VictorJuiz/thesis huggingface dataset:
Examining the relationship between genetic variation at G6PD and severe malaria
Keywords: G6PD
glucose-6-phosphate dehydrogenase
malaria
genetics

Glucose-6-phosphate dehydrogenase (G6PD) deficiency, a common heritable trait whose prevalence mirrors geographic patterns of historic malaria endemicity, is thought to confer a selective advantage owing to partial protection conferred against malaria. Direct evidence supporting this malaria protection hypothesis in the form of clinical association studies remains controversial, however, as conflicting results have been reported with respect to the strength and specificity of a protective effect, if any, conferred to carriers of G6PD deficiency-associated alleles.
This thesis examines genetic diversity at the G6PD locus, and then considers how such variation impacts both immediate molecular phenotypes and multifactorial clinical phenotypes. First, Chapter 3 presents a survey of variation at G6PD in several malaria-endemic areas, while Chapter 4 describes a novel technique for polymorphism discovery using pooled massively parallel sequencing. Next, in Chapters 5 and 6, I evaluate the link between genetic variation at the locus and G6PD enzyme activity, identifying major and minor determinants of G6PD deficiency state in an association study conducted in Kenya, and demonstrating a new technique for assaying G6PD deficiency at the level of an individual erythrocyte in a pilot project in Mali. Finally, Chapter 7 addresses the malaria protection hypothesis directly by conducting a fine-mapping case-control association study of severe malaria in the Gambia, where I found that G6PD deficiency alleles exhibited differential direction of association with respect to two important clinical syndromes-- trending towards risk conferred to severe malarial anemia, and protection with respect to cerebral malaria. Overall, these findings suggest that future clinical association studies should consider heterogeneity at the genetic level, as well as at the level of molecular and clinical phenotypes in order to achieve a better mechanistic understanding of the relationship between G6PD deficiency and severe malaria.
Comparative neurotranscriptomics in mammals and birds
Keywords: neuroanatomy
RNA-seq
transcriptome
birds
comparative neuroanatomy
sequencing
comparative neurotranscriptomics
mammals

In this thesis I apply new sequencing technologies and analytical methods derived from genomics and computer science to the neuroanatomy of gene expression. The first project explores characteristics of gene expression across adult neocortical layers in a representative mammal – the mouse. Amongst the thousands of genes and transcripts differentially expressed across layers, I found common functional characteristics of genes that define certain layers, candidate cases of isoform switching, and over a thousand apparent long intergenic non-coding RNA transcripts. The second project compares patterns of gene expression in the structurally diverged adult derivatives of the pallium in mice and chickens. Overall, gene expression levels were moderately correlated between the two species. While expression patterns of ‘marker’ genes were only poorly conserved in these regions, there nevertheless was significant conservation of cross-species marker genes for homologous structures, cell types and functionally analogous regions. Many aspects of these data from both projects can now be easily browsed and searched from custom-built web interfaces. In addition to generating unprecedented genome-wide resources for the neuroscience community to explore the functional and structural dimensions of gene expression amongst different pallial regions in mammals and birds, this work also provides new insights into the widespread evolutionary shuffling of adult marker gene expression.
Clinical trials in pleural disease
Keywords: empyema
Pleural disease

The focus of this thesis is on practice changing clinical studies which impact upon the day to day treatment of patients with pleural infection, answering specific questions on several aspects of patient management. Specific areas of assessment in this thesis include:
Assessment of the current evidence for optimal drain size choice in patients with pleural infection
Analysis and statistical modelling of a previous cohort of patients with pleural infection, in order to assess optimal drain size choice in pleural infection
The design, conduct and analysis of a 2 x 2 factorial multi-centre randomised, placebo controlled trial to assess the efficacy of two novel intrapleural agents (tPA and DNase) in aiding drainage in patients with pleural infection (The 2nd Multi-centre Intrapleural Sepsis Trial, referred to from here on as MIST2)
Validation work informing the primary outcome measure of MIST2, assessing the relationship between chest radiograph imaging of infected pleural effusion and CT measured volume of pleural fluid using novel digital measurement strategies
Targeting cell adhesion as a method of sensitising metastatic tumour cells to TRAIL-induced apoptosis
Keywords: TRAIL
cancer
metastasis

