VictorJuiz/thesis huggingface dataset:
Horizontal gene transfer and cooperation in bacteria

Bacteria are capable of a wide range of cooperative behaviours. It has been suggested that horizontal gene transfer, which is common in bacteria, could help to stabilise cooperation and prevent the invasion of non-cooperative cheats. Research on this hypothesis has largely focused on plasmids: genetic sequences found across bacteria that can often transfer to other cells. Here, I test two key predictions of this hypothesis across 51 bacterial species. Contrary to these predictions, I find that genes for cooperation are not more likely to be carried on: (1) plasmids compared to chromosomes; (2) more mobile plasmids compared to less mobile plasmids. Next, I explore characteristics of plasmids themselves. First, I examine correlations between three potential ‘life-history’ traits of plasmids: size, mobility and range. Second, I find that plasmid sequences are consistently enriched with A and T nucleotide bases compared to chromosomes, and explore two hypotheses for why this is the case. Finally, horizontal gene transfer can impact the content of bacterial genomes. To explore these impacts, I test whether bacterial species’ genomes become more variable with increasing environmental variability. Overall, in this thesis I consider the evolution of cooperation and horizontal gene transfer in bacteria, and how they may interact.

Keywords: comparative genomics
social evolution
plasmids
Advisor: West, S
Griffin, A
Ghoul, M
Investigating the functional requirement of nedd4l for mammalian hearing

The function of the NEDD4 (Neuronal Cell Expressed, Developmentally Downregulated, 4) E3 Ubiquitin Ligase protein family members, NEDD4L and NEDD4, has previously been studied. However, their potential involvement in the mammalian auditory system was only recently indicated. As such, studies were undertaken to investigate the requirement of Nedd4l and Nedd4 in the process of hearing using constitutive and conditional knockout (KO) mouse models. Auditory characterisation of Nedd4l KO mice identified an early-onset hearing loss by 3-weeks of age, which progresses to profound deafness by 8-weeks of age. Pathological assessment identified fewer synapses between inner hair cells and afferent neurons in 3-week old Nedd4l KO mice, and a subsequent progressive degeneration of hair cell bundles and spiral ganglion neurons. Molecular characterisation discovered decreased abundance of αENaC subunit in Nedd4l KO mice and identified NKCC1 as a potential NEDD4L substrate, suggesting that impaired endolymphatic ion homeostasis may contribute to the auditory dysfunction in Nedd4l KO mice. In addition, auditory phenotyping indicates that Nedd4 KO mice experience a high-frequency hearing loss, which is first detected by 8-weeks of age. These studies highlight the importance of the NEDD4L and NEDD4 ubiquitin ligase proteins in supporting auditory function. However, further investigations are required to fully elaborate upon their essential roles in mammalian hearing.

Keywords: Sensorineural Hearing Loss
Mouse Model Organisms
Advisor: Bowl, M
Bajo Lorenzana, V
Brown, S
Early British socialism and the "religion of the new moral world"

This thesis will be concerned with the question of the relationship between Owenite socialists and religion. In this thesis I will seek to untangle and disambiguate existing scholarly accounts of the relationship between Owenite socialism and religion. I will then identify how Owenites offer a re-conception of the nature of ‘religion’ as advanced through knowledge of the natural and social world, as a prospective source of solidarity which could serve as the unifying bond for communities, and as constituted by ethical conduct. I will demonstrate how these Owenites’ critique of contemporary religion was shaped by the particular conditions of the early nineteenth century, conditions which represented a problem to which they offered a solution. I then show how this solution was formed by drawing upon the traditions of natural theology, popular religion, deism, and Rational Dissent. I show how this solution was formed through a sincere and considered reflection upon the problem of religious truth. I will then show the importance of this reimagination of religion to their understanding of socialism. I demonstrate that these Owenites understood their socialism to be, in part, a project of religious reform, as rivalling the Oxford Movement and as a successor to the Reformation. Their religious interests were not an eccentric adornment to their socialism, an outdated residue yet to be shed and encumbering the development of a mature socialism, or merely instrumental to their temporal goals. Instead, their ambitions of religious reform were grounded in the philosophical preoccupations which animated their socialism. They conceived theological falsehoods as an obstacle to the triumph of socialism. And they argued that one should become a socialist, in part, precisely because it created the conditions for the popularisation of religious virtue. I conclude by identifying some implications of the argument of this thesis.

