VictorJuiz/thesis huggingface dataset:
System-level analysis of early signalling in T cells

The prevailing view of signal transduction is that it proceeds through the linear relay of information via sequential bimolecular interactions, involving, for example, Src homology (SH) 2 domains. It has been assumed that such interactions are highly selective, i.e. that the affinities of these interactions are several orders of magnitude higher than that for non-specific interactions. However, recent studies have suggested that the difference in affinities between so-called specific and non-specific interactions is not sufficient to support such a proposal. This therefore raises the question of how signalling pathway specificity is generated at all. To address this, we have taken a systems approach by expressing and purifying >90% of the SH2 domains identified in a T cell line using a next-generation sequencing-based transcriptomic analysis, and performed a systematic survey of the interaction of these SH2 domains with a set of potential phosphorylated peptides derived from the key signalling receptors of the T cell (including CD28, CTLA-4, PD-1, ICOS, BTLA, LAT and the CD3 subunits of the TCR complex), using surface plasmon resonance-based binding assays. Our results show that, instead of being highly selective for certain SH2 domains, the T cell-expressed receptors are very cross-reactive, such that each receptor is found to interact with ~50 different SH2 domains on average. In silico analysis based on these results confirms the expectation that affinity itself is not the sole determining factor for receptor specificity. Further exploration of the system using in silico simulations incorporating the absolute concentrations of SH2 domain-containing proteins measured in T cells using a proteomics-based approach, suggests instead that the specificity of SH2 domain recruitment by T-cell receptors is the result of systems effects, with expression levels of the signalling proteins being a major factor. Surprisingly, LCK, the most highly expressed SH2 domain in resting Jurkat, is predicted to dominate the binding of most receptors, suggesting a novel mechanism of Src kinase activation and function.

Keywords: SH2
T cells
signalling
Advisor: Davis, S
Towards a non-representational geography of artistic practice

Geography’s engagement with art has a long and varied history which, consistent with broader disciplinary developments, has progressed beyond a focus on the representational content of art products to consideration of artistic practices and experiences. However, persistent tendencies to consider artist, artwork and artistic spatiality as distinct and essential render the ‘geography of art’ under-equipped to address the emergence through artistic practice of particular, contingent, mutable and excessive spatialities and subjectivities. With its emphases on practice, affect and experimentalism, I draw on geographical and psychological non-representational thinking – philosophically, methodologically and analytically – to generate an account of such emergent spatialities and subjectivities. I explore artistic, material and implicit means through which they emerge, from within artistic practice, on both an experimental and auto-ethnographic basis. Working alongside participating artists, I varied the spatial and material conditions of our respective practices to encourage participants to do, think about and articulate their artistic practices differently, and employed interview techniques intended to facilitate access to and articulation from implicit or pre-reflective understanding.
Four substantive papers consider different aspects of artistic practice in the context of different theoretical literatures. Through these papers, I argue that artistic practice is a form a mythological thinking without explicit mythic content, and identify paired reciprocal processes of interrogation through which spatialities and subjectivities emerge. I propose that the combination of experimentalism and particular material affects within artistic practice sustains a skills-challenge imbalance, which drives further experimentation and generates increasingly individualized practices. I also argue that artistic practice provides both access to and articulation from implicit understanding, allowing the conveyance of implicit meaning both on its own artistic terms and by facilitating explication into linguistic form.
I conclude that, collectively, these varied aspects of artistic practice constitute interpenetrative processes whereby the material and implicit function as one, and that by attending to these processes through the creative and analytical means introduced here, geography’s capacity for a non-representational understanding of artistic practice is greatly enhanced.

Keywords: artistic practice
non-representational
geography
spatiality
post-phenomenological
subjectivity
psychology
Advisor: McCormack, D
A mathematical model for hydrocephalus

Hydrocephalus is a pathological condition of the brain, which is most commonly observed with infants, but can also be acquired at a later age. It is characterised by an abnormal accumulation of cerebrospinal fluid (CSF) inside the brain ventricules, accompanied by a considerable deformation of the surrounding brain tissue. Building on existing models, this work puts forward a mechanical model for the disease, based on quasi-steady, linearly poroelastic mechanisms. The model incorporates a strain dependence of the brain's permeability and also takes into account possible CSF absorption or production in the brain parenchyma, which leads to novel ideas about the development of different hydrocephalus types. The mechanisms are examined in three different geometries: a spherical symmetric, one-dimensional geometry, a cylindrically symmetric, two-dimensional geometry, and a three-dimensional geometry without any symmetry. Analytic as well as numerical methods are used to solve the model equations, yielding qualitative and quantitative predictions for the development and treatment of hydrocephalus. The thesis concludes with some notes about the use of finite deformation elasticity in poroelastic hydrocephalus models.
Freedom and its distribution

