VictorJuiz/thesis huggingface dataset:
Ligand binding and signalling by the T cell antigen receptor and CD28

Successful T cell activation depends on the recognition of antigenic peptides in the context of a Major Histocompatibility Complex molecule (pMHC) by the T cell antigen receptor (TCR), together with additional signals from co-stimulatory receptors such as CD28. Despite their importance, a thorough understanding of how TCR-pMHC binding properties relate to T cell functional responses remains unclear. In addition, there are no consensuses to the exact mechanism leading to CD28 receptor triggering.
Activation of CD28 is dependent on the phosphorylation of key tyrosine residues within its cytoplasmic domain by Src family kinases. Just like the TCRs, CD28 receptors are susceptible to perturbations of the local kinase: phosphatase ratio. The K-S model postulates that upon ligand engagement, large RPTPs such as CD45 are segregated from the area of close contact, resulting in increased relative kinase concentration and CD28 receptor triggering. This hypothesis was tested in chapter 3, where elongated forms of CD80 were examined for their ability to costimulate primary T cells. CD28 costimulation was indeed diminished and there was reduced CD45 segregation from the elongated CD80 molecules. Additionally, CD28 habouring key Y170F tyrosine mutations were less susceptible to CD28 signal abrogation by elongated CD80 molecules. Interestingly, elongated CD80 molecules remained much less effective in mediating costimulation even when pMHC molecules were also elongated, suggesting that TCR-pMHC and CD28-CD80 size matching is not critical for costimulation.
Despite the well-documented MHC-restriction requirement for TCR recognition, the relative energetic contributions of peptide versus MHC in TCR-pMHC interactions remain elusive. To address this question, the energetic footprints of four TCRs (1G4, JM22, A6 and G10) to HLA-A2 were determined via systematic alanine scanning mutagenesis on the HLA-A2 heavy chain in chapter 4. By targeting exclusive TCR contacting residues on the MHC, we conservatively estimate the contribution of MHCs for the four TCRs to range from 15% to over 70%.
Several models have been formulated in an attempt to relate TCR-pMHC binding properties to T cell activation. Validity of the models was tested in chapter 5 using a supra-physiological TCR. By mutating key residues within the cognate pMHC, we generated a panel of TCR-pMHC with affinities that varies up to 105-fold. These reagents were used to stimulate Jurkat and primary T cells transduced with the supra-physiological TCR. Results in the Jurkat T cell system demonstrated the presence of an optimal off-rate (koff) for TCR-pMHC interaction at low concentrations of pMHC concentration. The results argue against affinity models and the basic kinetic proofreading model for T cell activation.

Keywords: CD28
CD80
T Cell Receptor
Kinetic-Segregation Model
Advisor: van der Merwe, A
Quantum multiplicative hypertoric varieties and localization

In this thesis, we consider q-deformations of multiplicative Hypertoric varieties, where q∈&Kopf;x for &Kopf; an algebraically closed field of characteristic 0. We construct an algebra 𝒟q of q-difference operators as a Heisenberg double in a braided monoidal category. We then focus on the case where q is specialized to a root of unity. In this setting, we use 𝒟q to construct an Azumaya algebra on an l-twist of the multiplicative Hypertoric variety, before showing that this algebra splits over the fibers of both the moment and resolution maps. Finally, we sketch a derived localization theorem for these Azumaya algebras.

