VictorJuiz/thesis huggingface dataset:
p97/VCP regulates MRE11-dependent DNA and resection and alters cellular toxicity of ionising radiation

The ubiquitin-proteasome system (UPS) is responsible for most of the protein degradation in mammalian cells which represents a particular challenge in cancer cells that commonly have heightened protein stress. The AAA+ ATPase p97 is a central component of the UPS, where it functions in concert with its co-factors to bind and unfold ubiquitinated substrates from various cellular locations, including DNA break sites. The work in this thesis demonstrates that p97 functionally interacts with one of the main DNA double-strand break (DSB) repair complexes, MRE11-RAD50-NBS1 (MRN), and influences DSB repair pathway choice by disassembling MRN from chromatin after ionising radiation (IR). Inactivation of p97 blocks MRN complex disassembly from chromatin and sites of DNA damage upon IR, which results in excessive MRE11-mediated DNA end resection, leading to defective error-free homologous recombination (HR) and upregulation of the mutagenic single-strand annealing (SSA) pathway, resulting in cancer cell radiosensitivity. Mechanistically, p97 inhibition causes radiosensitivity through MRE11 nuclease accumulation, and cancer cell survival after IR is rescued when MRE11 is inactivated in combination with p97 inhibition. Furthermore, the small molecule ATPase inhibitor of p97, CB-5083, is well-tolerated and causes tumour cell killing after IR in vivo. These results suggest that p97 inhibitors might be used to improve cancer radiotherapy outcomes.

Keywords: p97
CB-5083
Ionizing radiation (IR)
single-strand annealing
genome stability
MRE11
DNA damage
homologous recombination
bladder cancer
DNA double-strand break repair
Advisor: Kiltie, A
Ramadan, K
Mechanisms underlying working memory in health and disease

Working memory (WM) — the means by which information is retained and manipulated over seconds — is a fundamental cognitive process that has been considered to have three phases: encoding, maintenance and retrieval. Although much research has focused on the first two of these, far less is understood about how information is retrieved from WM or how filtering of information in WM affects recall and forgetting, both in health and disease.
In the first part of the thesis, I gained mechanistic insight into the process of WM retrieval and the relationship between processing demands at different phases. Novel sensitive delayed-reproduction tests were developed, and mixture modelling of error applied to deconstruct the sources of error contributing to the pattern of recall performance. Additionally, to quantify the mechanisms of the decision process of recall, Hierarchical Bayesian Drift Diffusion modelling (HDDM) was implemented. In the second part, I investigated malfunctions of the underlying processes of WM in two different patient groups. First, I examined a rare group of people with medial temporal lobe (MTL) lesions following limbic encephalitis (LE). Second, as part of an experimental medicine study I assessed WM and the impact of emotional valence on WM in individuals with Parkinson’s disease (PD) both on and off citalopram, a selective serotonin reuptake inhibitor (SSRI).
Overall, the results demonstrated that the nature of retrieval cues can significantly affect memory reports, with more information at retrieval improving access to items in WM. Additionally, the quality of associative retrieval depends not only on the nature of the target, but also on features in a foil (distractor item) if this is also presented at probe, with the arrangement of non-spatial features modulating recall of relational information. Further studies provided data to suggest that filtering of information in WM is not a monolithic, single entity but rather underpinned by dissociable cognitive processes that engage with the different phases of memory.
Finally, results from the second part of this thesis provided evidence for a role of the MTL and hippocampal regions in relational WM binding. While serotonergic modulation with citalopram revealed a possible role of serotonin in processing negative emotional information in PD, no effects on WM were found. Together, this work provides novel insights into the mechanisms underlying WM retrieval, filtering and examination of the effects of processing demands induced at different stages of WM in the healthy brain. It also contributes to the understanding of memory disturbances in patients with MTL damage and PD.

