VictorJuiz/thesis huggingface dataset:
The three methyls: the function and therapeutic potential of histone H3K36 trimethylation
Keywords: homologous recombination
cancer
DNA damage
WEE1 inhibitor
SETD2
DNA replication
personalised cancer therapy
ATR inhibitor
CHK1 inhibitor
synthetic lethality
histone modification
epigenetics
H3K36me3

DNA is wrapped around proteins called histones, whose modification regulates numerous cellular processes. Therefore it is not surprising that mutations in the genes that modify the histones are frequently associated with human cancer. For example, mutations in SETD2, encoding the sole enzyme that catalyses histone H3 lysine 36 trimethylation (H3K36me3), occur frequently in multiple cancer types. This identifies H3K36me3 loss as an important event in cancer development, and also as a potential therapeutic target.
This thesis investigates the following questions: (1) how does the loss of H3K36me3 contribute to cancer development; and (2) what therapy can be used to kill cancers that have already lost H3K36me3.
To answer the first question, this thesis shows that H3K36me3 facilitates the accurate repair of DNA double-stranded breaks (DSBs) by homologous recombination (HR). H3K36me3 promotes HR by recruiting CtIP to the site of DSBs to carry out resection, allowing the binding of HR proteins (such as RPA and RAD51) to the damage sites. Thus it is proposed that error-free HR repair within H3K36me3-decorated transcriptionally active genomic regions suppresses genetic mutations which could promote tumourigenesis.
To answer the second question, this thesis reveals a clinically relevant synthetic lethal interaction between H3K36me3 loss and WEE1 inhibition. WEE1 inhibition selectively kills H3K36me3-deficient cells by inhibiting DNA replication, and subsequent fork stalling results in MUS81 endonuclease-dependent DNA damage and cell death. The mechanism is found to be synergistic depletion of RRM2 (ribonucleotide reductase small subunit), the enzyme that generates deoxyribonucleotides (dNTPs). This work reveals two pathways that regulate RRM2: one involves transcriptional activation of RRM2 by H3K36me3, and the other involves RRM2 degradation regulated by Cyclin-Dependent Kinase, CDK1 (which is controlled by WEE1, CHK1 and ATR). Based on this mechanism, the synthetic lethal interaction is expanded, from between two genes, to between two pathways. Supported by in vivo experiments, the study suggests that patients with cancers that have lost H3K36me3 could benefit from treatment with the inhibitors of WEE1, CHK1 or ATR.
Reconstructing collective action in the neoliberal era: the emergence and political impact of social movements in Chile since 1990   
Keywords: labour policy
education policy
social movements
Concertacion
neoliberalism
democracy
Chile

This dissertation investigates the emergence and impact of social movements in Chile since the reinstatement of democracy in 1990. Seeking to make an important contribution to the understanding of the reconstruction of collective action in post-transition Chile, I focus on two cases which have been particularly successful in questioning the benefits of market-friendly policies introduced by the military regime (1973-1989) and continued to a great extent by the Concertación governments (1990-2010). The first case is the 2006 Pingüino movement, named after the secondary school students’ penguin-like black and white school uniforms, which forced a substantial discussion on the education system’s segregating effects and its neoliberal underpinnings. The second case is the 2007 Contratista movement, composed of subcontracted workers of CODELCO – Chile’s main state-owned copper-extracting company. The Contratistas repoliticised a long-dormant debate on labour issues and revitalised a trade union movement which had been in decline in previous decades.
I draw on the Contentious Politics approach, which stresses social movements’ interaction with the institutional terrain, and explain the emergence of the Pingüinos and Contratistas as the result of three distinct but intertwined processes: the opening up of the structure of political opportunities involved in the rise of President Bachelet; the deeply felt discontent with the education and labour reforms introduced by the military regime and kept largely intact by the Concertación governments; and the movements’ adoption of non-hierarchical organisational forms as a way of reconstructing collective action ‘from below’. In terms of political impact, I show that both the students and the contract workers were successful in introducing issues onto the public agenda that were not there before the emergence of the movements. The extent to which this was translated into bills that reflected the concerns of the movements, however, depended on their capacity to continue to exert pressure on the government and to forge political alliances. In this way, I argue that the impact of the movements was indirect and followed a two-stage process through which first the Pingüinos and Contratistas influenced aspects of their external environment, namely, public opinion and political alliances, and then the latter influenced policy.
Overall, my research shows the links between processes at the micro-level (the development of organisational resources and grievance interpretation) and their subsequent impact at the macro-level (agenda-setting and policy impact) – a development that has undoubtedly acquired greater relevance and analytical urgency since the wide range of protests that have taken place around the world since 2011.
Velocity and attenuation structure of the mantle: constraints from differential properties of shear waves
Keywords: upper mantle
S-waves
attenuation

