VictorJuiz/thesis huggingface dataset:
Transcriptional checkpoint response SET in motion: role for miR-106b-5p and H3K36me3 in regulating E2F-dependent transcription

Non-coding RNAs are key regulators of mammalian gene expression, and their dysregulation has frequently been associated with tumourigenesis. Understanding how non-coding RNAs, and specifically miRNAs, contribute towards the aggressive nature of breast tumours by serving oncogenic or tumour suppressive roles, may help identify novel molecular biomarkers or therapeutic targets.
This thesis seeks to identify genetic drivers of altered miRNA biogenesis in breast tumours. Integrated analysis of genomic and transcriptomic data revealed recurrent amplification-dependent overexpression of AGO2 and its interacting partner, PABPC1. The analysis of mature: precursor miRNA ratios showed that AGO2 copy number amplification results in the preferential maturation of oncogenic miRNA species, including of the miR-106b/25 cluster, which promoted the silencing of known breast cancer-associated genes, such as E2F1, SETD2, and CDKN1A, during cancer evolution. Elevated miR-106b-5p expression caused premature S-phase entry, and both miR-106b-5p and p21 therefore demonstrated utility as prognostic markers for sensitivity to WEE1 kinase inhibition, which targets SETD2-deficient cancers.
Furthermore, this thesis presents an integrated analysis of miRNA-mRNA expression profiles in the response to ionising radiation and hydroxyurea treatment. This approach revealed that the early transcriptomic response to DNA damage and replication stress is universal and involves the inhibition of cell cycle progression through miR-124-3p-mediated downregulation of cytoskeletal genes. Furthermore, I identified a role for miRNAs in controlling the epigenome in response to external stresses, such as via the miR-7704-KDM6B axis, and further confirmed the regulation of SETD2-dependent H3K36me3 by miR-106b-5p, thereby providing a functional link between miRNAs and regulation of cell cycle progression.
In the final chapter, I built on emerging evidence showing that sustained E2F-dependent transcription is required for replication stress tolerance, primarily to prevent the generation of DNA damage under low nucleotide pool conditions. Here, I established a role for SETD2-dependent H3K36 trimethylation in facilitating E2F-target gene expression in S-phase. Loss of SETD2 caused reduced E2F1-binding to its target genes, as well as expression defects in a number of canonical E2F-transcripts, including CDT1, CDC6, and MCM2-7. Furthermore, E2F- and p53- gene expression changes following hydroxyurea-induced replication fork stalling were accompanied by global ATR/CHK1-dependent H3K36 trimethylation changes on the promoter regions of target genes. Taken together, these findings establish a central role for both miRNAs and SETD2-dependent H3K36me3 in the replication stress checkpoint and highlight a novel pathway through which SETD2 exerts its tumour suppressive effects.

Advisor: Humphrey, T
D'Angiolella, V
My neighbour the Animalien: constructing Japanese national cultural identity from invasive alien animal species discourse in the 21st century

In this study, I analyse the verbal and visual language used in Japanese mass media materials (newspaper pieces and a TV variety show) and state pamphlets to understand why the invasive alien animal as an Other persists despite decades of residency from a cultural angle, rather than ecological. As an example of banal nationalism, I examine this discourse for the languages in which 21st century national identity is expressed and constructed in terms of identity coordinates in space-time. With humans using these ‘animaliens’ as ‘space transformers’ and ‘time telescopes’ for self-reflection in their encounters, I find that invasive alien animals are also opportunistically used as props for teaching national cultural symbol literacy and the languages to express membership to the national culture. These languages are folklore, nostalgia and self-responsibility. Folkloric language turns individual self-exploratory fantasy spaces into nationalised exploratory fantasies. Nostalgia and self-responsibility languages build relationships with past and future-communities that serve the present. The alien animals’ Othering persists because it is useful to the majority. This approach to animaliens fills a literature gap where the human cultural coexistence with these animals has been largely ignored in favour of conservation biology.

