VictorJuiz/thesis huggingface dataset:
Host-microbiota interactions in mammals

The mammalian gut microbiota provides important functions for the host but at the same time varies greatly between species, populations, individuals and even within individuals over time. Drivers of this variation and particularly their relative importance remains poorly understood. Further, a large proportion of gut microbiota research has been conducted using the laboratory mouse as a model organism. However, laboratory mice inhabit an artificial world where individuals are inbred, the environment is stable, and microbial exposures are limited. As a result of domestication, the gut microbiota of laboratory mice differs in notable ways from that of their wild relatives, and studies investigating the gut microbiota of wild house mice have great potential to aid the interpretation of findings from the laboratory. In this thesis, I explore how the gut microbiota varies between laboratory and wild mice, and examine drivers of natural gut microbiota variation among and within wild mouse populations. I show that although wild mice have a compositionally and functionally more diverse gut microbiota with a faster turnover rate that is clearly shaped by their more complex environment, major patterns of gut microbiota assembly during early life are conserved between laboratory and wild house mice. Since the gut microbiota showed strong age-related variation, I developed a non-invasive epigenetic clock-based method for assessing age in wild mice, whose application showed promise for future studies estimating biological (if not chronological) age in this system. Gut microbiota composition was also influenced by spatial factors, with stronger effects on the fungal than bacterial components of the microbiota, and microbial transmission from soil was identified as one possible source of spatial variation. Finally, I investigate gut microbial ecology in a mammalian species that is quite the opposite of a model organism, the critically endangered Saiga antelope which suffers periodic mass mortality events. I characterise healthy gut microbiota in comparison to other similar species, providing important background for future conservation efforts, as well as contributing to our broader understanding of what shapes microbiota among mammals. Together the results from this thesis increase our understanding of the gut microbiota variation but also highlight challenges in studying the gut microbiota, in the laboratory and beyond.

Advisor: Maiden, M
Kock, R
Knowles, S
Spreading the word: practices of discipleship in early modern natural philosophy


The publication of De Revolutionibus Orbium Coelestium by Nicholas Copernicus in 1543 exerted major intellectual and disciplinary effects on the field of astronomy. By promoting a heliocentric view of the world, and not merely offering a series of technical improvements to cosmology, Copernicus also affirmed the need for scholars to have mathematical expertise in that part of astronomy that dealt with the physical reality of the heavens. “Mathematics is written for mathematicians” (Mathemata mathematicis scribuntur) became a rallying cry for later Copernicans, which recognized in this claim a sort of Pythagorean heritage. Indeed, in the preface of De Revolutionibus, Copernicus had unequivocally depicted himself as a staunch Pythagorean, declaring his original unwillingness to publish his work to avoid the comments of the “babblers” – or the unlearned. This work examines the institutional impact of Copernicus’s demand for technical expertise. As numerous scholars have shown, his statement was effectively a plea for astronomers to speak authoritatively in areas that had previously been the preserve of natural philosophers. However, I argue, it also inaugurated a new template for the relationship between master and disciple, a structure that would constitute the foundations underpinning the successful transmission of varieties of the “new philosophy”. As Copernicus claimed, it was only on the insistence of his disciple, the young mathematician Georg Joachim Rheticus, that he agreed to publish his work. The doctrine was recondite, difficult to acquire in its detail, and because of its unorthodoxy, easily misunderstood by any but the select few. The case of Copernicus represents the starting point of my doctoral research. In the decades following the publication of De Revolutionibus, novel discipleship practices became essential to the development and spread of what became known generically as the “new philosophy”. In this context, my work explores the fundamental role that the emergence of post-Copernican discipleship relations played in the achievements of the great new auctores Johannes Kepler, Galileo Galilei, and Isaac Newton. The analysis of these four cases offers a kaleidoscopic view of the evolution of the master-disciple relationship in astronomy and natural philosophy from 1530 to 1720, and highlights how different social, religious, and political contexts shaped this process both inside and outside the university.

