VictorJuiz/thesis huggingface dataset:
Engineering modular platforms for rapid vaccine development

Vaccines have saved more lives than any other medical intervention. Recombinant vaccines provide unmatched safety profiles, but at the expense of reduced immunogenicity. Virus-like particles (VLPs) resemble viruses in size, shape and repetitive arrangement but are devoid of pathogenic genetic material and therefore safe. Poor immunogens can be rendered immunogenic by display on VLPs. Successfully decorating VLPs is still a major challenge. Genetic fusion or chemical modification is often time-consuming and can lead to misassembly or misfolding, which obstructs generation of the desired immune response. SpyCatcher is a genetically encodable protein, previously engineered to form a covalent isopeptide bond to its peptide-partner SpyTag. Presented in this thesis are SpyCatcher-VLPs, based on the fusion of SpyCatcher to the bacteriophage VLP AP205. SpyCatcher- VLPs can be conveniently conjugated with SpyTag fused antigens, simply by mixing. I demonstrate the modularity of this approach by covalently linking several complex, cysteine-rich malarial antigens to SpyCatcher-VLPs, such as the transmission-blocking antigen Pfs25 and the blood-stage antigen CIDR. A single administration of Pfs25-SpyTag conjugated to SpyCatcher-VLPs induced potent antibody generation against Pfs25, even in the absence of adjuvant. Anti-Pfs25 antibodies induced by this platform conveyed potent transmission-blocking activity in the mosquito vector. The thesis further demonstrates the feasibility of more complex Catcher-nanoparticle architectures. The previously engineered SnoopCatcher covalently reacts with SnoopTag peptide and is orthogonal to the SpyCatcher / SpyTag pair. IMX313 is an engineered chimera of the multimerization domain of chicken complement inhibitor C4-binding protein. This work describes fusion of SnoopCatcher and SpyCatcher to IMX313, which yields independently addressable Catcher-moieties on a single IMX313 nanoparticle. Display of two antigens on one particle may enable single-particle, multi-disease vaccines as well as multi-stage vaccines to tackle immune evasion of parasites. The platforms presented should accelerate and enhance vaccine development and may create opportunities for imaging and metabolic engineering.

Keywords: VLP
Plug-and-display
Virus-like particle
Cancer Immunotherapy
SpyCatcher
Vaccine
Isopeptide bond
TBV
Transmission-blocking vaccine
Particulate vaccine
SnoopCatcher
Malaria
VLPs
Dually-addressable nanoparticle
Advisor: Howarth, M
Computational studies of structural motifs and cotranslational folding mechanisms in membrane and soluble proteins

Membrane proteins are an important class of drug targets, making up at least 25% of proteins in the human genome. In this thesis I investigated two aspects of alpha-helical membrane protein structures.
Firstly, I investigated kinks in alpha-helices, many of which are thought to have functional roles. Kinks are changes of direction in helices, often defined in a binary fashion, but here I move towards defining them on a continuum. I found that kink angles are not generally a conserved property of homologues, pointing either to their not being functionally critical or to their function being related to conformational flexibility. I found correlation in kink angles and conformational change upon activation in GPCRs, reinforcing the belief that helix kinks are key, functional, flexible points in structures.
Secondly, I turned to the biogenesis of alpha-helical membrane proteins, and how this might be used to improve structure prediction. These proteins are inserted into the membrane during the process of translation by the ribosome, therefore the N-terminus may be able to adopt its tertiary fold before the C-terminus is translated. I found a weak signal in a non-redundant set of structures that membrane proteins exhibit asymmetry between the N- and C-termini. This might be expected if they are folding cotranslationally, as had been seen in soluble proteins. Motivated by this, I predicted the structures of membrane proteins using SAINT2, a cotranslational structure prediction program, and achieved promising results. I developed SAINT2-ScafFold, which folds proteins around a rigid N-terminus, but the accuracy of prediction of the remaining protein was no better than when the entire chain was sampled. A membrane potential was implemented in SAINT2, which slightly improves the accuracy of models generated.
Finally, the SAINT2-ScafFold method was applied to the completion of homology models that do not cover the entire target. An RMSD of less than 5 Å was achieved in more than half of the cases where a terminal transmembrane helix of membrane protein structures was predicted. This was an encouraging result for the prediction of membrane proteins from partial templates, and could easily be extended to soluble proteins.