Advisor: Leopold, D
Hydrogen bonding phase-transfer catalysis with sodium azide and potassium cyanide

Hydrogen Bonding-Phase Transfer Catalysis (HB-PTC) enables use of alkali metal fluoride salts as reactive reagents in enantioselective catalysis and this platform has been successfully applied towards enantioselective fluorination. This thesis details a study into the structure and reactivity of hydrogen bonded azide and cyanide anions and the development of enantioselective reactions using sodium azide and potassium cyanide under HB-PTC for the synthesis of enantioenriched organoazide and organonitriles.
The first chapter introduces phase-transfer catalysis and discusses the advantages of HB-PTC. The second chapter presents a detailed study into the structure and coordination of hydrogen bonded azide complexes in both solid state and solution, and discusses the development and mechanistic study of an enantioselective azidation reaction with sodium azide under HB-PTC. The third chapter describes the structure and coordination of hydrogen bonded cyanide complexes in both solid state and solution and details the development of an enantioselective cyanation reaction with potassium cyanide under HB-PTC. The final chapter contains supporting information including experimental procedures and characterisation data. An appendix with additional crystal structures is also included.

Keywords: sodium azide
potassium cyanide
HB-PTC
hydrogen bonding
Phase Transfer Catalysis
Advisor: Gouverneur, V
‘Vendors keep this economy running’: economic informalisation and citizenship in Harare, Zimbabwe

The thesis offers a theoretical and empirical account of how and why ideas and practices of citizenship have changed under the impact of economic informalisation in urban Zimbabwe. This issue is critical as it sheds light on the changing relationships between individuals, who had to shift from the formal sector to the informal and political and civic actors. The thesis challenges and expands the existing literature on citizenship in Africa and Zimbabwe specifically by focusing on economic informalisation as a core transformation in the economic and political life of the country that has led to changes in people’s understandings and experiences of citizenship. It does so by looking at grassroots notions of citizenship as opposed to government definitions; by considering the impact of associational life in the informal sector on the understanding and practices citizenship; and by tracking subtle changes in people’s understanding of productivity, taxation, employment, and residence as key notions of citizenship under the impact of economic informalisation. It focuses on the 2013–2018 period, although it refers to economic and political developments in Zimbabwe from the colonial period onwards to explore their implications for citizenship in the urban informal sector. The thesis argues that economic informalisation in Zimbabwe has led to a great divide between the modernist thinking and survivalist reality, which has shaped politics at all levels and, accompanied by other socio-political and economic processes has significantly affected the political terrain of the country. On the individual level, the modernist thinking–survivalist reality disconnect has led to changes in political behaviours of informal sector actors. Individuals started disengaging from the state and the city and entering new debates about the nature of citizenship, engaging in associational life in the informal sector, shaping distinct notions and practices of lived citizenship relevant to their economic reality.

Keywords: informality
citizenship
Zimbabwe
modernity
economic informalisation
Advisor: Alexander, J
Exploiting prior knowledge in machine learning model design

The design of models which are appropriate for specific tasks is an important activity in machine learning. This thesis considers multiple ways in which knowledge about the task at hand can be incorporated into the design of a machine learning model: (i) by using Bayesian models, which incorporate prior knowledge in probability distributions; (ii) by designing models to respect the symmetries of the task; (iii) by adapting models in a practical setting. For Bayesian models, we propose a probabilistic numeric method for computing integrals which arise in the context of Bayesian inference. Respecting the symmetries of a task comes under the framework of group equivariance and invariance. We provide a theoretical investigation of Deep Sets, a prominent permutation-invariant model, and propose an extension of the SE(3)-Transformer, an SE(3)-equivariant model. Finally, we present an investigation of the application of machine learning techniques to problems in atmospheric physics, in which the relevant models are adapted to specific known features of the problem.

