VictorJuiz/thesis huggingface dataset:
Dual roles of p97 in DNA damage repair
Keywords: PARP inhibitors
PARPi
PARP1
ubiquitin
DNA damage

An organism’s genome is perpetually challenged by multiple types of DNA lesions. The variety of insults is reflected by an equally diverse range of overlapping DNA repair mechanisms essential for an organism to survive. One protein which has roles in multiple DNA damage repair (DDR) pathways is the segregase/unfoldase p97. p97 acts in a ubiquitin dependent manner to unfold and remove modified substrates, facilitating the enzyme cascades required for efficient DNA damage repair. We show here how p97 has dual actions in DNA damage repair. It can act as a facilitator of DNA damage signalling, through mediating ubiquitin signalling at double strand breaks (DSBs), while also acting as a direct DNA damage repair protein. p97 is able to directly repair DNA-protein crosslinks (DPCs) and DPC-like lesions, such as Top1-ccs and trapped PARP1 respectively. These are deleterious protein adducts on chromatin which otherwise cause cell death by blocking replication fork progression and global transcription.
Importantly, we find that p97 directly removes and repairs PARP inhibitor (PARPi) -induced damage, namely trapped PARP1. PARPi are of special significance as they are the first approved targeted DNA damage chemotherapy to be used in the clinic. We reveal here, novel mechanistic details of how cancer cells respond to the trapped PARP1 lesion. Trapped PARP1 is first SUMOylated by PIAS4 and sequentially ubiquitinated by the SUMO-targeted ubiquitin ligase (STUbL), RNF4. Trapped PARP1 ubiquitination recruits p97 via its cofactor UFD1. By inhibiting the PIAS4-RNF4-UFD1-p97 axis, we were able to cause substantial accumulation of cytotoxic trapped PARP1. Using inhibitors of p97, including CuET, the metabolite of approved anti-alcohol abuse drug disulfiram, we potentiated PARPi cytotoxicity in cancer cell lines. Of additional interest, we show that a cofactor of p97, the essential protease SPRTN, also acts to prevent accumulation of trapped PARP1.
The self-management of hypertensive pregnancies
Keywords: paternalism
mixed methods
self-management
pregnancy
patient empowerment

Background
Hypertension occurs in between 8 to 10% of pregnancies in the UK. While there has been a decline in maternal deaths from hypertensive disorders in pregnancy, it can still cause increased cardiovascular disease risk in later life. Therefore, better management strategies for hypertensive pregnancies, such as combining blood pressure monitoring, self-testing for proteinuria, and self-titrating blood pressure medication, are needed. In the general population, self-management interventions are becoming increasingly common place in the management of chronic conditions such as hypertension and diabetes. The evidence for self-management in pregnancy, however, is thin.
Methods
This thesis brings together qualitative and quantitative evidence on self-management to contribute to the evidence base for self-management interventions in pregnancy. A diagnostic accuracy study was conducted to determine the accuracy of proteinuria self-testing in pregnancy, and three qualitative interview and focus group studies with pregnant people and healthcare professionals were conducted to explore their thoughts on self-testing and self-management interventions.
Results
The diagnostic accuracy study showed that pregnant people are able to self-test in pregnancy with a similar accuracy to healthcare professionals. Meanwhile, the qualitative work revealed that while pregnant people and healthcare professionals find self-testing and the self-monitoring of blood pressure an acceptable self-management intervention that has the potential to empower patients, there were hesitancies from healthcare professionals, and some pregnant people, around the self-titration of blood pressure medication. Finally, a pervasive discourse of paternalism was explored in healthcare professional’s attitudes towards self-testing, and how the burden of self-management may affect pregnant people’s adherence to a self-management intervention.
Conclusion
This thesis has found that while there is an appetite, and growing evidence, for self-management in pregnancy from both pregnant people and healthcare professionals, both have concerns over self-titration of blood pressure medication. Self-management interventions in pregnancy are made more complex by paternalism, gatekeeping, concerns for maternity safety, and the unique burden of treatment that accompanies pregnancy – considering the additional life of the baby.
The framework of good administration: protecting individual interests and controlling public power
Keywords: damages in judicial review
good administration
conceptual borrowing
legitimate expectations
modified fiduciary approach
judicial review

