VictorJuiz/thesis huggingface dataset:
The role of interferon-gamma-mediated T cell collectivity on CD8+ T cell responses
Keywords: T cell
interferon-gamma

Immune responses towards intracellular pathogens and tumours rely on CD8+ T lymphocytes, whose function it is to kill infected or cancer cells, while sparing healthy tissue. CD8+ T cell immune responses are characterized by a remarkable degree of poly-clonality and poly-functionality. However, their overall population response is consistent and robust. Much research has focused on individual T cell activation, but how individual, heterogenous T cell responses are integrated at the population-level remains incompletely understood. Upon encountering their cognate antigen in secondary lymphoid organs, CD8+ T cells arrest for prolonged period of times around antigen-presenting cells forming dense cell clusters, which can function as communication hubs enabling T cells to directly communicate with each other and therefore directly modulate each other’s behaviour.
Here we investigated how CD8+ T cells regulate their response through direct T cell-T cell (T-T) communication, with a particular focus on the cytokine interferon-gamma (IFN-γ) and its effect on T cell responses. We found that specific deletion of the IFN-γ receptor on CD8+ T cells results in augmented expansion of antigen-specific effector T cells and in a skewing of the average functional avidity of the T cell repertoire, thus modulating multiple aspects of the response. In addition, we discovered that activating CD8+ T cells preferentially receive IFN-γ from other CD8+ T cells and furthermore that this IFN-γ-mediated communication between T cells is restricted to a specific time window during the activation phase of the response. Finally, we identified a specific CD8+ T cell subpopulation, so-called virtual-memory T cells, to function as the primary source of this early wave of IFN-γ. Altogether, this study highlights an underappreciated facet of the regulatory role of IFN-γ and virtual memory T cells on CD8+ T cell responses against infection.
Host-microbe interactions in inflammation-driven cancer
Keywords: neutrophils
immune system
microbiome
helicobacter hepaticus
inflammation
colorectal cancer
pepetidyl arginine deaminase

Colorectal cancer (CRC) is a heterogenous disease of the intestinal epithelium that is characterised by the accumulation of mutations and a dysregulated immune response. A growing body of literature now also illustrates that this is accompanied by an “oncogenic” CRC-associated microbiota, but whether this dysbiosis is a functional hallmark of CRC or merely a bystander effect of disease is unclear. Therefore, the aim of this DPhil project was to identify changes within the microbiome during cancer progression and the functional consequences. To achieve this, we induced dysbiosis in genetically susceptible mice by colonisation with the pathobiont Helicobacter hepaticus (Hh) followed by the treatment with the carcinogen azoxymethane (HhAOM).
Using a range of unbiased longitudinal approaches, we found a distal colon-specific neutrophil signature during tumorigenesis and identified 118 genes that were differentially expressed in HhAOM versus control mice, indicative of putative tumour-promoting properties. Amongst these, the enzyme peptidyl arginine deaminase 4 (PAD4) was upregulated in epithelial cells of early and late tumorigenesis. PAD4 was verified to play a functional role in cancer progression because therapeutic in vivo inhibition reduced tumour area. Alongside this observation, we discovered that Hh resides within established tumours but lacks the capability to drive CAC in gnotobiotic settings.
Collectively, our findings suggest that Hh-driven colitis triggers an early neutrophil influx into the distal colon which fosters a microenvironment that promotes tumour progression characterised by the expression of PAD4. These observations open new potential avenues to explore tumour-promoting function of neutrophil subsets in more detail and the role of the citrullination enzymes like PAD4 in CRC progression.
Constitutions
Keywords: social forms
technology
infrastructure
body
art

This collection consists of a series of texts and documentation of artworks that attend to modes of constituting social bodies. A constitution might allude to a map, a garment, a code, cosmogony, a body, a people, an agreement, or an enfolding process. These texts and works move the social through bodies—biological, political, infrastructural, and digital—and relate such bodies’ knowledge in various states of digest: partiality, fluidity, congelation, breakdown. They are reflections on consuming, ingesting, and metabolizing, or in other words, processes of incorporating and embodying. They are reflections on ways of moving through time and space. Somatic metaphors can include physical movement as well as how other entities move between bodies, like pathogens, or knowledge. Circulations lead us from inside out, modeling larger phenomena and technologies on bodily networks. Such networks might be reassimilated into bodies, as codes might likewise be embodied.
To be a body amongst others is a process of forming via transmission, to acknowledge that a body is an unstable assembly-in-process, a series of constitutions.
Design of multivalent DNA nanomaterials for use in cancer diagnostics and therapeutics
Keywords: DNA aptamer
cancer diagnostics
mRNA detection
DNA nanostructure
DNA nanoflowers

