VictorJuiz/thesis huggingface dataset:
An investigation of human regulatory T cell metabolic pathways
Keywords: regulatory T cells
immunetolerance
mitochondria
exosome
extracellular vesicles
immunology
immunometabolism

Regulatory T cells (Tregs) are essential to homeostatic immune tolerance. Clinical trials of autologous Treg cell therapy have demonstrated promising preliminary results, but there remain challenges to overcome including the problem of recipient-dependent expansion variability. Enhancing the suppressive function of expanded Tregs to reduce the required Treg dose would present a potential solution to this problem.
Cellular metabolism regulates immune cells through two interacting aspects: bioenergic and biosynthetic activities, and non-canonical activities of metabolic enzymes and intermediates. Early in vitro work has revealed distinct metabolic profiles between mouse conventional T cells (Tconvs) and Tregs. However, it remains unclear how the metabolism of human Tregs is regulated. A better understanding of the contrasting metabolic demands and regulation of function between human Tconvs and Tregs may uncover routes to target Treg-specific metabolic pathways in order to tune their activity as desired.
In this work, the immunometabolism of human Treg is investigated and new strategies revealed to harness elements of their metabolism for therapeutic use. In Chapters 3 and 4, I show that Treg display the ‘Warburg effect’ after T cell receptor stimulation alongside CD28 co-stimulation via the mTOR signalling pathway. Subsequently, I show that only naïve and central memory Tregs preferentially utilise glucose; suggesting that human Treg metabolism may differ due to their anatomical location. In contrast, effector memory Tregs and Tconvs have distinct metabolic characteristics: whilst Tconvs negatively alter effector function through limiting glucose metabolism, Tregs positively regulate their suppressive function by limiting mitochondrial energy metabolism. Furthermore, this metabolic regulation allows Tregs to enhance their suppressive activity towards Treg-resistant Tconvs which are characterised by their low mitochondrial mass. In Chapters 5 and 6, I investigate the mechanism of this phenomenon, and show that Tregs generate immunosuppressive extracellular vesicles (exosomes) by mitochondrial ATP synthase inhibition. Metabolomics data suggests that epigenetic alteration in Tregs through a change in mitochondrial metabolism intermediates. The donor-independent function of these small extracellular vesicles suggests a new potential therapeutic strategy in which Treg-derived extracellular vesicles could be used ‘off-the-shelf’.
The immunometabolic experiments presented in this thesis shine new light on the differential metabolic regulation of human Tregs and Tconvs, and reveal novel and potent mode of Treg immunosuppresive action that can be induced by modulating metabolism. By defining these pathways, new therapeutic strategies to immune regulation may be potentially revealed.
Techniques for stochastic spatial sensing in biology: from immunology to anthropology
Keywords: stchastic movement
hunter-gatherer
protein interaction
pair-correlation
Dunbar number
SHP-1
ZAP-70
integro-differential

There is a large branch of mathematics applied to biological problems, and many of these problems deal with the movement and behaviour of many bodies. Nevertheless, biology has many problems where the techniques used for mass movement is not accurate enough. In this thesis we use mathematical and computational tools applied to such biological problems where, furthermore, the relative position of each element is important to the outcome of the system. The first of the problems is in immunology, where we focus on the interaction between a protein hooked to the inside of a T cell and an enzyme floating in the cell's cytoplasm. The second biological problem we tackle on is in anthropology, where we ask ourselves whether nomadic groups of human can meet enough times in a year to maintain their friendships. In immunology we we propose models of integrate-partial differential equations with which we can compare experimental data from the laboratory or results from computational simulations, and gain information about the system’s reaction rates and particle lengths. These models use auto- and pair-correlation functions to take spatial effects into account. In Chapter 2 we deal with a dephosphorylating enzyme, SHP-1, and phosphorylated tails in the T cell membrane. In Chapter 3 we deal with a phosphorylating enzyme, ZAP-70, and both phosphorylated and dephosphorylated tails in the T cell membrane. In both chapters we find our models have a better fit to the experimentally obtained data, or the computational simulations in Chapter 3, than the traditional ODE models with mean-field approximation. These models also help as a proof of concept of what is thought to describe the interaction between the proteins involved.
Chapter 4 takes on the anthropological problem, where we seek to find what set of physical properties allow each human to meet 150 people (known as the Dunbar number) within a year. Although not many hunter-gatherer societies remain in the world, this question has more of a historical value, aiding in theories about the present-day hierarchical structure of society, the purpose of rituals such as gift-giving, and the importance of human interaction for mental health. Through the theoretical development we gain insight into stochastic movement in a grid. Agent-based simulations are used to provide the number of humans met for a range of possible parameters, such that, given a society's basic details, the particular number of meetings per person could be looked up. We find that, in the simplest case, hunter-gatherers would be able to meet with enough people during a year to maintain their community network in most scenarios. As is the nature of mathematics, the models here developed could in future be adapted for other biological or physical scenarios where elements engage similarly to the elements in each of our problems. After all, life is a mixture of disciplines to be described in the language of mathematics.
Clinical assessment of ChAdOx1 vectored vaccines against emerging pathogens
Keywords: adenovirus
chikungunya
emerging pathogens
MERS-CoV
zika
SARS-CoV-2
viral vector
vaccine
COVID-19

