VictorJuiz/thesis huggingface dataset:
Maternal antibody interference, immunisation schedules, and protective antibody levels in infants

Vaccination programmes have been a cornerstone of public health policy globally for many decades. Infant immunisation programmes prevent millions of infections worldwide each year. In many cases infection is not just prevented in the immunised infants, but also in the wider population through the induction of herd effects.
Whilst the efficacy and cost-effectiveness of infant immunisation programmes is well-established, the design of such programmes varies greatly from country to country. Within any single country, changes to the programme occur over time, when new vaccines are introduced, when the type or manufacturer of vaccines changes, or when there are changes to the number of doses, or the spacing of doses.
In this thesis I explore the waning of maternal transplacental antibody, its effect on the immunogenicity of infant vaccines, and the timing and spacing of infant doses. I review the statistical methods for determining an antibody correlate of protection for vaccine-induced protection against disease and use new methods to derive serotype-specific correlates of protection for pneumococcal conjugate vaccines against the acquisition of carriage in infants.
Using secondary analysis of serological data from 49 infant immunogenicity trials, I show that maternal antibody inhibits the immunogenicity of most infant vaccines. Higher antibody responses are observed in infants who commenced vaccination at an older age, independent of the interference caused by maternal vaccination. Current methods for determining antibody correlates of protection are not fit for purpose. Using generalised additive models of serological data I show that the antibody level associated with protection against pneumococcal carriage varies across serotypes, and is higher in low- and lower-middle income countries.
These findings on key factors that influence the immune response in infants will help policy-makers in the UK and worldwide to make informed evidence-based decisions to protect the population against disease.

Advisor: Pollard, A
Perera, R
Fanshawe, T
Sadarangani, M
Weathering change: climate change vulnerability and women in cocoa farming

Climate change is increasingly recognized as a hurdle to achieving development goals in developing countries and emerging economies. While mitigation is still a focus of many climate change activities, adaptation strategies are recognized as essential to respond to the current and projected impacts of climate change. The concept of vulnerability is often used to identify what adaptation measures must specifically address, and is discussed in terms of three components: exposure to shocks or long-term stress; sensitivity of a system to the event; and capacity to adapt. Women are considered a vulnerable demographic, because of their reduced access to land, financial and productive resources, and information. This dissertation integrates a vulnerability framework with gender considerations as a means to explore many of the factors influencing climate change vulnerability among women in a case study of cocoa farming in the Central Region of Ghana.
The research is based on semi-structured interviews with female members of three communities, representing a cross-section of the different associations with land and farm decision-making, ranging from primary operators of cocoa farms to producers of food crops on a spouse’s land for subsistence and local markets. The interviews highlighted the importance of income sources and diversification, access to information, and perceptions of empowerment and agency as contributors to vulnerability to projected climate change impacts. Women without direct access to cocoa generally had fewer assets at their disposal and shorter planning horizons that might lead to greater vulnerability. Despite these differences, most of the women demonstrated a positive outlook and future orientation that is often taken as a sign of adaptive capacity. This research demonstrated the need for more nuanced assessment of vulnerability among women, but also for rethinking the depiction of women as disempowered actors and the types of policies crafted to support climate change adaptation and development.

Keywords: vulnerability
climate change
Africa
gender
Advisor: Malhi, Y
Hirons, M
Investigating the role of Leucine Rich Repeat Kinase 2 (LRRK2) in human induced pluripotent stem cell derived macrophages

Mutations in Leucine Rich Repeat Kinase 2 (LRRK2) are the most prevalent cause of familial PD. Genome Wide Association Studies (GWAS) have linked its variants with increased risk of developing sporadic PD, inflammatory bowel disease, and leprosy, diseases commonly associated with inflammation and immune dysfunction. LRRK2 is predominantly expressed in a subset of immune cells, notably macrophages and microglia and has been implicated in innate immunity. Yet, most studies report conflicting results, and data are based on mouse models or in immortalised cell lines which do not faithfully recapitulate all aspects of tissue macrophages. In this thesis, macrophages and microglia differentiated from human induced pluripotent stem cells (hiPSCs) have been used as a genetically tractable tool that expresses LRRK2 at physiological levels from its endogenous promoter in its normal human chromosomal location. Using this physiologically relevant cell model, the aim of this thesis was to investigate the expression, subcellular localisation and role of LRRK2 protein in macrophages and microglia. This thesis maps the cleavage region of an N-terminal proteolytically cleaved form of LRRK2 in macrophages and shows that LRRK2 can form heterodimers of full-length and cleaved forms. My results demonstrate that LRRK2 is recruited to late phagosomes and that treatment of LRRK2 kinase inhibitors leads to the formation of LRRK2 super-coated phagosomes. However, I demonstrate that LRRK2 is not required for the acidification of phagosomes, and its role at the phagolysosome remains unresolved. Lastly, using hiPSC-microglia in co-culture with iPSC-cortical neurons, I demonstrate that in human cells, LRRK2 is robustly expressed in microglia and is undetectable in cortical neurons. In this co-culture model, under the conditions tested, inflammatory cytokine release was broadly unaffected by LRRK2 mutation or KO, although two different TNFα assay approaches gave conflicting results. This thesis provides novel insights into the role of LRRK2 in macrophages and microglia, and shows that hiPSC-macrophages and microglia can serve as a valuable platform to examine LRRK2 biology.