Cancer is one of the major causes of mortality nowadays, owing to the lack of accurate diagnostic and therapeutic techniques. DNA-based nanomaterials show extraordinary performance in cancer diagnosis and have applications in therapy, owing to their predictable secondary structures, small sizes, excellent biocompatibility, and programmability.
Rolling circle amplification (RCA) has been identified as a promising technique to make DNA nanomaterials, including DNA hydrogels, origami, nanoribbons, nano scaffolds and DNA nanoflowers (DNFs). These DNA nanomaterials have potential in a wide variety of applications, involving drug delivery, in vivo imaging, electronic circuit fabrication and therapeutics. However, there was a lack of chemistry to expand their functionality, which greatly limited their applications. To address this, we developed a strategy involving commercially available modified nucleoside triphosphates in RCA, resulting in densely modified products. The modified RCA products can then be functionalised by targeting moieties such as aptamer and peptide, which enhance their binding ability towards specific cancer cells.
The size of the RCA generated particles can be tuned through reaction time, Mg2+ concentration and the addition of polymers such as PLL and PEG. The PEGylated products can be labelled using the abovementioned method, leading to condensed fluorescent particles with better cellular uptake.
Additionally, a nanocarrier system based on cyclic DNA was designed and evaluated for mRNA detection in cells. The untemplated cyclisation of DNA through CuAAC chemistry was efficient, and the multivalent system showed an improved binding towards target cancer cells. However, the internalisation of the system by cells needs to be improved. Entrapment of the system in subcellular compartments was observed, which significantly increased the background signal.
Neural effects of prioritisation on working memory
Keywords: Memory
Reward
Feedback
Attention
EEG

Working Memory describes the cognitive ability to store information over short timescales, and use it to guide behaviour. It is strikingly limited, and we are only able to maintain small amounts of information in this short-term store. However, it is highly flexible and we are able to prioritise working-memory contents according to their relevance for behaviour. Such attentional prioritisation is associated with enhancements in working-memory performance. However, whether we use memories to guide behaviour should depend upon their quality and value. Thus, it is important to understand how we introspect upon working memory, evaluating and learning about its quality, and assign value to its contents. This thesis explores uncertainty and value in working memory. Chapter 2 examines how attentional prioritisation affects working-memory introspection. I show that attentional prioritisation improves the quality of introspection into working-memory contents. I also show evidence that feedback regarding the accuracy of recent confidence judgements is incorporated into working-memory confidence, shaping our beliefs about the quality of working-memory performance. Chapter 3 describes two experiments using electroencephalography (EEG) to explore how feedback regarding working-memory performance is processed. I show that uncertainty – manipulated externally by varying working-memory load, and carefully measured through subjective confidence judgements – is represented in the neural response to feedback. When feedback contains information regarding the quality of subjective uncertainty, I find evidence of a confidence prediction error that could facilitate learning about working-memory quality. Chapter 4 describes two novel experiments that explore how the value associated with objects held in working memory shapes performance. These experiments present reward information during working-memory maintenance to examine how reward influences the prioritisation of working-memory contents after encoding. I show that reward can guide the prioritisation of working-memory contents – even when reward is irrelevant to the task at hand. I demonstrate both global and item-specific benefits associated with reward-guided attentional prioritisation of working-memory contents. Finally, in Chapter 5, I discuss the findings of this thesis in a wider context, and remaining theoretical questions related to working-memory guided decisions.
Kings and the loyalty of the lay elite in England, 871-1016
Keywords: Bonds
Trust
Socio-political
Government
Diplomas
Kingship
Land-Law
Law
Charters
Loyalty
Charter
Anglo Saxon

At the heart of the late Anglo-Saxon political order lay a single relationship: the bond between the king and the powerful men of the realm. This thesis is concerned with the ways in which that relationship was established, then developed in written sources; centrally it will explore how kings forged such bonds with members of the lay elite. Chapter One argues that there is little evidence for the existence of a contemporary mentality in which kings attempted to use conceptual mechanisms to impose loyalty onto their men, either in legal or religious terms. Chapter Two proposes a new model for the analysis of royal diplomas for this period, wherein the strategic incentivisation of lay loyalty through the granting of bookland is revealed via the joint consideration of factors such as beneficiary status, rank, participation in the witan on the one hand, and estate size and location on the other. Chapter Three offers new interpretations of a range of extant royal policies from most reigns of the period in relation to the matter of loyalty, and demonstrates in this way that the surviving evidence for kings’ management of their relationships with their lay elites is overwhelmingly characterised by the same overarching principles of constancy, community and active leadership. The thesis concludes that the loyalty of the lay elite in this period could not be taken for granted by kings as a simple corollary of their consecration, but was instead actively cultivated and negotiated. Kings not only offered incentive programmes but created communities of shared interest, devising novel ways in which to define magnates’ identities through their loyalty to their king, and integrating those from frontier regions into the political and social fabric of West Saxon kingship.
Voices from a minor literature: reading the poetry of Else Morante, Amelia Rosselli, Patrizia Cavalli and Biancamaria Frabotta in Context (1968-1982)