Keywords: banal nationalism
invasive alien species
Japan
TV
identity construction
Advisor: Yamaura, C
Incorporation of biological factors in radiation therapy treatment planning

Radiation therapy plays a crucial role in the treatment of cancer. Major developments in the field, including 3D tomographic imaging, intensity modulation and novel particle modalities, have all contributed to iterative improvements in precise dose delivery. These advances have enabled highly conformal tumouricidal dose deposition with improved healthy tissue sparing. Proton therapy, in particular, has become an increasingly adopted modality due to its favourable depth-dose profile, allowing for much of the dose to be localised within the target region, with virtually no dose leakage to tissues beyond the target. However, physical dose does not tell the full story; radiobiological mechanisms and their intermodality differences must be well-understood, as these explain the processes by which the energy deposited in cells leads to cell death and, ultimately, to clinical outcomes.
Densely ionising particle tracks offer an enhanced cell killing efficiency over x-rays, which may be quantified through the relative biological effectiveness (RBE). The RBE is a multiplicative factor converting the proton dose to an x-ray dose equivalent that yields the same biological endpoint. In standard clinical practice a constant RBE of 1.1 is used, assuming protons are 10% more effective than x-rays for the same dose, though recently there has been an increased focus on more sophisticated, variable RBE models. Many decades of clinical experience with x-rays enables RBE-weighted proton dose planning under a familiar framework. The dose is shaped according to both absolute and volume-based tolerance doses. Although, in many modern treatment planning systems, dose-volume constraints (DVCs) are approximated as their exact formulation poses a non-convex optimisation problem.
This thesis proposes novel methods and recommendations for the inclusion of radiobiological factors in treatment planning through (1) a variable but pragmatic RBE model based on DNA double strand break induction, and (2) a flexible, projection-based inverse planning algorithm, suited to non-convex settings, that comprehensively addresses dose-volume effects through the exact modeling of DVCs. This author hypothesises that inclusion of these strategies will enable confident and effective treatment planning not only in terms of physical dose deposition but, crucially, in biological effect.

Keywords: feasibility seeking
double strand breaks
particle therapy
inverse problem
dose volume constraints
radiobiology
radiotherapy
proton therapy
Advisor: Van Den Heuvel, F
Hawkins, M
Vinko, S
Concert governance: how informal intergovernmental organizations orchestrate global governance


Concert governance is a defining feature of contemporary international organization: just as the Concert of Europe shaped 19th century international politics, informal intergovernmental organizations (IIGOs) like the G7 and G20 steer 21st century governance of global issues ranging from financial stability to technology regulation. States use IIGOs to govern indirectly by leveraging their collective power and influence to orchestrate other international institutions. Even though the field explores why states choose informal intergovernmentalism, how IIGOs orchestrate global governance has not yet received systematic attention.
In this thesis, I study IIGO orchestration through a series of interrelated research articles. I first identify the international origins of IIGO orchestration, highlighting the increased international issue complexity and state actor heterogeneity as key factors. I then examine the governance logic of IIGO orchestration, which walks a fine line between exerting control over the multilateral system and undermining the competence of the universal organizations that form its bedrock. I establish theoretically that IIGOs can manage this balance through strategic regime design and show empirically that the G7 and G20 embed universal organizations in differentiated regime complexes to govern cross-border regulatory challenges. Finally, I analyze the organizational foundations of IIGO orchestration, which raise questions about the limits of informality for supporting the expansive state interactions that accompany the orchestration of global governance. I theorize IIGOs’ functional scope and illustrate how the G20 adapted organizationally as it graduated from a crisis management vehicle to a global steering body.
By expanding the frontier of scholarly knowledge on IIGOs, the thesis also contributes more broadly to the study of indirect governance, regime complexity, and international institutions. While IIGO orchestration is consolidating as a pillar of global governance, this thesis provides a reference for academics and policymakers looking to study and shape multilateral responses to critical and emerging global issues.