Keywords: aging
filtering
hippocampus
retrieval
misbinding
processing demands
working memory
emotional valence
Parkinson's disease
serotonin modulation
limbic encephalitis
Advisor: Husain, M
Stokes, M
The synthesis of substituted tetramates for antibacterial studies

Chapter 1 gives a brief introduction into the history of antibacterial drug discovery, the previous work carried out in the Moloney group in synthesising antibacterial tetramates, and the rationale for this DPhil research project.
Chapter 2 describes the synthesis of tetramic acids from threo-phenylserine derivatives. It demonstrates how bicyclic tetramates could be obtained chemoselectively and diastereoselectively. Additionally, it was shown that a library of densely functionalised C7-carboxamidotetramic acids could be synthesised and these compounds have the ability to bind to metal ions and may exhibit tautomeric behaviour in solution.
Chapter 3 describes the synthesis of tetramic acids from erythro-phenylserine derivatives with excellent diastereoselectivity and chemoselectivity observed. Additionally, also described is the synthesis of C7-carboxamides and C7-acyltetramates, where it was shown that these compounds also bind to metal ions and may exhibit tautomeric behaviour in solution. Finally discussed is the diastereoselective reduction of bicyclic tetramates and Suzuki couplings with mesylates to form densely functionalised pyrrolidinone derivatives.
Chapter 4 describes the attempted synthetic methodology of obtaining C2, C4 and C7-functionalised tetramates from threo-phenylserine and allo/threo-phenylcysteine derivatives. Moreover, this chapter describes the synthesis of imidazolidine-derived tetramic acids in a chemoselective and diastereoselective manner, in which the C2 and C4-substituents are readily functionalised. However, a C7-carboxamide library could not be synthesised chemoselectively.
Chapter 5 discusses the antibacterial activity and physicochemical properties of tetramates synthesised. None of the compounds synthesised exhibited any bioactivity against E. coli, however, many compounds exhibited potent antibacterial activity against S. aureus. However, this activity was compromised when tested in the presence of human serum albumin and/or blood.

Keywords: medicinal chemistry
organic chemistry
Advisor: Moloney, M
An affinity for justice: ethics and apologetics in Lactantius' response to persecution

This thesis discusses Lactantius’ moral philosophy and understanding of justice, and explores the apologetic use he made of these ideas. The present study is the fullest treatment of Lactantius’ view of justice in any language, and the only one in English. Its methodology is philological; it combines a close reading of Lactantius’ corpus with a literary-historical investigation of the many sources he cites and of the ideological justification of the Diocletian persecution. I investigate how these sources govern the form and content of Lactantius’ arguments; his apologetic method means he often argues for Christian ideas from pagan sources and premises. Lactantius understands justice as meeting obligations and divides obligations into two domains: duties to God and duties to other humans. He does so by likening God to a Roman paterfamilias, which creates the obligations of worshipping God and of treating other humans as his children and one’s siblings. Lactantius arrives at this definition by reconfiguring Cicero’s understanding of natural law, which undergirds justice in de Legibus Book 1. Lactantius’ conception of justice thus adopts a Ciceronian framework, but fills it with Christian ideas which drive his ethics. Lactantius’ ethics were influenced by Cyprian’s selection of biblical quotations in ad Quirinum; contra Wlosok and Loi, I found no profound dependence upon the Hermetica. The study then situates Lactantius’ ethics in the intellectual context of his day. Lactantius’ understanding of justice is carefully constructed to respond holistically to the persecutors’ ideology and asserts that Christians embody the ideals of Roman virtue. Contrary to the suggestions of Digeser and Colot, he does not seek to Christianise the Roman empire, but rather to dissuade it from persecuting Christians.