Keywords: discipleship
natural philosophy
mathematics
early modern world
Advisor: Iliffe, R
Remodelling of the immune landscape and its effect of tumour immunity in a model of IFNy-insensitive murine melanoma

Loss of IFNγ-sensitivity by tumour cells appears to enable evasion against T cell-dependent cytotoxicity, as some cancers lacking IFNγ-signalling demonstrate clinical resistance to checkpoint immunotherapy. However, recent studies have demonstrated that IFNγ-resistant tumours can sensitize the immune system for improved anti-tumour immunity. As a pleiotropic cytokine, the functions of IFNγ appears to have disparate modalities depending on context and magnitude of signalling in the tumour microenvironment.
In this thesis, we adopted a B16F10 murine melanoma model deficient in IFNGR1 and hypothesized that IFNGR1KO tumours would outgrow WT tumours due to impaired antigen presentation to CD8+ T cells. Unexpectedly, IFNGR1KO tumours implanted into independent mice grew at equivalent rates despite minimal MHC-I/II expression on KO tumours. However, when WT and KO cells were admixed prior to implantation, the expected clinical phenotype was restored, as KO cells outgrew WT and preferential recruitment of CD8+ T cells in ‘WT zones’ is observed. To explain this paradox, we measured the levels of intratumoural IFNγ via ELISA and found an accumulation within KO tumours compared to WT. We hypothesized that this level of IFNγ is capable of triggering active re-modelling of the tumour microenvironment which in turn preserves anti-tumour immunity. Analysis of single-cell RNAseq data from tumour-infiltrating CD45+ cells found that transcriptional changes within the myeloid compartment to promote less pro-tumourigenic macrophages may be key to modulating tumour control. Consequently, future experiments will attempt to elucidate whether macrophages are the key to enabling CD8+ T cell-dependent anti-tumour responses in KO tumours. This work highlights MHC-independent pathways within the immune microenvironment which are absent or enhanced following loss of IFNγ sensitivity, to better understand the paradoxical effects of IFNγ on tumour control over time.

Keywords: immunology
cytokines
inflammation
cancer
Advisor: Gerard, A
Powrie, F
Measuring the impact of reduced antibiotic use in hospital settings using electronic health records

Hospital inpatient antibiotic use has increased year-on-year in the NHS despite considerable investments in stewardship activity. Although hospitals have financial incentives to reduce overuse, current antibiotic reduction targets are modest and hospital stewardship leads have expressed significant concerns about the safety of achieving antimicrobial reduction targets, due to fears of under-treatment leading to patient harm. To reassure practitioners and the public that substantial reductions in antibiotic use could be safe, this thesis begins by exploring associations between variation in hospital-level antibiotic prescribing and patient-level clinical outcomes in 36 million general medicine admissions in England. I use this analysis to estimate what system-wide reductions might, at least in theory, be safely achieved if higher-using hospitals could replicate the prescribing practices of low-using hospitals. I then use patient-level antibiotic and outcome data to investigate the causal effect of using shorter versus longer antibiotic courses by treating time-varying antibiotic use as sequence of non-randomised nested “trials”. Although observational analyses cannot prove shorter antibiotic courses are safe due to the potential for residual confounding, finding no evidence of harm can help to justify the evaluation of antibiotic reduction strategies in randomised experiments for unbiased inference. To inform its adoption in other acute care settings, the thesis then addresses two key questions emerging from the recently completed ARK-Hospital cluster-randomised trial, which tested a multifaceted behaviour change intervention to reduce antibiotic overuse in general medicine. Since the intervention effect varied widely by site, I examined the role of 26 contextual factors as potential mediators of impact, to better understand sources of this between-site variation. Finally, although the intervention had a modest impact on antibiotic prescribing trends overall, trends in non-ARK sites are unknown, and I therefore compared ward-level prescribing trends in ARK vs non-ARK sites to understand whether the intervention had a greater (or lesser) impact than suggested by the trial-site specific analysis alone. The thesis discusses the analytic challenges of using routine electronic databases to compare antibiotic treatment durations and evaluate antimicrobial stewardship initiatives, and highlights the implications of specific data quality and accessibility issues for investigators and policy makers. Overall, the thesis demonstrates the need for high-quality health-record-linked e-prescribing systems to support robust assessments of the impact of antibiotic reduction strategies.