Keywords: G7
IIGO
rising powers
global public goods
international institutions
G20
money laundering
transgovernmentalism
concert diplomacy
orchestration
technology
financial regulation
global governance
Advisor: Mattli, W
Snidal, D
The predictive view of Bayesian inference

This thesis considers the direct connection between the prediction of future observations and Bayesian inference. Using prediction as a guide, we generalize the Bayesian framework and introduce new methodologies for parameter inference and model selection which improve scalability and performance under model misspecification.
We begin with an introduction in Chapter 1 on methodologies for generalizing Bayesian inference, including the Bayesian bootstrap and general Bayesian updating. A summary of the current role of prediction in Bayesian inference is then provided.
In Chapter 2, we present a novel perspective on Bayesian inference which points to missing observations as the source of statistical uncertainty. We formally connect the Bayesian posterior on the parameter with the joint predictive distribution on the unobserved remainder of the population. Using this connection, we introduce the martingale posterior, which generalizes the Bayesian posterior. The martingale posterior only requires the elicitation of a predictive model, thus removing the need for the likelihood and prior. We discuss notions of predictive coherence and further introduce new nonparametric predictive models based on a bivariate copula update.
In Chapter 3, we investigate the computational benefits of Bayesian nonparametric learning using the Dirichlet process. This is closely related to the Bayesian bootstrap and is a special case of the martingale posterior. We find that the method is robust to model misspecification and is highly scalable due to its parallelizable nature. We further demonstrate that the posterior bootstrap, which approximately samples from the nonparametric posterior, is particularly proficient at targeting multimodal posteriors.
In Chapter 4, we introduce a notion of coherent model scoring under general Bayesian updating. We then explore the formal connection between the Bayesian marginal likelihood and cross-validation, and introduce a cumulative cross-validation score which alleviates some of the deficiencies of the marginal likelihood.
We provide a summary and discussion of future work in Chapter 5.

Keywords: Bayesian nonparametrics
Bayesian bootstrap
marginal likelihood
predictive inference
Advisor: Holmes, C
Learner strategies when listening to teacher talk in EMI settings

As English Medium Instruction (EMI) is becoming widespread in both secondary and higher educational settings, listening to the teacher speaking in English becomes an everyday task for many students who are taught mainstream curriculum subjects in their second language (L2). The strategies students use during such a listening task are of importance for teaching practitioners aiming to enhance learners’ comprehension of academic content in English. This mixed-methods study looks at L2 strategies used by EMI upper-secondary students (N = 20) of B2-C2 Common European Framework of Reference (CEFR) proficiency levels when listening to teacher talk. It explores which strategies learners use when they begin EMI, whether their strategies differ according to listening abilities, and whether strategies develop or change over a six-month period of EMI exposure. The data have been collected from a questionnaire, a lesson observation, and follow-up interviews at two time points. The findings show a wide variety of strategies and two most common strategy combinations deployed by the participants. No statistically significant correlation between strategy use and listening abilities has been found; however, differences in approaches to note-taking and summarisation/appropriation between participants with lower and higher listening abilities have been detected. Some development in strategy use over time has been recorded. The implications for teaching strategies are discussed.

Keywords: L2 listening strategies
listening strategies
listening abilities
learner strategies
self-regulation
EMI
Advisor: Rose, H
(Not)withstanding minority rights: re-thinking Canada's notwithstanding clause

On October 22, 2018, Ontario Premier Doug Ford announced that he would be using the Canadian Charter of Rights and Freedoms notwithstanding clause to override an Ontario Superior Court decision which held that his government’s municipal election legislation was unconstitutional. Ford went so far as to say that he ‘won’t be shy’ about using the clause in the future. Several months later, Quebec Premier Francois Legault used the notwithstanding clause in legislation to ban the wearing of religious symbols in public service roles. The recent actions of both Ford and Legault reignited the debate over the notwithstanding clause, upon which current scholarship is dominated by discussions of balance of power between the legislative and judicial branches. In this paper, I argue that the current scholarship that focuses primarily on the relationship between the courts and legislatures, overlooks the threat the notwithstanding clause poses to constitutional minority rights protections. Ford’s threat and Legault’s use of the notwithstanding clause reveal the ways in which minority rights are uniquely vulnerable to the current Canadian constitutional structure and must be further examined.