Keywords: Azumaya algebras
Representation Theory
Braided Tensor Categories
Quantum Algebra
Advisor: Kremnitzer, Y
Aqueducts and water supply  in the towns of post-Roman Spain (AD 400-1000)

Despite the recent interest in late antique archaeology and the increasing number of publications on the transformations of towns (both in Spain and in the Roman world as a whole), the concern shown towards aqueducts has been almost non-existent. Some studies have focused on exceptional local examples, such as Rome or Constantinople, but there have been neither general nor regional syntheses of the chronology of the abandonment of aqueducts on a broad regional scale. This thesis consequently fills this gap in our knowledge by offering an all-encompassing study and compilation of the available material and written evidence for aqueducts in Spain in Late Antiquity, it looks at aqueducts in the late Roman period, and how they evolve through the Visigothic and the Umayyad centuries.
For this purpose, each aqueduct in the Iberian Peninsula is assessed according to the available information and studied in its wider urban context. By the end of the thesis it is possible to put forward some clear results on the degree of continuity of aqueducts in Spain. The information is used to analyse how the presence or absence of aqueducts affected the development of urban settlement and housing patterns away from a traditional Roman context. Aqueducts had not been at first an essential part of urban life, yet by Late Antiquity they had become so intimately related to it that the end of aqueduct supply modified urban landscapes. Finally, I present various scenarios to explain why aqueducts ceased to function and how the various elite groups of the period (urban aristocrats, the Church, the Visigothic monarchy and the Umayyads) tried to take over the control of the aqueducts, as they were not only extremely useful functional monuments, but also reminders and legitimising links to the Roman past.

Keywords: Visigothic Spain
Roman urbanism
Roman Spain
water supply
Umayyad Spain
aqueducts
Advisor: Ward-Perkins, B
Roman constructions of fortuna

This thesis investigates the Roman idea of fortuna, by examining its representation in different media (coins, cults, philosophy, and literature) and the thought worlds which these media inhabited. Drawing chiefly on evidence from the late Republic and the first two centuries of the Empire, I examine the interactions between the meanings of fortuna and the contexts in which they occur, showing how fortuna was used to construct understandings of broader social processes. Chapter 1 charts how various groups and individuals appropriated the religious character of fortuna into discourses of power to promote their interests, from the first archaic cults through to Imperial fortunae. By propitiating fortuna, the founders and worshippers of these cults attempted to ‘tame’ fortuna by representing themselves or the groups to which they belonged as particularly favoured by this deity. Chapter 2 examines how literary authors used fortuna to talk about ideas of social status, luck, chance, and fate. How these authors chose to describe fortuna, or which powers they chose to ascribe to her, were choices frequently determined by the text’s relationship to the structures of Roman power. Chapter 3 examines the iconography of fortuna on Imperial coins, for which I used a statistical methodology to quantify her numismatic representation. This sets our understanding of the interconnections between numismatic iconography and cultural and political history on a firmer basis and allows us to analyse more precisely how fortuna was imagined in imperial ideology. I look at the periods in which fortuna was most often deployed and when her iconography and legends underwent the greatest changes, discussing the political and cultural contexts that motivated these uses. Chapter 4 addresses philosophical conceptions of fortuna. I look at what was peculiarly Roman about how Roman Stoics and Epicureans figured fortuna in their physics and ethics, focusing especially on the philosophical and cultural implications of their concern with fortuna.

Keywords: roman
coins
chance
cult
luck
fortuna
Advisor: Morgan, T
Motion correction and parameter estimation in DCE-MRI sequences: application to colorectal cancer

