VictorJuiz/thesis huggingface dataset:
Structure-guided optimization of immunogens for emerging arthropod-borne viruses

Mosquito-borne arboviruses, such as flaviviruses and alphaviruses cause millions of infections every year and raise public health concerns worldwide, yet, there are no approved vaccines or specific treatments for the majority of them. There is also an urgent need for improved diagnostics and intervention methods to tackle these. This thesis aims to contribute to improved diagnostics and intervention methods focused against flaviviruses (Zika and Dengue) and alphaviruses (Chikungunya and Mayaro) by improving serological diagnostic tools, testing of new vaccine candidates or discovery of new drug targets based on both immunological and structural studies. In the first and second chapter, the production and purification of flaviviruses envelope (E) and non-structural (NS1) glycoproteins in mammalian cell culture along with that of envelope glycoprotein of alphaviruses are described. These reagents are used for immunomonitoring of arboviral vaccines in both, pre-clinical and clinical studies, in particular for ChAdOx1 Zika and Chikungunya vaccine candidates under Phase I clinical trials. These chapters detail the development of ELISA-based serodiagnosis of ZIKV, DENV and CHIKV using volunteers’ sera from an endemic region in Mexico. In addition, these chapters describe the assessment of immunogenicity and efficacy of MVA based Zika vaccine candidates and the ChAdOx1 based CHIKV vaccines. In the third chapter and the final chapter, the expression and characterisation of alphavirus virus-like particles (VLP) are described for structural studies coupled to immunogenicity and efficacy studies, using in vivo and in vitro approaches. Progress has been made on the determination of their cryo-EM structures to understand its glycan structural targets and interactions with the host-cell receptors such as MXRA8. Finally, future plans are discussed for the production of monoclonal antibodies against MAYV and CHIKV using hybridomas for further Cryo-EM study of MAYV VLP–MAYV specific or CHIKV cross-reactive neutralising mAb to reveal the critical epitopes to understand and design structural guided vaccines against alphaviruses.

Advisor: Reyes-Sandoval, A
Bowden, T
Huiskonen, J
Becoming queen: voices, bodies, and technologies in drag lip-sync performance

Lip-syncing is foundational to drag performance. While it may have had rather humble beginnings, responding to exigencies of frugality rather than artistry, drag lip-syncing has become a highly refined and stylised mode of performance, but also one that has been left relatively unexamined. This thesis seeks to interrogate drag lip-sync performance from a variety of angles, providing solid theoretical frameworks for how lip-syncing functions as well as its unique attraction and self-actualising benefits for the performing queen. To this end, I split the thesis into four sections – The Silent Voice, The Imaginary Voice, The Material Voice, and The Queer Voice – and draw my conclusions through the help of five London-based drag queens: ShayShay, Rodent, Sue, Bougie, and Ruby. I begin by looking at lip-syncing’s theoretical importance to voice studies, arguing that lip-syncing evidences a special type of “silent voice”, a voice that is generated through silence, and also a voice that reflects the extimate silence of all speech acts. In the second section, I am more concerned with why drag queens choose to lip-sync, and what benefits it holds for the queen. Through psychoanalytical and ethnographic work, I argue for a complex series of identifications that take place, across multiple bodies and voices. The third section attends to the affective materiality of lip-syncing, first by theorising the necessity of loud sound in lip-sync performance and an attendant type of listening I coin as “haptic aurality”, and second by exploring the limits of the body in lip-syncing through an analysis of a performance by ShayShay. Finally, I turn to the queer voice – a voice that speaks queerly in its structure, but also to queer people through affective ties of memory and sound. Ultimately, this thesis seeks to uncover what lip-syncing can teach us about more typical acts of voicing, and also to make clear the abundant variety of ways in which drag queens use lip-syncing creatively in order to gain confidence and self-surety. As such, lip-syncing is conceived of throughout as, at base, a political act. Lip-syncing is a site of relation, an active creative process, and one that aids the performing queen in a constant process of becoming.

