VictorJuiz/thesis huggingface dataset:
The role of SNPs in the management of cancer in the broader population
Keywords: Single Nucleotide Polymorphisms
TP53
CRISPR/Cas9
Testicular Germ Cell Tumours
omics

Heterogeneity is a pervasive concept in oncology and underpins many of the biggest challenges facing the field. Patients presenting with tumours which appear similar on the surface, can respond very differently to clinical management. Novel methods are urgently required to understand heterogeneity in cancer and to translate this information into the clinic. Studies of twins and familial cancer syndromes have indicated that a substantial proportion of cancers could be heritable but that rare, highly penetrant germline mutations cannot explain this phenomenon. The remaining 'missing heritability' is likely to be explained by common, less penetrant variants including Single Nucleotide Polymorphisms (SNPs). SNPs can associate with differential disease risk, with response to therapy and with the development and behaviour of tumours. Moreover, there is associative evidence that SNPs can inform drug response. However, a key blockade to the clinical translation of promising SNPs is the difficulty in elucidating the mechanistic function of susceptibility loci. In this thesis, we address this challenge by investigating the effect of p53 pathway SNPs on tumours and unpicking the molecular mechanisms underpinning these effects.
In Chapter Two, we experimentally model a SNP found in a p53 response element which associates with Testicular Germ Cell Tumours with one of the highest odds ratios identified for a cancer-risk SNP to date. This SNP leads us to uncover a novel, pro-tumour, negative feedback loop which is driven by the ability of wild-type p53 to upregulate KITLG expression. Moreover, we demonstrate that inhibition of this axis combined with p53 activation has a synergistic effect on cell death and could be a therapeutic opportunity for refractory TGCT. In Chapter Three, we employ high-throughput omics technologies and data mining to establish the molecular mechanisms underpinning the synergistic effect on cell death in TGCT cells while in Chapter Four, we leverage multi-omics datasets to identify possible repurposing opportunities for this combinatorial therapy. Our work in TGCT highlighted a novel therapeutic strategy to reactivate wild-type p53 by inhibiting oncogenic axis driven by p53 target genes. In Chapter Four we investigate whether other p53 target-genes could have pro-survival function in cancer types which infrequently mutate TP53. In Chapter Five, we highlight that the p53 pathway is enriched for genes which harbour pleitropic SNPs and focus on a partiuclar SNP in the TP53 polyadenylation signal. We provide evidence for its long-lasting effects on tumours and shed light on the molecular mechanisms which could underpin these effects.
The analyses presented in this thesis support previous publications indicating that common germline genetics could inform management of heterogeneity in cancer. We provide proof-of-principle that cancer-risk SNPs can uncover novel cancer biology which can in turn shape therapeutic design.
The interrelation of EU law with inter se international agreements of the EU member states
Keywords: EU law
Conflict
Inter Se Agreements
International Law
Conflict Resolution
International Agreements
Conflict Avoidance
Achmea

This thesis examines how EU law interrelates with international agreements concluded between EU Member States inter se when a conflict between their norms can be identified. Chapter One starts by distinguishing between the different types of international agreements that may co-exist with EU law and argues that conflicts between EU law and inter se agreements need to be approached as conflicts of treaty norms on the international plane, using the conflict avoidance techniques and conflict resolution rules of international law. Against this background, Chapter Two examines and discards the premise that EU law constitutes a ‘new legal order’, highlighting the nature of EU law as international law. Chapter Three then examines the position of EU law within international law, identifying EU law as an autonomous sub-system within public international law, in the sense of a broadly conceived ‘self-contained regime’. Chapter Four moves on to define the notion of ‘conflict’ between EU law and inter se agreements and provides the conceptual framework, within which it is to be grasped. Chapter Five explores the available conflict avoidance techniques, identifying two interrelated, yet distinct interpretative methods applicable to the context of this thesis: first, the principle of systemic integration, enshrined in Article 31(3)(c) of the Vienna Convention on the Law of Treaties (VCLT); and second, the principle of a consistent-with-EU-law interpretation of inter se agreements, as a special application of the principle of harmonious interpretation applied in international law. Finally, Chapter Six identifies the rules governing conflict resolution in the interrelation of EU law with inter se agreements: first, Article 59 VCLT on the implicit abrogation of an earlier agreement by the conclusion of a later one between the same contracting parties; second, Article 30 VCLT, to the extent that it codifies the pacta tertiis principle of public international law; and third, the principle of primacy of EU law, which operates as a lex specialis, carving out the lex posterior conflict rule enshrined in Articles 30(3) and 30(4)(a) VCLT.
Horizontal gene transfer and cooperation in bacteria
Keywords: comparative genomics
social evolution
plasmids

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.
Investigating the functional requirement of nedd4l for mammalian hearing
Keywords: Sensorineural Hearing Loss
Mouse Model Organisms

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.
Hydrogen bonding phase-transfer catalysis with sodium azide and potassium cyanide
Keywords: sodium azide
potassium cyanide
HB-PTC
hydrogen bonding
Phase Transfer Catalysis

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.
‘Vendors keep this economy running’: economic informalisation and citizenship in Harare, Zimbabwe
Keywords: informality
citizenship
Zimbabwe
modernity
economic informalisation

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.
Exploiting prior knowledge in machine learning model design
Keywords: Equivariance
Equivariant models
Bayesian methods
Permutation invariance

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.
The role of CRTH2+ CD8+ T cells in severe asthma
Keywords: T cells
Tc2
Th2
asthma
COPD
CRTH2

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.
A search for the direct detection of dark matter via annual modulation with the full XMASS-I dataset
Keywords: Physics
Backgrounds
Direct Detection
Annual Modulation
Particle Physics
PMT
Light Yield
Spin Independent
XMASS
Dark Matter
Optical Parameters
Xenon

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.
Visible light photocatalysis: mechanisms and reaction development
Keywords: energy transfer
visible light
chemistry
photochemistry

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.
Causal relevance of inflammation to cardiovascular disease
Keywords: cardiovascular disease
IL-6
mendelian randomization
inflammation
target validation using human genetics
interleukin-6
IL-6R
genetic epidemiology

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.
Investigation of early-diverging land plant metabolism
Keywords: plant evolution
phylogenetics
metabolic modeling
gibberellins
suberin
marchantia polymorpha
land plants
brassinosteroids
sporopollenin
algae
plant metabolism
cutin
computational bioloigy
bryophytes

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.