VictorJuiz/thesis huggingface dataset:
Assessment of novel pre-erythrocytic malaria vaccines in humans

Falciparum malaria remains one of the leading infectious causes of morbidity and mortality worldwide. Though the search for an effective vaccine has seen unprecedented advances in recent years and one of the leading vaccine candidates, RTS,S/AS01 is going to enter pilot deployments in Africa in 2018, there has been no vaccine that has demonstrated durable high level efficacy. This thesis describes four Phase I and Phase II clinical trials assessing novel pre-erythrocytic malaria vaccines in healthy adult UK volunteers.
R21 has been developed at the Jenner Institute, University of Oxford. This is an improved RTS,S construct, an antigen derived from the pre-erythrocytic circumsporozoite protein, which is an abundant coat protein involved in sporozoite development and hepatocyte invasion. R21 comprises recombinant particles expressing the central repeat and the C-terminus of the circumsporozoite protein (CSP) fused to the Hepatitis B surface antigen (HBsAg), but without the excess of unfused HBsAg protein found in RTS,S. Both RTS,S and R21 predominantly function by inducing antibodies against the circumsporozoite protein. In addition to humoral immunity, it is widely recognised that T-cell mechanisms are likely to play an important role in malaria immunity and heterologous prime-boost regimes using viral-vectored vaccines have been shown to induce potent T-cell responses. ChAd63-MVA ME-TRAP is a regime that has been developed in the Jenner Institute and the first of the clinical trials described in Chapter 3 assesses the safety and immunogenicity of adjuvanting this regime with a novel saponin-based adjuvant, Matrix-MTM. This trial showed that this regime was safe, well tolerated and did not result in any immunological interference.
R21 had never been administered to humans prior to the work described in this thesis. In Chapter 4, I describe two Phase I clinical trials assessing the safety and immunogenicity of R21 given at varying doses administered with two different adjuvants, Matrix-M (MM) and AS01B. Both these trials showed that R21 was safe and well tolerated when administered with either adjuvant and elicited comparable humoral immune responses to RTS,S/AS01B even at one-fifth of the dose (10μg). This formed the basis to test the efficacy of R21/MM, which had a favourable reactogenicity profile, using controlled human malaria infection in malaria-naïve UK volunteers. High level efficacy (&GT; 80%) is reported in Chapter 5 with a three-dose schedule of 10/10/10μg R21/MM given 4 weeks apart. This provides the first evidence of proof-of-concept that this vaccine regime should be tested in malaria-endemic populations.

Advisor: Ewer, K
Hill, A
Seamount morphology, distribution and structure of the Southwest Indian Ridge

Ultra-slow spreading ridges have a full spreading rate of less than 20 mm/yr, and show deviations from the fundamental characteristics identified at faster spreading rates; however, they are poorly studied compared to faster spreading ridges. In this thesis we aim to build on previous studies in order to further characterise the unique processes occurring at the ultra-slow spreading Southwest Indian ridge (SWIR). This is an exploratory study utilising novel and existing bathymetry, gravity, video imagery data to understand tectonic and volcanic processes along the ridge crest from triple junction to triple junction. We conduct a series of studies which focus on the axial valley morphology, large seamount morphology, the distribution of small seamounts and large seamounts on the ridge, and admittance studies.
We show that the long wavelength trends in geophysical data, geochemical data, and axial valley morphology are well correlated. These variations reflect along-axis changes in the crustal and mantle structure, governed by the thermal structure of the ridge. Seamounts provide important morphological evidence of the volcanic and tectonic processes beneath the Earth's surface. We use detailed morphological investigations to show that volcanic and erosional processes on six large seamounts are controlled by the local faulting and melt migration mechanisms. We investigate the distribution of seamounts on the ridge using a numerical algorithm, and demonstrate a lower seamount density than faster spreading ridges. We show that the seamount population statistics vary along the ridge due to changes in the degree of partial melting, magma conduit availability, and melt focussing mechanisms; the locations of three proximal hotspots coincide with increases in the estimated magmatic flux. Finally, best fit elastic thicknesses are determined using a 3D windowed admittance technique, which was tested using synthetic data. We construct a combined convection-flexure model to account for misfits between the observed data and existing flexural theoretical models. The average elastic thickness varies between 7 km and 12 km, and we show a strong dependence on spreading rate.