Keywords: Lip-syncing
Phenomenology
Performance studies
Queer theory
Lipsynching
Psychoanalysis
Drag queen
Synchrony
Advisor: Stanyek, J
The role of the microbiome in musculoskeletal disease: a focus on tendinopathy

Although pathogenesis of musculoskeletal diseases is incompletely understood, the role of inflammation is now accepted to be important. The microbiome - all non-human microbiota residing in humans – is increasingly of interest as a potential trigger of musculoskeletal disease. Using surrogates for an altered microbiome state (dysbiosis), this thesis employed three scientific approaches to determine whether the microbiome has a role in tendinopathy.
Firstly, epidemiological (case-control, cross-sectional studies) approaches identified and verified an association between inflammatory bowel disease (IBD) and tendinopathy (OR 2.11, 95% CI 2.08-2.15) and rate of IBD in tendinopathy patients (standardised rate of 19.7%); and confirmed the association between IBD and RA (OR 1.88, 1.70-2.07). Secondly, pharmaco-epidemiological (case-control) techniques found an association between beta-lactam and tetracycline antibiotics, (OR 1.59, 1.57-1.60 and OR 1.08, 1.06-1.11 respectively) and tendinopathy. Similar trends were found between beta-lactam and quinolone usage and tendon ruptures (OR 1.42, 1.27-1.58 and OR 1.11, 0.97–1.27 respectively). Index RA was associated with beta-lactam and quinolone use (OR 1.32, 1.26-1.38 and OR 1.23, 1.16-1.29 respectively). These associations were dose-dependent and demonstrated a temporal association. Moreover, a self-controlled case series study found an association between RA flares and sulphonamide and trimethoprim use between one and twelve months after prescription.
Thirdly, an experimental murine model of tendinopathy was validated (at 72-hours, two-weeks and ten-weeks post-injury). This showed reproducible tendinopathy-relevant changes in histological scores (including calcification) and gene expression (RNAseq). This model was propagated using mice raised in germ-free (GF) or specific pathogen free (SPF) conditions at ten-weeks post injury. There was no significant difference in histological scores, however, significantly lower ossification was observed in mice raised in GF conditions (0.0058mm3 ±0.0017 in GF vs 0.0488mm3 ±0.0197 in SPF, p<0.0001).
This thesis demonstrates an association between dysbiosis (IBD, antibiotic usage, SPF over GF conditions) and tendinopathy, suggesting a role for the microbiome in tendinopathy. Further work should investigate the mechanism by which the microbiome mediates tendinopathy.

Keywords: musculoskeletal
epidemiology
microbiome
rheumatoid arthritis
data science
tendinopathy
Advisor: Carr, AJ
Prieto Alhambra, D
Vincent, TL
Snelling, SJB
Holomorphic Yukawa couplings in heterotic string theory

This thesis is concerned with heterotic E8 ×E8 string models that can produce quasirealistic N = 1 supersymmetric extensions of the Standard Model in the low-energy limit. We start rather generally by deriving the four-dimensional spectrum and Lagrangian terms from the ten-dimensional theory, through a process of compactification over six-dimensional Calabi-Yau manifolds, upon which holomorphic poly-stable vector bundles are defined. We then specialise to a class of heterotic string models for which the vector bundle is split into a sum of line bundles and the Calabi-Yau manifold is defined as a complete intersection in projective ambient spaces.
We develop a method for calculating holomorphic Yukawa couplings for such models, by relating bundle-valued forms on the Calabi-Yau manifold to their ambient space counterparts, so that the relevant integrals can be evaluated over projective spaces. The method is applicable for any of the 7890 CICY manifolds known in the literature, and we show that it can be related to earlier algebraic techniques to compute holomorphic Yukawa couplings. We provide explicit calculations of the holomorphic Yukawa couplings for models compactified on the tetra-quadric and on a co-dimension two CICY. A vanishing theorem is formulated, showing that in some cases, topology rather than symmetry is reponsible for the absence of certain trilinear couplings. In addition, some Yukawa matrices are found to be dependent on the complex structure moduli and their rank is reduced in certain regions of the moduli space.
In the final part, we focus on a method to evaluate the matter field Kahler potential without knowing the Ricci-flat Calabi-Yau metric. This is possible for large internal gauge fluxes, for which the normalisation integral localises around a point on the compactification manifold. We illustrate the procedure on CICYs embedded in the ambient space P1 × P3, and express our result in terms of globally defined moduli.

