VictorJuiz/thesis huggingface dataset:
Synthesis of deuterated phosphatidylinositol phosphates

Phosphatidylinositol phosphates (PtdInsPn) are intracellular signalling molecules that are important in many key biological processes, in particular Ca2+ signalling pathways. Dysfunction of these processes has been implicated in numerous diseases including diabetes and many cancers. Some aspects of PtdInsPn signalling have been heavily investigated; PTEN, PKC/Akt, PtdIns3K and PtdIns4K are all important therapeutic targets that have seen much attention in industrial endeavours. Inositol-based probes and tool compounds for these targets typically incorporate a fluorescent tag or photo-crosslinking group, usually at the lipid tails. It is increasingly apparent that the nature of the lipid chains plays a key role in determining the sub-cellular localisation of the PtdInsPn and hence modification of the lipids is potentially detrimental to the biological function of the tool compounds. An additional challenge in the development of inositol-based tools compounds is the difficult and lengthy syntheses that are employed to obtain the target compounds. To address this, we have developed a novel asymmetric route that allows rapid synthesis of PtdIns and PtdIns(4,5)P2. This route has been designed to allow incorporation of multiple deuterium atoms onto the myo-inositol ring (C-perdeuterated). To achieve this, we began with the aromatic compound quinol and built up the myo-inositol ring piecewise, allowing for deuterium incorporation. This methodology utilised a Pd-catalysed dynamic kinetic resolution on a conduritol B derivative to form optically-pure myo-inositol derivatives in high e.e. (&GT;99%) toward the synthesis of D6-PtdIns(4,5)P2. The incorporation of deuterium into these compounds should be minimally disruptive to their biological activity, while the difference in molecular mass between the endogenous and tool compounds enables their use in a range of biological assays. In addition, the incorporation of the deuterium onto the myo-inositol ring will allow for the detection of downstream effects relating to the myo-inositol ring post-hydrolysis of PtdIns(4,5)P2 to be observed, which is currently not possible with other probes.

Keywords: Deuterium Labelling
Phospholipids
Advisor: Conway, S
Sanganee, H
Discourses of identity in contemporary East Asian Music: Chen Yi, Unsuk Chin and Karen Tanaka

Discourses of identity in East Asian new music are often limited to tracing ethnographic materials or conceptual influences from the composers' cultures of origin. Existing analytical approaches tend to look for the musical features that are emblematic of the cultures in question, and to map relationships between the contemporary and traditional musical aspects. Composers who resist employing their native traditions as musical tropes, however, problematise discussions of their identity and are consequently overlooked in studies of identity politics.
This thesis therefore examines questions of identity through a focus on three contemporary composers who, in diverse ways, challenge and complicate essentialising expressions of East Asian identity: Chinese composer Chen Yi (1953-), Korean composer Unsuk Chin (1961-) and Japanese composer Karen Tanaka (1961-). All of them came to Europe or the United States to hone their skills in the mid-1980s and have since developed their musical careers in the Western world. They have been selected for examination due to their radically different reactions to the East-meets-West question; namely, Chen Yi's embracing of cultural fusion; Unsuk Chin's reaction against cultural fusion; and Karen Tanaka’s lack of interest in cultural fusion. To demonstrate this variation, this thesis analyses the works of these composers, their personal viewpoints and the critical reception of their works. Beyond discussing conventional notions of identity and difference, this dissertation explores the ways in which these composers complicate their perceived dissimilarity by embracing a 'universal music' ideal.
Chapter One explores Chen Yi's musical identity as defined by her idea of 'cultural translation' and her musical goal of enhancing intercultural communication; where Chen Yi affirms cultural fusion, her work contributes to the traditional idea of 'East-meets-West'. Chapter Two examines an alternative approach in the case of Unsuk Chin, who consciously avoids the practice of cultural hybridity by locating her work squarely within the Western tradition. Chapters Three examines the works of two Japanese composers – Toru Takemitsu and Karen Tanaka – who focus their attention not on cultural fusion but on natural themes. The first section of Chapter Three presents Toru Takemitsu's Japanese-based philosophy of the co-creative bond between nature and humanity, which serves as a foil for Karen Tanaka's evolving, observational relationship with the natural world. To conclude, I compare the identity choices and the musical representations in the three case studies of Chen Yi, Unsuk Chin and Karen Tanaka. By gaining a better understanding of each composer’s music, this thesis aims to provide a more expansive discourse of identity formation in contemporary East Asian art music, and to offer a critical rethinking of what counts as an 'Asian perspective' in this field.

