VictorJuiz/thesis huggingface dataset:
The effects of hypoxia on the anti-tumour immune response

Hypoxia is an adverse prognostic feature in cancer, conferring resistance to treatments including immunotherapy. In this thesis, image analysis of human tumour histology samples and murine models is utilised to evaluate some aspects of the interactions between tumour oxygenation, cellular oxygen sensing and immunity.
In Chapter 1, a novel image analysis pipeline is validated and utilised to analyse the distribution, relative to hypoxia, of tumour infiltrating leukocytes in pimonidazole-treated head and neck squamous cell carcinomas before comparing the observed distributions to those in clear cell renal cell carcinoma, a tumour characterised by perturbed oxygen sensing. Leukocyte-specific distribution patterns were shared by both tumour types, with lymphoid cells largely restricted to better oxygenated perivascular regions and myeloid cells being more diffusely distributed including within profoundly hypoxic necrotic regions.
In Chapter 2, this pipeline is used to evaluate immunohistochemically labelled hypoxia, vascular and immunological markers in lung cancer samples from participants in a clinical study evaluating whether atovaquone, an oxidative phosphorylation inhibitor, reduces tumour hypoxia. Although scoring of all markers was equivalent between groups, given that atovaquone-treated tumours were more hypoxic at baseline, this may represent a meaningful finding.
Chapter 3 concerns histological phenotyping of transgenic mice in which hypoxia-inducible factor (HIF) was up-regulated through reversible prolyl hydroxylase domain-containing protein 2 (Phd2) gene silencing, leading to regulatory T lymphocyte dysfunction and autoimmunity.
Given that regulatory T lymphocytes suppress anti-tumour immunity, in Chapter 4, the effects of host Phd2 silencing are assessed in murine tumour models. Disappointingly, this intervention affected neither tumour growth nor immune contexture.

Advisor: Pugh, C
The bridge, insurance and the fund: Building uncertain city futures in Dar es Salaam

Drawing upon eighteen months of fieldwork between 2016 and 2018, this thesis provides an ethnographic account of culturally mediated and materially founded emergent forms of urban life in Dar es Salaam. The fieldwork was mainly conducted in close proximity to two ‘field sites’: the Nyerere Bridge, popularly known as the Kigamboni Bridge; and East Africa’s largest pension fund, a parastatal pay-as-you-go pension scheme whose investments financed the building of the bridge together with the Tanzanian government. The thesis begins by setting out on a short journey some 680 meters across Kurasini Creek, the tidal creek stretching through central Dar es Salaam that divides the dense downtown neighbourhoods from the lofty Kigamboni district in the south. As we venture over the Nyerere Bridge, however, we are embarking on a much longer journey, one of insurance, of how risky urban futures are negotiated, based on participant observation, mapping and archival work, extended interviews and conversations with operators, bureaucrats, managers, politicians, worker, engineers, and residents, all implicated in ‘city-making’.
The thesis is divided into four parts. Part I consists of the first three chapters: introduction, theoretical outline, and methodology. The three middle parts are ethnographically driven and structured by a tripartite engagement, each part of which - the bridge, insurance and the fund - includes two chapters each. The thesis ends with a concluding chapter.

Keywords: world city
Tanzania
insurance
social security
uncertainty
insurance urbanism
temporality
urban imaginaries
people as infrastructure
pensions
welfare
providential fund
Dar es Salaam
worldliness
infrastructure
popular insurance
futurity
Advisor: Sarró, R
Keith, M
Confession and cartography: religion and the mapping of Poland-Lithuania

The religious aspect of early modern cartography remains under-appreciated, and little-understood. It has been overlooked, above all, because of a tenacious assumption: that cartography was secularised by the Ptolemaic revolution. In recent years this assumption has been challenged, but our knowledge remains severely limited; this is particularly true with regard to the great religious changes of the period: the Reformation, Counter-Reformation, and confessionalisation – a gap which this thesis is intended to fill. It approaches this issue through the lens of a case study, the cartography of the Polish-Lithuanian Commonwealth, from the later-16th to the early-18th century, and is guided by the question: ‘how did cartography respond to the religious changes within early modern Europe?’. In five chapters, it approaches this question from different angles: (1) the changing border of Europe (and continuing fear of paganism), (2) the idealised purification of Christendom in Georg Braun’s Civitates Orbis Terrarum (1572-1617), (3) the struggle to map confessional diversity (approached through a deconstruction of the mapping of the bishop) (4) the response to confessionalisation in the cartography of the Deluge (1655-60), (5) the place of cartography within Counter-Reformation Marian devotion.
Cartography proved highly responsive to the religious changes of the age, responding in a multiplicity of ways, that were much more diverse and complex than the Catholic/Protestant binary that has often defined our understanding. It was much more sensitive to changes in people’s minds, however, to their beliefs, fears and agendas, than to changes on the ground – and its response was also limited by the nature and deficiencies of the cartographic medium, which inhibited, in particular, its ability to depict religious diversity. It was an important cultural space where these religious issues were engaged with, and it is argued that cartography could, therefore, serve as a unique and valuable source for historians of religion.