This dissertation develops a new theory of specific and overall socio-political freedom and discusses its role in normative political theory. The aim is to dissolve some of the conceptual confusions that have often beset previous discussions and to develop a theoretical framework with which to approach questions of public policy.
This dissertation consists of three parts.
In the first part, I develop a new account that specifies under which conditions a person is specifically free and when she is unfree to do something. It is shown that republican accounts of freedom are unsatisfactory and that a trivalent liberal account that equates freedom with ability is most plausible. A new analysis of unfreedom is defended according to which a person is made unfree (as opposed to merely unable) to do something only if she would have this freedom in a better and available distribution that another person could have foreseeably brought about.
In the second part, I discuss how to move from an account of specific freedom and unfreedom to a measure of overall freedom. I develop a new and simple aggregation function and argue that the measurement of overall freedom requires both quantitative and evaluative factors.
In the third part, I then discuss what role freedom should play in a theory of distributive justice. Instead of freedom deontologically constraining the reach of distributive justice, freedom should be one of its distribuenda. I will first discuss how best to distribute freedom across a person’s lifetime and how this impacts on discussions of paternalistic policies. It will then be shown that we ought not simply maximise freedom between persons, not aim to give everyone enough freedom nor aim at equal freedom. Instead, distributing freedom requires a principle that combines maximisation with a concern for fairness.

Keywords: measurement
Freedom
liberty
republicanism
liberalism
justice
Advisor: Miller, D
Broome, J
A siRNA screen to identify molecular determinants of tumour radiosensitivity

The effectiveness of radiotherapy treatment could be significantly improved if tumour cells could be rendered more sensitive to ionising radiation without altering the sensitivity of normal tissues. However, many of the key mechanisms that determine intrinsic tumour radiosensitivity are largely unknown. This thesis is concerned with the identification of novel determinants of tumour radiosensitivity. A siRNA screen of 200 genes involved in DNA damage repair was conducted using γH2AX foci post-irradiation as a marker of cell damage. This screen identified POLQ as a potential tumour-specific contributor to radioresistance. Subsequent investigations demonstrated that POLQ knockdown resulted in radiosensitisation of a panel of tumour cell lines, whilst having little or no effect on normal tissue cell lines.
It was subsequently shown that POLQ depletion rendered tumour cells significantly more sensitive to several classes of cytotoxic agents. Following exposure to etoposide, it was found that tumour cells depleted of POLQ had reduced RAD51 foci formation, suggesting that POLQ is involved in homologous recombination. A homologous recombination assay was used to confirm that POLQ depletion does indeed result in reduced homologous recombination efficiency.
These findings led to the investigation of the clinical significance of tumour overexpression of POLQ. The clinical outcomes of patients with early breast cancer were correlated with tumour expression levels of POLQ. It was found that POLQ overexpression was correlated with ER negative disease and high tumour grade, both of which are associated with poor clinical outcomes. POLQ overexpression was associated with extremely poor relapse free survival rates, independently of any other clinical or pathological feature. The mechanism that causes this adverse outcome may in part arise from resistance to adjuvant chemotherapy and radiotherapy treatment. These findings, combined with the limited normal tissue expression of POLQ, make it an appealing target for possible clinical exploitation.

Keywords: DNA polymerase theta
siRNA screen
POLQ
tumour radiosensitivity
Advisor: McKenna, G
OER provision practices in context: a socio-technical study on OpenCourseWare initiatives in Spain