Advisor: Deane, C
Shi, J
Kelm, S
Beastly spaces: geomorphism in the literary depiction of animals

In 2010, Simon Estok observed that, "the most immediate question ecocriticism can ask is about how our assumptions about animals affect the natural environment". In this thesis, I respond to this challenge by generating a sustained conversation between the hitherto surprisingly distinct fields of animal studies and ecocriticism. I do this by formulating a new critical concept, that of the geomorphic animal, which I use to show how literary representations of animals often expose the many complex ways in which they constitute space rather than simply inhabiting it. This, in turn, should make them central to future ecocritical readings.
I focus on two periods, medieval and modern; the broad historical and generic scope of this thesis is intended to demonstrate the conceptual validity and robustness of geomorphic readings. Chapter One shows how concerns with death and symbiosis are expressed through the earth-bound activities of the geomorphic animals of the Exeter Book riddles. Chapter Two examines geomorphic whales in texts deriving from two related traditions: the Book of Jonah and the Physiologus. Chapters Three and Four focus on modern theatre, which affords distinctive ways of articulating the spatial implications of geomorphism. Chapter Three discusses the literary representation of museums and zoos in terms of the interpretative complexities generated by staging and spectacle. Chapter Four, focusing on mediation, discusses the interplay between animals, viewpoints and place in theatre, also taking into account particular issues arising from the adaptation of plays into films. This argument paves the way to addressing the geomorphic depiction of marginalised humans and human groups, suggesting the critical potential of geomorphism as a means of furthering feminist and post-colonialist aims.

Keywords: whales
geomorphic
zoos
theatre
riddles
medieval
Equus
Patience
hondwyrm
Advisor: Bose, M
Shepherd-Barr, K
Academia - industry collaboration in translational medicine

Collaboration between academia and industry has been the focus of numerous government reports and initiatives over the past 15 years, and is increasingly recognized as an effective way to capitalize on the UK's world-class research base. However, there is a need to further understand the role of such collaborations in the field of translational medicine, where the path to market is particularly lengthy, expensive, and risky, due to complexities associated with the clinical trial process.
This research uses a mixed methods approach to investigate collaboration in translational medicine at the University of Oxford. The project comprises three principal stages. First, a broad understanding of the current landscape of academia-industry collaboration in translational medicine was obtained by administering a questionnaire to academics who had received industry funding. Next, a deeper understanding of the barriers to collaboration was sought through semi-structured interviews with 27 academics. Finally, potential strategies to reduce practical barriers to the collaboration process were investigated through interviews with members of three groups within the university who interact directly with industry: Research Services, Oxford University Innovation, and Business Development.
This research constitutes the first empirical study on university-industry collaboration in translational research in the United Kingdom. It contributes to existing theory through the development of a new theoretical framework for the evaluation of barriers in terms of a) the practicalities of the collaboration process, b) the institutional environment and c) presiding cultures. Through these analyses, differences in experiences of barriers to collaboration emerged for clinical and non-clinical researchers. Furthermore, industry was seen as playing a crucial role in the translation of new therapeutics, especially in the funding of research that was perceived as being ‘too risky’ for Research Councils. Thus, reducing barriers to university-industry collaboration was seen as important to the realisation of public benefit from university research. Barriers were seen as being overcome, or avoided, via the formation of relationships between academics and companies at several different levels; while systems exist within the university to facilitate this, awareness and uptake of these systems was poor amongst the study population. Finally, if universities are to deliver impact as a key metric of performance, incentives within the university need to reward academics for commercialisation activities, in addition to publication. Through the suggestion of long and short-term strategies and a detailed analysis of industrial collaboration in this setting, this research has implications for both university and government policy.

Keywords: translational medicine
drug development
collaboration
academia industry collaboration
gene therapy
Advisor: Gill, D
Barker, R
The agency of smaller powers: Belarus in international relations

Smaller powers wield agency in the international system and they do so in many cases independently of institutions. This is problematic not only from the perspective of realism, where 'might is right,' but also from the perspective of liberalism which argues that smaller powers use institutions to obtain policy objectives. This thesis considers this problem in respect of the new states that emerged from the former Soviet Union at the end of 1991, with particular focus on Belarus which is a least-likely case for smaller power agency given its alliance with Russia and few institutional memberships. Through a detailed case study of Belarus's foreign policy, I first argue that smaller power agency has been articulated in a regional context when the smaller power withdraws its consent to the regional order. While Belarus has generally consented to Russia's regional primacy or hegemony since 1991, this consent is not unconditional, and the violation of regional interstate norms by Russia caused Belarus to make efforts to renegotiate the rules underpinning the regional order. My second, related argument is that differentiation from the regional power, Russia, proved crucial for the formulation of independent policy positions by the smaller power's officials, and, in turn, that differentiation of opinions among the smaller power's elite granted flexibility to monitor and adapt its actions (that is, allowed the smaller power to wield agency). It did so without outright provoking the regional power to intervene in the smaller power, and instead kept the regional power engaged. The findings receive tentative support from auxiliary study of other post-Soviet smaller powers, and recapitulate the merits of the neoclassical realist research agenda.