Keywords: Parkinson's disease
LRRK2
Macrophages
iPSC
Advisor: Cowley, S
James, W
Hyperglycaemia induced immunomodulation of macrophages in diabetic vascular disease

Background: The mechanisms by which diabetes increases atherosclerosis and cardiovascular disease risk even after glucose normalisation remains unclear. We hypothesised that: (i) hyperglycaemia alters cellular metabolism; (ii) these changes drive pro-inflammatory responses, which remain altered after glucose normalisation and (iii) these increase atherosclerosis in vivo.
Methods and Results: Hyperglycaemia alters monocyte, macrophage and hematopoietic stem cell (HSC) metabolism, significantly increasing glycolysis (FDR=0.02, human monocyte non-targeted metabolomics screen). In vitro, hyperglycaemia increased pro-inflammatory macrophage gene expression upon LPS + IFNy stimulation (IL-6, p<0.001) and both monocyte adherence to activated endothelium and macrophage uptake of modified lipid (p<0.001); all responses were normalised by the glycolytic inhibitor dichloroacetate (DCA) or 2-deoxy-glucose (2DG). Bone marrow derived macrophages (BMDM) from diabetic mice, grown in physiological glucose retained heightened pro-inflammatory responses, indicating hyperglycaemic memory in the HSC niche as well, as differentiated cells. To understand if diabetic HSC memory has a role in driving disease in vivo, bone marrow from diabetic mice (vs. wild type control) was transplanted into LDLR-/- mice. After 12 weeks, plaque burden in the aortic root (p=0.036) and plaque lipid content (p=0.0076), were greater in the mice receiving cell from the diabetic donor, confirming a memory effect. To investigate the mechanism underlying hyperglycaemic memory, ATAC-seq analysis was performed on diabetic and wild-type (WT) HSCs. Differential peak analyses indicated that cells from diabetic mice had an altered chromatin structure, potentially mediated through the increased histone modifications H3K27ac and H3K4me3 (P<0.01). These histone modifications are normalised by DCA. Motif analysis revealed that binding sites for the transcription factors PU.1, CTCF and RUNX1 are significantly enriched in peaks differentially present in diabetic HSC.
In conclusion: Diabetic hyperglycaemia alters HSC and macrophage metabolism to induce epigenetic changes which increases their pro-inflammatory responses and drives atherosclerotic disease in vivo. PU.1, CTCF and RUNX1 have been previously associated to chromatin priming elements. This novel demonstration of immunological memory may help to explain why targeting elevated glucose is often ineffective in reducing cardiovascular risk in diabetes.

Advisor: Akbar, N
Choudhury, R
Fast gates and mixed-species entanglement with trapped ions

Building a quantum computer is one of the outstanding contemporary goals in physics. Trapped-ion qubits are among the most promising contenders, achieving the highest precision gates out of all platforms. However entangling gates have previously only been performed in a regime where their speed is limited by the motion of the ions in the trap. The work in this thesis demonstrates entangling operations beyond this speed limit. In addition, entanglement of different species of ion has been performed. This is an important step towards building a scalable quantum computer, by being able to interface and connect trapped ion qubits via photonic links.
We demonstrate mixed-species entangling gates using a method that requires only a single laser for both species. In an experiment demonstrating the technique with two isotopes of calcium, 40Ca+ and 43Ca+ , we achieved a Bell state fidelity of F = 99.8(6)%. We also perform a Bell test with the two different isotopes, achieving a violation of the CHSH inequality by 15 standard deviations with CHSH parameter S = 2.228(15), without making a fair-sampling assumption. We then use the same gate mechanism to perform an entangling gate on two different atomic species, 43Ca+ and 88Sr+ . In a proof-of-principle experiment we achieved a Bell state fidelity of F = 83(3)%.
For achieving faster two-qubit gates we shape the amplitude of the laser pulses driving the gates. The pulse shapes are specifically designed to yield low error rates and be insensitive to the optical phase of the driving field. We perform an entangling gate with fidelity F = 99.78(3)% in tg = 1.6 μs, a factor of 20 − 60 times faster than the previously highest-fidelity trapped ion gates with only a factor ≈ 2 increase in gate error. We also demonstrate entanglement generation within 480 ns, less than a single period of the centre-of-mass motion of the ions.