Based on the idea of broadening access to learning opportunities for all by means of new Information and Communication Technologies (ICTs), the Open Educational Resources (OER) movement has gained ground during the first years of the 21st Century while capturing the imagination of educators, university leaders, policy-makers and opinion leaders all over the globe. Drawing on socio-technical theories and adopting a case study research design, which involved the analysis of both qualitative and quantitative data, this thesis addresses the manifold tensions and paradoxes that may emerge out of the interplay between a highly predefined model of OER provision and the everyday realities and institutional contexts of different higher education settings. In particular, it focuses on the process of implementation by Spanish universities of OpenCourseWare (OCW) initiatives, a widely adopted model of OER provision that was originally devised at the Massachusetts Institute of Technology. By examining the enactment of technology as a situated phenomenon, this study sheds light on the roles that OCW initiatives play in relation to the strategic orientation of universities and how the actual involvement of scholars in the creation of this type of materials is often curbed by some entrenched institutional arrangements and prevailing academic cultures. The findings of this thesis have theoretical as well as practical implications, which suggest that the replication of models of OER provision outside the specific settings in which they were originally devised is a rather problematic endeavour. More generally, it supports the idea that the implementation of ICTs must be always accompanied by social structures that are mindful and respectful of local specificities and institutional arrangements. Another key conclusion is that, if universities are genuinely committed to broadening access to higher education opportunities and supporting participation in life-long learning by means of ICTs, it is crucial to understand the ways and extent to which OER initiatives can actually contribute to achieving such goals.

Keywords: Open Educational Resources
Higher Education
OpenCourseWare
Social Informatics
Advisor: Eynon, R
Meyer, E
New main group and rare earth ring-opening polymerisation catalysts

This Thesis describes the synthesis and characterisation of new Group 2, Group 3 and lanthanide amide, alkyl, halide, borohydride and alkoxide complexes, and their uses as catalysts for the living ROP and immortal ring-opening polymerisation (iROP) of rac-, L, D- and meso-lactide.
Chapter One introduces cyclic esters and possible mechanistic pathways leading to polyesters by ROP. Living and immortal ROP, including their kinetic characteristics are discussed. An overview of ROP from an industrial perspective and a literature review are also given.
Chapter Two describes the synthesis and characterisation of a new series of magnesium and zinc amide, alkyl, halide, borohydride and alkoxide complexes supported by a carbazole-bis(dimethyloxazoline) ligand. Their activities towards the ROP of rac-, L- and meso-lactide are presented. Detailed mechanistic studies using spectroscopic techniques are discussed and a new mechanism is proposed.
Chapter Three describes the synthesis and characterisation of a new series of calcium, strontium, yttrium, lanthanum and samarium amide, alkyl, halide, borohydride and alkoxide complexes supported by a carbazole-bis(dimethyloxazoline) ligand. Their activities towards the ROP of rac-, L- and meso-lactide are presented. Detailed mechanistic studies using spectroscopic techniques are discussed.
Chapter Four describes the synthesis and characterisation of a new series of magnesium, calcium, strontium, yttrium, lanthanum and samarium amide, halide and borohydride complexes supported by a chiral carbazole-bis(isopropyloxazoline) ligand. Their activities towards the ROP of rac-, L-, D- and meso-lactide are presented.
Chapter Five contains experimental details and characterising data for the new complexes reported in this Thesis.
CD Appendix contains .CIF files for all the new crystallographically-characterised complexes.

Keywords: magnesium
rop
lactide
ring-opening polymerisation
Advisor: Mountford, P
Modelling and comparing protein interaction networks using subgraph counts

The astonishing progress of molecular biology, engineering and computer science has resulted in mature technologies capable of examining multiple cellular components at a genome-wide scale. Protein-protein interactions are one example of such growing data. These data are often organised as networks with proteins as nodes and interactions as edges. Albeit still incomplete, there is now a substantial amount of data available and there is a need for biologically meaningful methods to analyse and interpret these interactions.
In this thesis we focus on how to compare protein interaction networks (PINs) and on the rela- tionship between network architecture and the biological characteristics of proteins. The underlying theme throughout the dissertation is the use of small subgraphs – small interaction patterns between 2-5 proteins.
We start by examining two popular scores that are used to compare PINs and network models. When comparing networks of the same model type we find that the typical scores are highly unstable and depend on the number of nodes and edges in the networks. This is unsatisfactory and we propose a method based on non-parametric statistics to make more meaningful comparisons. We also employ principal component analysis to judge model fit according to subgraph counts. From these analyses we show that no current model fits to the PINs; this may well reflect our lack of knowledge on the evolution of protein interactions. Thus, we use explanatory variables such as protein age and protein structural class to find patterns in the interactions and subgraphs we observe. We discover that the yeast PIN is highly heterogeneous and therefore no single model is likely to fit the network. Instead, we focus on ego-networks containing an initial protein plus its interacting partners and their interaction partners. In the final chapter we propose a new, alignment-free method for network comparison based on such ego-networks. The method compares subgraph counts in neighbourhoods within PINs in an averaging, many-to-many fashion. It clusters networks of the same model type and is able to successfully reconstruct species phylogenies solely based on PIN data providing exciting new directions for future research.