Keywords: paganism
Jews
Polish-Lithuanian Commonwealth
Marian devotion
18th century
Protestant
bishops
confessionalisation
pilgrimage
16th century
Georg Braun
religion
Reformation
cartography
Erik Dahlbergh
counter-reformation
Catholic
Lithuania
prayer
forest
wood
deluge
hierophany
civitates orbis terrarum
17th century
Poland
sacred space
maps
Advisor: Nowakowska, N
The colloidal liquid-gas interface: kinetics of phase separation, confinement and optical manipulation

In this thesis, the colloidal liquid-gas interface is studied. First, the evolution of colloidal gas-liquid phase separation in a colloid-polymer mixture through nucleation and growth is addressed. Using confocal microscopy, different statepoints are observed and three different mechanisms are found in distinct regions of the phase diagram: at low polymer concentration the colloidal liquid droplets coalesce until they fill the field of view, at higher polymer concentration, the colloidal liquid droplets stick to each other continuously throughout the entire observation period, and at the highest polymer concentration probed, the droplets stick to each other until a certain point where their size remains constant. Growth laws are computed and compared to theoretical predictions. The structure of the patterns formed as phase separation takes place and the motion of the growing droplets are analysed for each mechanism. Next, the thermal capillary waves of the colloidal liquid-gas interface in confinement are observed with confocal microscopy. The line tension as well as the dispersion relation are measured. The relaxation times of the modes of the fluctuations are measured and compared to theoretical predictions. Then, a tightly focused beam of laser light is used to nucleate a droplet of colloidal liquid into the colloidal gas phase for different laser powers and different heights above the colloidal liquid-gas interface. The kinetics of the growth and final size of the droplet were found to be unaffected by laser power and height above the colloidal liquid-gas interface. The kinetics of the growth of the droplet reveal that the growth is driven purely by electrostrictive effects and not by thermal gradients induced by the laser light. Finally, the evaporation of liquid droplets nucleated with optical tweezers is studied through fluorescence microscopy after the laser used for tweezing was switched off. From solving the diffusion equation, the diffusion coefficient of the colloids into the gas phase is measured. It is found not to vary with the height above the liquid-gas interface or the laser power used to nucleate the droplets. For droplets grown at a height of 20 microns, droplets sink at a constant velocity as they evaporate and interact with the liquid-gas interface below them.

Keywords: physical chemistry
optical tweezing
colloid
polymer
phase separation
Advisor: Dullens, R
Aarts, D
Investigating the role of lipids for membrane protein complexes using native mass spectrometry and molecular dynamics simulations

The work described in this thesis is a combination native mass spectrometry experiments, molecular dynamics simulations and scientific software development. It consists of three results chapters which each chapter describing a distinct project with a focus on one of the aspects above.
In chapter 3, I employed molecular dynamics simulations in a collaborative project on using surface-induced dissociation to probe the effect of lipid binding on the stability of oligomerisation interfaces. My simulations offer a rationale of lipid bind- ing to different locations to explain these stability differences. In addition, I contributed to experiments to probe the molecular features of these interfaces through site-directed mutagenesis to weaken these interfaces.
Chapter 4 describes my investigation on lipid binding to a bacterial potassium channel, MthK. Native mass spectrometry and molecular dynamics simulations are used to characterise lipid binding after initial experiments indicated endogenous lipids being bound to MthK. Cardiolipin has been revealed to bind specifically to MthK. These results are compared to the eukaryotic homologues through further simula- tions. A part of this chapter outlines different approaches to obtain the in vivo stoichiometry. Among these approaches I employed SoLVe-MS, which leads to very complex mass spectra. The analysis of these spectra sparked the development of the program described in chapter 5.
In the final results chapter, a web-based program for the analysis of native mass spectra, NaViA, is described. This program allows one to analyse native mass spectra through a visual user interface directly in a web browser. In addition, it offers auxiliary tools to facilitate the analysis as well as the ability to save and load sessions for sharing spectra including analysis or depositing them for publication. The ease of use and the instructive auxiliary tools make it a valuable addition to the suite of software available for the analysis of native mass spectrometry.