Keywords: Trapped ions
Advisor: Lucas, D
Essays on the political economy of development: the role of democracy and institutions

Political institutions shape the structure and incentive systems of economies and are therefore essential for development. This thesis consists of three chapters that analyse and empirically study questions of different topics on the political economy of economic development, focussing on accountability, political capture, and democracy more generally. Chapter 1 analyses the effects of increases in the salience of electoral accountability on selection into politics in a context where accountability mechanisms are prone to political capture. The analysis examines recall referenda in Peruvian municipalities and demonstrates that candidates in municipalities where a recall election took place are on average less educated and less experienced. Furthermore, elected mayors in those municipalities exhibit less effort in office. The findings can be explained by political capture of recall referenda, which discourages high-quality individuals from competing for office and also reduces incentives for incumbents in office. Chapter 2 explores strategic behaviour of non-state actors during a prolonged transition period. The chapter provides evidence that non-state actors in Colombia strategically exploit the period between peace negotiations and demobilisation to expropriate land in order to consolidate their future economic and political power. Weak state capacity, relatively far-reaching impunity, and the multi-year length of the transition period allow non-state actors to influence the transition process in their interest and to pursue personal gain. In Chapter 3, I empirically examine the relationship between democracy, government size, and redistribution in a global country panel. Using within-country time series variation in dynamic panel model regressions and instrumental variable estimation, I find that democratisation is associated with significant increases in redistribution but not with higher government expenditure or taxation per se. The effects are considerable in the long run, leading to an increase in redistributive taxes and expenditure of up to 20%. Democratisation’s impact is, however, heterogeneous. I explore and discuss a number of dimensions along which the effects on redistribution vary.

Advisor: Bond, S
Hoeffler, A
A ‘seedbed’ for post-colonial leaders

This thesis explores the transition between an imperial and post-colonial world by assessing the intellectual and political education of post-colonial leaders from India, as well as Africa, the West Indies and Canada, who studied at the London School of Economics and Political Science [LSE]. The period under scrutiny, from the end of World War I to the early 1950s, witnessed an increasing number of students from British colonies studying in UK universities, with LSE in particular becoming one of the most diverse in the country. At the same time, a number of factors combined to make LSE a fruitful place to examine the larger themes of higher education’s place in late imperial history, the intellectual background of post-colonial leaders and the role of internationalism in nationalist movements. This includes the expansion of LSE’s faculty to include the Marxist Professor of Political Science Harold Laski [1926-50], who developed close relationships with colonial students, the School’s leading role in the research and teaching of the social sciences and its location in central London, which positioned it within walking distance of myriad organisations that offered students the opportunity to network with co-nationals and peers from other colonies while actively engaging in contemporary debates.
The overarching argument is that the classes and political experiences overseas students at LSE were offered promoted graduates inclined towards particular varieties of internationalism, socialism and a belief in the power of the social sciences to transform society by facilitating expert advising and planning. In doing so, LSE was both highly progressive but also less radical than previously thought, demonstrating consistency with nineteenth and early twentieth century notions of the imperial ‘civilising mission’ and reformed liberalism.

Keywords: LSE
Liberalism
Harold Laski
Internationalism
British Empire
Socialism
India
Advisor: Misra, M
Owen, N
Properties of voltage-gated Na+ channels in pancreatic beta-cells

Nav channels in rodent β-cells predominantly exhibit a hyperpolarised voltage-dependence of inactivation, which is so characteristic that it can be used for functional identification of β-cells. A smaller Na+ current component (10-15%) also exists that inactivates over physiological membrane potentials and contributes to action potential firing. It has been proposed that the currents contributing to inactivation over vastly different membrane potentials reflect the contribution of different Nav α-subunits. The aim of this thesis was to investigate the contribution of individual Nav channel α-subunits to the behaviour of Nav current inactivation in β-cells and to gain insight into the underlying mechanism(s) of channel regulation. TTX-resistant variants of the Nav subunits found in β-cells (NaV1.3, NaV1.6 and NaV1.7) were used to isolate currents from individual α-subunits expressed in insulin-secreting Ins1 cells and in non-β-cells (including HEK, CHO and αTC1-6 cells). Nav1.7 inactivated at 15-20mV more negative membrane potentials than Nav1.3 and Nav1.6 in Ins1 cells. Meanwhile, all Nav subunits inactivated at ~20-30mV more negative membrane potentials in Ins1 cells than in HEK, CHO or αTC1-6 cells reflecting α-subunit and cell-specific differences in the inactivation of Nav channels. In Ins1 and primary β-cells, but never in the other cell types, widely different components of Nav inactivation (separated by 30 mV) were also observed following expression of a single type of Nav α-subunit. The more positive component exhibited a voltage-dependence of inactivation similar to that found in HEK/CHO cells. The more negative inactivation in Ins1 cells does not involve a diffusible intracellular factor because the difference between Ins1 and CHO persisted after excision of the membrane. We propose that biphasic Nav inactivation in insulin-secreting cells reflects insertion of channels in membrane domains that differ with regard to lipid and/or membrane protein composition.