Keywords: apologetic literature
Roman religion
Virtue
Ethics
Lactantius
Diocletian
persecution
piety
Divine Institutes
Early christianity
Justice
Advisor: Edwards, M
Scalable inference in state-space models

This thesis provides a set of novel Monte Carlo methods to perform Bayesian inference, with an emphasis on a state-space modelling framework. The thesis comprises three self-contained research papers. The first paper works at the interface of modelling and inference, extending existing work to develop a new model for medium and high-dimensional data possessing step-changes changes in the correlation structure. A bespoke inference routine is developed, with experimental results demonstrating the speed-up of convergence to equilibrium under a novel alteration of a particle Gibbs sampler for change-point detection. The second paper is concerned with the problem of obtaining unbiased estimators for the smoothing problem in state-space models. New methodology is developed leveraging recent developments in unbiased Markov chain Monte Carlo (MCMC) in conjunction with a particle independent Metropolis–Hastings Markov kernel. We show that the resulting coupling time can be precisely characterised. As a result, it is possible to study the large sample limit of the coupling time to help guide the choice in an algorithmic tuning parameter (the number of particles in this case). The third and final paper develops this methodology further, to obtain unbiased estimators for MCMC algorithms in settings where the likelihood may be unavailable to evaluate pointwise. The motivation for this work is to find a simple means by which to parallelise exact Bayesian inference in state-space models. The focus is primarily on pseudo-marginal algorithms and particle MCMC, in which the mixing behaviour of the algorithm is typically polynomially ergodic. In this setting we propose new methodology to allow the obtention of unbiased estimators of expectations of stationary distributions of these Markov chains. In addition, we extend existing results to both prove the validity and characterise the computational efficiency of these estimators, in terms of algorithmic tuning parameters. We evaluate the resulting methodology on otherwise intractable state-space and latent variable models, including a multivariate probit model popular in econometrics and a nonlinear state-space model arising in neuroscience. Additional algorithmic extensions are provided and subsequently applied to a parameter inference problem in a high-dimensional Ising model.

Keywords: state space model
coupling
Markov chain Monte Carlo
unbiased estimation
Monte Carlo
parallel computation
particle filter
Corrosion and hydrogen pickup mechanisms of zirconium alloys

Zirconium alloy cladding isolates the nuclear fuel rods from water coolant in a nuclear fission reactor, but in this harsh environment experience high temperature aqueous corrosion and hydrogen pickup (HPU). The segregation of minor elements such as iron, niobium and antimony greatly affects the corrosion and HPU of Zr alloys, but often this segregation occurs at a scale too small for most characterisation techniques to observe. Atom probe tomography (APT) enables the 3D analysis of elemental distributions on the atomic scale using time-of-flight spectroscopy. .
The corrosion and HPU of Zr-Nb alloys with 0.5-2.5 wt% Nb were examined using APT. The oxygen-saturated metal region at the oxide/metal (O/M) interface increases with instantaneous oxidation rate and deuterium segregation to oxide grain boundaries and pores that probably contain hydrogen have been observed. The ratio of hydrogen isotopes showed that where the D-containing signal was higher, deuterium segregation to grain boundaries was more likely..
Fe around β-Nb particles and on metal grain boundaries is redistributed during oxidation. This redistribution results in Fe enrichment in the oxide which would correlate with the space charge compensation predicted to decrease HPU. During oxidation, Nb leaches out from the β-Nb precipitates to the oxide matrix. Preliminary analysis on Sb-containing samples has been carried out and weak Sb segregation to metal grain boundaries has been observed. Irradiation also causes redistribution of Fe and Nb, particularly Fe in the vicinity of oxide grain boundaries and Nb leaving the β-Nb particles under irradiation, resulting in the formation of small Nb clusters. The results of this study show that APT can observe changes of elemental distributions on the atomic scale which is vital to understanding how Zr alloys behaves during corrosion.