Traditional vaccine development strategies are costly and time-consuming which makes them unsuitable for clinical assessment of new vaccines in the context of infectious diseases outbreaks. Platform technologies provide substantial manufacturing advantages and have the potential to significantly reduce these limitations to clinical development in health emergencies.
Adenovirus vectors were initially developed as gene transfer vehicles for the treatment of rare genetic conditions, and over the past decade have been under investigation as a platform technology for vaccine development. A replication-deficient adenoviral vector based on the simian adenovirus type Y25 and named ChAdOx1 was first evaluated in clinical trials in 2012 as a universal influenza vaccine candidate. Since then, and before this work began, ChAdOx1 vectored vaccines had been administered to 160 healthy adult volunteers as part of clinical trials of candidate vaccines against influenza, tuberculosis, and malaria.
This project consists of an assessment of ChAdOx1 vectored vaccines against emerging pathogens and its suitability as a platform technology for accelerated R&D and response to epidemic threats. Safety, immunogenicity, and efficacy profiles for ChAdOx1 vectored vaccines against chikungunya, Zika, MERS-CoV and SARS-CoV-2 viruses are presented here. These data have substantially contributed to the approvals of the ChAdOx1 vectored COVID-19 vaccine, now in use in over 180 countries.
Context dependencies in decision making
Keywords: decoy effect
perceptual distraction
reference dependence
decision making
context dependence

Irrelevant information should not affect our decisions. Yet, our choices are often swayed by contextual input that is entirely unrelated to the decision at hand. This is true for perceptual judgments pertaining to the appearance of a visual stimulus, as well as for more abstract evaluations of economic prospects. My thesis examines three specific instances of context-dependent behavior across the realms of perception and economics. Across all studies, I charted the behavioral signatures of context-dependent choices via careful experimental manipulation. I combined this behavioral data with simulations of mathematical models to arbitrate between different theoretical accounts of the mechanisms underlying context-dependent decision making. My first study investigated how the context provided by an additional (decoy) alternative sways economic choice between two target options. It mapped decoy influence across the full attribute space of possible decoy definitions. My second study examined the influence that an irrelevant distractor stimulus wields on perceptual decisions. It combined psychophysical measurement with regression-based and reverse correlation analytic approaches to shed light on the functional form of distractor effects. Finally, my third study probed the mechanisms driving context-dependent categorization decisions. It measured the contributions of putative drivers of contextual influence combining novel analytic techniques with experimental design controlling for potential confounds. Across the three studies, normalization-based information processing schemes emerged as a common theme. Viewed through the normative lens of efficient neural coding, normalization provides a compelling account for the observed patterns of context-dependent choice behavior.
Re-organising a fractious regulatory space: the #FeesMustFall protests and the regulation of tuition fee decisions in South Africa
Keywords: South Africa
universities
regulatory space analysis
higher education
student protests
regulation

My thesis offers a unique case study of how ongoing crises and continual government interventions can sap the financial and organisational capacities necessary to implement (and contest) regulation. Based on 60 semi-structured interviews and a review of pertinent government policy documents, I analyse how the regulatory space of tuition fee decisions by South African public universities was reconstituted by the 2015 to 2017 Fees Must Fall protests and their attempted settlements.
I modify how regulatory space analysis has traditionally been used: by treating regulatory spaces as dynamic and evolving; by viewing the boundaries of regulatory spaces as porous and overlapping; and by developing how the resources of authority, organisational capacity, and wealth are understood. My application of this re-envisioned regulatory space analysis reveals that tuition fee decisions were regulated by the calibration of the interactions between three main actors, and the four income streams on which universities rely.
Cumulatively, these calibrations shape: what is taught or researched, by who, to or for whom; who could learn what, where, and at what cost; and who paid what portion of that cost. They also prescribe the fora in which tuition fee decisions are made, and who participates in those fora. The protests and their attempted settlements reconstituted this regulatory space. An increasingly fragile link developed between fee determinations and student financial aid. Furthermore, new actors occupied dominant positions, and resources cascaded through this space - into and from cognate spaces.
My analysis highlights the limits of what regulation can achieve. I re-iterate the importance of the place of space, underlining the binding constraint South Africa’s macroeconomic deterioration placed on this regulatory space. I also discuss how government failure may undermine the regulatory regime operating in a regulatory space. My thesis reveals the insights which can be garnered from applying a regulatory lense to momentous political upheavals.
No other world? Postcolonial inheritance in Anglophone world writing