Advisor: Allison, R
Macfarlane, N
Young men at Oxford (1830-80) Routes into consumption and debt

Young men's consumption, especially that of students at Oxford, has not received much attention from scholars although they participated fully in the economic life of the University town by becoming customers, indeed often compulsive shoppers, as numerous Chancellor’s Court and bankruptcy court cases suggest. My thesis provides a window onto male students’ consumer culture and indebtedness, especially their link to the ‘credit system’. 'Conspicuous consumption' and overspending was a marker of undergraduate culture which had two dialectical dynamics: students tried to position themselves in their community by displaying the signs and habits of the elite; and, simultaneously they went through a process of individualization, expressing particular tastes and their own extravagance. These processes reflect how students learnt their future roles as rulers by managing their private interests and public image, but also by developing a consumer experience, a majority of them becoming prudent economic agents. This dissertation explores consumption from both an individual and collective perspective. In particular it examines juvenile agency, going beyond the clichés of the 'great masculine renunciation' and the idea of prominent female shopping, reconstructing the different paths undertaken by young men, from their first steps into consumption, to consumption routine. It builds on diverse disciplines including social and economic history, retailing and advertising, education, law and gender studies to tackle a gap in the history of consumption, capitalism and trade in Oxford. Between 1830 and 1880, student consumerism was intertwined with the university reforms and the rise of competition between tradesmen. This study assesses education costs and budget constraints; commercial practices such as 'touting freshmen'; students’ social background and insolvency; the use of long-term credit as a tool to drive consumption; and the formation of male identities through the purchase and display of different goods.

Keywords: Masculinity
Consumption
Student
Business
Gender
Credit
Oxford
Trade
Advisor: Humphries, J
The emission and transport of volcanic sulphur dioxide

Volcanic emissions make an important contribution to the atmospheric sulphur budget. The volcanic contribution of sulphur to the atmosphere is poorly defined due to uncertainties in the amount of sulphur ejected, its distribution by sulphur species and the height of injection. Also there is little or no ground-based monitoring of many volcanoes, and little knowledge of sulphur emitted by degassing and other non-explosive volcanic processes. The altitude of volcanic injections of SO2 is therefore poorly understood, but of great importance when considering the chemistry and movement of the SO2. SO2 reaction rates vary with height and atmospheric composition: SO2 injected into the troposphere will relatively quickly leave the atmosphere as acidification of rainfall; in the stratosphere, however, SO2 is oxidised to H2SO4, which in aerosol form can remain and affect climate processes for many years. Sulphate aerosols affect the Earth’s radiative balance through scattering of sunlight, and are therefore an important factor when considering climate change.
Atmospheric sulphur compounds derive from a variety of sources. The largest direct source of SO2 is from volcanic emission, though it also indirectly stems from conversion from carbonyl sulphide (OCS), the most abundant atmospheric sulphur species.
Satellite-based instrumentation is a vital tool for the analysis of volcanic eruptions. Here the IASI instruments, Fourier transform spectrometers on the MetOp platforms, are used to study medium to large eruptions between 2008-2012. The vertical distribution of SO2 is investigated with respect to the local height of the tropopause, which is then further used to estimate the total atmospheric mass of SO2 as a result of these eruptions. These eruptions are also plotted in terms of their latitude variation, and a large difference between the hemisphere loadings is shown.
The trajectory model HYSPLIT is used in conjunction with the IASI instru- ment to investigate both the injection height of SO2 plumes and their chemistry. A number of forward trajectories are generated for the duration of the eruption at a series of initial altitudes and the final positions a given time later are compared against the IASI retrieval. It is found that the injection height determined is on average lower than those presented in literature, but that the principle of the analysis is sound. The time frame of the investigation is found to be too short to draw any meaningful conclusions about the plume chemistry.