Keywords: notwithstanding clause
the override
Canadian Charter of Rights and Freedoms
Section 33
minority rights
Advisor: O'Regan, K
The impact of genetic drift on the distribution and uses of linkage disequilibrium

With the advent of Genome Wide Association Studies (GWAS), researchers have gained unprecedented access to data in order to examine associations between variants and complex traits and diseases. To analyze these studies, researchers have typically utilized measurements of Linkage Disequilibrium (LD) from the GWAS population or from a reference population which may be genetically drifted relative to the GWAS. However, these measurements are only point estimates and thus, do not capture the stochastic nature of forces such as recombination and genetic drift. Moreover, point estimates from reference populations do not take into consideration errors and inconsistencies in the ancestral composition between the reference and GWAS population. Therefore, in this thesis, we instead model LD as a distribution and demonstrate the extent to which statistical genetic applications can be improved in terms of their robustness and calibration by modelling uncertainty in LD.
First, we characterise the distribution of LD and demonstrate that genetic drift between populations can result in a high degree of variation of the measurements of LD. Additionally, we demonstrate that this variation leads to variation downstream within the accuracy of statistical genetic applications including summary statistic imputation and fine-mapping.
Secondly, to generate LD measurements in a genetically drifted population, we use a reference population and weight the individual reference haplotypes. We demonstrate how repeatedly sampling these weights provides a process to obtain the distribution of LD in the drifted population and how the weights can be updated in a marginal fashion.
Thirdly, using GWAS summary statistics and a reference population, we derive a Maximum Likelihood Estimate (MLE) which infers both the level of noise in the GWAS population as well as the drift between the GWAS and the reference population.
Lastly, we show that by repeatedly updating the weights on our reference haplotypes while incorporating GWAS summary statistic data leads to a method to infer the in-sample distributions of LD from a GWAS. The benefits of our approach over using LD obtained from a reference population is illustrated in the context of fine-mapping admixed populations.
We end by discussing more sophisticated methods for generating our weighted reference haplotypes, the ability to leverage distributions of LD in statistical genetic applications and the effective and efficient data sharing of LD distributions.

Keywords: statistics
genetics
Advisor: McVean, G
Davies, R
Intentional community: a qualitative analysis of social organization in a mixed-income neighborhood

Mixed-income housing policy initiatives in the United States have attempted to reduce the social disorganization associated with concentrated urban poverty. Using a Portland, Oregon HOPE VI project as a single case study site, this thesis examined how residents’ socio-economic status, correlated closely with tenure, informed neighborhood choice, social networks, social exchange and informal social control. The latter three concepts underpin collective efficacy for children, which provided the theoretical framework for this thesis. Research methods relied on 42 in- depth interviews with parents and adolescents from rented and owned homes, 10 in-depth interviews with Housing Authority of Portland staff members and neighborhood observation over a span of four months. The study revealed differences between lower-income renters’ and higher-income owners’ framing of neighborhood choice; these frames informed subsequent approaches to social ties, social exchange, and informal social control in the neighborhood.
Parents’ social networks typically did not span across tenures but adolescents’ networks were more flexible; families’ varied use of Portland’s school choice program influenced the nature of these ties and other elements of social organization in the neighborhood. Institutional resources, in the form of staff employed in youth services and community building efforts, were particularly important to social capital activation among renter families. Finally, governance forums and public spaces informed territoriality in the neighborhood and the related perception of boundaries between rented and owned households. The theoretical implications of this research relate to the utility of mixed-income housing policy as a tool for poverty reduction, as well as how social dynamics are informed by socio-economic status and delineated by physical space.