Cancer is one of the leading causes of premature deaths across the world today, and there is an urgent need for imaging techniques that can help in early diagnosis and treatment planning for cancer patients. In the last four decades, magnetic resonance imaging (MRI) has emerged as one of the leading modalities for non-invasive imaging of tumours. By using dynamic contrast-enhanced magnetic resonance imaging (DCEMRI), this modality can be used to acquire information about perfusion and vascularity of tumours, which can help in predicting response to treatment.
There are many factors that complicate the analysis of DCE-MRI data, and make clinical predictions based on it unreliable. During data acquisition, there are many sources of uncertainties and errors, especially patient motion, which result in the same image position being representative of many different anatomical locations across time. Apart from motion, there are also other inherent uncertainties and noise associated with the measurement of DCE-MRI parameters, which contribute to the model-fitting error observed when trying to apply pharmacokinetic (PK) models to the data.
In this thesis, a probabilistic, model-based registration and parameter estimation (MoRPE) framework for motion correction and PK-parameter estimation in DCE-MRI sequences is presented. The MoRPE framework is first compared with conventional motion correction methods on simulated data, and then applied to data from a clinical trial involving twenty colorectal cancer patients. On clinical data, the ability of MoRPE to discriminate between responders and non-responders to combined chemoand radiotherapy is tested, and found to be superior to other methods. The effect of incorporating different arterial input functions within MoRPE is also assessed.
Following this, a quantitative analysis of the uncertainties associated with the different PK parameters is performed using a variational Bayes mathematical framework. This analysis provides a quantitative estimate of the extent to which motion correction affects the uncertainties associated with different parameters. Finally, the importance of estimating spatial heterogeneity of PK parameters within tumours is assessed. The efficacy of different measures of spatial heterogeneity, in predicting response to therapy based on the pre-therapy scan alone are compared, and the prognostic value of a new derived PK parameter the 'acceleration constant' is investigated. The integration of uncertainty estimates of different DCE-MRI parameters into the calculation of their heterogeneity measures is also shown to improve the prediction of response to therapy.

Advisor: Schnabel, J
Jenkinson, M
Brady, M
The processing of conversion in English : morphological complexity and underspecification

This thesis investigates a subset of the lexical items which appear to be involved in the phenomenon of conversion in English. In its most canonical form, conversion involves pairs or sets of word forms which share both their phonological (and orthographic) form as well as some element of meaning, but which seem to belong to di↵erent word classes. In this study, the focus is on the relationships (or lack thereof) between monosyllabic verbal and nominal forms in conversion pairs.
The investigation takes as a starting point the patterns of linguistic behaviour within and across these pairs. The situation which is revealed is complex, but not unsystematic. Instead, it is shown that in many cases, the relationship between the nominal and verbal forms is clearly asymmetrical. In contrast to these clearer patterns, however, there are also a number of cases wherein the relationship appears to be more symmetrical in nature. In view of the complexity of the situation, the question of how to best model the linguistic behaviour of such forms has been a subject of some debate in the literature. A variety of theoretical explanations for these relationships have been proposed, though none has managed to account for the wide range of data. This study therefore suggests a mixed model, in which asymmetrically-related forms are involved in a derivational morphological process, while symmetrical forms represent inflected forms of a single lexeme which lacks a specification of word class.
However, given the fertile – and in no way settled – research background, the primary contribution of this study is an experimental exploration of how these forms and the relationships between them might be synchronically represented in the mental grammar of current speakers. To that end, three behavioural experiments are conducted with a view to uncovering how di↵erent types of conversion items are processed, and how information about their processing might inform our theoretical understanding.
The results of these experiments suggest that the processing of these forms is indeed in line with the patterns of symmetry and asymmetry found in their linguistic behaviour, and suggests that some conversion pairs may be involved in a derivational process, while others may not be pairs at all but rather a single, underspecified lexical entry. However, in addition to the results concerning the forms which display clearer patterns of behaviour, it is suggested that the patterns across the phenomenon of conversion as a whole may best be understood as a continuum, rather than all suggesting a single underlying pattern of mental representation.

Keywords: zero derivation
morphology
linguistics
psycholinguistics
word recognition
English language
Advisor: Lahiri, A
Aspects of non-adiabatic molecular collision theory

This thesis is concerned with non-adiabatic effects in alkali / halogen collision systems. After a general survey of non-adiabatic molecular collision theory, and its application to such systems, calculations have been performed relating to three topics :
(i) Vibrational energy distributions resulting from electron transfer collisions between alkali metal atoms and halogen molecules are often treated by the multi-curve crossing approach to the classical path approximation, in the form of two approximations, one valid at high collision energy, the other at low energy; the performance of these is evaluated over a wide energy range by comparison with the results from an "exact" multi-curve crossing approach.
(ii) Classical trajectory calculations for reactive alkali / halogen collisions are performed using a simple ionic potential energy surface, developed earlier to model the weakening of the halogen bond by the metal ion immediately after the electron transfer. Detailed comparison is made between the results and those from experiment; good agreement is obtained for K/I2 and comparison of the results for K/I2 and Cs/I2 indicates that this effect is not merely dependent on the charge of the ion.
(iii) The population of ground and excited sodium atoms resulting from Na/I charge neutralisation collisions is investigated using the multi-curve crossing approach. Although it has been suggested that population inversions may be produced by such a process, it is shown that this is only possible at extremely high collision energies.