Keywords: molecular dynamics
BK channel
SemiSWEET
scientific software
membrane proteins
native mass spectrometry
ion channels
K channels
potassium channels
protein-lipid interactions
cardiolipin
Advisor: Robinson, C
Stansfeld, P
Sansom, M
The role of CD2 in recognition of weak antigens and its implications for adoptive cell transfer

Adoptive cell transfer (ACT) of genetically modified T cells expressing engineered T cell receptors (TCRs) holds potential in the treatment of cancer. However, concerns about off-tumour toxicities continue to hinder widespread adoption of TCR-T cells. Current mitigation strategies against off-tumour toxicity such as affinity tuning, kill switches, and logic gates, can sometimes compromise the efficacy of ACT. In this work, we postulate that the human CD2 co-receptor can mediate off-tumour toxicities in ACT, and we propose the targeted manipulation of the CD2/CD58 axis to ameliorate these toxicities. We engineered a Chinese hamster ovary line and used it as a surrogate antigen presenting cell (APC), generating a xenogeneic platform to quantitatively study the role of human CD2 in enabling T cell recognition of low density and/or low affinity ligands (weak antigens). Using Jurkat and primary human CD8+ T cells, we found that, when disrupting the CD2/CD58 axis through CD2 ablation, T cell antigen sensitivity was reduced by 4-15 fold. In co-cultures between Jurkats and the T2 archetypal APC line, transducing the Jurkat effectors with elongated CD2 chimeras generated modest reductions in sensitivity (2-8 fold), a phenomenon that might be attributable to disruption of the CD2/CD58 canonical binding. Moreover, we showed in CD8+ T cells that CD2 knockout appeared to ameliorate the previously reported low affinity, self-pMHC cross-reactivity of the affinity enhanced wt/c51 TCR. Taken together, our results suggest that CD2 might contribute to two types of off-tumour toxicity observed in ACT, namely on-target/off-tumour and off-target/off-tumour cross-reactivity. Therefore, routine manipulation of the CD2/CD58 axis could provide a way of enhancing ACT safety when using engineered TCRs. Our findings could be applicable to other synthetic receptors, provided they exploit the CD2 co-receptor as TCRs do.

Keywords: Adoptive Cell Therapy
Immunotherapy
T cell immunology
CD2
Adoptive Cell Transfer
Adhesion receptors
Advisor: Dushek, O
Longitudinal modelling of genetic risk for common diseases

Recent large cohort studies follow participants for tens of years to collect their medical histories, allowing longitudinal analysis of many complex diseases. These datasets are typically accompanied by genotype data, whose effects on diseases are typically estimated as static values without reference to potential age varying effects. In this work we developed methods to study the relationship between genetic variations and complex diseases as a function of age. In the first step, we developed methods that focus on a single disease at a time, which we applied to infer the age-varying genetic risk profiles for common complex diseases. When applying the methods to 24 common diseases in the UK Biobank, we found a common decreasing pattern of genetic risk effect for several complex diseases, after using a frailty model to adjust for unobserved risk factors such as environmental factors. In the second step, we developed methods that look at many common diseases simultaneously, which we applied to infer age-dependent multi-morbidity profiles under a low-rank representation framework. We analysed the shared genetic variations underlying clusters of diseases as well as the genetic heterogeneity among subtypes of diseases implied by the comorbidity profiles. When jointly modelling 349 Phecodes that have more than 1000 occurrences in the UK Biobank, we identified several disease topics that contain genetically- correlated diseases. When assigning incident diseases in the UK Biobank to these topics, several complex diseases are stratified into subtypes that have different genetic profiles. Our results suggested that genetic risks are modulated by contexts including age and comorbid diseases. To better predict disease incidences and identify biological pathways, genetic information should be modelled jointly with other information available in biobank data sets.

Keywords: Low-rank representation
Multi-morbidity
Survival analysis
Genetic subtypes
EHR
Bayesian statistics
longitudinal data
epidemiology
Frailty model
genetics
Advisor: McVean, G
Holmes, C
Creation and chaos: myth and ideology in the ancient Near East and the Bible

This thesis reframes comparative mythological methodology in the context of recent developments in evolutionary anthropology. In doing so, it applies new insights into the origins and function of supernatural concepts in storytelling to biblical, Mesopotamian, Northwest-Semitic, and Egyptian myths.
Part 1 provides a broad overview of past theories and identifies a lack of methodological attention to ideological aspects of myth. It outlines Pascal Boyer’s minimal counterintuitiveness (MCI) paradigm and builds on it to arrive at an empirical definition of myth. Expanding further on this definition, a context-specific approach is developed, enabling a broad reading of myths as vehicles for group identity signals. Separately, the agency of mythographers and their original audience is reemphasised against universalist readings; myths are explicitly framed as deliberate and actively-composed texts.
Part 2 applies these insights to the well-preserved Mesopotamian mythical corpus, using the well-preserved creation and chaos myths from Sumerian, Assyrian, and Babylonian contexts as examples. A close reading of these texts against the background of MCI theory demonstrates their authors’ (or editors’) concern with contemporary politics, and reveals the in-group-specific nature of supernatural concepts utilised. Furthermore, a diachronic analysis of the key text, Enūma elîš, and its reception demonstrates that the promulgation of, and engagement with, these supernatural concepts was actively shaped by changing ideological concerns in different political contexts.
Part 3 raises a further methodological complication by introducing Hutcheon’s theory of adaptation. Combining MCI theory with this approach, this part considers the effect of adaptation on MCI concepts using several (likely adapted) biblical myths as case studies. Inthis context, the compositional process of the adaptations (Gen 1; Ps 29; Ps 104) must be understood as prescriptive, creating a new theological paradigm for its audience, rather than describing an existing one.