Keywords: corrosion
atom probe tomography
hydrogen pickup
Zirconium
Advisor: Grovenor, C
Moody, C
Bagot, P
Community structure of ants in Brunei rain forest

This thesis examines the patterns in the ground and low-vegetation ant community of primary lowland dipterocarp forest in Brunei, South East Asia.
The first experimental chapter establishes the importance of ants as the numerically dominant taxon of the forest floor litter arthropod community, how many species were found in a hectare of forest, and the probable minimum asymptotic number of species for each of four sampling methods. The amount of small fragments of litter is found to vary across the plot, increasing in the valley, and best explains differences in species richness of samples. Species richness is highest in the valley. Faunal, rather than microhabitat factors, are found to be the best predictors of certain litter species' abundance.
Chapter three shows that colony dispersion is not a good method with which to investigate competition in this habitat at present. The ground dwelling ant community are more often clumped than over-dispersed, but patterns are impossible to interpret in the light of ecological theory without knowing the biology and population dynamics of the species well. I show by reanalysis that two major flaws in a similar study by Levings and Franks (1982) confound their claim that overdispersion of ant colonies occurs in Panama. This result has implications for many other similar studies of spatial dispersion as evidence of competition.
Chapter four examines whether there is a predictable dominance hierarchy in the bait responsive species foraging in the litter and on tree trunks. No evidence of such a hierarchy was found, although significant temporal patterns unexpected from diel cycles imply avoidance of some species by others. Differences in recruitment ability were found between tree and ground foraging species and these correlated with speed to locate and persistence at baits. A method is offered to test whether ant species are solitary foragers.
Chapter five shows that there is no clear relationship between niche overlaps and association, i.e. avoidance of colonies or foragers at baits. Low temporal overlap and high food overlap were found, but did not appear to be related.

Advisor: May, R
Elmes, G
Taming metals: the use of leaded bronze in early China, 2000–1250 BC

It has long been known that leaded bronze, an alloy consisting primarily of copper with the addition of tin and lead, was widely used in early China, starting from around the second millennium BC. The additional lead distinguishes this metal from common bronze, the copper-tin binary alloy, used by most other Early Metal Age civilisations in Eurasia. The reasons behind the use of leaded bronze have not been fully examined in previous literature.

In this thesis, the discussion of metallurgical technologies and the studies on material properties are combined with four case studies of early metal-using communities to reinvestigate the use of leaded bronze in early China. With this approach, the thesis challenges the wide held notion that lead was consciously added by the craftspeople, mainly to facilitate the casting. Instead, I argue that the widespread of leaded bronze objects was mainly due to both the socio-economic concerns in making bronze ritual vessels in Central China and the recycling and reuse of the metals by other communities around Central China. Moreover, the seemingly common use of leaded bronze does not reflect a uniform acceptance of a single set of knowledge and know-how. Rather, people in different communities responded differently to this new material and chose to engage it in different ways.

This study on leaded bronze provides us with a new perspective to recognise the complexity and diversity of technology and material culture in early Chinese communities. Meanwhile, through the active discussion on the theoretical frameworks and research methods for archaeometallurgy and material culture studies, I also suggest approaches which may be useful in future studies of early metallurgy and other craft production.

Keywords: material culture studies
archaeology of China
bronze
archaeometallurgy
China
metallurgy
leaded bronze
Advisor: Pollard, M
Firms, productivity and innovation in low-income countries

This dissertation consists of three empirical essays on firms, productivity and innovation in low-income countries. Chapter 1 examines whether changing management practices to encourage bottom-up innovation leads to beneficial information flows from production workers on lower hierarchical levels to higher-level management with the power to implement ideas. In a three-month field experiment with 1,600 workers in a Bangladeshi garment factory, I find that providing structured peer-to-peer lunches for workers to discuss ideas significantly improves the quantity and relevance of ideas which are implementable in the firm, driven by changes in workers’ ease of submissions and their aspirations. Additional encouragement from trained supervisors, however, comes at the cost of suppressing voice on critical topics about supervisors, which works through a perceived deteriorated voice climate. Chapter 2 (with Christopher Woodruff, Atonu Rabbani and Rocco Macchiavello) explores the impact of a low-cost group-based management training programme on productivity and working conditions in 25 Bangladeshi garment factories, with significantly positive effects on workers. Practices aimed at improving communication on the production floor are found to be more effective than technical and production-related practices, and lead to positive effects on human-resource related outcomes. Chapter 3 (with Ferrán Vega and Christopher Woodruff) analyses detailed line-level data in a Bangladeshi garment factory over a period of five years to examine the role of low-level autonomy in the process of adaptation to a negative productivity shock, caused by switching to a ‘faster fashion’ production model imposed by industry demands. We find that performance differences can be traced back to varying degrees of autonomy exercised by production managers in deviating from pre-determined plans.