Keywords: antimicrobial stewardship
antibiotics
electronic health records
mortality
cluster-randomised controlled trial
secondary care
Advisor: Walker, A
Peto, T
Llewelyn, M
Applications of stochastic analysis and algebra to machine
learning

In this thesis we consider the application of tools from stochastic analysis and algebra to statistics and machine learning. Most of these tools are different forms of what has become known as signature methods. The signature has been discovered and rediscovered in a few different areas of mathematics in the last 70 years. In short, it maps a path evolving in a vector space to a group enveloping that same space. The reason it is so useful for statistics is twofold: One, its set of invariances is highly desirable in many applications, and two, its image group is highly structured making it particularly amenable to mathematical study using algebraic tools.
The primary aim here is to study how one may use the signature to express statistical properties of a given path, and how these properties can be applied to machine learning. This aim manifests itself as - among other things:
- a new type of cumulants for signatures that have unique combinatorial properties and can be used to characterise independence of paths,
- cumulants on reproducing kernel Hilbert spaces which are related to the signature cumulants, even though signatures are not used explicitly,
- a generalisation of the signature to other types of feature maps into non-commutative algebras,
- a feature map with an initial topology that captures properties of the filtration of stochastic processes,
- and a family of scoring rules with associated divergences, entropies and mutual informations for paths that respect their group structure.
These are divided into separate, self contained chapters that can be read independently of one another.

Keywords: Signature cumulants
Kernel learning
Adapted topologies
Entropy
Stochastic analysis
Scoring rules
Kernelized cumulants
Signatures
Advisor: Oberhauser, H
A tale of two civitates: on the origins and meaning of the concept of subsidiarity

This work traces back the origins of the principle of subsidiarity to second Temple Judaism and the constitution, based on spiritual authority, of an autonomous intermediary sphere between political authority and individuals. It argues that the foundational premise of the subsidiarity tradition derives from ancient Jewish sources, and not from Aristotelian thought or the ancient Greek social reality. Then it argues that Jewish intermediacy is the basis of Christian intermediacy, characterized by universalism and the belief on the already here presence of the kingdom of God, as developed by Jesus of Nazareth and Paul of Tarsus. Christian intermediacy, in turn, is presented as the basis for the Christian political ambivalence that characterizes patristic political thought, which considers the Roman Empire as both a providential instrument of God and a new Babylon. This ambivalent perspective was inclined towards a providential vision of the Empire because of the conversion of Constantine, who inaugurated subsidiarity by combining the “negative” obligations of intermediacy with the “positive” obligations of a Christian Emperor to help the Church. Nonetheless, Constantinian subsidiarity evolved over the life of the Emperor into an overreaching and controlling doctrine of divine kingship, which was afterwards resisted politically and theologically by figures like Athanasius of Alexandria, Hilary of Poitiers, Ambrose of Milan, and Augustine of Hippo. This process culminated in a dispute about the proper form of subsidiarity and in a theoretical detachment of Church and Empire. Augustine of Hippo transformed subsidiarity into a general ethical principle, independent of the contingent relationship between the Roman Empire and the Christian Church. He also philosophically reinstalled ambivalence at the centre of Christian political theory and denied any special role for Rome and its emperors in the divine economy of salvation. Thomas Aquinas’ concept of subsidiarity, which has been frequently presented as the first formulation of the principle, is in fact strongly attached to Augustine’s one. His innovation consisted in systematizing the principle as a principle of justice, starting from Augustine’s ethical formulation of it. The thesis ends by arguing that this original conception of subsidiarity attached to Christian ontology is in tension, but not necessarily in contradiction, with the modern secular order, and that the present ambiguity of the principle can be explained by that tension.