Keywords: Elsa Morante
female writing
Félix Guattari
Biancamaria Frabotta
Gilles Deleuze
minor literature
Patrizia Cavalli
Amelia Rosselli

This thesis constitutes the first monograph to analyse the poetry of Elsa Morante, Amelia Rosselli, Patrizia Cavalli, and Biancamaria Frabotta in context. It investigates the entangled networks of personal, political, and literary exchanges between these poets and their texts in the ‘long seventies’ (1968-1982). With the aim of problematizing the difficult heritage of the category ‘scrittura femminile’ within the Italian context, it uses the categories of ‘minority’ and ‘minor literature’ – as theorised by Gilles Deleuze and Félix Guattari – as an aid for the revaluation of women’s poetry. One of the most common tendencies of literary criticism sees women’s poetry as the product of a series of isolated, eccentric, and exceptional ‘cases’. Conversely, the category of ‘minor literature’ allows us to produce a contextual reassessment of their poetic work following two main threads: first, the ‘de-territorialization’ of their poetic language which entails several innovations introduced in their metrical systems, the macrostructures of their books, and the cultural references at the core of their poetry collections; second, the ‘political aim’ intrinsic in the treatment of their lyric subject. This thesis contributes an innovative viewpoint to existing scholarship on Italian women’s poetry, gender studies, and lyric theory by further problematising received notions of ‘scrittura femminile’, literary reception, and anti-canonicity. In turn, it also allows us to relocate the poetry of Morante, Rosselli, Cavalli, and Frabotta within an interconnected system of transnational, transcultural, and transhistorical literary influences.
Practical security solutions for serial data bus networks
Keywords: MIL-STD-1553
cybersecurity
infrastructure
IDS
vehicle cybersecurity
CAN

For decades, manufacturers incorporated computers into vehicles, weapon systems, and numerous pieces of modern infrastructure, networking them together via serial data bus networks. These networks took direct control away from the operator in the name of efficiency and safety, but we now know this bargain came at the cost of security. By having no authentication in the design, anyone communicating on the network can create harmful effects. The natural solution to this problem is to redesign these networks to support authentication, but abandoning decades of vital infrastructure would be unfathomably expensive. The only option is to continue using our existing equipment, but to develop a way to add security in an efficient and cost effective manner. However, there are an innumerable number of ways to design and implement a serial data bus network. This thesis lays out a methodology for taking a serial data bus network, understanding it, and designing a security patch for it. To illustrate the utility of our methodology, we implement two proof-of-concept intrusion detection systems. The first improves upon existing CAN detection techniques by using a standardized data field to abstract the state of the system. The second takes advantage of the architecture of MIL-STD-1553 to more efficiently detect new messages on the network. Our protocol-specific approach is emphasized by our development of new attacks on the CAN protocol. Finally, this thesis produces an evaluation framework for the prevention and detection systems increasingly being deployed to these vehicle and weapon system networks. Our framework generates a score for defenders, such that they know exactly what attacks and attack vectors their system can detect and prevent. By looking at multiple protocols, from ground vehicles to fighter aircraft, we highlight how a protocol targeted security approach creates more accurate, more efficient, and more practical technology, to detect even the most advanced attackers.
Optimising NMR spectroscopy through method and software development
Keywords: optimisation
NMR spectroscopy
analytical chemistry
NOAH supersequences
pure shift NMR

Solution-state nuclear magnetic resonance (NMR) spectroscopy is one of the most important analytical techniques in modern organic chemistry. A series of ‘core’ NMR techniques is widely used for the routine characterisation of organic molecules, ranging from 1D 1H and 13C experiments to more complex 2D experiments such as COSY, HSQC, HMBC, and more. Nonetheless, there remains much room for developments in NMR, especially considering the increased complexity and quantity of molecules which are being studied. This thesis describes multiple approaches towards improving the quality, as well as the speed, of NMR data acquisition.
In chapter 1, I first set out the quantum mechanical formalisms required for the analysis of NMR pulse sequences. The work which follows may be divided into three sections:
• Improved techniques for pure shift NMR (chapter 2). In a pure shift experiment, the effects of all homonuclear scalar couplings are suppressed, leading to highly-resolved spectra where each multiplet is collapsed into a singlet. A variety of theoretical and experimental approaches are used to search for pure shift methods which have both high sensitivity and low artefact intensity.
• On-the-fly optimisation of NMR experiments (chapter 3). Here, I couple NMR acquisition with derivative-free optimisation algorithms which seek to minimise a cost function measured using spectral data. The resulting software, called POISE, allows experiment parameters to be tailored specifically for each sample and spectrometer in a fully automated fashion. The use of POISE to improve spectral sensitivity and purity is demonstrated on a wide-ranging series of NMR experiments.
• Accelerated 2D NMR data collection (chapter 4). NOAH supersequences allow multiple 2D experiments (‘modules’) to be acquired in the time of one, through the careful manipulation of different magnetisation pools. This chapter contains work on pulse sequence development, including new NOAH-compatible modules, as well as improvements to various pre-existing modules. The GENESIS website, which creates Bruker pulse programmes for arbitrary NOAH supersequences, is also described here.
Liberal democracy, competition, and the institutional limits of markets
Keywords: institutions
moral limits of markets
media
competition
legal representation