Keywords: Equivariance
Equivariant models
Bayesian methods
Permutation invariance
The role of CRTH2+ CD8+ T cells in severe asthma

Type 2 inflammation of the airways is present in most patients with asthma, and some patients with chronic obstructive pulmonary disease (COPD). The molecular drivers of the type 2 immune response include the cytokines IL-4, IL-5, and IL-13, produced by activated type 2 T helper (Th2) and type 2 cytotoxic T (Tc2) cells. Expression of the prostaglandin D2 (PGD2) receptor chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) has been associated with type 2 T cells, and CRTH2+ T cells in the blood and lung have been linked to the severity and endotype of asthma. In a new study of 127 participants, blood CRTH2+ T cell counts were not associated with asthma severity or endotype, and instead appeared to be driven by other factors such as smoking history and biological sex. Airway CRTH2+ T cells were detectable in the sputum, and airway CRTH2+ Th cells correlated with sputum eosinophils. The sensitivity and specificity of CRTH2 as a marker of type 2 T cells was assessed ex vivo, showing that CRTH2 is a more sensitive marker of Tc2 (~80 %) than Th2 (~50 %) cells. CRTH2+ CD8+ T cells were isolated from peripheral blood mononuclear cells (PBMCs) and expanded without addition of polarising cytokines, retaining a stable type 2 identity. Cultured CRTH2+ CD8+ T cells could be stimulated by multiple pathways: through the T-cell receptor, by PGD2-CRTH2 interactions, or by alarmin cytokines. The transcriptomic response of CRTH2+ CD8+ T cells was specific to each stimulation. The gene expression patterns of activated CRTH2+ CD8+ T cells highlighted their capacity to contribute to type 2 inflammation, but also revealed novel links to genes and biological processes associated with asthma. These data support future study of CRTH2+ CD8+ T cells in the human airways.

Keywords: T cells
Tc2
Th2
asthma
COPD
CRTH2
Advisor: Hinks, T
Xue, L
Klenerman, P
Pavord, I
A search for the direct detection of dark matter via annual modulation with the full XMASS-I dataset

Astrophysical observations indicate that the observable matter that forms the stars, planets and life as we know it only constitutes 5% to the total energy density of our universe. Dark matter and dark energy make up the remainder, 26% and 69% respectively. While the nature of dark energy is still largely speculative, gravitational effects of dark matter have been widely observed and place constraints on its nature. Many candidates that could form dark matter have been ruled out over the years due to the lack of astrophysical signatures they would imply or lack of production, annihilation and direct detection signals in experiments or instruments that have sensitivity for these signals.
XMASS is a single-phase dark matter direct detection experiment. The detector houses 832 kg of liquid Xenon within its active volume and has been operational for over 5 years (the current longest for any noble liquid experiment), resulting in a 3.53 ton year exposure. Two annual modulation analyses are presented in this thesis, one based on the previous XMASS modulation analysis and then my own one that introduces a new classification technique and a new approach to χ2 minimisation that is less reliant on Monte Carlo based evaluation of systematic uncertainty. The obtained 90% confidence level upper limit for the spin independent interaction cross section (σ 90%SI) between Weakly Interacting Massive Particle (WIMP) dark matter and standard model nucleons has been halved to 3.6 × 10-39 cm2 for a WIMP of mass 4 GeV with respect to the previous XMASS modulation analysis and has a minimal value of 1.2 × 10-43 cm2 for a WIMP of mass 40 GeV.