Keywords: Yukawa couplings
complete intersection Calabi-Yau manifolds
line bundle models
Advisor: Lukas, A
Light-powered transmission in a bioinspired synthetic nerve

Electronic devices which seamlessly interface with living tissues have considerable potential. However, conventional technologies are restricted by inherent mechanical, chemical, and electrical differences which exist at the biotic-abiotic interface. Innovative approaches are therefore required to overcome these limitations and enhance device functionality. This thesis details the fabrication of a new bioelectronic device - a synthetic nerve - which is soft, tetherless, and powered by light. Imitating neurobiological architectures, the synthetic (non-living) nerve is a cable-like bundle of synthetic axons that conveys sensory information over centimetre distances. The components of the neural device are nanolitre aqueous droplets and hydrogel fibres, connected through functionalised lipid bilayers. At the sensory end of the synthetic nerve, signalling is initiated by photochemically-driven proton pumps: archaerhodopsin-3 and bacteriorhodopsin. Following rapid phototransduction, bioelectrical signals are directionally transmitted along the conducting axon and into the synaptic terminals. Mimicking natural cells, chemical neurotransmitters are then released from these synaptic terminals, initiating functional outputs downstream. In this way, signalling within the synthetic nerve resembles the electrochemical communication used by living cells: conducting ions and translocating molecules in the process (albeit using different mechanisms). Parallel transmission of discrete electrochemical signals can be achieved by patterning the conducting pathways in 3-dimensions. Finally, photoinduced communication is demonstrated in a simple hybrid tissue. These light-powered synthetic nerves are a valuable contribution to the development of electrode-free, soft bioelectronics for applications in medicine, robotics or computing.

Advisor: Bayley, J
Methods towards computational catalyst design

Identifying active, selective and stable catalysts computationally remains an unsolved prob- lem with numerous benefits in chemistry and the wider world. Determining reaction free energy barriers enables such a classification and relies on predictions from calculations or chemical intuition. By understanding how a biomimetic metallocage achieves catalytic profi- ciency towards a [4+2] cycloaddition more active catalysts are proposed to require enhanced flexibility and electron deficiency (Chapter 3). In combination with automated approaches to construct host-guest geometries and generating transition states (Chapters 3 & 5) the efficient methodology enables screening new metallocages for a reaction to become routine. A method to improve the accuracy of calculated reaction free energy differences is proposed that uses a more realistic expression for the translational entropy contribution for solution- phase solutes (Chapter 4). Towards calculating accurate free energy differences by dynamics sampling, an efficient method for training machine learned potentials is proposed en-route to fast yet accurate molecular force fields (Chapter 6).

