VictorJuiz/thesis huggingface dataset:
Understanding the interplay between RUNX1 and Polycomb proteins in leukaemias with fusion proteins

RUNX1 is a critical regulator of the development of the haematopoietic system and a frequent target of genetic alteration in leukaemia. In addition, wildtype RUNX1 is required for maintenance of disease in leukaemias with fusion proteins, including MLL-AF4 and RUNX1-RUNX1T1 leukaemias. However, the exact mechanisms of how RUNX1 shapes the chromatin landscape and impacts gene regulation in normal and leukaemic cells remain elusive. In this thesis, it was investigated how RUNX1 binding affects the recruitment of gene-regulatory proteins and impacts the transcriptional regulation of its target genes, and how its binding is affected by the chromatin landscape. Using a refined intracellular tethering system, it was shown that RUNX1 alone is sufficient to recruit co-activators and the transcriptional machinery, and also co-repressors, including Polycomb group (PcG) proteins. In turn, it was shown that the chromatin environment affects the ability of RUNX1 to bind to its binding sites, as gains in the repressive histone marks H3K27me3 and H3K9me3 reduce RUNX1 binding. In addition, the existing chromatin landscape impacts RUNX1-mediated recruitment of co-factors. More specifically, at active sites RUNX1 promotes recruitment of co-activators, while at PcG-repressed genes RUNX1 binding stabilises PcG recruitment. By further investigating RUNX1-mediated recruitment of PcG proteins, it was shown that a key function of RUNX1 is the stabilisation of Polycomb Repressive Complex 1 (PRC1) in MLL-AF4 ALL and RUNX1-RUNX1T1 AML. PcG mutations are found in a subset of RUNX1-RUNX1T1 and RUNX1-mutant leukaemia patients and are often associated with a worse clinical outcome, but the mechanistic details of the functional RUNX1-PRC1 cooperation have not been investigated. In this thesis, it is shown that the RUNX1-RUNX1T1 fusion protein, and other truncated RUNX1 mutant proteins lacking the RUNX1 C-terminal region, cannot associate with PcG proteins. In these leukaemias, a key role of wildtype RUNX1 is to stabilise PcG binding at PcG-repressed genes, including a subset of genes upregulated in PcG-mutant RUNX1-RUNX1T1 patients. Overall, these results demonstrate that an important function of RUNX1 is to maintain PcG repression and that this activity is disrupted in RUNX1-mutant leukaemias, particularly those with PcG mutations, thus providing a mechanistic explanation for the positive selection of leukaemic clones with RUNX1/PcG mutations.

Keywords: RUNX1-RUNX1T1
RUNX1
MLL-AF4
transcription factors
Polycomb proteins
Advisor: Milne, T
Roberts, I
Anarchist deracialization and Hirano Imao in Transwar Japan (1920–1970s)

The prewar and postwar division in the historiography of Japan has obscured intellectual and practiced continuities that transcend it. An investigation of anarchist influences on Hirano Imao’s (1900–1986) thought and action from 1920 to the early 1970s unveils a transwar continuity of what I call anarchist deracialization. Anarchist deracialization points to the intellectual deconstruction of racial hierarchies by dismantling the category of race itself, accompanied by a form of non-essentialist action guided by mutual aid and direct action. I argue that Hirano’s promotion of science and a view of nature predicated on equality and diversity became a foundation for his postwar relief campaign in Japan towards mixed-race children and their mothers. This thesis unveils a form of thought and action that I argue lied outside of imperialist, nationalist, and Western democratic discourses and cannot be understood through the frameworks of identity politics and strategic essentialism.