Keywords: Remote sensing
Stratospheric
Dispersion model
IASI
Sulphur
Volcanic
Advisor: Grainger, D
Dudhia, A
Nervous hands, stolen kisses, and the press of everyday life: touch in Britain, 1870-1960

This thesis provides a history of the sense of touch in modern Britain. Seeking out fugitive intimacies and incidental brushes of lover and stranger alike, it argues that far from being a natural constant, what, how, and why people touched, and what they felt when they did, has a history. Through five case studies of different domains – the mind sciences, visual impairment, public transport, law, and commercialized leisure – it explores how these uses changed, and how they transformed Britons’ understandings and experiences of their bodies. Both as a practice and a metaphor, from making space on the bus to keeping ‘in touch’, touch established the distinctions that Britons made between their bodies and the world and themselves and others. In doing so, touch crucially shaped histories of law, labour relations, scientific experiment, education, and love in the early twentieth century. But it also reformulated the very distinctions of selfhood – distinctions of inner self and outer body, person and thing – on which our accounts of modernity are based.
By tracing a history of touch, then, this thesis turns touch into a means of critique. It challenges histories of modernity for which selfhood is a substance rather than produced only through particular social relationships. But it also proposes a new way of thinking about selfhood as an immanent relationship the self has with itself through use of the body. Through historically specific ways of touching, early twentieth-century Britons shaped not only their experience of themselves as bodies, but also the boundaries defining them as selves. Their selfhood was, in short, what they did with the body through touch. By exploring the history of touch between 1870 and 1960, this thesis therefore offers an alternative account of British modernity and a way of re-examining histories of selfhood within and beyond modern Britain.

Keywords: Subjectivity
Governmentality
Modernity
Selfhood
Touch
Advisor: Houlbrook, M
Whyte, W
Robust model predictive control

This thesis deals with the topic of min-max formulations of robust model predictive control problems. The sets involved in guaranteeing robust feasibility of the min-max program in the presence of state constraints are of particular interest, and expanding the applicability of well understood solvers of linearly constrained quadratic min-max programs is the main focus. To this end, a generalisation for the set of uncertainty is considered: instead of fixed bounds on the uncertainty, state- and input-dependent bounds are used. To deal with state- and input dependent constraint sets a framework for a particular class of set-valued maps is utilised, namely parametrically convex set-valued maps. Relevant properties and operations are developed to accommodate parametrically convex set-valued maps in the context of robust model predictive control. A quintessential part of this work is the study of fundamental properties of piecewise polyhedral set-valued maps which are parametrically convex, we show that one particular property is that their combinatorial structure is constant. The study of polytopic maps with a rigid combinatorial structure allows the use of an optimisation based approach of robustifying constrained control problems with probabilistic constraints. Auxiliary polytopic constraint sets, used to replace probabilistic constraints by deterministic ones, can be optimised to minimise the conservatism introduced while guaranteeing constraint satisfaction of the original probabilistic constraint. We furthermore study the behaviour of the maximal robust positive invariant set for the case of scaled uncertainty and show that this set is continuously polytopic up to a critical scaling factor, which we can approximate a-priori with an arbitrary degree of accuracy.
Relevant theoretical statements are developed, discussed and illustrated with examples.

Keywords: Polytope Operation
Parametric Convexity
Set-Valued Map
Advisor: Cannon, M
Deciphering the function of obesity-associated regulatory elements within FTO

Genome-wide association studies have repeatedly shown that the strongest association with obesity arises from variants in the first intron of FTO. The intronic FTO variant rs1421085 is within an adipocyte-specific enhancer and that risk allele carriers have increased IRX3 and IRX5 expression in early adipogenesis (Claussnitzer et al., 2015). Additionally, the same human risk variant was linked to decreased AKTIP, RPGRIP1L and FTO expression in iPSC-derived neurons (Stratigopoulos et al., 2016). These data point towards several likely causal transcripts and tissues at the FTO locus and essentially, several likely mechanisms. Importantly, whether any of the high-risk variants at the FTO locus has any effect on the organismal level has not been addressed so far. The aim of my DPhil project was to use novel gene manipulation strategies in vivo to mechanistically dissect the Fto regulatory circuitry in mouse to pinpoint causal transcripts their effector tissues and to unravel their physiological role in body weight regulation . Using publicly available as well as my own genomic data (ATAC-seq) revealed that the intronic FTO regulatory element in human adipocytes is conserved in mouse pre-adipocytes. Manipulation of the corresponding motif in mouse (by deleting 82 nucleotides at the mouse orthologous region around rs1421085) resulted in depot- and sex-specific alteration of target genes Irx3 and Irx5 in pre-adipocytes. In addition to recapitulating many of the human findings in mouse, my results further unravelled a new level of regulatory complexity at the FTO/Fto locus. When these mutant mice were put on a high fat diet, I found a reduction on overall fat-mass that could be linked to altered mRNA levels of Irx3 and Irx5 in pre-adipocytes. Using a number of genetic techniques, I further showed that Irx3 regulates several processes during adipocyte development, amongst which is modulation of mitochondrial function. In summary, my findings provide new insight into how variants in FTO intron 1 affect adipocyte development and more specifically how IRX3 affects early adipocyte differentiation.

Advisor: Cox, R
Cantley, J