Keywords: Southeast Asia
world
postcolonial
South Asia
Anglophone writing

This thesis theorises Anglophone world writing as a meta-genre that pivots between the localised politics of English and the transnational pressures of the Anglo-American book market in the period 1990-2010. Written from the perspectives of India, Malaysia, the Philippines and Singapore, my dissertation explores networks and circuits of literary imagining, which bring into visibility the charged contexts of writing English literature in postcolonial societies. By discussing selected novels, short stories and poetry from the four countries under study, the thesis foregrounds literary world-making as a unique and imaginative endeavour that both challenges and extends the scripting of locality in mobility. Amidst the inherited concerns of decolonisation, nation building and cross-border cultural flows, local literary traditions and contemporary writing practices continue to inflect and pluralise the Anglophone in resistance to the Anglosphere.
Throughout its four chapters, the thesis foregrounds a readerly stance to Anglophone world writing as inheriting and expressing ongoing postcolonial processes in the long durée. My argument examines the work of the Indian diasporic writer Kiran Desai; the mobile Malaysian novelists Preeta Samarasan and Tan Twan Eng; the Filipino-Australian novelist Merlinda Bobis and Filipino fictionist Rosario Cruz-Lucero; and the Singapore poets Arthur Yap, Joshua Ip and Hamid Roslan. Anglophone world texts are textured by the play of enlarged, decentred cartographies (ch 1) and the contours of fictional memory, which inscribe alternative historical loci (ch 2). World-characters are both mythic and spectral in their interrogation of unfinished postcolonial processes (ch 3), while the literary voice in standard English is fruitfully fissured by an aberrant and startling range of English-ing (ch 4). By making a field distinction between “Anglophone world” and “Global Anglophone,” this dissertation returns the Anglophone to locations where the universalising pressures of global English are reterritorialised and revitalised as heterogenous, living literatures.
"After Giambologna": The value of replication and material innovation in late Medicean Florence
Keywords: Medici
Bronze sculpture
Massimiliano Soldani Benzi
Material art history
Pietro Tacca
Giambologna

This dissertation focuses on a period in Florentine art, beginning in the last years of Giambologna's life and ending with the demise of the Medici Grand Duchy, that is often brushed aside due to its perceived imitative practices and supposed lack of artistic innovation. In the grand narrative of Florentine art, Giambologna is considered to be an innovator while his artistic descendants were seen as mere copyists. While he produced inventive designs, they, in his shadow, were simply remaking objects that are now identified in museum catalogues and auction houses as "after Giambologna." My project evolves from a simple question: why did replicative practices flourish under the late Medici Grand Dukes?
I answer it by investigating how central the Medici's control of the means of production–which included the artist himself–was to the processes of production as well as reproduction of works of art in the seventeenth century. By combining the stories of individual artists with an explication of the court structure, I expose how the court encouraged and rewarded forms of technical and material innovation that were made possible through replication.
Essays on model selection
Keywords: martingale difference
serial correlation
information criteria
auxiliary regression
LTS estimation
model selection
nonstationarity
normality test
nonlinear time series
robust regression
cumulant based

This dissertation has two goals. Firstly, we consider the problem of model selection for nonlinear time series models and study an auxiliary-regression-based test for serial correlation. Under the assumption of martingale difference errors, rejection of the test would imply model misspecification in the adopted functional form or insufficient dynamic specification. The proposed test allows for the presence of stationary and/or non-stationary variables, and the test statistic follows a standard chi-square distribution asymptotically. Monte Carlo simulations show that the proposed test has good finite sample properties.
Secondly, we investigate how to choose the correct model in least trimmed squares (LTS) regressions when the underlying data is contaminated with outliers. This amounts to the problem of choosing the number of outliers to be trimmed. We propose conditions under which information criteria based and cumulant based methods yield consistent estimation of the true model under a location-scale framework. We also extend the classical Jarque-Bera test to test for the normality of non-outlying error terms. Numerical studies are conducted to compare the performance of these methods.
Off to a great start! “start-offs”, knowledge and performance
Keywords: organizational knowledge
social embeddedness
employee (co-)mobility
emergent effect
self-selection
start-up formation
strategic resources
organizational strategy

