next case-study is devoted to the comparison of two plays with similar plots but different network structures, and includes a more detailed analysis of the speech of the characters in the two plays.
The third case-study focuses on the representation of women in 19th-century Russian drama and attempts to combine ‘distant’ and ‘close’ reading methods, to explore the full capacity of the digital approach. It is followed by a final section discussing the applicability of the methods to contemporary plays from the Soviet period and the beginning of the 21st century, with a greater focus on the limitations of the methodology.
The work is rounded off with a concluding section, in which an overview is provided of the general structural evolution of Russian-language drama, alongside a discussion of the potential for further research in this area.

Keywords: computational linguistics
digital literary studies
social network analysis
Russian drama
digital humanities
Advisor: Curtis, J
Bullock, P
Are atypical workers worse off? Essays on temporary and part-time employment in Europe

This doctoral thesis contributes to research on socio-economic inequalities associated with two types of atypical employment, part-time and temporary work. Paper 1, entitled “Wage differences between atypical and standard workers in European countries: Moving beyond average effects” shows that wage penalties associated with temporary and part-time employment differ across the wage distribution, based on a sample of seven European countries. Temporary employment is associated with significant wage penalties that decrease but largely remain significant towards the upper end of the wage distribution. In contrast, wage differences between part-time and full-time workers are smaller and range from part-time penalties at lower deciles of the wage distribution to non-significant differences or premiums at the top. Paper 2, “Bridge for some, trap for others? Career phase variation in the long-term wage growth of temporary workers”, examines whether the long-term wage growth consequences of temporary employment differ by career phase. Focusing on Germany, it shows that the wages of early-career temporary workers eventually converge with those of permanent workers, while temporary workers at later career stages experience long-term wage divergence. This variation can partially be attributed to differences in the subsequent labour market careers of temporary workers. Paper 3 is entitled “Does atypical employment come in couples? Evidence from European countries”. It examines whether partner atypical employment affects own atypical employment, based on a sample of 29 European countries. The results show that partner temporary employment increases the likelihood of own temporary employment. Accumulation of part-time employment is also observed, albeit at a smaller scale. Finally, paper 4, entitled “Accumulation or mitigation? The impact of atypical employment in couples on joint labour income” looks at the effect of part-time and temporary employment in German couples on couples’ joint labour income, and gender differences therein. Both temporary and part-time employment in couples are associated with a negative income effect, which becomes insignificant for part-time employment once adjusting for working hours. There is also some indication that disadvantages are more pronounced when male partners are in atypical employment compared to when female partners are atypically employed.

Advisor: Bukodi, E
Damping and fretting of frictional contacts in the steady-state

Contacts in mechanical assemblies are often subject to a constant load together with an oscillatory component. The latter might originate from vibration such that the component experiences a high number of load cycles. Different dissipative processes affect the steady-state behaviour of the assembly. In terms of contacts the most apparent is friction along the interface, which might lead to surface damage. Locally, the contact might act as a stress raiser, such that the material in the neighbourhood experiences plastic deformation. Cracks nucleating from the damaged surface and propagated in each load cycle are another limiting factor for the component's life. All these effects can be studied individually, but in reality they will affect each other to a certain degree. After a review of analytical and asymptotic contact descriptions, this thesis aims to describe the interaction between interfacial slip and other dissipative or life-limiting effects. A graphical method is presented to determine if a given loading causes the material in the contact region to reach the onset of plasticity. The limits of the elastic regime are explored and evaluated with this method.
Strong analogies exist between plasticity and slip. Shakedown, a process in which the generation of residual stresses in the first load cycles counteracts further dissipation, is one example. In the context of plasticity the residual stresses are generated due to plastic deformation, while it is due to relative slip displacements in the context of friction. However, it is shown that principles, established in the context of plasticity, are not generally transferable to friction. Repeated frictional slip may lead to surface degradation with a reduction of the contact extent. Simple calibrations are derived between the external contact loading and multipliers characterising the stress field around the edge of the resulting contact. Following the same basic idea makes it possible to identify crack tip stress intensity factors of cracks nucleating from the contact region. These intensity factors characterise the stress field around the crack tip, but also are used to assess the crack propagation per load cycle.

Keywords: asymptotic analyses
shakedown
fretting wear
partial slip
stress intensity factor
coupled contact
distributed dislocations
fretting fatigue
half-plane contact
Advisor: Hills, D
Translation and circulation of Romanian and Slavonic biblical books in the Romanian lands: a textual analysis of the sixteenth century Apostolos and Psalter texts

This thesis is concerned with the early rise of old Romanian as a written language, as represented by the textual traditions of biblical books translated from Church Slavonic. My primary sources are limited to sixteenth-century manuscript and printed books of the Apostolos and Psalter texts in Romanian and the relevant primary sources of the Slavonic tradition. In answering the questions of why and how the earliest Romanian writings appear, I argue that the philological study of the source tradition of the texts, that is, the Slavonic tradition, as well as of the textual varieties identified in the Romanian primary sources, can help us understand better the way in which Romanian came to be used as a literary language.
After a brief Introduction to the sources and method of philological analysis, Chapter one investigates the history of book production and circulation in the Romanian lands between the fifteenth and sixteenth centuries and gives some essential historical context to the cultural dynamics defining the voivodeships of Moldavia, Wallachia, and the principality of Transylvania at the time.
Chapters two and three analyse in depth the textual traditions of the Psalter text first, and then that of the Apostolos: each chapter identifies the source tradition of the respective text and provides an affiliation diagram of the Romanian sources.
Chapter four explores the translation and revision techniques employed in rendering and subsequently altering the text of the Apostolos and the Psalter.
The Conclusions draw together the information from the previous chapters and survey the prospects for further avenues of investigation.

Keywords: church Slavonic
comparative philology
Old Romanian
bible translation
Psalter
Apostolos
Advisor: Maiden, M
Cleminson, R
Learning and memorization via predictive coding

Neural networks trained with backpropagation achieved impressive results in the last decade. However, training such models requires sequential backward updates and non-local computations, making it challenging to parallelize at scale, implement in novel hardware, and is unlike how learning works in the brain. Neuroscience-inspired learning algorithms, such as predictive coding, have the potential to overcome these limitations and advance beyond current deep learning technologies. This potential, however, has only recently gained the attention of the community. As a consequence, the properties of these algorithms are still underexplored. In this thesis, I  aim at filling this gap by exploring three interesting properties of predictive coding: First, there exists a variation of predictive coding that is equivalent to backpropagation in supervised learning, second, predictive coding is able to perform powerful associative memories, and third, it is able to train neural networks with graphs of any topology. The first result implies that predictive coding networks can be as accurate as standard ones when used to perform supervised learning tasks. The last two, that they are able to perform tasks with a robustness and flexibility that is lacking in standard deep learning models. I then conclude by discussing future directions of research, such as neural architecture search, novel hardware implementations, and implications in neuroscience. All in all, the results presented in this thesis are coherent with recent trends in the literature, which show that neuroscience-inspired learning methods may have interesting machine learning properties, and that they should  be considered as as a valid alternative to backpropagation. 

Advisor: Lukasiewicz, T
Ceylan, I