Keywords: south-west indian ridge
admittance
seamount morphology
Advisor: Watts, T
Genetic regulation of membrane trafficking, exosome secretion, growth and dense-core granule biogenesis in the Drosophila accessory gland

Many epithelial cell types, particularly those in glands, employ distinct regulated and constitutive secretory pathways to perform their functions. Understanding how membrane trafficking and secretion are coupled to other cellular functions like growth, which is also thought to be linked to secretory and endocytic functions, is fundamental to cell biology and to certain pathologies such as diabetes and cancer. During my DPhil, I have been developing the secondary cells (SCs), which reside in the male Drosophila accessory gland, as a new in vivo system to dissect out the genetic regulation of membrane trafficking and its link to secretion and cell growth. SCs are epithelial cells located at the distal tip of each accessory gland. They contain a number of large intracellular compartments (>5 μm diameter) allowing membrane trafficking to be easily visualised. This in turn makes scoring specific trafficking phenotypes in normal and genetically manipulated cells very reliable.
Using imaging of both live and fixed cells, I show that SC compartments have specific Rab signatures characteristic of both secretory and endolysosomal compartments. The late endosomal and lysosomal marker, Rab7, is predominantly found on acidic compartments whilst Rab11, a slow recycling endosomal marker, is localised on the membranes of about ten non-acidic compartments containing dense-core granules (DCGs) and the protease angiotensin-converting enzyme (ANCE). I show that Rab GTPases regulate the maturation and number of compartments, the secretion of intraluminal vesicles, called exosomes, and the growth of SCs. Rab11 and Rab7 appear to control the balance between large non-acidic and acidic compartments in SCs, while Rab35, which coats smaller fast-recycling endosomal compartments (~1 μm), also controls the number of these large compartments.
BMP signalling regulates SC growth and membrane trafficking. Using knockdown experiments, I show that all components associated with BMP signalling are involved in this process. Interestingly, I demonstrate that as well as ANCE, Dpp, the fly homologue of mammalian BMP 2 and 4, is localised inside DCGs of SCs. Dpp is the predominant ligand controlling SC growth and exosome secretion via autocrine and paracrine mechanisms. Interestingly, mating elicits the secretion of DCG compartments (DCGs), a process dependent on the Synaptosomal-associated protein 24kDa, SNAP24. BMP pathway activation is also increased in a Dpp-dependent fashion, presumably as a result of Dpp secretion, and it accelerates the rate of DCG biogenesis. I propose a model in which Dpp regulates the replenishment of DCGs in response to release via an autocrine feedback loop.

Advisor: Wilson, C
The effects of dopaminergic modulation on model-based reinforcement learning

A functional polymorphism (Val158Met) in the catechol-O-methyltransferase (COMT) gene influences cortical dopamine and prefrontal cortex function in humans, both of which are important in learning and decision making. Moreover, dysfunction in the brain's dopamine circuits and mechanisms of decision making is observed during acute stress.
Mammals are thought to use two evaluation strategies in decision making, model-based and model-free reinforcement learning (RL), which have complementary strengths and weaknesses in terms of computational demand and statistical efficiency. Model-based is frontal cortex-dependent and reflects goal-directed behaviour, while model-free relies on the reward prediction errors from the striatum and reflects habits.
The aim of this thesis was to investigate how acute stress influenced RL, whether RL is altered in a mouse model of altered COMT activity, and if COMT-genotype influences the effects of acute stress on RL.
I tested RL in both wild-type mice and transgenic mice carrying the human Met158 allele. They were tested on a novel, multi-step, probabilistic RL task - the rodent two-step task - which can dissociate the influence of model-free and model-based RL on decision making. I used vehicle injections to induce acute stress.
The acute injection stress markedly impaired model-based learning and shifted decision- making towards more model-free in wild-type animals. No COMT-genotype difference on RL was observed when the mice were not stressed. However, Met homozygotes appeared to be less affected by injection stress on both model-based and model-free RL.
Consistent with findings in humans, I show that acute stress shifts mice towards a more model- free pattern of RL. This highlights the potential confounding effects of injection stress in pharmaco-behavioural experiments. Although formal tests for interactive effects of stress were not possible in some cases, I found that that Met homozygotes appear less sensitive than wild-type animals to the negative effects of injection stress. I hypothesise that this is because they have a greater cognitive reserve that, although unutilised at baseline, can step in when faced with increased cognitive demand resulting from environmental factors (in this case, acute injection stress). These findings suggest that subtle COMT genotype differences in behaviour might be amplified under conditions of stress, providing a potential explanation for some of the controversies seen in the human literature linking COMT genotype and cognitive function.

