VictorJuiz/thesis huggingface dataset:
Regulatory T cells in rheumatoid arthritis: the role of TNF-α receptor signaling and DNA methylation

Anti-TNF-α therapy has revolutionised the management of inflammatory arthritis, leading to improvement of symptoms and signs of rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis, as well as inhibiting radiographic progression in rheumatoid arthritis, and psoriatic arthritis. However, despite its success in the majority of patients with inflammatory arthritis, about 20-40% of patients are resistant to anti-TNF-α treatment and few patients (10% or less) achieve long-term remission. Several studies suggest that TNF-α receptor 2 (TNFR2) plays an immunoregulatory role in arthritis and that the interruption of TNF/TNFR2 interaction contributes to resistance to anti-TNF-α therapy and to some of the adverse effects associated with anti-TNF-α therapy. The objective of the work presented in this thesis was to gain a deeper understanding of TNFR signalling in rheumatoid arthritis with particular emphasis on a sub-population of lymphocytes known as regulatory T cells (Tregs).
Firstly, an association was shown between TNFR2 signaling and TGF-β in regulating the expression of the Treg associated transcription factor, FoxP3. I further assessed the effect of TNFR signaling on CpG methylation at the FoxP3 locus by bisulfite sequencing. The result showed that TNFR2 deficiency leads to increased level of DNA methylation in the proximal promoter of FoxP3.
Secondly, I investigated the role of TNFR signaling in arthritis. As expected, TNFR1-/- mice were found to be relatively resistant to arthritis. In contrast to TNFR1-/- mice, higher incidence and increased disease activity were observed in TNFR2-/- mice compared to wild-type mice. In addition, the results showed that TNFR2 deficiency leads to decreased numbers of Tregs, reduced FoxP3 expression of Tregs, reduced expression of immune inhibitory markers and increased production of pro-inflammatory cytokines in arthritis.
Thirdly, I investigated the therapeutic potential of DNA demethylating agents in the treatment of RA. It showed that the DNA demethylating drug, decitabine, ameliorated collagen-induced arthritis (an animal model of rheumatoid arthritis) and promoted Treg suppressive function whilst inhibiting pathogenic Th1/Th17 cells.
These findings highlight the therapeutic potential of strategies to boost Tregs by TNFR2 agonists or DNA demethylating agents and suggest that it may be possible to achieve long term inhibition of pathogenic inflammation using this approach.

Advisor: Williams, R
Feldmann, M
Phenotypic modelling of the polyfunctional T cell response

T cells are important mediators of adaptive immunity and promising agents in immunotherapies. When T cell receptors (TCRs) on the surface of CD8+ T cells detect pathogenic peptides presented by major histocompatibility complexes class I (pMHC) on antigen-presenting cells (APCs), a complicated intracellular signalling process is initiated that results, among other functional responses, in the secretion of cytokines to fight the pathogenic threat. An overwhelming number of molecular components that are involved in the translation of the pMHC stimulus into an appropriate cytokine response have been identified, but a mechanistic understanding of how the quality of the pMHC stimulus, i.e. pMHC dose and affinity, determines the response phenotype is lacking. Here, reductionist T cell stimulation experiments were combined with a coarse-grained phenotypic modelling approach to identify prevailing modules that shape the phenotype of cytokine secretion in response to stimulation with pMHC. CD8+ primary human T cells transiently produced the four cytokines TNFα, MIP-1β, IFNγ and IL-2 and adaptation was paralleled by rapid and sustained TCR downregulation. Direct fitting of a phenotypic model constructed from known features of T cell signalling to the experimental data showed that TCR downregulation was sufficient to explain adaptation as well as other striking features of the cytokine response, including high-dose suppression (bell-shaped dose-response curve). Interestingly, secretion of TNFα, MIP-1β, IFNγ and IL-2 ceased at similar time scales and appeared equally sensitive to pMHC dose and affinity, contrary to previous reports. These findings thus suggest that T cells possess an intrinsic adaptation mechanism and reveal a surprisingly uniform early activation phenotype for multiple cytokines.