This dissertation focuses on “start-offs,” new organizations that “start off” their entrepreneurial journey well by virtue of their pre-entry conditions that may retain an imprint of the incumbent’s competitive advantage. I explore how pre-histories, initiation processes, and initial conditions shape new firm behavior and outcomes far into the future. In particular, this dissertation pays attention to the pre-entry knowledge-related resources and relations embedded in and across individual founding members. Based on the analysis of a comprehensive longitudinal data set that spans 30 years, I argue the underlying mechanisms through which higher-level constructs emerge from micro-level entities, such as individuals embedded in organizations or their opportunities, provide important implications for linking new firm growth and strategy. This dissertation seeks to make contributions to systematically understanding how a competitive advantage is gained when path-dependent pre-entry factors are successfully transferred, reintegrated, and leveraged to implement a strategy.
Women in Britain’s Pakistani diaspora and their relationship with formal and informal Labour, 1962-2002
Keywords: oral history
women's employment
British-Pakistani
modern British history
migration
unpaid labour
community history
British-South Asia

This thesis is a comparative study of British-Pakistani women’s relationship with formal and informal labour in Middlesbrough and Oldham. The period begins in 1962, when the Commonwealth Immigration Act was enacted, and ends in 2002, when the Nationality, Immigration and Asylum Act was implemented and the ‘Life in the United Kingdom’ test was proposed.
Across time and between places and generations, women made decisions about their labour, often to cope with the demands of motherhood, family and community life. Twenty-nine interviewees, who migrated from Pakistan to Middlesbrough and Oldham across the period or grew up in these towns, highlighted how aspirations and opportunities for work changed over time and how their gender, class and race affected their labour experiences. Changes in local labour markets, access to adult education and English literacy, for example, had significant consequences on migrant women’s work choices. Moreover, for second-generation interviewees who were born or grew up in Britain, compulsory education made forms of labour, such as professional work, more accessible. Crucially, every interviewee, both first and second-generation, described how they were not considered economically independent wage-earners and were rarely prepared for formal work. Instead, they were expected to marry as teenagers, have children and undertake domestic responsibilities. For migrant women in particular, who were often non-English speaking and, at times, illiterate, waged employment was largely inaccessible.
Whilst interviewees rarely participated in formal waged labour in a workplace, several women undertook work that was crucial in supporting the long-term settlement of their families and communities. Some of this work was paid, such as self-employment, yet often women described how most of their labour, beyond domestic responsibilities, was unpaid and voluntary. In other words, solely focussing on British-Pakistani women’s formal waged labour participation, rather than acknowledging the breadth of their paid and unpaid work, is both limiting and reductive.
Understanding the epigenetic regulation of stem cell fate in planarians using functional genomics
Keywords: Stem cell
Planaria
MBD
Epigenetics
Next-generation sequencing

Planarians owe their remarkable regenerative capabilities to somatic pluripotent stem cells or neoblasts which, as the only dividing cells in the body, are able to differentiate into all cell types. Research into planarians so far has established the cellular and molecular basis of regeneration, stem cell pluripotency and differentiation. Recent studies using single-cell transcriptomics have improved our understanding of neoblast heterogeneity and the different cell types in planarians. Yet, the epigenetic mechanisms underlying neoblast pluripotency and the determination of cell fate remain understudied. This work aims to understand the epigenetic regulation of stem cell fate in planarians using an array of next-generation sequencing methods.
Planarians have a single methyl-CpG binding domain protein, MBD2/3, which is part of the NuRD complex that regulates transcription. Planarians lack endogenous cytosine methylation. Research into the role of MBD2/3 in an organism free of DNA methylation can provide important evolutionary insights into its DNA methylation-independent role. I show that knockdown of Smed-mbd2/3 affects both regeneration and tissue homeostasis. Using markers for stem cells and progeny, Smed-mbd2/3 was found to be essential for differentiation but not for stem cell maintenance. The different stem cell sub-populations were also unaffected by the knockdown of Smed-mbd2/3. To determine the targets of MBD2/3 involved in the lineage commitment of stem cells, I analysed the transcriptome of stem cells and stem cell progeny after knockdown of Smed-mbd2/3 at two time points. Genes misregulated after the inhibition of Smed-mbd2/3 were identified and will form an important resource to identify new markers of stem cell differentiation.
The identity of cis-regulatory elements remains elusive in planarians. Accessible regions of chromatin in the three planarian cell compartment were identified using ATAC-seq. ChIP-seq of planarian neoblasts was performed and correlated with gene expression and open regions of chromatin to identify putative enhancers. Information from the three types of sequencing datasets was used to create a catalogue of enhancers with different combinations of enhancer properties. This lays the groundwork for further studies to provide a better understanding of the heterogeneity of planarian stem cells and identify gene regulatory networks specific to the progression of different lineages.