Advisor: Child, M
Functional analysis of the ALS/FTD associated gene FUS using a novel in vitro genomic DNA expression system

Aggregations of fused in sarcoma (FUS), a multifunctional RNA processing protein, define a pathological subtype of both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), whilst mutations in the FUS gene are causative for ALS. To model the impact of FUS mutations, expression vectors containing the entire genomic sequence of FUS, up and downstream regions, and native promoter sequences have been generated. The constructs have been tagged with an mCherry fluorescent tag, and three separate pathological mutations (R244C, R521C, and P525L) have been separately inserted. Transgenic mice have been generated using the WT and P525L FUS vectors to provide a highly physiological model of FUS in disease.
Within transfected HEK293 cells, insertion of the P525L and R521C FUS mutations leads to relocalisation of FUS from the nucleus to the cytoplasm. R521C and P525L mutant FUS incorporates into cytoplasmic aggregations of untranslated mRNA and RNA binding proteins known as stress granules. The strong relocalisation seen with P525L-FUS is associated with a gain of cytotoxicity. Reversal of this cytoplasmic relocalisation by demethylation of FUS rescues this cytotoxicity, suggesting a toxic gain of cytoplasmic function in the majority of FUS mutations. By contrast, insertion of the R244C mutation leads to neither relocalisation, stress granule association, nor cytotoxicity. Notably the R244C mutation, located away from the nuclear localization domain in which the majority of FUS mutations are found, leads to the presence of smaller FUS fragments in western blot analyses. These fragments appear not to be due to splicing defects in FUS but rather are due to post-translational modifications or aberrant protein cleavage. These data suggest an alternative pathway for FUS toxicity based upon a nuclear loss of function.

Keywords: frontotemporal dementia
bacterial artificial chromosome
recombineering
FUS
amyotrophic lateral sclerosis
Advisor: Wade-Martins, R
Ansorge, O
"Foreign talent": desire and Singapore's China scholars

This thesis addresses the “foreign talent” situation in Singapore with an ethnographic account of the lived experiences of immigrant PRC students on scholarships, or “PRC scholars.” For some two decades, the Singapore government has annually recruited middle school students from China in their hundreds, selecting them through tests and interviews, granting them full scholarships at either pre-undergraduate or undergraduate level, and, very often, “bonding” them to work subsequently in Singapore for a number of years. Wooed and appropriated in such a way as prized potential human capital, PRC scholars exemplify the Singapore state’s desire for “foreign talent.”
In the first decade of the twenty-first century, as the influx of all manners of “foreign talent” into the small city-state gathered pace, local sentiments and discourses of resentment arose. The local-vs-“foreign talent” problem became a serious strain on a city and people proud of their cosmopolitanism. This thesis analyzes the “foreign talent” situation through the ethnographic “macro-trope” of desire. It argues that “foreign talent” is a site of convergence and divergence, collusion and collision, accommodation and contestation, fulfillment and failure of various individual, sociocultural, and political desires and longings.
Through the lens of desire, and its psychoanalytic undertones and insights, this thesis looks ethnographically into the PRC scholars’ “foreign talent” journeys in nuanced ways. Based on ethnographic fieldworks carried out in a Chinese middle school and a Singaporean university, the thesis shows how Chinese students are constituted as specific subjects of desire, and how they subsequently develop certain perceptions, attitudes, and stereotypes about the local “other” as well as about themselves after arriving in Singapore as “foreign talent.” Infused with multifarious desires, the PRC scholars’ experiences are often characterized by angst and dissatisfaction; yet it is also argued that generative subjective transformations take place precisely amidst these dynamics and pragmatics of desiring.
Ultimately, this thesis seeks to make possible an ethical re-imagination of the “foreign talent” situation in Singapore from the perspective of desire; to provide an account of the so far little-studied Chinese migrant students in the context of Singapore; and to speak more broadly to the cultural and subjective dimensions of human experiences in the context of educational mobility, identity politics, and globalization.