Keywords: T lymphocytes
T cells
Cancer Immunotherapy
Cell Signalling
Adaptation
Immunology
Systems Biology
Advisor: Dushek, O
van der Merwe, P
Apathy and effort-based decision making: a cognitive mechanism underlying amotivated behaviour

Apathy is a common, debilitating but poorly understood disorder of motivation that manifests in reduced goal directed behaviours. The integration of cost and reward information about potential actions is central to normal motivated behaviour. This thesis will argue that disruption of this normal process – often termed effort-based decision making – underlies the clinical syndrome of apathy.
Two broad sets of questions are investigated to address this hypothesis, in clinically apathetic patients with either Parkinson’s disease (PD) or a genetic form of cerebral small vessel disease (SVD). Firstly, are apathetic patients hypersensitive to effort costs, or insensitive to rewards when making decisions about potential actions? Do these changes associated with apathy map onto physiological alterations in reward processing and disruption of anatomical regions that underlie normal effort-based decision making? And do these behavioural changes occur along the same axis as those induced by dopamine depletion? Secondly, using an ecological framework of decision making in which participants must compare current (foreground) reward information to the background reward context to guide adaptive behaviour, this research explores whether apathy is associated with aberrant use of background reward information, and how this interacts with the dopaminergic system.
The studies demonstrate effort-based decision making is disrupted in patients with apathy, driven by reduced incentivisation by the rewarding outcomes of actions rather than hypersensitivity to effort costs themselves. Reward insensitivity manifests in both behavioural choices and physiological responses to incentives, is associated with reduced white matter integrity in tracts connecting regions crucial for effort-based decision making, but occurs along a separate mechanistic axis to changes induced by dopamine depletion. Furthermore, whilst healthy human decision makers are remarkably sensitive to changes in background reward environment, apathy changed the influence of this information – dependent on dopaminergic tone. Together, the work in this thesis presents evidence that disruption of a specific cognitive process underlies the apathetic syndrome. This advances understanding of normal motivated behaviour and identifies potential therapeutic avenues to treat this important clinical syndrome.

Keywords: Foraging
Motivation
Apathy
Dopamine
Decision making
CADASIL
Parkinson's Disease
Reward
Advisor: Husain, M
Apps, M
Understanding the role of Caspr2 in the developing cerebellum

Despite receiving renewed attention due to the revelation it is involved in higher cognitive functions, we still know little about how the cerebellum develops and operates. Studies suggest Contactin-associated protein-like 2 (Caspr2), a member of the Neurexin superfamily, has a cerebellar function. However, the cellular and molecular bases for this remain unknown.
An initial assessment of the spatio-temporal expression pattern of Caspr2, using immunohistochemistry and biochemical fractionation, suggested that Caspr2 is expressed at specific synapses in the developing cerebellum. Little is known about the function of Caspr2 at synapses and so the Caspr2 domain exposed to the synaptic cleft, the Caspr2 extra-cellular domain (ECD), was focused on. The addition of recombinant Caspr2 ECD to organotypic cerebellar slice cultures prepared from Cntnap2-/- mice rescued a dendritic morphology defect observed in untreated cultures, suggesting Caspr2 affects cellular morphology during cerebellar development. To understand the molecular basis for this effect, a pull down assay was used to identify the synaptic binding partners of Caspr2. Unexpectedly, mass spectrometry analysis of this experiment revealed that the Ca2+ channel Inositol 3,4,5- trisphosphate receptor type I (IP3R1) is a cognate partner of Caspr2 at synapses in the developing cerebellum. Further biochemical assays revealed both that the Caspr2-IP3R1 interaction underlies the regulation of cellular morphology by Caspr2 and that Caspr2 may modulate cytoplasmic Ca2+ levels. Combined with data from co-immunoprecipitation assays suggesting that Caspr2 interacts with the IP3R1 poreforming domain, these data are consistent with Caspr2 acting via IP3R1 to regulate cellular morphology during cerebellar development, most likely by directly affecting the IP3R1 pore region environment.
Together, these experiments therefore reveal novel cellular and molecular roles for Caspr2 in the developing cerebellum. As well as improving our understanding of the nervous system, knowledge such as this will likely be increasingly clinically relevant, given the previously overlooked links between the cerebellum and cognition.