Keywords: Physics
Backgrounds
Direct Detection
Annual Modulation
Particle Physics
PMT
Light Yield
Spin Independent
XMASS
Dark Matter
Optical Parameters
Xenon
Advisor: Wark, D
Martens, K
Visible light photocatalysis: mechanisms and reaction development

This thesis describes the development and mechanistic investigations into novel photochemical transformations mediated by visible light.
Chapter one introduces key concepts pertaining to excited state chemistry, mainly the interaction between matter and light, fundamental photophysical events, and the subsequent changes in physical and chemical properties that ensue upon excitation.
Chapter two provides an overview of recent developments into visible light mediated [2+2] photocyclizations, with the emphasis being placed on photocyclizations of indoles. Although the synthesis of cyclobutanes via photochemical [2+2] processes is highly facile, deviations from standard behaviour do occasionally occur, leading to the formation of novel chemical scaffolds. Here we describe the development of an interrupted [2+2]-photochemical process that leads to the formation of highly functionalized heterocycles with the aid of visible-light mediated energy transfer catalysis.
Chapter 3 describes mechanistic investigations into the regioselectivity of the visible light mediated photocyclization of 2-N-arylamino-cyclohexenones bearing an ortho-iodo substituent. These substrates undergo cyclization exclusively on the carbon bearing the iodine substituent, which upon loss of the iodine atom, leads to the formation of iminium ions capable of trapping numerous nucleophiles. The reactivity displayed by these substrates is completely orthogonal to that of their 2-aryloxy analogues, which lead to the cyclization at the ipso-H position. Here we investigate the mechanism of this transformation with the aid of quantum chemical calculations.

Keywords: energy transfer
visible light
chemistry
photochemistry
Advisor: Smith, MD
Rhodium-catalysed enantio- and diastereoselective C(sp2)-C(sp3) cross-coupling reactions

In this thesis, we describe a series of Rhodium-catalysed enantio- and diastereoselective C(sp2)–C(sp3) cross-coupling reactions and perform brief mechanistic studies in order to understand their underlying mechanisms.
In Chapter 1, cross-coupling reactions are introduced and recent developments in catalytic asymmetric Suzuki–Miyaura type cross-coupling reactions are summarised.
In Chapter 2, a series of asymmetric Rh-catalysed Suzuki–Miyaura type cross-coupling reactions between racemic allyl chlorides and aryl- and alkenylboronic acids are presented. These dynamic kinetic transformations (DYKATs) proceed via the stereoselective formation of pseudomeso Rh-π-allyl complex, followed by enantiodetermining reductive elimination. This allows for the control of multiple stereogenic centres in a single reaction step. Synthetic applicability of this method was demonstrated with a concise synthesis of the prostaglandin analogue Tafluprost.
In Chapter 3, we contribute to the long-standing problem of asymmetric cyclobutane synthesis and present Rh-catalysed cross-coupling reactions between cyclobutenes and arylboronic acids. After an initial asymmetric carbometallation step, the Rh-cyclobutyl intermediates can undergo chain-walking or C–H insertion enabling reductive Heck reactions, 1,5-additions and homoallylic substitution reactions. The synthetic applicability of these highly enantioselective transformations is demonstrated with formal syntheses of the drug candidates Belaperidone and PF-04862853. This work represents the first asymmetric carbometallation of cyclobutenes, which occurs despite a very small release in olefinic strain.
In Chapter 4, an asymmetric hydroacylation of cyclobutenes with salicylaldehydes is presented. Acyl cyclobutanes can be obtained with excellent enantio- and diastereoselectivity. Further, this reaction serves as a proof-of-concept that Rh-catalysed hydrometallation of cyclobutenes is feasible and will likely guide the development of other Rh-catalysed hydrofunctionalisation reactions.