Keywords: political theology
patristics
Jewish-Christian
subsidiarity
Advisor: Bejan, T
Yowell, P
#AfricaToTheWorld: Economic emancipation and identity affirmation in the age of global digital media

The thesis explores a particular historical moment: the integration of Nigerian music into the global flows of popular culture, popularly referred to as the “Africa to the world” movement by professionals and fans alike. The research is based mainly on ethnographic data from what is commonly referred to as the “Nigerian music industry,” a fluid network of structures and mobile agents organized around hubs all along the Nigerian ethnoscape, with Lagos its key nod. Data collection involved a year of physical ethnography in Lagos, several months of participant-observation and interviews in Istanbul, London, Dubai, and Paris, as well as four years of digital ethnography.
Through the individuated mode of cosmopolitan success that Nigerian artists embody, the thesis explores the articulation of mobility, identity, and future-making in the age of global digital media. In particular, it takes seriously the popular hopes associated with the symbolic inclusion of “Africa” in the transnational commercial landscape in order to interrogate how imaginative, discursive, and affective practices interact with political economic processes. As masses of youths across the continent and diaspora root for music professionals who work tirelessly to hijack the structures of global capitalism and become “billionaires,” the thesis questions the empirical relevance and analytical power of seemingly entrenched and stable power dynamics inscribed in conceptualizations such as global/peripheral or capitalist/informal. It aims to move beyond categories that have limited emic resonance in order to analyze emancipatory world-making projects deployed by a postcolonial and post-privatization generation that appears to have internalized the flexible condition.

Keywords: Nigerian popular culture
afrobeats
globalization from the South
Lagos
digital capitalism
African youth
global media
Advisor: Pratten, D
Identification and functional validation of pathogenic small nucleotide variants in patients with craniosynostosis

Craniosynostosis, the premature fusion of the cranial sutures, affects ~1 in 2,000 live births. It is a heterogenous disorder with documented monogenic, polygenic, chromosomal, and environmental causes. Although many patients with a genetically determined cause harbour a variant in one of just seven genes, or have a chromosomal abnormality, there is a long tail of rarer genetic diagnoses with over 60 genes known to be recurrently mutated. Despite the recent uplift in knowledge of the genetic causes of craniosynostosis and the biogenesis of the cranial suture, there remains a suspected 10% of undiagnosed patients with a putatively pathogenic monogenic cause. In my analyses I aimed to target this subset of patients to delineate novel genetic causes of craniosynostosis. Using data generated from genome and exome sequencing I developed systematic pipelines to screen for small nucleotide variants. This approach identified 8 variants that explained the phenotype of previously undiagnosed patients (n = 114) enrolled in the UK 100,000 Genomes Project (100kGP) and highlighted additional candidate genes for further scrutiny. The candidate genes were included alongside 35 additional genes with reasonable evidence for involvement in craniosynostosis in a panel-based resequencing analysis of 617 individuals without a genetic diagnosis. Through this approach, I identified 8 diagnostic variants and 15 additional candidate variants. Drawing on the identification of pathogenic variants from the UK 100kGP, my resequencing analysis, and genes identified through other sources, I undertook experiments to explore and functionally validate the likely pathophysiological mechanisms associated with variants in three genes (PRRX1, PTCH1, and SPRY1) by using immunofluorescence, mouse models, and RNA and protein assays. Overall, this work has achieved improved diagnostic pipelines for craniosynostosis, and rare disease more widely, and has also served to delineate three new genetic causes of craniosynostosis by providing a key evidence base to support variant pathogenicity.