Keywords: Model-based learning
COMT
Prefrontral cortex
Reward Prediction Error
Reward learning
Mice
Catechol-O-methyltransferase
Dopamine
Injection stress
Stress
Advisor: Tunbridge, E
Walton, M
Drugs, addiction and the state in Iran: the art of managing disorder

This thesis explores the politics of drugs and addiction in Iran in light of processes of state formation. The case of Iran provides a paradigm of what has come to be known as the ‘War on Drugs’ in a political and cultural setting that has been characterised, by most of the area studies literature, by other investigations and scholarly questions. Iran, nevertheless, represents an outstanding case for the study of the War on Drugs; it is at the geopolitical crossroads of international drug routes, it has one of the world highest rates of drug 'addiction' – estimated at between 2-3% and 6-7% of the entire population – and it has progressively seen the rise of synthetic, industrial drugs, such as methamphetamines (shisheh). The thesis situates the phenomenon of drug use in the social and political history of Iran with a particular attention to the transformations taking place after the Islamic Revolution in 1979. It provides a genealogical map of policy experimentations in the field of drugs, while it also casts light on the rationale that governs the formation and transformation of state practices vis à vis drugs, especially during the reformist and post-reformist period (1997-2013). To do so, the research combines extensive archival research using Persian sources (newspapers, reports, films, memoires, etc.) starting from the early 1900s, with ethnographic fieldwork in public clinics, rehab centres, drug using hotspots and, more generally, the street. The outcome is an in-depth engagement with narcotic politics, which unearths unstudied dynamics of Iran’s contemporary politics and society. Instead of moralising approaches, what is unveiled is a state that adopts both rhetoric and practice that are secularised and in tune with Western models of policymaking. Eventually, the thesis reveals how the image of the Iranian state has not only been misplaced, but it has also been a myth.

Keywords: Drugs
Ethnography
Iran
Politics
Addiction
Emergence of cardiac function and cell types during early embryogenesis

The heart is the first organ to form and function during embryonic development. Over the past few years, research on cardiac development has focused on uncovering the genetic mechanism controlling cardiac differentiation and clarifying the embryonic origin of the different cardiac lineages. The study of the physiological mechanisms behind cardiac function has proven instrumental for our understanding of heart disease and the interplay between different cardiac cells. However, there is not an extensive body of literature on the role of physiology on early embryonic development, especially on cardiac development. In this thesis, I present my work on the early stages of heart development, focusing on the events occurring from the formation of the cardiac crescent to the linear heart tube stage.
This thesis is divided in 3 result chapters. In the first result chapter (chapter 3), I present the methods I developed to perform live imaging of mouse embryos, including calcium imaging, and to extract quantitative information.. On the second result chapter (chapter 4), I described the work I performed investigating the physiological mechanisms of early heart development, their role in cardiac differentiation, and a detailed single-cell RNA sequencing analysis of early heart development. On the last result chapter (chapter 5), I explore preliminary data on a potential contribution of endodermal cells to the formation of the heart.
The work presented here has led to the discovery of Spontaneous Asynchronous Calcium Oscillations (SACOs) in the early cardiac mesoderm and a key role for NCX1 in regulating these oscillations and cardiac differentiation. Single-cell RNA sequencing analysis suggests a potential role for Naca and Fbxo32 in regulating early cardiac function. I have also identified potential new markers for both the First and Second Heart Field. Lastly, I found evidence that the endoderm may be contributing to the Second Heart Field, although the function of these cells is still unclear.

Advisor: Srinivas, S
Development of (Z)-alkenylsilane coupling methodology and application towards the synthesis of incednine

This thesis describes the development of methods for the synthesis of incednam, the aglycon of incednine, via Hiyama cross-coupling. An early chapter discusses the efforts to improve upon previous efforts to access major building blocks. This is followed by a chapter focusing on the development of a novel strategy to access more reactive dimethyl alkenylsiloxanes and their applications. Finally, this new strategy is applied to the synthesis and different approaches to assemble incednam are explored.

Advisor: Anderson, E
Citizen Marx: the relationship between Karl Marx and republicanism

Karl Marx's relationship to republicanism proceeds in three stages: he began his political career as a republican, he subsequently transitioned to communism, and then he finally reconciled his republicanism and communism.
Marx's early political writings reveal his commitment to central republican ideas, including popular sovereignty, widespread political participation and universal suffrage. These commitments led him to reject absolute and constitutional monarchy. But they also led to a critique of the modern republic, which Marx argued gave insufficient space for citizens to participate publicly for the common good. He thus gives a republican critique of the republic.
Marx's disillusionment with the ability of a modern republic to deliver human emancipation eventually led him to transition to communism. He now argued that the republic would be a bourgeois republic, which would subject the proletariat to the capitalist. He attacked republicans for neglecting social depredation in favour of political reform. However, his transition to communism also carried with it several republican commitments. Unlike the many apolitical versions of communism at the time, Marx insisted that the workers had to establish the republic before communism could emerge. He also extended key republican political ideas, including the objection to arbitrary power, to the social sphere. But what was absent was an account of a more participatory and accountable political alternative to the modern republic.
However, the experience of ordinary workers carrying out the legislative and public administration of Paris during the Commune, led Marx to return to many of those early republican themes. He celebrated ordinary citizens' capacity for self-government and advocated popular control over the state and transforming representative democracy into popular delegacy. He came to realise that these political structures were essential to achieving the social goals of communism. He thus came to a synthesis of his early republicanism and later communism.