Keywords: Caspr2
cerebellum
cellular morphology
Inositol 1,4,5-trisphosphate receptor type 1
Advisor: Becker, E
Seiradake, E
Exploring the Kingdom of Brycheiniog: an integrated archaeological approach in an early medieval landscape

Research into the formation and growth of early medieval kingdoms in Wales is limited by a considerable paucity of archaeological and documentary evidence. Compounded by a bias of ‘high status’ sites within the Historic Environment Record and the literature, the scholarly tradition has remained focussed on the scant material remains and intermittent historical sources. In contrast, this thesis argues that for a new perspective on the socio-economic environment of these polities, research using a suite of relevant and bespoke landscape archaeology tools, particularly with the aim of understanding the natural environment affordance, be elevated in priority.
Guided by archaeological and theoretical frameworks which anchor the research, an innovative, ‘bottom-up’ methodological approach is advocated and applied to one such early medieval kingdom, the Kingdom of Brycheiniog, in mid-Wales (c. AD 500-1066). To ascertain the extent to which Brycheiniog has an expression in the landscape, a suite of early medieval indicators are identified, cross-examined and contextualised against the affordance of the natural environment. These indicators form the basis for establishing characteristics of the Kingdom such as activity hubs, networks and economy.
The results of this analysis reveal attributes of a kingdom with inherently Irish characteristics in the early medieval period. Activity hubs, indicated by early ecclesiastical sites, ogam stones, the Llangorse Lake crannog and pre-AD 1200 place-names, are centred along riverways and Roman roads, particularly around Llangorse Lake and the River Llynfi catchment in the upper Usk valley. Emerging from the research is a region rich in economic potential and natural resource, well connected to the Irish-sea trading-sphere, via its rivers, which flow into the Severn Estuary.

Advisor: Griffiths, D
Investigating a role for telomeric transcription in cancer

A constitutive hallmark of cancers is the extension of telomeric DNA. Approximately 85% of cancers extend their telomeres through the upregulation of the enzyme telomerase; whereas the remaining proportion use a recombination-based method known as Alternative Lengthening of Telomeres pathway (ALT). Tumours that exhibit the so-called ‘ALT’ pathway include: pancreatic neuroendocrine tumours, astrocytoma and osteosarcoma. The prognosis for many of these tumours is poor and the development of novel therapies is therefore an important unmet need.
Recent work has shown, however, that ALT cancer cells exhibit some characteristic hallmarks which include; a near universal loss of the chromatin remodelling factor ATRX and increases in the transcription of a long non-coding RNA from telomeres, denoted TERRA. This project aims to determine: a) do increases in TERRA transcription facilitate the ALT pathway and b) could targeting of the TERRA transcript be a viable therapeutic approach for the treatment of ALT cancers?
Consistent with a role for TERRA in facilitating ALT we demonstrate that ALT positive cancer cells exhibit changes in the nuclear distribution of TERRA, with clear telomeric foci detectable via RNA-FISH. Furthermore, we demonstrate that the use of LNA GapmeR antisense oligonucleotides can be used as a strategy to deplete TERRA levels. Importantly depletion of TERRA correlated with a loss in C-circles, a major marker of an active ALT pathway. Future work will determine how this affects longterm viability and whether this provides potential for therapeutic intervention in ALTpositive cancers.