Due to its selectivity in killing cancer cells, Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) has provided a potential new agent for cancer treatment. However, despite promising pre-clinical results, it appears that TRAIL therapies will be most effective when used in combination with a sensitizing agent. In light of previous evidence suggesting that cell adhesion could influence sensitivity to Tumour necrosis factor family ligands, this thesis presents a study of the effects of disrupting matrix adhesion on the sensitivity of human MDA-MB-231 breast and 1205Lu melanoma cell lines to TRAIL-induced apoptosis.
This was investigated using a number of models including i) culturing cells on normal and low attachment plates; ii) disrupting the transcription of genes involved in cell attachment and spreading in MDA-MB-231 cells using shRNA to Myocardin-related transcription factors-A and B (MRTF-A/B); iii) disrupting the integrin signalling pathway using inhibitors or siRNA to β integrin subunits, talin, integrin-linked kinase (ILK), focal adhesion kinase (FAK) and SRC. With the exception of ILK depletion, disruption of cell adhesion and spreading in all models resulted in sensitisation to TRAIL-induced apoptosis. Cells under these conditions also showed alterations in death receptor signalling and amplification of intrinsic apoptosis pathway signalling through caspase-9. Both MRTF-A/B depleted cells and those treated with the SRC family kinase inhibitor PP2 showed alterations in signalling through ERK1/2. When investigated in an experimental model of metastasis in mice, FAK and SRC inhibitors increased the clearance of MDA-MB-231 cells from the mouse lung when used in combination with recombinant human TRAIL therapy.
By utilizing these models, the work in this thesis has shown that disrupting cell adhesion could provide a new combination strategy to sensitise tumour cells to TRAIL therapy.
Imagined security : collective identification, trust, and the liberal peace
Keywords: democratic peace theory
international relations theory
trust
international relations
international politics

While not uncontested, the finding that liberal democracies rarely, if ever, fight wars against each other represents one of the seminal discoveries of international relations (IR) scholarship. Nevertheless, 'democratic peace theory' (DPT) – the body of scholarship that seeks to explain the democratic peace finding – still lacks a satisfactory explanation for this phenomenon. In this thesis, I argue that a primary source of this failure has been DPT's failure to recognize the importance of collective identification and trust for the eventuation of the 'liberal peace'. Building on existing DPT scholarship, most of it Realist or Rationalist in its inspiration, but also employing insights from Constructivist and Cognitivist scholarship, I develop a new model of how specific forms of collective identification can produce specific forms of trust. On this basis, I elaborate a new explanation of the liberal peace which sees it as arising out of a network of trusting liberal security communities. I then elaborate a new research design that enables a more rigorous and replicable empirical investigation of these ideas through the analysis of three historical cases studies, namely the Canada-USA, India-Pakistan, and France-Germany relationships. The results of this analysis support the plausibility of my theoretical framework, and also illuminate four additional findings. Specifically, I find that (1) IR scholarship needs a more nuanced understanding of the interaction between agents and structures; (2) 'institutionalized collaboration' is especially important for promoting collective identification; (3) DPT scholarship needs to focus more attention on the content of the narratives around which collective identification takes place; and (4) dramatic events play an important role in collective identification by triggering what I term catharses and epiphanies. I close the thesis by reviewing the implications of my findings for IR and for policymakers and by suggesting some areas worthy of additional research.
Schooling and beyond: essays on skill formation and learning in deprived contexts
Keywords: education
shocks
poverty
skill-formation
skills