Keywords: ecomusicology
cross-cultural confluence
contemporary opera
musical identity
Advisor: Aspden, S
Model presswomen: ‘high-minded’ female journalism in the mid-Victorian era

This study contributes to current critical discussions about the figure of the Victorian woman journalist. Most previous scholarship on nineteenth-century female journalism has focused either on women's anonymous writings or on their contributions to conventionally feminine genres like serial fiction and prose articles on domesticity and fashion. Although women's campaigning journalism has attracted some attention, especially from historians of feminism, its role in the professionalization of women writers has gone largely unexamined. Consequently, it has been assumed that female journalists did not write on social and political issues, unless they wrote anonymously or as reformers with little interest in developing careers as presswomen. This thesis radically revises this view by showing the mid-century rise of female journalists who wrote on serious social and political topics and earned national and international repute. They broke the codes of anonymity in a number of ways, including signing articles in their own names and developing distinctly female personae. They presented themselves as model middle-class professional authors: knowledgeable, financially independent and vocationally committed. They proved, by example, women's fitness for conventionally masculine lines of journalism. By examining their careers in the periodical press, my thesis offers the first in-depth analysis of 'high-minded' female journalism in Victorian England.
Beginning with the 1850s, the thesis is organised around certain key developments in the periodical press, such as the debates about professional authorship, discussions of the plight of single women and the nature of female work, and the advent of signed publication. It examines the rise of prestigious presswork by women through the study of three distinct, yet overlapping models of the female professional journalist: the feminist journalist, the mainstream reform journalist, and the foreign correspondent. It then discusses the representation of women's high-minded journalism in the domain of fiction. The study ends in the 1880s, noting how these mid-Victorian models of women's presswork influenced the discussion and practice of female professional journalism in the 1890s.

Keywords: Nineteenth-century literature
Victorian journalism
Victorian feminism
Victorian women's professional authorship
Advisor: Shuttleworth, S
The catechumenate in late antique Africa: Augustine of Hippo, his contemporaries and early reception (ca. 360-530 AD)

In the late antique West, every individual becoming Christian first entered the community as a catechumen (catechumenus). Many spent several years in this status called the catechumenate, only ending with baptism and the acquisition of the membership of the faithful (fideles). This thesis considers the catechumenate not only as an initiation but as a peculiar way of being Christian. It demonstrates the fluid nature of Christian membership and shows how clerics strove to develop their authority over catechumens to build a cohesive community in a context of rivalry between churches and polemical controversies. The catechumenate both enabled converts to adhere progressively to the community and constituted an opportunity for clerics to set a standard path of progression, enforce discipline and define what it meant to be a Christian. This thesis opens up new avenues to study the process of Christianisation by stressing the continuous significance of the catechumenate for the formation of Christian communities in late antiquity. After an introduction, Chapter Two focuses on Augustine’s recollections of his time as a catechumen. Chapter Three looks at Augustine to investigate more broadly the practices of catechumeni, shedding light on the pervasive polemical context in which they are discussed. Chapter Four provides case studies on the cross put on the forehead to manifest Christian membership and the treatise De fide et operibus, exploring how Augustine aimed at shaping practices and ideas. Chapter Five investigates contemporary evidence: first an African canon regulating the ritual participation of catechumeni, then sermons describing unique rituals of the baptismal preparation and demonstrating that practices often varied locally. Chapter Six compares the sixth-century letter exchanges between Ferrandus and Fulgentius with John the Deacon’s letter to Senarius, showing the enduring importance of the catechumenate in the West and the creative reception of earlier African sources addressing recurrent pastoral problems.

Keywords: late antiquity
catechumens
initiation
conversion
baptism
Africa
history of christianity
christianisation
religious identity
augustine
Advisor: Leyser, C
McLynn, N
Multi-agent exploration of indoor environments under limited communication constraints

This thesis considers cooperation strategies for teams of agents autonomously exploring an unknown indoor environment under limited communication constraints. The primary application considered is Urban Search-and-Rescue, although other applications are possible, such as surveying hazardous areas. We focus on developing cooperation strategies that enable periodic communication between the exploring agents and the base station (human operators). Such strategies involve an inherent trade-off between allocating team resources towards facilitating communication and increasing the speed of exploration.
We propose two classes of approaches to address this problem: using opportunistic rendezvous to guide the team behaviour, and explicitly arranging rendezvous between agents. In the opportunistic approach, the allocation of team resources between exploration and communication can be indicated with a single numerical parameter between 0 and 1 -- the return ratio -- which leads to complex emergent cooperative behaviour. We show that in some operating environments agents can benefit from explicitly arranging rendezvous. We propose a novel definition of a rendezvous location as a tuple of points and show how such locations can be generated so that the topology of the environment and the communication ranges of agents can be exploited. We show how such rendezvous locations can be used to both improve the speed of exploration and to improve team connectivity by allowing relays to contribute to the overall exploration.
We evaluate these approaches extensively in simulation and discuss their applicability in search-and-rescue scenarios.