Keywords: management
development economics
innovation
organizational learning
Bangladesh
empowerment
Advisor: Woodruff, C
Quinn, S
Investigating the molecular and physiological roles of BUD23-dependent protein translation

The human ribosome is extensively modified, containing at least 288 distinct modification sites. Current literature suggests that most ribosomal modifications serve to stabilise the tertiary structure of the ribosome, however this fails to explain why ribosomal RNA (rRNA) modifications tend to cluster in functionally important regions that are vital for translation. Their spatial organisation and high level of conservation throughout all eukaryotes strongly suggest that rRNA modifications are instead responsible for the regulation of ribosomal function. BUD23 is a putative methyltransferase that is responsible for modifying a key residue on the small ribosomal subunit. It also has a second independent function in small ribosomal subunit biogenesis, where its presence is essential for correct ribosomal maturation. While BUD23's role in small ribosomal subunit maturation has been well characterised, studies have failed to determine any functional consequences of its methylation activity. This has led to the idea that the methylation event may be non-essential, or is imparted simply as a quality control marker. Over the course of this project, I aimed to investigate the role of BUD23, with particular focus on the in vivo consequences of its function.

By generating two unique mouse models of BUD23, I have established that BUD23 attenuates mitochondrial and metabolic function, and have implicated that this is as a result of its methylation activity. In addition, I have generated a homology model of human BUD23 to explore the mechanisms underlying its core functions, and point to a functional purpose for the existence of the methyl mark on the small ribosomal subunit. Overall, this thesis implicates that BUD23 is responsible for the regulation of tissue and organismal energy balance in a highly selective manner, promoting a selective translational advantage to metabolic transcripts. Its loss has profound implications, resulting in global metabolic defects as a consequence of ribosomal failure.

Keywords: ribosome
methylation
metabolism
mitochondria
translation
BUD23
Advisor: Hodson, L
Baxter, M
Ray, D
Bechtold, D
Identification and characterisation of candidate monoclonal antibody Ebolavirus therapeutics

Multiple species of Ebolaviruses can cause outbreaks of devastating disease with high mortality. The 2014 outbreak in West Africa, focused attention on efforts to develop effective vaccines and therapies to save lives. Since then, vaccines and first generation therapies have been developed and approved for use. The only therapies to have shown any efficacy in human clinical trials are monoclonal antibodies (mAbs) targeting the Glycoprotein (GP) on the virus surface. However, they are limited in potency and breadth of activity as they target only Zaire ebolavirus (EBOV), yet Sudan ebolavirus (SUDV), Bundibugyo ebolavirus (BDBV) and Tai Forest ebolavirus (TAFV) also cause human disease. The aims of this thesis were to generate a panel of mAbs that could bind to GP from all species of Ebolaviruses that cause human disease, then to characterise the mAbs to select candidates to enter the pipeline of next generation therapies progressing to in vivo study. Using high throughput methods a panel of nineteen anti-GP mAbs were isolated, six of which could recognise GP from all four Ebolaviruses that have caused human disease. These mAbs were characterised in a range of in vitro assays focusing on their ability to neutralise pseudoviruses coated with Ebolavirus GPs. The panel of mAbs was subjected to a range of complementary biochemical assays to map their epitopes, and the epitope of one mAb, 11886, was characterised in more detail. 11886 is of interest to progress to in vivo study as it is able to neutralise all pseudoviruses so far tested and investigation of its epitope suggests that it binds a similar footprint to other broadly protective mAbs in the literature, but neutralises the virus via a different mechanism or mode of binding.

Keywords: ebolavirus
monoclonal antibodies
Advisor: Draper, S
Townsend, A
Lightwood, D