Although much progress has been made in determining the three dimensional distribution of seismic wave velocities in the Earth, substantially less is known about the three dimensional distribution of intrinsic attenuation. In this study variations in attenuation and shear velocity of the Earth's mantle are constrained using measurements of differential travel time and attenuation.
The data are broadband displacement SH seismograms filtered to have energy in the period range 8 to 20 s. Broadband data are used as they should allow a more accurate estimation of body wave attenuation to be made. The seismograms are obtained from over 600 globally distributed earthquakes of magnitude, Mw, 5.5 or greater.
Two new methods for determining differential travel times and differential t* values from multiple S phases are presented. The first of these, referred to as the "waveform fitting method" is used to analyse approximately 4300 SS and S waveforms and around 1000 SSS and SS waveforms resulting in differential SS-S and SSS-SS travel times, and corresponding values of differential attenuation represented by t*. The second method, referred to as the "spectral ratio method" is used to analyse approximately 3200 SS and S and around 900 SSS and SS waveforms.
The differential travel times and t* values are inverted to obtain models of the lateral variation of shear velocity and lateral variation of q(mu) where q(mu) =1/Q(mu). The models explain the data well but have limited depth resolution. The velocity models show good correlation with previous studies, in particular, low velocities are observed underlying spreading ridges and convergent margins and high velocities are observed under continental regions. The q(mu) model shows shield regions to be less attenuating than PREM, with ridges appearing as highly attenuating features.
Models of shear velocity and attenuation are also obtained by combining the body wave dataset of this study with the surface wave datasets of Van Heijst (1997) and Selby (1998).
The theological vision of Reinhold Niebuhr's "The irony of American history"
Keywords: Reinhold Niebuhr
American Foreign Policy
Theology and Politics

Reinhold Niebuhr remains at the center of a national conversation about America's role in the world, and commentators with divergent political and religious positions look to his 1952 work, The Irony of American History, in support of their views. In this study, Scott R. Erwin argues that an appreciation of Niebuhr's theological vision is necessary for understanding the full measure of Irony and his perspective on life more broadly. Such a study is important because many individuals reading Irony today fail to acknowledge the central role that his Christian beliefs played in his writings. Niebuhr described his theological vision as being 'in the battle and above it,' and, it was this perspective that led Niebuhr, in Irony, to assert that America must both take 'morally hazardous action' in combating the aggression of the Soviet Union and engage in critical self-evaluation to prevent the country from assuming the most odious traits of its Cold War foe.
Niebuhr developed his theological vision over the course of the 1930s and 1940s through engagement with Christian doctrine, as most readily seen in his academic works such as The Nature and Destiny of Man, and engagement with current events, as seen in his many journalistic writings during this period. By focusing primarily on Niebuhr's writings between 1931 and 1951, Erwin traces the development of his Christian interpretation of human nature and history, establishes how it informed his theological vision, and reveals how that theological vision underlay his writings on current affairs.
Land, distributive politics and rural governance in reform China
Keywords: China
urbanization
politics and government
land use
rural development

This thesis is concerned with distributive politics arising from land development and territorial changes in reform China. It adopts a historical institutionalist approach in examining the evolution of rural institutions, with a specific focus on the rural shareholding cooperative and the village joint stock company. It argues that despite the move towards the market in the reform era, core elements of the state socialist redistributive economy imposed upon rural society in the Maoist era have been sustained and reproduced in the two reform-era institutions. The re-collectivisation of the village through the shareholding reform has provided the institutional foundations for the continued deployment of redistributive power and the reproduction of paternalistic relations that generate expectations of the fulfilment of an implicit social contract.
This thesis argues that while the reforms have helped to hold the village together in the midst of drastic territorial change, the very operation of the institutions may be generating endogenous pressures for change as they heighten propensity of power abuse and produce unequal distributive outcomes. These internal contradictions were exacerbated by the checun gaizhi reform, which abolished grassroots organisations of self-governance and created semi-private entities, which by their straddled nature were not subjected to any effective mechanisms of checks and balances. This privatisation of rural governance has profound implications on rural outcomes. By comparing and contrasting the divergent trajectories undertaken by three villages that shared similar characteristics, this thesis sheds light on some of the deeply problematic aspects of rural governance in contemporary China.
Supersymmetry and electroweak fine tuning
Keywords: Supersymmetry