Keywords: social capital
mixed-income
housing
Advisor: Kemp, P
Rethinking punitive damages

Punitive damages are a species of non-compensatory damages. Their principal purpose is to punish the defendant for his or her wrongful conduct. This thesis is the first monograph-length treatment dedicated exclusively to this contentious remedy. Through empirical, historical and doctrinal analysis, it illuminates the practical operation of the remedy and assesses its appropriateness. The thesis is divided into three parts. Part I explores the relevant law and its normative underpinnings. Part II provides an empirical survey of nearly 600 decisions on punitive damages delivered by courts at first instance and on appeal between 1964 and 2020 in all parts of the UK (with the exception of Scotland which does not recognise the remedy). The empirical analysis examines various assertions made in the case law and academic literature regarding the operation of the remedy by treating them as testable hypotheses and reveals the extent to which these assertions conform with the empirical evidence. Part III assesses the main limitations on the availability of punitive damages in English law in light of the normative basis of the remedy, its history and the empirical findings. The two limitations examined are the confinement of punitive damages awards to specific categories of case (the ‘categories test’) and to specific types of wrongs (‘cause of action restrictions’). It is argued that these restrictions are unjustified and should be abolished. The thesis concludes that the circumstances in which punitive damages are currently available should be expanded and that their availability should depend on an assessment of the defendant’s conduct rather than the case category or the formal classification of the wrong in which the claimant sues.

Keywords: remedies
law of obligations
punitive damages
exemplary damages
private law
Advisor: Goudkamp, J
MU'TAQAL Machine: Power, Gender and Identity in Egypt's Political Prisons, 1948-1981

This thesis charts the history and evolution of a mass-incarcerating regime of detention, disappearance and torture in Egypt between 1948 and 1981. In seeking to explain Egypt’s carceral present, it traces, for the first time, the history of the Egyptian Mu‘taqal [political prison], from its emergence as a powerful instrument of government in the aftermath of the Second World War, through to its entrenchment as a mainstay of post-colonial governance by the newly independent state and by successive regimes thereafter.
Drawing on archival sources in Cairo, London, Aix-en-Provence and Amsterdam, organisational and party records, prisoners’ memoirs and testimonies, literary and visual cultural production, and over 250 interviews with members of various communist and Islamist organisations, in Egypt and in exile, it tells the history of the Mu‘taqal from the perspective of its chief protagonists, the political prisoners themselves.
The thesis critically examines the operation of power and resistance in contestations over the gendered identities of prisoners. Interrogating the idea that confinement and torture in authoritarian regimes reflect the workings of an irrational or brutish state, it illustrates that power contestation in the Mu‘taqal extended far beyond the limited and clichéd repertory of torture and hunger-strikes. Rather, emergent public discourses on respectability, ideals of ‘real manhood’, and the tenets of the nuclear family as the basis of the nascent Egyptian nation, were all distilled by the Mu‘taqal into a panoply of gendered disciplinary discourses and acts which sought to deny its inhabitants the label, recognition and identity of ‘political prisoner’.
The thesis argues that the state’s subjection and subjugation of incarcerated dissidents fundamentally relied on the state’s ability to debase mu‘taqalin’s gender identities, and that gender served as the primary terrain on which political prisoners’ sought to assert their autonomy and (re)constitute themselves as agents in the historical process.

Keywords: Political Prisoners
Political Violence
Muslim Brotherhood
Sexuality
Middle East
State Formation
Prison
Carceral capitalism
Political Movements
Arab Left
Gender
Ritual
Political Thought
Political Islam
Carceral state
Torture
Egypt
Advisor: Gildea, R
Ryzova, L