This thesis puts forward a framework of good administration in judicial review that encompasses two limbs. The first limb safeguards a claimant’s individual interests while the second limb allows the claimant to assert the collective interest of the public in the control of public power. The objective is to provide courts and commentators with a holistic and structured framework which is capable of guiding and informing their approach to procedural issues of standing and waiver, administrative discretion and remedies in judicial review.
In order to enhance the protection afforded to these interests under this two-pronged framework, this thesis adopts a more nuanced approach towards the public and private divide and explores whether judicious conceptual borrowing is capable of offering new answers to difficult issues. For instance, to obtain guidance on how procedural issues of standing and waiver should be addressed under the framework, this thesis undertakes an examination of how these issues are addressed in systems dealing wholly with public wrongs like criminal law and how they are dealt with in private law.
This thesis also considers how the protection afforded to legitimate expectations, which constitute important individual interests under the first limb of the framework, may be enhanced by adapting contractual and estoppel principles. This thesis then examines how a modified fiduciary approach may offer additional protection for the public interest in the control of public power under the second limb of the framework. To demonstrate that conceptual borrowing is capable of functioning as a two-street, this thesis also considers how public law concepts may enhance the control of contractual discretion. The final substantive chapter of this thesis explores how the private law notion of damages may elevate the protection afforded to the interests under both limbs of the framework.
Therapeutic targeting of PRMT5 and mutant ACVR1 in paediatric glioma
Keywords: diffuse intrinsic pontine glioma
H3K27M
DIPG
diffuse midline glioma
ACVR1
ALK2
PRMT5
pediatric high grade glioma

Diffuse Intrinsic Pontine Glioma (DIPG) is a universally fatal paediatric brainstem tumour with a median overall survival of 9-11 months. The unique genetic, anatomical and developmental identity of the tumour means that there are currently no effective chemotherapies or targeted therapies. This thesis aimed to identify and characterise novel targets for the treatment of DIPG. Potential therapeutic opportunities arise from the frequent mutations found in histone H3 (H3K27M) and kinase ACVR1 found in DIPG tumours. A screen of epigenetic protein inhibitors revealed that the viability of the patient-derived DIPG cell line HSJD-DIPG-007 was highly sensitive to arginine methyltransferase (PRMT) inhibitors, particularly in ACVR1 mutant lines. The PRMT5 inhibitor LLY-283 was identified as the most promising lead for its potent inhibition of DIPG viability and the recognised role of PRMT5 in the regulation of the cell cycle and stemness. RNA-sequencing and phenotypic analyses revealed that LLY-283 did not induce cell death, but reduced stemness and invasiveness, altered metabolism and restored H3K27me3 levels in DIPG cells. Through collaboration with Ángel Montero Carcaboso, LLY-283 was tested in an orthotopic murine xenograft model of DIPG. LLY-283 reduced infiltration of DIPG cells into the murine forebrain, but did not prolong survival, perhaps reflecting inadequate drug exposure. In parallel, the CRISPR/Cas9 system was used to correct the causative G328V ACVR1 mutation in DIPG cells. The resultant isogenic DIPG cells demonstrated slowed proliferation after correction of ACVR1 mutations, rather than a complete growth arrest as observed with published shRNA mediated ACVR1 knockdown. Surprisingly, the isogenic cell lines also showed comparable sensitivity (GI50) to PRMT5 and ACVR1 inhibition, suggesting other genetic differences contribute to the variation in treatment sensitivity between DIPG cell lines. My findings highlight the value of isogenic DIPG cell lines for interrogating the effects of individual tumorigenic mutations. It remains incredibly challenging to develop new strategies to treat DIPG. This thesis supports the future design of combination treatments for DIPG and provides new experimental tools to aid their development.
Local and global well-posedness of compressible navier-stokes equations
Keywords: navier-stokes equations
compressible flow
partial differential equations
eulerian coordinates
fluid dynamics
Lagrangian coordinates