Advisor: Rorsman, P
Chibalina, M
Hydrodynamic optical-field-ionized plasma waveguides for laser plasma accelerators

This thesis documents the experimental development of low-density hydrodynamic optical-field-ionized (HOFI) plasma channels. Results from two experiments are presented; the first, a proof of concept experiment, performed in Oxford, demonstrating for the first time that the formation of low-density (&Tilde;1017 cm-3) hydrodynamic plasma channels was possible using optical-field-ionization. The second experiment, performed at Astra-Gemini TA2, aimed to demonstrate the generation of low-density axicon-formed HOFI plasma waveguides and subsequently to demonstrate high-intensity guiding in those waveguides at the highest available repetition rate.
In the Oxford experiments, short (2-4mm) HOFI plasma channels were generated in hydrogen with a spherical lens and probed with longitudinal interferometry. The channels had on-axis densities between 1.6 × 1017 cm-3 and 1 × 1018 cm-3 and matched spot sizes of order 30μm to 60μm. A computational investigation into the guiding properties of the measured plasma channels indicated that they would be suitable as plasma waveguides.
In the experiments at Astra-Gemini TA2, HOFI plasma channels up to 16mm in length were generated in hydrogen using an axicon. These were probed with both longitudinal and transverse interferometry and had on-axis densities as low as 2 × 1017 cm-3 . These waveguides were subsequently used to successfully guide high-intensity (>1017 W cm-2) pulses over the full 16mm or 14.5 Rayleigh ranges, with a maximum throughput of 60 % observed for the higher intensities. The variation in guiding with pressure and with guided beam intensity was investigated experimentally. It was found that the high-intensity guided pulse modified the HOFI plasma channel, with the result of increasing the relative throughput of the guided beam.

Keywords: interferometry
optical-field-ionization
low-density
HOFI
LWFA
laser plasma
plasma waveguide
LPA
high-intensity
hydrodynamic
laser wakefield accelerator
axicon
laser plasma accelerator
Sedov-Taylor
guiding
OFI
Advisor: Hooker, S
Bayesian nonparametric methods for dynamics identification and segmentation for powered prosthesis control

Robots need to be able to adapt to their surroundings. Robots whose core function relates to the rehabilitation and assistance of humans, need to be able to adapt to humans. But not all humans, one human in particular: their user. This is an adaptive control problem which speaks of the need for powered prostheses to have anthropomorphic adaptive capabilities. However, it is inconceivable that all possible movements, dynamics and tasks can be preprogrammed into such a system. Prostheses, like robots, need to be able to learn and improve, either by themselves unsupervised, or with the help of human supervision.
The United States alone is home to more than two million amputees, where below-knee amputations is the most common form. The same country is also home to 4.7 million stroke survivors, many of whom could make use of rehabilitation robots. Vascular diseases, such as diabetes, cause 54% of all amputations and the number of diabetes and pre-diabetes cases in the United States currently exceeds 100 million and growing.
Whilst this thesis does not attack the root causes, it does present a three pronged approach for framing the adaptive control problem required for effective rehabilitation. We develop methodology that structures the problem into one of learning a control framework for lower extremity active prosthetics. First, we consider incidence detection as a key element of any control strategy. We study the dynamics of falling under the aegis of classification and state-space modelling. We use the standard Kalman smoother to inpaint missing observations. Then dimensionally reduce the feature space to demonstrate increased classification accuracy, compared with our reference study.
Secondly, we move to the temporal segmentation of similar time-series. This is done using the Bayesian nonparametric paradigm within the framework of state-space modelling and probabilistic programming. Models are rarely correct for real world data. Rather than comparing models that vary in complexity, this approach fits a single model that can adapt its complexity to the observations. This unbounded analysis of the state-space is required given the need for the proposed control framework to grow with new observations.
Finally, we investigate multiple incidents of walking velocity, and propose a learned control strategy able to smoothly transition between the incidents. We combine Gaussian process regression with impedance control, and gait-cycle regression to form a locomotion envelope. The learned control capabilities allow the wearer to smoothly transition between self-selected velocities.

Keywords: State-space modelling
Prostheses
Probabilistic programming
Time-series
Healthcare robotics
Signal processing
Advisor: Wood, F
Posner, I
Osborne, M