Keywords: Genesis
Bible
Comparative mythology
Ideological criticism
Minimal Counterintuitiveness
Creation myth
Advisor: Barton, J
Southwood, K
Essays on information, asset bubbles, and economic policy

This work consists of three self-contained essays tackling independent research questions pertaining to information constraints, asset price bubbles, economic policy, or a combination thereof.
The first chapter tackles the problem of growing income inequality by weighing the effectiveness of an array of fiscal policies currently available to policy-makers. To do so, I evaluate the impact of alternative forms of public expenditure in an overlapping generations framework where households' ability to invest in the education of their offspring is constrained by various sources of heterogeneity. I find that the optimal use of public funds consists in a combination of public grants aimed at improving educational quality and an increase in the upper limit of student loans. The subsequent panel data analysis corroborates my results and suggests that parental income remains the largest determinant of earnings and inequality.
In Chapter 2, I turn my attention to the challenges posed by imperfect information about the source of asset price movements. I develop a New Keynesian model where stock prices contain a fundamental and a bubble component, both unobservable to agents and the central bank, who are forced to speculate about their value. I use this model to analyse the implications for investors' behaviour and monetary policy. I find that, under perfect information, a systematic increase in interest rates in response to growing bubbles exacerbates market volatility and welfare losses. For high levels of noise, the central bank should reverse its policy stance. However, due to the continuous underestimation of the size of bubbles, policy responses are perpetually inadequate.
Finally, Chapter 3 explores the extent to which cognitive biases can explain market anomalies such as the formation of large financial bubbles. To this end, I develop a stochastic bubbles framework with imperfect information about the probability of a future market crash, where investors are overconfident about the accuracy of their knowledge. I put forward a number of generalisable propositions about the relationship between overconfidence and bubbles in general equilibrium frameworks. In particular, I find that overconfidence can play a key role in the existence of bubbles and is able to rationalise excessive market movements. I quantify my results and test the validity of the framework in a numerical analysis.

Keywords: imperfect information
income inequality
overconfidence
asset pricing bubbles
monetary policy
fiscal policy
Advisor: Zanetti, F
Dynamic buckling instabilities in fluids and solids

Many natural phenomena encountered in nature may be understood through the paradigm of buckling instability. Examples include the design of columns in structural engineering, the folding of geological formations, the collapse of blood vessels, and the fragmentation of uncooked spaghetti, to name only a few. The phenomenon of buckling has traditionally been seen only as a nuisance, but more recently it has also proven useful as a potential tool for pattern formation, particularly at small scales. Many studies have focused on the features of static buckling, particularly pattern formation.
This thesis focuses on how dynamic buckling affects the spontaneous selection of patterns in a number of canonical problems.
We first study the effect of curvature on dynamic buckling in circular geometries. We study the pattern observed when a ring made of either a viscous liquid or an elastic solid is subject to a suddenly applied external pressure. We develop numerical schemes to study the evolution of the ring’s profile and compare those results to linear stability analysis. A weakly nonlinear analysis is performed to understand the behaviour of the observed shape beyond the onset of instability, with results that compare well with both numerical and experimental work.
In the late stages of instabilities, buckles merge — the wrinkle pattern coarsens. To understand this coarsening we consider the non inertial problem of a beam sit- ting on a viscous layer. We explain how wrinkle coarsening occurs as the result of wave dispersion and quantify coarsening by presenting an asymptotic analysis of the governing equation. We also study the effect of confinement and show that it has a crucial effect on coarsening at late times. We develop an analytical expression for the effect of confinement, which allows us to better explain previously published experimental data. Finally, our numerical solution reveals a new regime as the wavelength of wrinkles become comparable to the size of the system. In this regime the dynamics is relatively slow with the system remaining for long periods with one particular mode before rapidly switching to another. We study this regime, the so-called temporal cascade, in detail.
The problems we are considering have different geometries and different material constitutive relations, but highlight a number of common themes. Mathematically, those systems are described by a Partial Differential Equation with a global constraint whose numerical solution is found by framing it in the language of Differential Algebraic Equations.

Keywords: dynamic buckling
wrinkling
buckling
pattern formation
temporal cascade
coarsening
Advisor: Vella, D
Griffiths , I