Keywords: Singapore
desire
student migration
China
foreign talent
identity
imaginary
Advisor: Mills, D
Obligations erga omnes as multilateral obligations in international law

So-called obligations erga omnes, owed to the international community as a whole, including all States, now form part of positive international law. These obligations protect some of the most basic values of present-day international relations. Examples include the obligations not to commit genocide or torture, to uphold the most basic human rights, to respect the self-determination of peoples, and so on.
However, there is little agreement as to what these obligations imply, how they have come about, and how to identify them. In the literature, at least, there is widespread agreement that obligations erga omnes are different in essence and in nature from obligations owed by one State to another State, so-called obligations inter partes. In turn, this —alleged— radical conceptual break severs obligations erga omnes from a wealth of norms that exist in present-day, general international law, but whose origins lie farther back in time.
This thesis attempts to reconcile obligations erga omnes with obligations arising in classic, general international law. It explores what it means to be owed an obligation and how it came to pass that most obligations were owed inter partes. The particular way in which sovereignty came to be conceived and the furtherance of sovereignty, at the expense of other values, forms the pattern that gave rise to obligations inter partes. But even at that time, exceptions to this pattern existed which brought about obligations analogous to those owed erga omnes today. Relevant state practice will be analysed.
If obligations erga omnes could have been created in classic international law, it is unjustified to maintain that obligations erga omnes represent so radical a break with the past. Obligations erga omnes are aggregates of bilateral, primary obligations. From this perspective, it is possible to identify these obligations, their consequences, and to discern their origins.

Keywords: State Responsibility
Wesley Newcomb Hohfeld
Jus Cogens
Peremptory Norms
Obligations Erga Omnes
Bilateralism
Multilateralism
Obligations Erga Omnes Partes
Public International Law
Sovereignty
Advisor: Lowe, A
Zinc transport across cell membranes

The mechanism of zinc transport has been investigated in red cells from normal humans, lampreys, sheep, sickle cell anaemia patients and in bovine chondrocytes. In all the cell types investigated except for lamprey red cells, zinc transport is mainly via the anion exchanger (band 3), which accounts for over 80% of total measured zinc uptake, when the medium contains no zinc binding ligands. Zinc uptake via the band 3 pathway is stimulated by the presence of bicarbonate (5mM) and inhibited by treatment with DIDS or SITS (10andmu;M). This anion-dependent mechanism represents the major route for zinc transport across the cell membrane in vitro. The presence of the zinc binding ligands albumin and histidine in the media greatly reduced the uptake of zinc via the anion exchanger due to the decrease in free zinc concentration. Histidine, in addition to its chelating effect, shows a specific facilitating effect on zinc uptake in all the cell types. This stimulating effect of histidine was stereospecific (significantly different between L-, and D-histidine) in red cells from normal humans and sickle cell anaemia patients, but not in red cells from lampreys, sheep, and bovine chondrocytes. Evidence from all cell types strongly suggests that the stimulus is due to the cotransport of zinc and histidine via the histidine transport systems, which are system L, and y* in normal human and sickle red cells; a non-stereospecific L-like system in lamprey red cells and bovine chondrocytes; system C or unknown specific histidine transporter in sheep red cells. The amino acid linked zinc uptake may represent a physiologically significant mechanism for zinc transport into cells.

Advisor: Ellory, J
Ellory, C