Advisor: Duarte, F
McGrady, J
Structural studies of bacterial adhesion

Adhesion to abiotic and biotic surfaces is essential for numerous bacterial developmental processes including biofilm formation. While the general role of adhesins in biofilm formation has been explored, the arrangement of these structures on the cell surface and how these structures interact with substrates at the molecular level remain unclear. In this project, the CupE chaperone usher fimbriae of Pseudomonas aeruginosa and the holdfast polysaccharide of Caulobacter crescentus were investigated as models of proteinaceous and polysaccharide-mediated adhesion respectively.
Using structural biology methods, including electron cryomicroscopy (cryo-EM) and electron cryotomography (cryo-ET), this thesis provides molecular details of a previously uncharacterized mechanism of polysaccharide adhesion. The holdfast is a polysaccharide adhesin which is anchored to the surface of C. crescentus by a defined molecular complex made up of the HfaABD proteins. The HfsDAB secretion proteins are required for assembly and localization of the HfaABD anchor, which spans the outer membrane of the stalk tip. The anchor protein HfaB is the major component of the anchor complex located on the periplasmic side of the outer membrane, while HfaA and HfaD are located on the cell surface. HfaB is the critical component of the complex, without which no HfaABD complex is observed in cells. Finally, anchor densities are present along the cell envelope of other alphaproteobacteria including Asticcacaulis and Hirschia spp., supporting a conserved mechanism in holdfast anchoring.
Additionally, this thesis provides insight into the regulation, structure and physiological role of archaic CupE fimbriae in P. aeruginosa. Deletion of the PA2133 phosphodiesterase gene upregulates CupE filaments under static conditions, indicating that filament assembly is promoted upon c-di-GMP elevation and surface sensing. CupE fimbriae are a major contributor to biofilm formation in DPA2133 mutants, with increased biofilm formation at the air-liquid interface, as well as cell clustering and organisation at the microscopic level. The diameter of CupE filaments is ~4 nm, consistent with fimbriae of the archaic s-clade. The cryo-EM structure of native CupE, at a resolution of 4.5 Å, reveals a single-start, helical morphology that does not resemble the tubular structure of classical chaperone usher assemblies. These findings provide the first structural insights into a fully assembled, archaic chaperone usher filament in bacteria and support CupE fimbriae function as an adhesin during biofilm formation.

Keywords: caulobacter
cryo-EM
cryo-ET
chaperone usher protein
holdfast
pseudomonas
Advisor: Bharat, T
Tang, C
Essays on networks and development 

Social networks can impact individual outcomes by hampering social learning, propagating incorrect misperceptions, and upholding inefficient rules. This thesis studies how individual decisions can be impacted by the social networks they are embedded in. In the first chapter, I theoretically show that individual behavioural idiosyncrasies can adversely affect the choices of their peers and the long-run beliefs of society. I find that an individual's network position along with their behavioural type determines whether societal beliefs converge accurately and how quickly they do so. In the second chapter, my co-author and I use structural estimation techniques and experimental evidence to show that network-induced misperceptions can prevent individuals from engaging in inter-personal dialogue around mental health. We use secondary data to illustrate how belief-correction interventions can have network-dependent heterogeneous short-term and long-term impacts. Then, we run such an intervention with individuals affiliated to an NGO in New Delhi and find that it strengthens social ties by increasing engagement with the community. In the third chapter, I find that individuals who lie on multiple shortest paths in rural borrowing networks are less likely to take actions that can result in a loss of network links. I find that these agents are less likely to travel outside the village for work and that these decisions exhibit strategic complementarities.

Advisor: Dercon, S
Teytelboym , A
The host determinants of treatment outcomes of multi-drug resistant pulmonary tuberculosis

Multidrug-resistant tuberculosis (MDR-TB) has been an emerging public health problem. MDR-TB is a fatal disease whilst treatment of MDR-TB is prolonged but less effective and toxic. Inter-individual variations in clinical presentation and treatment response have been reported in tuberculosis (TB). Identifying host determinants for MDR-TB is important in the search for adjunctive therapy to improve treatment outcome for MDR-TB. This thesis aims to evaluate the impacts of three host factors of leukotriene A4 hydrolase (LTA4H) genotype, diabetes mellitus (DM) and vitamin D on clinical presentation, treatment response and treatment outcome of pulmonary TB patients, particularly MDR-TB.
The first results chapter, chapter 3, illustrates the picture of increasing MDR-TB in Ho Chi Minh City, Vietnam, from 2011 to 2015 and its risk factors for poor treatment outcomes.
In chapter 4, LTA4H genotype showed no significant association with clinical presentation, bacterial burden, extent of lung damage, treatment response or outcome in 312 MDR-TB and 600 drug susceptible (DS) TB patients. Although a potential marker for host-targeted therapy for TB meningitis, this genotype does not appear to be such for pulmonary TB.
In chapter 5, the detrimental effect of DM on clinical presentation, bacterial load, disease severity, increased inflammation and treatment response was clearly observed in pulmonary TB. Although not a significant risk factor for mortality and poor treatment outcome, DM prolonged sputum culture conversion of MDR-TB and should be considered as an important host factor to adjust for.
Chapter 6 reveals the association between vitamin D and extent of lung damage, severity and inflammatory response through blood biomarkers among 309 MDR-TB and 301 DS-TB patients. Vitamin D deficiency caused an adverse effect on MDR-TB, but not on DS-TB during treatment. The work of this thesis has provided more evidence on host factors in efforts to improve treatment outcomes for pulmonary MDR-TB.