Keywords: capitalism
socialism
democracy
Karl Marx
republicanism
communism
Advisor: Leopold, D
Mechanisms of cone dysfunction in inherited retinal degenerations

This thesis examines the mechanisms of cone dysfunction in two different inherited retinal diseases: Achromatopsia and Retinitis Pigmentosa (RP). The first, minor, component of the thesis explored and characterised the loss of cone function in a novel mouse model of achromatopsia (cpfl10). The second, major, component of the thesis explored the loss of cone function in a mouse model of RP. I hypothesised that the cone function lost in RP could be restored using AAV vectors to over-express down regulated cone genes. This thesis subsequently developed and tested two AAV vectors delivering CRX and OPN1LW genes to photoreceptors in RP mice.
Achromatopsia is a congenital condition characterised by absent or diminished cone function due to mutations of a single gene, typically those involved in the cone phototransduction cascade. This thesis provides a detailed phenotype of a novel cpfl10 mouse model of Achromatopsia that arose spontaneously in a local mouse colony. The causative (NM_013927)c.692G>A; p.(R231H) missense mutation in Cngb3 was also identified and explored.
Retinitis pigmentosa (RP) is an inherited retinal degeneration in which secondary loss of cones follows the initial death of genetically abnormal rod photoreceptors. Strategies to prolong cone photosensitivity or survival would offer an important treatment. Such universal interventions could be effective regardless of which genetic mutation is underlying primary rod death.
The molecular mechanisms by which cone photoreceptors lose photosensitivity in RP are poorly understood. I examined the gene expression profile of the cone phototransduction cascade in the Rho-/- mouse model of RP and correlated these changes to declining retinal function. The cone opsins were substantially down-regulated, as was the photoreceptor transcription factor Crx. I hypothesised that the cone function lost in RP could be restored using AAV vectors to over-express these down regulated cone genes. Using an AAV gene therapy vectors, I delivered the human homologs CRX and OPN1LW to the retinas of the same Rho-/- mouse model. Both vectors successfully transduced photoreceptors and RPE cells across three different doses. Transduced retinas did not show any improvement in cone function or survival.
Whilst the observed down-regulation of cone genes correlates with cone function loss, it appears that both down-regulation and dysfunction arise from an unknown common cause. Ongoing research into mechanisms of metabolic starvation, oxidative stress and trophic factors in cone cell death offer promise for a common intervention to rescue cone photoreceptors.

Keywords: Ophthalmology
Advisor: MacLaren, R
Aslam, S
OFDM-based relay systems for next generation networks

The performance of four newly proposed orthogonal frequency-division multiplexing (OFDM)-based relay systems with different application scenarios are analyzed in this thesis. The first scenario that is studied relates to the bulk and per-subcarrier relay selections, which can be regarded as two extremes of the performance-complexity trade-off in multi-carrier relay selection. Specifically, the outage performance yielded by these two selection schemes is analyzed in spatially random networks where relays are randomly distributed. Subsequently, a novel selection scheme for OFDM-based relay systems is proposed by combining conventional bulk and per-subcarrier selections. The asymptotic outage performance of the combined selection scheme in the high signal-to-noise (SNR) region is analyzed, and it is found that the combined selection can achieve the optimal outage probability without using the full set of available relays for selection. Hence, a satisfactory solution to the performance-complexity trade-off can be obtained. Apart from conventional application scenarios, OFDM-based relay systems with relay selections are also analyzed in more practical scenarios, e.g., device-to-device (D2D) communications. However, due to the adoption of underlay D2D communication protocol, power control mechanisms are thereby necessary to be applied to mitigate the interference to conventional cellular communications, which lead to a series of new analytical challenges. Meanwhile, to incorporate with new modulation techniques, OFDM-based relay systems are also combined with index modulation (IM). Then, an adaptive OFDM-IM is proposed for two-hop relay networks to enhance the system reliability when there is only one relay, and relay selection is thereby infeasible. Specifically, in this proposed adaptive OFDM-IM, the mapping schemes between a bit stream and indices of active subcarriers are adaptively selected by a certain criterion. All these analyses for a variety of cases given in this thesis constitute a comprehensive analytical framework for OFDM-based relay systems in next generation networks.

Advisor: Coon, J
O'Brien, D