The well-posedness theory of the full compressible Navier-Stokes equations (CNS for short) has been an important subject in the development of mathematical physics. For the spherically symmetric flow, even though many favourable regularity properties may be expected for its similarity to the one-dimensional equations, there are still a large number of open questions remaining unsolved. Two central difficulties of spherically symmetric CNS are the coordinate singularity at the centre of symmetry, and the upper/lower bounds of density.
In Chapter 1, the Cauchy problems of CNS for the general multidimensional flows, both with and without spherical symmetry, are introduced. Then a heuristic analysis on the Lagrangian coordinate transformation is conducted, which gives insight to the strategies used in the later chapters. Finally, several previous progresses on the well-posedness theory of CNS are highlighted at the end of this chapter.
In Chapter 2, the global-in-time existence of a spherically symmetric weak solution to the Cauchy problem in Eulerian coordinate is obtained. The main strategy is to construct a sequence of approximation problems posed in finite annular domains. This circumvents the problem of coordinate singularity at the origin. Moreover, they are also formulated in the Lagrangian coordinates, so that one can obtain a-priori estimates which are uniform with respect to the dimension of annular domains. The weak solution is then constructed as the limit of approximate solutions in the original Eulerian coordinate. The main result of this chapter is produced in collaboration with Gui-Qiang G. Chen and Shengguo Zhu.
In Chapter 3, for the Lagrangian approximation problem introduced in Chapter 2, the existence and uniqueness of a local-in-time strong solution are shown. This is done via the Picard iteration scheme, however some major difficulties arise due to the fact that second order differential operators in momentum and energy equations is quasilinear under the Lagrangian formulation. To resolve this, a set of a-priori bounds on each iterative solutions is established so that the quasilinear operators are elliptic at each iterative step. Moreover, the time dependent high regularity estimates for linear iterative solution are carefully derived so that Banach Fixed-point theorem can be applied to obtain the desired solution.
In Chapter 4, it is proved that the local-in-time strong solution in Chapter 3 can be extended to all time by bootstrap argument. Moreover, global-in-time strong solutions in the unbounded Lagrangian domain are also obtained by taking the limit of outer and inner radii of annular domains. The main difference of this chapter compared to Chapter 2 is that the limit is taken in the Lagrangian coordinates, and the initial data are assumed to have higher regularities.
Topics in quantum gravity and quantum field theory
Keywords: quantum field theory
statistical models
quantum gravity

In this thesis, we analyse three different quantum systems via operator and path integral techniques: 'two-dimensional Causal-Dynamical-Triangulations (CDT) coupled to hard-dimers', 'scalar solitons' and `Quantum Random Walks (QRW) on the Cayley tree'.
In our first project, we extend previous work on CDT coupled to hard dimers -- which is a discretized model of two-dimensional quantum gravity coupled to matter -- and solve this model exactly with all dimer types present subject to a single restriction. We find that, depending on the dimer fugacities, there are, in addition to the usual gravity phase of CDT, two tri-critical and two dense-dimer phases. We establish the properties of these phases, computing their cylinder and disk amplitudes, their scaling limits and their associated continuum Hamiltonians.
In our second project, we investigate scalar solitons in the framework of quantum field theory. We construct general soliton creation operators and compare these with like operators found by Mandelstam in the sine-Gordon model. We find evidence for the fact that the sine-Gordon soliton is the Thirring fermion only at coupling β2 = 4π. We then go on to compute the first quantum corrections to the radius of the kink in the ϕ4 model in two dimensions.
In our third project, we analyse QRWs on the Cayley tree via the generating function method and derive a set of polynomial equations which determine this model exactly. We establish properties of the spectrum of the time-evolution operator U and solve the `perturbed' eigenvalue equation in U.
Modelling human-like decision making and social trust using probabilistic programming
Keywords: game theory
decision making
expected utility
trust
probabilistic programming
cognition