Keywords: vitamin D deficiency
Diabetes mellitus
host factors
LTA4H genotype
treatment outcomes of multi-drug resistant tuberculosis
Advisor: Thwaites, G
Nguyen, T
The relationship between occupation characteristics and mortality in England and Wales, 2003–2017

Jobs are an important determinant of mortality, influencing health through both the direct effects of physical exposure and psychological conditions, and the indirect effects of income, social status and lifestyle. This project investigates the relationship between job characteristics and incidence of mortality. 51 interpretable characteristics were extracted by factor analysis from the US Occupational Information Network (O*NET) database, and linked at the occupation level to the UK Office for National Statistics Longitudinal Study. The sample consisted of n = 279,368 individuals from England and Wales whose occupations were recorded at the 2001 UK census. Cox proportional hazards regression models were used to examine the relationship between the occupation features and mortality over 15 years of follow-up (2003–2017). Models were fit which adjusted for socioeconomic status—as measured by education, marital status, housing status and vehicle ownership—and for self-reported health in 2001.
Repetitive work contexts—characterised by repetitive tasks, repetitive physical motions, high levels of automation and time pressure—predict the greatest mortality risk, with a hazard ratio of 1.39 (1.24, 1.56) under the model adjusted for socioeconomic status. Other results support previous findings, such as greater job control (here measured as “self-directedness”) and more technical occupations predicting lower mortality. These results are likely due to a mixture of the direct and indirect effects of occupations, as well as potential residual confounding. Further evaluation of the results—including model goodness-of-fit and sensitivity to alternative analysis choices—would be desirable.

Keywords: factor analysis
occupation
mortality
prospective
proportional hazards
ONS LS
O*NET
Advisor: Evans, R
Valuation struggles in the Ecuadorian Amazon: oil ‘non-conflicts’ and the inevitability of change among the Quichua people of the Lower Napo River

The thesis investigates the acceptance of the ITT oil extraction project by the Quichua communities of the Lower Napo River, in the Ecuadorian Amazon, and the consequences of such a project on people and territories. It sheds light on the structural mechanisms behind the apparent inevitability of oil extraction, development and change in the ribera – despite the struggles each step of incorporation triggers and ultimately leading to the weakening of already-weakened subsistence economies and an ecological crisis at the local level. The thesis seeks to reconceptualise the frameworks of ecological and cultural distribution conflicts – developed by Martinez-Alier (2002) and Escobar (2008) respectively in Political Ecology to explain the opposition of indigenous and poor people to ecologically damaging projects in their territories – in order to contribute to the search for solutions to the global ecological crisis which is at the heart of the project Ecological Economics. It argues, in particular, that because 1) valuation at one point in time is different from values and 2) values change in the process of change, indigenous people might embrace ecologically damaging projects in their territories in spite of their ecological and cultural ‘difference’ (Escobar, 2008), and in the name of ‘equality’. Oil extraction might thus result in non-conflictive, yet problematic situations rather than conflict. It follows that the challenge, rather than the use of alternative decision-making tools (such as multi-criteria analysis), which would allow a ‘better’ choice between various alternatives which are not satisfactory anyway, lies in the design of development alternatives which would go beyond the recurrent dilemma between ‘difference’ (the preservation of culture and the environment) and ‘equality’ (development), systematically faced not only by a growing number of indigenous people around the world but by the human species as a whole, in the context of an unprecedented ecological crisis.

Keywords: ecological economics
multi-criteria analysis
oil conflicts
valuation struggles
ecological crisis
indigenous people
political ecology
Advisor: Rival, L