This thesis explores learning and formation of cognitive and non-cognitive skills within formal and non-formal environments, as well as the impact of migration on fertility behaviour in three separate empirical studies. In two of the papers (Chapters 2 and 4) I utilise a 13 year individual-level panel data-set from rural Tanzania, while the third one (Chapter 3) is based on cross-sectional data that I collected in urban Bombay slums in 2007. I consider skill acquisition and learning in a number of spheres. First, I adopt the conventional notion of school-based learning and examine the role of income shocks in evolution of schooling inequalities, in rural Tanzania. I find evidence of shock-induced permanent changes in the schooling of those affected by the shocks in later childhood (age 7-13), 10-13 years later. Further, I find suggestive evidence that the household short-term labour response may to be one of the mechanisms for these long-term effects. Next, I broaden the definition of learning to include acquisition of non-cognitive skills. Although there is growing recognition of the importance of these, there is no evidence, within a developing country context, on effectiveness of interventions targeting them. The second paper is an evaluation of a long-term non-formal schooling intervention in Bombay slums, which works on raising non-cognitive skills, including self-esteem, a sense of agency, and aspirations of children. It shows that, like cognitive skills, non-cognitive skills can be effectively raised through sustained intervention, offering evidence of substantial positive programme effects. The final paper turns to examining the impact of migration among young women on fertility behaviour. Econometric panel data methods are combined with an instrumenting strategy to offer evidence of a causal positive impact of migration on the age at which women start having children, which is shown to be likely to have permanent effects on total fertility. The findings are most consistent with the presence of temporary post migration disruption effects.
Engineering cytochrome P450BM3 into a drug metabolising enzyme
Keywords: catalysis
P450
protein electrochemistry

Directed evolution studies by Whitehouse et al. identified several variants of P450BM3 (CYP102A1) with enhanced substrate oxidation rates across a range of substrates. This thesis describes the use of these ‘generic accelerator’ variants, in combination with selectivity altering mutations to engineer P450BM3¬ for the oxidation of pharmaceuticals. Using engineered variants the non-steroidal anti-inflammatory drug diclofenac was metabolised to the primary human metabolites 4′- and 5-hydroxydiclofenac, with total conversion of 2 mM substrate by 5 μM enzyme. The local-anaesthetic lidocaine and the steroid testosterone were similarly metabolised to human metabolites. This is the first report of a drug compound being totally converted to the human metabolites by a P450BM3 variant, and is also the first report of lidocaine metabolism by a P450¬BM3 variant. The engineered variants are akin to CYP3A4, the primary human drug metabolising enzyme, as they show activity towards a range of compounds including anionic, cationic and neutral drugs. This range of activity is at the expense of NADPH coupling, which remains low with these substrates. In order to more fully understand the origin of the rate enhancing properties of the generic accelerator variants, spectroelectrochemical, stopped-flow and kinetic studies were performed. A custom optically transparent thin layer electrode system was designed and fabricated for use in spectroelectrochemical titrations. A spectroelectrochemical cell and gold mesh electrode were designed and used in spectroelectrochemical investigations of P450BM3 variants, as well as other P450s and their redox partners. These spectroelectrochemical, stopped-flow and kinetic studies, in combination with X-ray crystal structures provided insight into the origin of the rate enhancing properties of these enzymes and supplied the first example of the complete characterization of the thermodynamic and kinetic properties of WT and mutant P450BM3 for the oxidation of a non-natural substrate. The generic accelerator variants are, in the resting state, in a more catalytically ready conformation than the WT enzyme, and reorganization energy barriers appear to be lowered, so that fewer substrate-induced structural changes are required to promote electron transfer and initiate the catalytic cycle.
International perceptions and African agency: Uganda and its donors 1986-2010
Keywords: aid
agency
Africa
donors
Uganda