Effective collaborations between humans and machines necessitate the modelling of human cognitive processes and complex social attitudes such as trust, guilt or shame. Robots can take an active role in reducing misuse if they are able to detect human biases, inaccurate beliefs or overtrust, and make accurate predictions of human behaviour.
To that end, we propose cognitive stochastic multiplayer games, a novel paramet- ric framework for multi-agent human-like decision making, which aims to capture human motivation through mental, as well as physical, goals. Our framework enables expression of cognitive notions such as trust in terms of beliefs, whose dynamics is affected by agent’s observation of interactions and own preferences. Agents are modelled as soft expected utility maximisers, which allows us to capture the full range of rationality, from imperfections characteristic of human rationality, to fully rational robots. A key contribution is a novel formulation of the utility function, which incorporates agent’s own, as well as other agents’, emotions and takes into account their preference over different goals. Heuristics and mental shortcuts that people use to approximate what they cannot observe are captured in the framework as mental state estimation functions.
We implement the model using a probabilistic programming language called WebPPL. Our tool supports encoding of cognitive models and simulating their execution based on stochastic behavioural predictions it generates. Conversely, given a set of data, the tool may be used to learn characteristics of agents using Bayesian techniques. The software has been designed to be modular, so that probabilistic models of affection developed by others may be integrated. We validate our tool on a number of synthetic case studies, demonstrating that cognitive reasoning can explain experimentally-observed human behaviour that standard, equilibria- based analysis often overlooks.
To evaluate the framework in a human-robot interaction setting, we have designed and conducted an experiment that has human participants playing the Trust Game against a custom bot we developed. Participants in the game (humans or bots) are randomly assigned the role of an investor or investee. Results of our study show that predictions of human behaviour generated by our tool are on par with, and in some circumstances superior to, the state of the art. Unlike other approaches, our model integrates behavioural observations with prior beliefs and captures how one agent’s behaviour affects actions of their opponent.
Security assumptions in post-quantum cryptography
Keywords: cryptography

This thesis analyses the assumptions present in security proofs of post-quantum cryptosystems using Koblitz and Menezes' critique to guide the focus points. The classical analysis focusses in particular on isogeny-based and multivariate polynomial cryptosystems. Firstly, we present attacks against hardness assumptions on derivative computational problems arising in protocols for isogeny-based undeniable signature schemes. Secondly, we provide upper bounds on the solving degree of over-determined systems of n+l multivariate polynomials in n variables as an alternative to the degree of regularity, which gives a heuristic upper bound. We finish with an analysis of the resources of a quantum adversary, providing an improved method for quantum gate approximation that gives shorter sequences by a factor of 9/7.
Urban Italianate architecture in Britain with particular reference to London c.1800-c.1865
Keywords: Italiante
Victorian architecture
town planning
architecture

This thesis examines the sources, critical reception and practice of the Italianate in British urban architecture c.1800-1865. In the past, the term ‘Italianate’ has largely been applied retrospectively in an attempt to categorise a manner of building wherein the architectural grammar, or at least the regional accent, of Italy can be observed to have informed the ornament and form of a building. However, within the bracket of the Italianate there existed a wide degree of variation, often too extreme to be understood as subgenres. I have used the term ‘Italianate’ to mean urban astylar structures designed and erected in Britain, while seeking to show that, for its contemporaries, the Italianate was defined by a rejection of historicism, practical urban requirements and a typological understanding of urban architecture. My research focuses on the emergence and early evolution of an urban Italianate and this has led me to look at its origins and development in London. The British (primarily English) architectural press also forms a ‘geographical’ locus, which at that time was chiefly metropolitan. The 1800-c.1865 timeframe has been chosen to encompass both the Italian tours of early practitioners and the cessation of the Italianate as a ‘new’ form of architecture. This thesis demonstrates that urban Italianate was in fact the nineteenth-century urban vernacular and succeeded because it enabled debates about ‘style’ to be circumvented and allowed for regulatory compliance. But, beyond this, this thesis will seek to open early-nineteenth-century urban architecture to wider debate, by refuting the Picturesque as a defining aspect of early-nineteenth-century architectural practice, and demonstrating that, far from seeking to break with eighteenth- century architecture, many early-nineteenth-century architects wished to engage with what they saw as the roots of their profession.
Infrastructure justice and humanitarianism: blockchain's promises in practice