Keywords: genes
clinical genetics
craniosynostosis
Advisor: Wilkie, A
Twigg, S
Taylor, J
Identification of epigenetic regulators of RNA editing mechanisms

This thesis looks to identify up-regulating mechanisms of ADAR 2 (Adenosine deaminases acting on RNA 2) through investigation of 52 novel small-inhibitor small molecules provided by the Structural Genomics Consortium (SGC, 2022). These small molecules were incubated with neuronal-2A mouse cells containing a CRISPR engineered construct, this doxycycline-induced construct was formed of a stem loop with a point mutation with mCherry and eGFP proteins respectively either side of the stem loop. The point mutation meant that the stem loop, along with the eGFP, was not translated, therefore levels of RNA repair could be measured by quantifying the ratio of eGFP/mCherry fluorescence. Upon identification of five significant up-regulators of RNA editing activity, and eight significant down-regulators, we repeated the treatment but this time extracted RNA and performed a qPCR which revealed that these identified treatments significantly effected either the expression of ADAR1, ADAR2 or both. It was interesting to note that bromodomain inhibitors appeared to have the greatest transcriptional effect upon ADARs. Next we used siRNA to knock-out ADAR 1 and ADAR 2, then repeating the fluorescence experiment. It is interesting to see that whilst ADAR 1 was seen to be up-regulated, inhibition of ADAR 1 did not inhibit transcriptional effects of treatment. On the other hand, inhibition of ADAR 2 led to decrease in efficacy of small molecule treatment. This thesis goes on to present the results of bromodomain 7 inhibition and it's effect upon ADAR, arguing that bromodomains are a key regulator of ADAR activity, as well as identifying potential targets in the treatment of neurogenetic diseases.

Keywords: bromodomain
pharmacology
genetic
ADAR
neurogenetics
Advisor: Rinaldi, C
Hong Kong EFL pre-service teachers’ readiness for technology integration into future teaching practices: An explanatory sequential mixed methods study

The significance of integrating Information and Communication Technology (ICT) into Englishas a Foreign Language (EFL) education is widely recognised in modern EFL teaching practices. Teachers are expected to demonstrate professional expertise and proficiency in digital skills fromtheoutset of their teaching careers. This requirement has become particularly prominent in the aftermathof the outbreak of the COVID-19 pandemic, which forced a shift from physical classrooms to onlineplatforms. However, there has been limited research examining whether EFL pre-service teachers areready for technology integration before they enter actual classrooms.
Using an explanatory mixed methods research design, this study investigates the readiness for technology integration of EFL pre-service teachers from two universities in Hong Kong by exploringtheir knowledge, self-efficacy, and prior experience in technology integration. An online questionnaire is designed to examine their Technological Pedagogical Content Knowledge (TPACK) and self-efficacy for integrating technology into EFL teaching. Follow-up interviews are conductedtounderstand participants’ self-reported survey results and factors that influence their readiness levels.
The synthesis of quantitative and qualitative findings reveals that pre-service teachers’ readinessfor technology integration is influenced by a blend of experiential and contextual factors, with their technological experiences during teaching practicums playing a prominent role. While the majorityof EFL pre-service teachers exhibit a moderate level of preparedness, the considerable disparities inreadiness, particularly between the highest and lowest scores, underscore the necessity of teachertraining programmes to enhance their readiness for technology integration in their future classrooms. These findings hold theoretical significance as they offer a holistic perspective, combining knowledge-based and self-efficacy-based insights, into the factors influencing the varying levels of pre-service teachers’ technology integration readiness. Additionally, this dissertation offers practical suggestions for teacher-training programmes. These include diversifying ICT courses for pre-serviceteachers, furnishing comprehensive professional training to both teacher educators and pre-serviceteachers on integrating content, pedagogy, and technology effectively, and fostering pre-service teachers’ ability to address technical issues and meet the varied needs of their students. Moreover, considering participants’ eagerness for continuous professional growth, this study contends that teacher-training programmes should facilitate communication and collaboration among pre-serviceteachers across universities and afford them opportunities to attend cutting-edge technology exhibitions, thereby immersing them in innovative teaching practices.

Keywords: TPACK
self-efficacy
technology integration readiness
EFL pre-service teachers