This thesis investigates the place of African states in the international system and seeks to understand what space exists for aid-dependent governments to exercise agency in relations with donors. In exploring these issues I focus on the case of Uganda’s NRM regime which has enjoyed very substantial international support despite its increasingly authoritarian nature, destabilising regional policy and questionable human rights record. The two central questions posed are therefore: ‘why has Uganda benefited from such uncritical international support and what role has the NRM regime itself played in bringing about this situation?’ The thesis also compares Uganda’s experience to those of Ethiopia, Kenya and Rwanda to demonstrate the broader relevance of these questions.
I argue that donors have taken a lenient approach to Uganda because they perceive it as valuable as an economic success story, an ally in the ‘War on Terror’ and a guarantor of regional stability. The study stresses, however, that these perceptions are just that: perceptions. They do not necessarily reflect reality nor are they formed without input from Africa, as some inadvertently suggest. Indeed, the principal contention of this thesis is that these three donor perceptions of Uganda have been actively constructed, moulded, managed and bolstered by Kampala itself in an effort to shore-up international support. Using a variety of ‘image management’ strategies the regime has succeeded in convincing its donors to see it as a valuable ally worth supporting. The same is true of the Rwandan and Ethiopian governments, I suggest, but not of the Kenyan. In doing so, the thesis contends, Kampala has carved out a subtle but substantial degree of agency in relations with donors and this raises important questions for scholars and policy-makers.
Allele specific silencing of proteins at the neuromuscular junction
Keywords: Congenital myastenia
RNAi
AChR
slow-channel syndrome
siRNA

RNA interference (RNAi) is a post transcriptional gene silencing mechanism that allows potent and specific silencing of cognate mRNA transcripts. Selective silencing can be used to dissect complex polygenic diseases, elucidate the function of known genes and provide a tool for genetic therapy. Its use in the case of dominant inherited disorders including disorders of the central nervous system, depends on its ability to confer single nucleotide discrimination between normal and mutant gene alleles.
In this thesis the ability of RNAi effector molecules to provide single nucleotide specificity was examined by targeting two dominant inherited mutations of the acetylcholine receptor that cause slow-channel syndrome. Allele-specific silencing was achieved for one mutation. The other mutation was also silenced but not in an allele specific way despite employing known techniques for increasing single-nucleotide specificity.
The model used in this thesis is the congenital myasthenia slow-channel syndrome. This is a dominant inherited disorder of the neuromuscular junction which is both well-characterised and more readily accessible compared to the central nervous system, thus provides a prototype for development of allele-specific RNAi therapeutics. Here we describe a new transgenic animal model of the slow-channel syndrome and show good representation of the human disorder.
The need for defining the characteristics that determine the effectiveness and the specificity of RNAi effectors at single-nucleotide level, along with the future uses of the newly described animal model are discussed.
An avant-garde theological generation: the Fourvière Jesuits from 1920 to 1950 and the 'Crise Entre-Deux-Guerres'
Keywords: 20th Century Catholic Theology
Ressourcement
Nouvelle Theologie
Henri de Lubac
Jean Danielou
Fourviere

This thesis seeks to offer a clearer understanding of the Jesuit theologians and philosophers who comprised the group known the 'Fourvière Jesuits'. Led by Henri de Lubac and Jean Daniélou, they formed part of the nouvelle théologie, an influential French reform movement that flourished from the 1930s until its suppression in 1950. After identifying a certain lacuna in the secondary literature, this thesis attempts to remedy certain historical deficiencies by constructing a history both sensitive to the wider intellectual, political, economic, and cultural milieu of the French interwar crisis, and that establishes continuity with the Modernist crisis and the First World War.
Chapter One examines the modern French avant-garde generations that have shaped intellectual and political thought in France, providing context for a historical narrative of the Fourvière Jesuits more sensitive to the wider influences of French culture. This historical narrative of the Fourvière Jesuits follows four stages. Chapter Two examines the influential older generations that flourished from 1893 to 1914, such as the Dreyfus generation, the generation of Catholic Modernists, and two generations of older Jesuits, which were instrumental in the Fourvière Jesuits' development. Chapter Three explores the influence of the First World War and the years of the 1920s, during which the Jesuits were in religious and intellectual formation, relying heavily on unpublished letters and documents from the Jesuits archives in Paris (Vanves). Chapter Four analyses the crises of the 1930s, the emergence of the Fourvière Jesuits' wider generation, and their participation in the intellectual thirst for revolution. Chapter Five examines the decade of the 1940s, which saw the rise to prominence of the members of the generation of 1930, who, thanks to their participation in the resistance, emerged from the Second World War, with significant influence on the postwar French intellectual milieu.
Communities, innovation, and critical mass: understanding the impact of digitization on scholarship in the humanities through the case of Tibetan and Himalayan studies
Keywords: Tibetan and Himalayan Studies
Humanities
Internet
libraries