Keywords: Robotics
Multi-Agent Systems
Advisor: Cameron, S
Bounds on computation from physical principles

The advent of quantum computing has challenged classical conceptions of which problems are efficiently solvable in our physical world. This raises the general question of what broad relationships exist between physical principles and computation. The current thesis explores this question within the operationally-defined framework of generalised probabilistic theories. In particular, we investigate the limits on computational power imposed by simple physical principles. At present, the best known upper bound on the power of quantum computers is that BQP is contained in AWPP, where AWPP is a classical complexity class contained in PP. We define a circuit-based model of computation in the above mentioned operational framework and show that in theories where local measurements suffice for tomography, efficient computations are also contained in AWPP. Moreover, we explicitly construct a theory in which the class of efficiently solvable problems exactly equals AWPP, showing this containment to be tight. We also investigate how simple physical principles bound the power of computational paradigms which combine computation and communication in a non-trivial fashion, such as interactive proof systems. Additionally, we show how some of the essential components of computational algorithms arise from certain natural physical principles. We use these results to investigate the relationship between interference behaviour and computational power, demonstrating that non-trivial interference behaviour is a general resource for post-classical computation. We then investigate whether post-quantum interference is a resource for post-quantum computation. Sorkin has defined a hierarchy of possible post-quantum interference behaviours where, informally, the order in the hierarchy corresponds to the number of paths that have an irreducible interaction in a multi-slit experiment. In quantum theory, at most pairs of paths can ever interact in a fundamental way. We consider how Grover's speed-up depends on the order of interference in a theory, and show that, surprisingly, the quadratic lower bound holds regardless of the order of interference.

Keywords: Generalised probabilistic theories
Quantum computation
Advisor: Coecke, B
Barrett, J
Resolution of proteotoxic stress in the endoplasmic reticulum by ubiquitin ligase complexes

The eukaryotic endoplasmic reticulum (ER) is a multifunctional organelle, primarily responsible for the folding and maturation of secretory proteins, as well as lipid metabolism, calcium homeostasis, ubiquitin-dependent signalling and cell fate decisions. ER-associated degradation (ERAD) oversees protein folding and delivers misfolded proteins for degradation by the proteasome via ubiquitin conjugation mediated by RING-type E3 ubiquitin ligases. An intact ERAD is crucial to cellular homeostasis, as unresolved protein imbalances cause ER stress that ultimately lead to apoptosis. The human ER accommodates at least 25 E3s, however our understanding is mostly limited to Hrd1 and AMFR/gp78, both of which have a defined function in ERAD. To understand the contribution of ER E3s to cellular and organelle homeostasis, this study used mass spectrometry of purified E3 complexes to identify cofactors and build interaction networks of ER-resident E3s. These findings will form the foundation for investigating the biological roles of these ubiquitin ligases. Transcriptional analysis highlighted the centrality of Hrd1 among all ER-resident E3s in response to protein misfolding in the ER. Additionally, the contribution of individual Hrd1 complex components to resolving proteotoxic stress was assessed using a misfolded antibody subunit (IgM heavy chain), rather than conventional pharmacological treatments. The ERAD components essential for substrate degradation and survival under proteotoxic stress were identified, highlighting the pivotal role of Hrd1, its cofactor SEL1L and the Derlin family members. Finally, it was demonstrated that autophagy induction in response to proteasome inhibition is key to relieve the burden of protein misfolding in the ER, as it sustained the survival of cells defective for ERAD. Importantly, this study proposes a potential involvement of Hrd1 in signalling from the ER to autophagy, suggesting potential crosstalk between the ERAD and autophagic pathways.

Keywords: protein degradation
proteotoxic stress
Hrd1
endoplasmic reticulum
E3 ubiquitin ligase
Advisor: Christianson, J
Characterisation of the genomes of brain metastases