Low scale supersymmetry (SUSY) is a compelling solution to the electroweak hierarchy problem. However, increasingly strong limits on the masses of superpartners, first from LEP and now the LHC, mean that the simplest models require significant fine tuning. This thesis is dedicated to the study of a possible alternative low energy superpartner spectrum, natural SUSY, in which only superparticles directly involved in stabilising the electroweak scale are light, alleviating collider limits and potentially reducing tuning.
After reviewing how low scale SUSY is motivated by the hierarchy problem, we build a model of SUSY breaking and mediation that successfully generates a natural SUSY spectrum. This also suppresses the first two generation fermion Yukawas, and leads to small parameters in the hidden sector, which are required for successful SUSY breaking. A challenge in models of natural SUSY is raising the physical Higgs mass to 125 GeV, and we study the possibility that this could occur through the addition of a singlet to the theory. If stops are very light, the coupling of the singlet to the Higgs needs to be so large that it becomes nonperturbative before the scale of grand unification, raising the concern that precision gauge coupling unification may be upset. However, we find that this is not necessarily the case. Rather it is possible this could correct for the present &bsim; 3% discrepancy in the two-loop minimal supersymmetric model's unification prediction.
We then turn to the fine tuning in models of natural SUSY, emphasising that this should be measured with respect to the theory's ultraviolet (UV) parameters. We show that the first two generation sfermions can be made relatively heavy, beyond LHC reach, without introducing tuning. However, the gluino generates a significant tuning through the stops during the renormalisation group flow. As a result, there is no fine tuning benefit in reducing the stop masses below (50 - 75)% of the weak scale gluino mass, and we obtain strong lower bounds on the tuning of theories compatible with collider limits. We also study theories with Dirac gauginos, which have relatively low fine tuning even if the scale of mediation is high. Finally, we consider the effect of relaxing a common assumption and allowing the hidden SUSY breaking sector to modify the running of the visible sector soft masses. This may plausibly occur in realistic models and could dramatically reduce the fine tuning of SUSY theories.
Diving behaviour and activity patterns of the invasive American mink, Neovison vison
Keywords: biotelemetry
activity patterns
time-depth recorders
diving behaviour
American mink

Semi-aquatic mammals have evolved to forage in both aquatic and terrestrial environments, and they generally lack locomotor specialisation for either. Having relatively unspecialised adaptations, some semi-aquatic species are generalist foragers, and their activity and diving patterns provide insight into constraints on their foraging behaviour.
The recent miniaturisation and improved accuracy of logging devices allow remote data collection from small (<1kg), shallow-diving species. The development of analytical methods has lagged behind technological advances (and techniques developed for fully aquatic animals do not account for the variability of behaviour typical of semi-aquatic animals and their switching between terrestrial and aquatic environments). I applied and developed novel analytical techniques to identify activities and diving patterns of a semi-aquatic mustelid, the American mink (Neovison vison), fitted with Time-Depth Recorders (TDRs). Using a hidden Markov model (HMM) algorithm allowed me to classify dives into three states to identify clustering, and describe sequential diving patterns by mink. TDRs were used to determine active/inactive periods on the basis of rapid TDR temperature changes, and this method was validated empirically. Having developed this methodology, I applied it to 18 datasets collected from 14 mink in lowland England. Terrestrial activity of mink was positively related to ambient temperature (across both sexes), however aquatic activity, especially diving, appeared to be more influenced by daylight than by temperature. Mink showed intersexual differences, with males being more nocturnal and more active on land, and females more diurnal, and more persistent in diving. There was considerable variability between sexes and individuals.
This is the first study to use HMM to classify the dives of a semi-aquatic animal, and the first to use TDR temperature records to identify mammalian activity patterns. These methods will be generally applicable to animals that make rapid transitions between environments and have thus far been difficult to study.
Passing through time: painting and cinema in the works of Julian Schnabel
Keywords: visual arts
fine art
painting
film
cinema
Julian Schnabel

THIS STUDY examines the intersection of painting and cinema through the oeuvre of American artist Julian Schnabel. A controversial painter who came to prominence in the contemporary art world of the eighties, the study begins by contextualizing Schnabel within the art critical debates of the period. Addressing and revising the perceived reputation of the artist, the first chapter re-positions Schnabel predominantly as an inheritor of various traits of post-war American painting, in particular the somatic, affective and existential treatment of the canvas characteristic of action painting.
The body of the study proceeds to compare the ways in which Schnabel’s cinematic practice borrows, extends and thus affirms many of his painterly approaches. Examining his four major film works (Basquiat, Before Night Falls, The Diving Bell and the Butterfly and Miral) in tandem with his paintings, these chapters plot major confluences between the two media, in particular Schnabel’s overall use of a subjective, phenomenological method. Crucially, this aesthetic approach is shown to be in the service of an existential as opposed to epicurean aim, as it is most overtly expressed in his use of the objet trouvé and the dedication.
The study ends by changing the vector of analysis to trace how Schnabel's foray into the cinema may have influenced the aesthetic of his paintings, and subsequently how a reproductive medium such as film is able to push the boundaries of painting, not necessarily to announce its death.
Ultimately, the goal of this study, beyond the monographic examination of a single artist, is to propose ways in which the medium of film has contributed to an evolving understanding of visual representation. For, unlike the modernist premise, the assumption is that it is precisely through the interaction and absorption of various formats that a medium can change, evolve and expand.
Freedom as response-ability: agency and artistic creativity in the work of Martin Heidegger
Keywords: philosophy of language
agency
Heidegger
artistic creativity