This thesis addresses a particular class of problems affecting liberal democracies worldwide, namely, that some of their most central institutions—the electoral system, the legal system, and the free press—are undermined by their partial or complete subordination to the market. I provide a comprehensive normative analysis of this class of problems and answer the following questions: is it justifiable to place limits on markets in certain institutional goods (e.g., legal representation and the reporting of news), and if so, what should those limits be?
Arguments for limiting markets are not novel. In recent decades, a shared fear of market expansionism has developed into a vast normative literature, the ‘Moral Limits of Markets’. This body of scholarship introduced new normative questions about markets and brought to the fore markets that have been hitherto underexplored.
Yet, as I argue in the first part of the thesis, despite its richness and importance, this literature suffers from a significant weakness: it fails to properly analyse normative issues arising from the clash between markets and liberal democratic institutions. In response, I develop a novel institutional account of the limits of markets in liberal democracies.
An intermission between the first and second parts of the thesis is devoted to the concept of competition. Competition is the key element in the institutional infrastructure of modern liberal democracies. Thus, a proper account of competition is necessary to assess the normative foundations of present-day institutional designs. I offer such an account, arguing that there are two concepts of competition, each leading to different normative requirements for institutional design. Only one is compatible with markets.
Finally, in the second part, I apply my account to markets within two key political institutions in liberal democracies—the legal system and the media—and provide normative guidelines concerning their proper limits.
Sleek divines and beaux esprits: the universities and the system of knowledge in England, c.1690-1750
Keywords: textual criticism
early career scholars
public sphere
polemic
vernacularisation
Oxford and Cambridge
universities

Despite recent attempts to reassess the culture wars of early Enlightenment England as conversations between educated individuals about pivotal and often technical matters, academics of the period continue to feature in narratives of intellectual change as the gatekeepers of a decrepit religious establishment. The famous contention of John Henry Newman that universities are at best locations for the ‘diffusion and extension of knowledge’ but not for its advancement thus lives on, and has only been heightened by the persistent supposition among historians that the eighteenth-century English universities ‘surrendered their cultural leadership’. This thesis, however, presents an altogether new perspective on the relationship of Oxford and Cambridge to the wider intellectual life of the period, with a focus on the neglected polemical and scholarly writings of ‘early career’ scholars. During a period coloured by anti-institutional sentiments, young scholars in the universities worked tirelessly to defend the system of knowledge that underwrote the curricula of their institutions, and, indeed, academic authority at large. They also aspired to operate smoothly within, and ideally govern, a rapidly expanding vernacular ‘public sphere’, aware that their task of defending the Church of England depended upon them successfully doing so. In my account, the shortcoming of the eighteenth-century English universities in terms of the relative dearth of impartial ‘research’ publications was not a result of their being impervious to ‘polite’ society but rather of their obsessive and often very successful attempts to engage with it.
The role of serine metabolism in B lymphocytes
Keywords: B cell
immunology
lymphocyte
Germinal centre
biochemistry

The serine synthesis pathway (SSP) has been identified as highly upregulated in metabolically active cells and feeds into 1C metabolism, helping to generate biosynthetic material for cell proliferation and cell survival. The SSP in the context of GC B cells has not been previously explored, and therefore, I sought to determine its role. I found no effect on proliferation or viability of serine and glycine deprivation on wild type B cells. I identified upregulation of the SSP during activation in replete media, which was further amplified when depriving B cells of serine and glycine. Immunoglobulin production is relatively decreased when stimulated B cells are cultured without serine and glycine. However, using B cell conditional phosphoglycerate dehydrogenase (PHGDH) knockout mice, following immunisation, there was a relative increase in IgG1+ GC B cells. When I activated and cultured B cells from Phgdh KO mouse in vitro, I also found a relative increase in IgG1+ B cells. Phgdh KO mouse B cells did not survive or proliferate without serine and glycine in vitro. Together, my findings indicate that the SSP, as well as serine and glycine availability, is involved in B cell proliferation and viability, as well as in the molecular control of immunoglobulin expression. These findings could help in understanding ways in which the SSP can be manipulated for clinical treatment of cancers and autoimmune disease.