Keywords: Transcription
Cancer
Telomere
Advisor: Clynes, D
New Ireland, old objects: negotiating colonial relations through collections from 1875 to 1885

In this thesis I study collections of material culture made in the early colonial period in New Ireland. I look at the collections made by three men who collected in New Ireland at various times and in different ways between 1875 and 1885: the missionary Reverend George Brown, the trader Thomas Farrell, and Hugh Romilly, a British government official. I use these collections, in conjunction with historical records, to examine the nature of change in New Ireland society, focusing particularly on the period 1875-1885.
Studying the collections reveals that New Irelanders were keen to experiment and to trade during this period. For the most part, they remained in control of trade, not only of what was being traded in and out, but also of where this trade took place. Ritual art production on New Ireland was rich and varied during these years. Life changed more considerably after 1900, with a sharp decline in population probably causing the most profound changes. There was less variety in artistic output and a number of traditions died out. Ritual life remained strong, however, and New Irelanders continued to produce many ritual art works.
In the 1870s and 1880s, many men, and a few women, travelled away from New Ireland to work on plantations. Others engaged with their visitors in different ways, independently exploiting the opportunities supplied by trading stations, mission stations and recruiters. Whilst the colonial encounter in New Ireland disrupted the lives of many New Irelanders, for the most part people successfully embraced change without diminishing what had long been a strong, dynamic and adaptive ritual life.

Advisor: Gosden, C
X-ray powder diffraction as a non-destructive tool for characterising laser wakefield betatron radiation

Laser wakefield accelerators provide a relatively simple means of generating bright X-rays beams which are useful across many fields and industries. To achieve this, a sufficiently powerful laser is required and just a few centimetres of gas. In contrast, other bright X-ray sources, such as synchrotrons, require significantly more infrastructure and can span many hundreds of metres.
This thesis looks at a novel diagnostic technique based on X-ray diffraction from a powder in order to characterise X-ray beams with large shot-to-shot variations. The mechanics behind the method, named XCERP diffraction, are presented and the results of simulations are provided as a proof of principle study. XCERP diffraction is shown to be able to retrieve details of the energy spectrum and the beam divergence in a single shot without prior knowledge of the spectral shape.
A campaign at the Centre for Advanced Laser Applications in Munich focused on the first experimental demonstration of XCERP diffraction. The results reveal that an increased level of radiation shielding was required as a source of ionising radiation was found to be present whenever an electron beam was generated. This source of radiation is thought to have obscured potential X-ray diffraction.
An investigation of the unknown radiation source was performed using GEANT4. From simulations of the CALA target chamber, it was found that the CCD of interest would have been subjected to both bremsstrahlung radiation and stray electrons when an electron beam is steered into a steel floor. Further simulations show potential methods of reducing the flux of particles reaching the CCD.
Finally, the designs of an electron spectrometer and filter array are described in detail to measure properties of the electron bunches and betatron radiation produced during an experimental campaign at the Astra Gemini laser facility.

Keywords: Electron spectrometer
Powder diffraction
XCERP diffraction
Image analysis
Betatron radiation
Ross filter
Spectral reconstruction
Single photon counting
X-ray diffraction
Geant4
Advisor: Hooker, S
More-than-rational modelling: the pragmatics and politics of social simulation in fisheries management

Social simulation methods such as agent-based modelling are making inroads into the tool sets of economists and environmental scientists. Responding to critiques of mainstream economic models, agent-based modellers promise increased behavioural realism by modelling the more-than-rational aspects of economic action in socio-ecological systems. This thesis examines agent-based modelling in fisheries management by ethnographically following the efforts of an international scientific consortium to develop an agent-based fisheries model on to the sites of its intended use at the West Coast of the United States. In a dialogue with pragmatic and performative accounts of modelling in science and technology studies, economic sociology, and geography, this project offers an empirically grounded contribution to debates about the politics of knowledge in environmental science and the performativity of economics. The thesis elaborates a relational and materialist account of social simulation and documents how the practices of agent-based modellers are entwined with the politics of fisheries management. The thesis finds that scientific aspects of the agent-based model like agent algorithms and coupling decisions were co-produced with its political context of model use; that efforts to reform the array of calculative practices enacting fisheries economies contend with infrastructural relations between science and policy; and that computational policy optimisation rests on assumptions about policy process that are at odds with its political dimension. As a result, the thesis argues that more-than-rational modelling unsettles rationalist notions of science, economics, and policy, disclosing instead the socio-materiality of scientific modelling, the normative dimension of economic calculation, and the irreducibly antagonistic aspects of politics at work in a scientific effort to reform economic modelling for fisheries management. The thesis concludes by suggesting that recovering the normativity of rational calculation and the politics of knowledge in the analytical framework of economic performativity contributes to understanding the production of economic difference in the context of geographical debates about marketised environmental governance.