The origin of this thesis can be traced back to a deceptively simple question that struck me when reading Hegel for the first time: What, if anything, can be made of human freedom when we live in a world that has a profound impact on who we are and what we do? Unhappy with the way existentialist reactions to Hegel characterized freedom as our ability to step out of our world and determine our identity through our own decisions and will, but nevertheless inspired by Heidegger’s depiction of human agents as always already in the world, this thesis answers the aforementioned question by turning the existentialist conception of freedom on its head: that is, instead of characterizing freedom as detached decisionism, I argue that freedom is a function of our ability to recognize and respond to the disparate demands our world places upon us. Specifically, and unlike Heidegger’s existentialist interpreters, I read Heidegger’s account of authenticity as a case of engaged-agency in which we clarify the possibilities others make available and then act accordingly. There is, however, a certain limitation to this interpretation of human agency: namely, that treating freedom as an active response to the wants and needs of others binds the agent to possibilities present in her current situation and therefore fails to capture the kind of freedom we associate with cultural transformation or artistic creativity. Hence, this thesis addresses a second set of questions: What conditions make historical change possible? And how is it that artists are able to alter the world? In response to the first query, I turn to Heidegger’s claim that we are in truth and in untruth as well as his discussion of Gelassenheit to argue that the play between the possibilities present in a particular culture and those that are excluded by it along with a release from our present activities create the conditions for cultural transformation. In reply to the second question, I examine Heidegger’s account of the happening of truth and show how thinkers and artists are able to reveal the possibilities concealed in their culture through the creative use of language. Finally, I contend that the freedom associated with cultural transformation and artistic creativity is also a form of responsibility insofar as the success of a given transformation depends on others recognizing that transformation as valuable and thus worthy of their support.
Development of spontaneous isopeptide bond formation for ligation of peptide tags
Keywords: SpyCatcher
SpyTag
Split-Protein
SpyLigase
Protein Ligation

Peptide tags are ubiquitous in the life sciences, with roles including purification and selective labeling of proteins. Because peptide tags are small they have a limited surface area for binding and hence usually form low affinity protein interactions. These weak interactions limit the uses of peptide tags in cases that require resistance to forces generated with macromolecular architectures or protein motors. Hence a way to create a covalent interaction with a peptide tag would be useful. It was found possible to create a covalent bond-forming peptide tag using the spontaneous isopeptide chemistry of the CnaB2 domain from the Gram-positive bacterium Streptococcus pyogenes. In the CnaB2 domain a reactive Lysine forms an isopeptide bond with an Aspartic acid, catalyzed by a Glutamic acid, creating an internal covalent linkage. Subsequently it was shown that the CnaB2 domain could be split into two parts, a domain with the Lysine and Glutamic acid called SpyCatcher and a peptide with the Aspartic acid called SpyTag, such that the isopeptide covalent linkage can be formed when SpyCatcher/SpyTag are mixed together. SpyCatcher/SpyTag was applied in this thesis and showed functionality in a wide array of scenarios. SpyCatcher/SpyTag covalently linked within the cytosol of E. coli, on surface membrane proteins of HeLa cells, and regardless of whether SpyTag was located on the N- or C-terminus or an internal site. Crystal structures of SpyCatcher/SpyTag were then obtained and it was found possible to shrink the SpyCatcher by 32 residues to a core domain of 83 residues. To create an even smaller covalent linkage system, SpyCatcher was split further to generate a protein (SpyLigase) ligating two peptide tags. The β-sheet with the reactive Lysine was removed from SpyCatcher and called KTag. SpyLigase could covalently link SpyTag and KTag. SpyLigase-induced ligation was independent of the location of SpyTag/KTag on the target proteins and was applied to create affibody polymers, which were shown to improve magnetic isolation of cells with low tumor antigen expression. Through this work protein-protein covalent linkage systems were refined and generated that have future applications for the creation of unique macromolecular structures, cellular labeling, and protein cyclization.