Advisor: Fletcher, SP
Causal relevance of inflammation to cardiovascular disease

Cardiovascular disease (CVD) is a major cause of premature deaths and disability globally. Inflammation, the response of the immune system to damaging stimuli, was reported to contribute to CVD risk, with key inflammation-associated proteins (e.g. interleukin-6 [IL-6] signalling) targeted in recent clinical trials. I investigated whether components (IL-6 and IL-6 receptor [IL-6R]) and markers (C-reactive protein [CRP] and fibrinogen) of the IL-6 signalling were associated with CVD risk, with the aim of identifying relevant therapeutic targets for CVD.
First, using a nested case-control study design in the prospective China Kadoorie Biobank (CKB), I reported that in Chinese adults higher plasma CRP concentrations, but not plasma fibrinogen levels, were log-linearly associated with higher risks of major coronary events, ischaemic stroke (IS), and intracerebral haemorrhage (ICH). However, prior genetic studies have reported null associations of plasma CRP- associated genetic variants with CVD risk, precluding CRP as a therapeutic target for CVD.
To investigate potential therapeutic targets, I used genome-wide association studies of CRP in CKB and in Europeans to derive genetic instruments representing the IL-6R and the IL-6 ligand. The IL-6R instrument was a non-synonymous genetic mutation in the IL6R locus (rs2228145-C) and reportedly mimicked the effects of tocilizumab (an IL-6R antagonist). The IL-6 instrument was composed of three genetic variants in CKB and a single genetic variant in Europeans (rs1880241-G) near the IL6 locus. The CKB/EUR IL-6 genetic instruments were, therefore, constructed to broadly represent effects of lower IL-6 signalling. Using a two-sample Mendelian randomization approach, I showed that although the IL-6R instrument, associated with lower plasma CRP, was associated with a lower risk of coronary heart disease (CHD) phenotypes in both CKB and Europeans, there was no evidence of an association of the IL-6 instrument with CHD in either population. Additionally, on trans-ethnic meta-analysis, there was weak evidence that the IL-6R instrument was associated with a lower risk of IS and a higher ICH risk but with consistent estimates observed with the IL-6 instrument.
In conclusion, although the observational study supported the role of inflammation in CVD, the null association of the IL-6 instrument with CHD in both the Chinese and Europeans with weak evidence of lower and higher risk of IS and ICH, respectively, questions the net therapeutic value of targeting IL-6 signalling for CHD.

Keywords: cardiovascular disease
IL-6
mendelian randomization
inflammation
target validation using human genetics
interleukin-6
IL-6R
genetic epidemiology
Advisor: Holmes, M
Walters, R
Investigation of early-diverging land plant metabolism

The terrestrialisation of embryophytes was preceded by, and precipitated, the evolution of diverse metabolic capabilities to aid growth and survival on land. A broad understanding of metabolism across all land plants is important for the discovery of novel metabolic enzymes and pathways which may be used commercially and to design metabolic engineering strategies for crop improvement. However, metabolic research has mainly focused on a small number of angiosperm crops and model plants. The research described in this thesis was carried out with the goal of correcting this knowledge bias, using bioinformatic and computational techniques to characterise metabolism, and its associated evolutionary processes, in early-diverging land plants.
The work is presented as three manuscripts. In the first I used metabolic modelling to investigate central metabolic fluxes in the liverwort Marchantia polymorpha, which exhibits extremely low carbon assimilation rates as a consequence of the low mesophyll conductance characteristic of bryophytes. I found that my constrained stoichiometric model of Marchantia was unable to achieve experimentally-defined growth rates without increasing carbon conversion efficiency by requiring either a very low cell maintenance cost, or some form of nocturnal carbon recycling. In the second manuscript I carried out a comparative analysis of secondary metabolism across the Chloroplastida, using homologous relationships between metabolic genes in 72 land plants and algae. The findings, supported by gene absences/presences in a further 305 plant and algal transcriptomes, elucidate details of the evolution of several phytohormone and biopolymer biosynthetic pathways. Finally, I used phylogenetic profiling and co-expression analysis to identify candidate genes associated with the previously discussed biosynthetic pathways. The results were validated by the identification of several known gene associations, and additional genes with various potential functional relationships with the pathways in question were detected.

Keywords: plant evolution
phylogenetics
metabolic modeling
gibberellins
suberin
marchantia polymorpha
land plants
brassinosteroids
sporopollenin
algae
plant metabolism
cutin
computational bioloigy
bryophytes
Advisor: Sweetlove, L