Brain metastases are generally associated with a poor prognosis. The number of metastases, location and control of extracranial disease typically influences the management of patients. Treatment options are currently limited and are dependent on the clinical context. Interventions include surgery and stereotactic radiosurgery with few metastases, with whole brain radiotherapy serving a role in patients with several metastases. In recent years, there have been increased efforts directed towards early phase trials to address the role of targeted biological agents towards pathogenic drivers namely, EGFR, HER2 and BRAF. Due to the location and appropriateness of the clinical situation biopsies are impractical in these patients.
In this DPhil, I have characterised the genomic landscape of a cohort of brain metastases of 4 colorectal, 7 ductal breast and 7 lung adenocarcinomas. Analysis of genomes involved: characterisation of mutation burdens, spectra and signatures, profiling copy number aberrations, driver gene discovery and reconstructing the clonal architecture of the genomes. Unpaired primary tumours from The Cancer Genome Atlas, and published reports served as a comparative tool to evaluate the degree of heterogeneity compared to primary tumours.
The brain metastases generally resembled primary tumours with regards to mutation burdens, spectra and signatures. Drivers of primary tumours including those targeted by current biological agents were generally, though not universally located in major clonal groups in the metastases.
Increased chromosomal instability was observed in the metastases. Although my sample size was modest the brain metastases had an increased number of copy number alterations in comparison to primary tumours. Furthermore, my findings suggest that chromothripsis may occur more frequently in brain metastases. Elucidating mechanisms involved in chromosomal instability in the future will provide further insight into tumour evolution and potential targets for new therapeutic interventions.

Advisor: Tomlinson, I
Explaining security and defence integration: the case of Europe

What is driving the European Union (EU) to integrate in matters of security and defence? Why has the EU since the 1990s, and in fits and starts, built up defence institutions, published strategic documents, or launched security missions around the world? This dissertation suggests an answer to these questions that hinges on there being a security community in Europe within which states do not feel threatened by one another. Understanding the level of trust EU states have in one other as well as its bearing on the way they engage in negotiations about the management of their security is of fundamental importance when attempting to make sense of the emergence of the EU as a security actor.
States within Europe’s security community and during the period covered by this thesis (1990-2016) suffered numerous external security shocks. These ranged from shifts in the geopolitical landscape surrounding them, to terrorist attacks to immigration crises. Shocks of this nature exposed the externalities of non-cooperation to policymaking elites in EU Member States, ultimately pushing them to seek the elevation of crisis management to the EU level. The outcome of the intergovernmental negotiations that followed each external shock depended on the degree of strategic interest overlap across EU states. This thesis makes evident that as EU integration in other fields progressed a form of spillover occurred where strategic interests converged and a common security and defence policy became an ever more attractive proposition.
The narrative suggested in the following pages also explains why EU Member States have sometimes been forced to attend to their security and defence affairs alone. This occurred when they were faced with a crisis with little impact on the strategic interests of other members of the security community. The complicated interactions between the EU and the North Atlantic Treaty Organization (NATO), in turn, can also be seen through this theoretical lens and with the Alliance shielding Europeans from shocks or from the management of their consequences, therefore disincentivizing further EU integration in the field of security.
By taking the perspective of EU member states and looking at specific shocks and the reactions they produced the following pages provide an innovative take on a much-studied but poorly-understood subject. They also seek to bring together two relevant but almost entirely disconnected sets of literatures: broader international relations theory and empirical works on European security.

Advisor: Toft, M
Zielonka, J
Markers of synovial inflammation in cohorts at risk of knee osteoarthritis

Background and objectives. Knee osteoarthritis (KOA) is a leading cause of disability in the developed world. Additionally, it is possibly linked with premature mortality. Low-grade inflammation is associated with a high risk of non-traumatic KOA incidence but also with metabolic syndrome. Knee injury is a major risk factor for KOA and is associated with an inflammatory response. Heterogeneity of both the symptoms and progression makes early identification of individuals at risk difficult. The aim of this thesis was to examine the diagnostic value of selected biomarkers to identify microscopic synovitis, examine their predictive value for KOA development and any association with excess premature mortality.
Methods. Four serum biomarkers, COMP, resistin, C3M and CRPM, all linked with both knee pain and synovial or systemic inflammation, were selected and an additional sonographic marker was tested. Data from two cohorts has been utilised for the purpose of this thesis: the Oxford Knee Injury Cohort, a prospective study of NHS patients with recent ACL and/or meniscal injuries, and the Chingford women’s study, a community-based prospective cohort with over 23 years of follow-up.
Results. Cross-sectionally, sonographic markers correspond well with microscopically defined post-traumatic synovitis. Two biomarkers, COMP and resistin, were associated with development of incident radiographic KOA (RKOA), while two others, C3M and CRPM, predicted development of painful RKOA independently to age and BMI. High C3M levels and presence of painful RKOA were associated with premature mortality. Knee pain alone, especially in presence of RKOA was an independent predictor of mortality, but RKOA without pain was not.
Conclusion. These results support the use of the studied biomarkers in complex predictive models for development of KOA and associated premature mortality. Taking the competing risk of death into account is an important consideration in this field

Keywords: biomarkers
knee osteoarthrits
Advisor: Newton, J
Price, A
Watt, F
Arden, N