Advisor: Whatmore, S
Landström, C
Analysis of complete contact problems with particular reference to gas turbine engines

Frictional contacts are often found in different engineering assemblies (for e.g., dovetail/fir-tree contact) and are frequently subjected to constant centrifugal loads, vibration and other forms of cyclic loads and cause a damage phenomenon called fretting fatigue. Fretting occurs mainly due to the oscillatory micro-slip between contacting interfaces and accelerates the nucleation and early propagation of cracks, and thereby causes a significant reduction in the fatigue life of the engineering components. Therefore the aim of this thesis is to study elaborately the behaviour of complete contacts, especially the interfacial conditions, in the long run to minimize the occurrence of fretting damage.
An asymptotic solution has been formulated for a particular case of complete contact, where the edge of contact is located near to an adjacent wall of material and separated by a finite clearance. Semi-infinite crack, wedge and trench asymptotes were used to investigate the behaviour of the edge of contact, when the side clearance is negligible, infinite and finite respectively. The interfacial requirements, namely the edge closure criteria and minimum coefficient of friction needed for adhered conditions, are established for various internal edge angles.
The second part of my thesis concerns the study of wedging behaviour in complete contacts found in blade root assemblies. A contact is considered to be wedged when the friction present at the interface is enough to retain the deformed configuration in the absence of external load. However wedging occurs for the specific case where the coefficient of friction exceeds a particular value. A condition for the occurrence of wedging was derived in terms of the internal dovetail angle. Finite element simulations of the dovetail assembly have been carried out and the results are compared with the analytical calculations.
Attention has also been focussed on the numerical aspects of the work, where a finite element code exploiting the static reduction method was implemented for Rolls-Royce proprietary software SC03, to solve quasi-static frictional elastic contact problems. At present level of implementation, the procedure is intended to work for two dimensional, frictional contact problems where the contact interface is located approximately along a straight line.

Advisor: Hills, D
Cherukunnath, N
Serial verb constructions in Barayin: Typology, description and lexical-functional grammar

Barayin is an East Chadic language spoken by around 5000 people in the Guera region of the Republic of Chad. This dissertation examines a particular type of syntactic construction in the language, serial verb constructions, from the perspectives of typological (or comparative) syntax, descriptive grammar, and the formal syntactic theory of Lexical-Functional Grammar (LFG). Typologically, serial verb constructions are problematic because they represent a heterogeneous set of multiverb constructions that have features that do not fit into traditional syntactic categories like subordination, conjunction and adjunction. Part A of this dissertation describes these problematic features in detail, providing a succinct overview of the literature which can serve as a resource for field linguists describing similar constructions. Part B of the dissertation gives a detailed description of the morphology, syntax and semantics of serial verb constructions in Barayin. These chapters contribute to our knowledge of the world’s languages by documenting a complex syntactic phenomenon in an area of the world where most of the languages are significantly understudied. The most common type of SVC in Barayin involves a deictic motion verb. The motion is normally (but not always) understood to take place prior to the activity or state predicated by the main verb. The formal analysis of Barayin SVCs in Lexical-Functional Grammar in Part C uses recent developments in the theory to show how argument sharing in SVCs can be represented in a connected s-structure that conforms to the standard mechanisms of LFG. The approach is compared to two previous analyses of complex motion predicates in other languages which appeal to a non-standard formal mechanism to model complex predicates.

Keywords: Barayin
Lexical-Functional Grammar
Chadic
Typology
Advisor: Dalrymple, M