Keywords: network analyses
subgraph count statistics
protein age and degree
threshold behaviour in networks
k-words statistics
alignment-free network comparison
protein interaction networks
ego-networks
Advisor: Deane, C
Reinert, G
Light, photophobia and headache:  an investigation of visually-induced migraine

Exacerbation of headache by light is a major symptom in migraine. A recent study unraveled the non-image forming (NIF) visual pathway to be a key component underlying photophobia in migraine. Several lines of evidence also indicate that an altered cortical excitability may render migraineurs more susceptible to attacks, although it is unclear whether the cortex is more or less excitable. Accordingly, this thesis investigated the link between migraine, visual systems and brain responsiveness using three complementary approaches. To begin with, I assessed the response of the NIF visual system to light of different wavelengths in healthy subjects. My results provided the first neuroimaging evidence that the suprachiasmatic nucleus (SCN) of the NIF system displays a sustained response to blue light but not to other wavelengths. This highlights the unique property of the SCN for mediating the circadian cycle, which some investigators have suggested drive the periodicity of migraine attacks.
Next, I examined the interictal cortical sensitivity to light and visual stimuli in migraine. The fMRI results revealed a hypo-excitable response to diffuse illumination in migraineurs compared to healthy controls. The response, however, did not differ when subjects were exposed to a more aversive flickering checkerboard stimulus. Furthermore, the phenomenon appeared to be magnified in a group harboring the TRESK variant, who may be considered an extreme form of the migraine spectrum. This suggests that the initial cortical hypo- excitability may serve as a protective mechanism against further attacks. Surprisingly, I found no disturbance of glutamate, GABA and NAA in the visual cortex of interictal migraine subjects, arguing against the notion that these metabolites may mediate the protective mechanism or predispose the brain to migraine attacks. Finally, I optimized the PCR and prepared a DNA pool of 741 migraineurs and 416 controls for sequencing four candidate genes including TRESK and OPN4. Variants identified in these genes that associate with migraine may provide mechanistic insights into how genetic backgrounds alters neuronal and brain responsiveness and how this in turn increases migraine liability.
Taken together, my studies reveal cortical hypo-excitability in patients with migraine between attacks and established a foundation for future studies including the NIF visual system in migraine. Longitudinal studies will also help unravel compensatory from primary changes in the migraine brain.

Keywords: trigger
DNA sequencing
magnetic resonance spectroscopy
suprachiasmatic nucleus
DNA pooling
photophobia
genetics
visual system
headache
light
visual cortex
magnetic resonance imaging
polymerase chain reaction
circadian cycle
cortical excitability
migraine
Advisor: Bridge, H
Cader, MZ
Verborum ordo – ordo verborum: the placement of the dependent genitive in Classical Latin

In this thesis I examine the placement of the dependent genitive relative to its head noun in Classical Latin prose. The corpus is drawn from the works of four first-century B.C. authors: Caesar, Cicero, Sallust and Varro. The thesis itself is split into two main sections, a qualitative analysis and a quantitative analysis.
The qualitative analysis discusses a number of factors that may influence genitive position, drawn from literature on the subject as well as my pilot studies. These factors are information structure, the genitive’s grammatical function, discontinuity, lexical category, animacy, prepositions governing the head noun, reported speech, idioms, lexical items, and grammatical number of the genitive. This analysis examines individual instances of genitive position in context, providing examples and counter-examples of the ordering patterns found with each potential factor.
The qualitative analysis suggests that a number of these factors have an effect on genitive position, particularly information structure. These results are tested by the quantitative analysis. By performing a multivariate statistical analysis using the programme GoldVarb, the combined effects of multiple factors are determined and the statistically significant factors ranked in order of importance and strength of effect. The statistics show that information structure is the most important of the factors. Other significant influences are the presence of prepositions, the function of the genitive and its lexical category.
By combining the two types of analysis, qualitative and quantitative, this thesis shows in detail how the factors combine to influence word order, which of them are independent, which interact, which are important and which have little to no effect at all, resulting in a better understanding of the data and the way that the contextual factors work together to produce the variant orders of the dependent genitive.

Keywords: Latin
genitive
quantitative analysis
word order
Advisor: Willi, A
Probert, P