The dominant discourse surrounding academic research libraries today is one of change and scholarship in the humanities has seen a similar revolution in practice. Yet, most of the documented changes in either have been ascribed to the availability of online journal materials. Despite the accessibility of millions of rare, digitized primary resources freely available on the web, little has been done to understand the impact of these materials on either the practice of scholarship or on libraries. The research described in this proposal is an investigation into digitization projects involving rare and closely guarded materials and the effects of these projects on humanities scholarship. This thesis uses both qualitative and quantitative measures to:
Assess the impact of digitized primary resources on the work of humanities scholars;
To construct a model based on the findings that explains current use of digitized primary sources; and
To discuss the implications of these findings for academic research libraries.
The research questions are answered through a detailed analysis of the role of digitization in the field of Tibetan and Himalayan studies. The author presents detailed evidence of how digitization is changing the inputs, practice, and outputs of scholarship in this field, as well as the characteristics of digitization that have led to these changes. Importantly, these findings separate out the success of individual projects from the success of digitization across the field as a whole. Support for community and innovation as well as the presence of critical mass across the field are stressed as the three most significant factors.
Finally, the implications of these findings are assessed within a newly proposed model of academic libraries. This “scholar-centric” model is intended to provide both a theoretical framework for the research findings as well as a normative provocation for structuring future research and discussions about the role of academic libraries and their presence online.
Group 2 ring-opening polymerisation catalysts
Keywords: Group 2 catalysts
ring-opening polymerisation

This Thesis describes the synthesis and characterisation of new Group 2 tetrahydroborate, alkoxide and organohydroborate complexes and their uses as catalysts for the living ROP and immortal ring-opening polymerisation (iROP) of ε- caprolactone and rac-lactide.
Chapter One introduces cyclic esters and possible mechanistic pathways leading to polyesters by ROP. Living and immortal ROP, including their kinetic characteristics are discussed. An overview of ROP from an industrial perspective is also given.
Chapter Two describes the synthesis and characterisation of a new series of Group 2 tetrahydroborate complexes supported by a 3-methyl, 5-tert-butyl tris(pyrazolyl)hydroborate ligand. Their activities towards the ROP of ε-caprolactone are presented. Detailed mechanistic studies using spectroscopic techniques are discussed and a new mechanism is proposed.
Chapter Three describes the ROP of rac-lactide using the Group 2 tetrahydroborate complexes introduced in Chapter Two, including their mechanistic studies.
Chapter Four introduces the new immortal ROP using trialkyl borate and organoborane derivatives as chain-transfer agents (CTAs). The immortal ROP of ε- caprolactone and rac-lactide using Group 2 initiators with trialkyl borates/organoboranes as CTAs from either in situ generation or external addition is discussed. Possible immortal ROP pathways using this new class of CTAs are illustrated.
Chapter Five details the synthesis and characterisation of a new series of Group 2 organohydroborate complexes. The ε-caprolactone and rac-lactide ROP activity shown by the complexes presented is discussed and compared with those obtained from the corresponding tetrahydroborate analogues.
Chapter Six contains experimental details and characterising data for the new complexes reported in this Thesis.
CD Appendix contains .CIF files for all the new crystallographically-characterised complexes.