Keywords: web3
refugees
infrastructure
justice
blockchain
aid
ethnography

Proponents of the decentralised database technology blockchain suggest it will revolutionise the aid sector by allowing money and data to be exchanged more equitably, efficiently, transparently, and securely. Blockchain is widely expected to improve refugee identification, cross-border remittances, supply chain management and more. However, humanitarian blockchain projects are nascent and there is a lack of critical scholarship on how the promises for blockchain are playing out in practice. This thesis provides the first comprehensive, theoretically informed, empirically grounded case study of the use of blockchain in humanitarianism. I investigate the imaginaries, uses and effects of blockchain in anthropological terms, based on close-up work with the key stakeholder communities connected to a pilot project in Jordan’s refugee camps, which in 2019 began using blockchain to deliver financial aid to Syrian refugee women. Drawing together a range of perspectives on the same project, I show how the aspirations for this new technology materialise, in support of some priorities—those of UN donors, agencies and their corporate and government partners—at the expense of others—aid workers and refugees.
Building on critical data studies, infrastructure studies, and aid and migration studies, I put forward the theoretical frame of infrastructure justice. With this, I advance scholarship on socio-economic injustices and political hegemonies in the digital age. I argue that injustices are experienced, extended, and contested through three interlocking dimensions of infrastructure: subjectivities, timescapes, and materialities. I demonstrate how strongly affective cultural and subjective experiences with blockchain—involving suspicion, ignorance, mystification, and faith—connect with the asymmetrical regulation of information, material resources and strategic interests over space and time. This thesis gives fresh insight into how radical, emergent technology implemented at socio-economic margins both challenges and is incorporated into the structures of global governance, and in particular how it is experienced by its presumed beneficiaries.
DNA damage repair proteins as determinants of sensitivity to platinum chemotherapy
Keywords: oesophageal cancer
biomarker
DNA damage repair
platinum chemotherapy
interstrand cross-link

DNA damage repair proteins are determinants of sensitivity to platinum chemotherapy in preclinical models and in patients with cancer. The XPF- ERCC1 heterodimer incises DNA strands adjacent to platinum-DNA adducts and is essential for repair of platinum-DNA interstrand cross-links (ICLs). High expression of ERCC1 has been correlated with lack of response to platinum chemotherapy, but less is known about the value of XPF in predicting response to platinum-based chemotherapy. MUS81- EME1 is also involved in replication-coupled ICL repair. The role of MUS81 as a biomarker for response to platinum-based chemotherapy has not been examined.
This project tested the hypothesis that high tumour levels of the DNA repair proteins XPF and MUS81 are associated with lack of response to platinum chemotherapy.
In the first part of this thesis, microarray analysis of gene expression in samples from patients with oesophageal adenocarcinomas treated with neoadjuvant oxaliplatin-fluorouracil demonstrated an association between high levels of genes encoding ICL repair proteins (including ERCC1, MUS81 and EME1) and poorer clinical outcomes. In addition, functional pathway analysis suggested a link between down regulation of cell cycle and anti- apoptotic pathways and response to treatment.
In the second part, high levels of XPF and MUS81 proteins in pre-treatment biopsies were correlated with worse outcomes following neoadjuvant oxaliplatin-fluorouracil chemotherapy for oesophageal adenocarcinoma. It was found that, in keeping with the microarray results presented in the first part, high pre-treatment levels of the G2/M-phase marker Cyclin B1 were associated with worse clinical outcomes. The relationship between XPF and MUS81 levels and response to DNA cross-linking agents in colorectal and anal cancers was also studied.
In the third part, it was demonstrated in vitro that reducing levels of XPF and MUS81 proteins increased sensitivity of colorectal and oesophageal cancer cells to oxaliplatin treatment.
These data suggest that XPF and MUS81 have the potential to be developed as biomarkers for clinical response to oxaliplatin-based chemotherapy.