Keywords: anarchist modernity
Remi's Association
anarchist deracialization
1953 Society
“Mixed-blood Children Relief Campaign"
transwar
mixed-race
Hirano Imao
transnational history of Japan
konketsuji
Advisor: Konishi, S
Modelling of the microglial response to neuronal α-synuclein aggregation

Parkinson’s disease is the second most common neurodegenerative disease, characterised by α-synuclein aggregation and loss of dopaminergic and other types of neurons. Inflammation, the activation of microglial and other immune cells in response to pathology, is a well-documented feature of the neurodegenerative process. Yet, it remains unresolved whether inflammation prevents or promotes the degeneration of dopaminergic neurons in Parkinson’s disease. One reason for this knowledge gap is the lack of relevant human experimental models to study the interaction between neurons and microglia in response to pathological α-synuclein. In this study, I sought to establish human ex vivo and in vitro models to decipher the microglial response to neuronal α-synuclein aggregation that was triggered by the addition of de novo generated fibrils. Using mouse organotypic cultures, I showed that microglia are activated in response to aggregation. In a novel iPSC-based dopaminergic neuron-microglial co-culture model, I found that α-synuclein aggregation and aggregate-induced neuronal loss were mitigated by the presence of microglia. Gene expression studies and whole transcriptome analyses revealed an association between this beneficial phenotype and a transition from a homeostatic to a disease-related microglial gene expression profile. Further, pilot single cell RNA sequencing data revealed treatment specific clusters and biological pathways. Altogether my data showed that under certain conditions, microglia exert a beneficial effect in response to neuronal α-synuclein aggregation and identified morphological changes, cytokine secretion and disease-specific pathways that underpin this process. Further validation of these findings could offer immunological targets for disease modifying therapies in Parkinson’s disease.

Keywords: aggregation
Parkinson's disease
microglia
neuroinflammation
Advisor: Tofaris, G
Quiver varieties and moduli spaces of sheaves on singular surfaces

We investigate several types of Nakajima quiver varieties and their connection to the Kleinian singularities 𝐂2/Γ.
Such quiver varieties have many good properties: they are for instance irreducible and have symplectic singularities, in particular they are normal.
The first part of this thesis introduces Nakajima quiver varieties, together with the necessary background on projective Deligne-Mumford stacks and framed sheaves. Following that, we prove that the punctual Hilbert schemes (when taken with their reduced scheme structures) Hilbn(𝐂2/Γ) are examples of Nakajima quiver varieties.
We then show that there is a type of 'orbifold Quot scheme' generalising the Hilbert scheme, which can also be identified with a Nakajima quiver variety.
Following this, we investigate another generalisation of the Hilbert scheme: that of a moduli space of framed sheaves on a certain stack compactifying 𝐂2/Γ. We show that this moduli space exists as a quasiprojective scheme. We are unable to show that it is isomorphic to a Nakajima quiver variety, but we show that it carries a canonical morphism to a Nakajima quiver variety, and this morphism is a bijection of closed points.
We end by sketching some potential further directions of investigation.

Keywords: Moduli spaces of framed sheaves
McKay correspondence
Quiver varieties
Advisor: Szendrői, B
Breaking the rules : the impact of transnational migration on religion, music and occupation in the Dominican Republic

‘Breaking the rules: the impact of transnational migration on religion, music and occupation in the Dominican Republic’ is an exploration of how processes of transnational migration have changed the way that mainstream Dominican society perceives marginalized groups and their cultural practices. The thesis focuses on a community of rural poor descended from slaves known as Monte Cruz, located outside of the city of Bani on the south-central coast of the Dominican Republic. People from this area have migrated to Boston and other northeastern U.S. cities in the past three decades. Migrants have revitalized their homeland religion of Dominican Vodut as a strategy for overcoming the challenges and risks of travelling, living and working in the U.S. The transnational context in which these traditions are carried out has given rise to the de-stigmatization of expressive cultural practices of music and religion, so that Vodú has become more visible and widespread, music genres of religious palo are increasingly played in non-sacred contexts, and the brothel music of bachata has become popular in mainstream elite circles. Transnational migration creates transformations in other spheres of home society that are changing traditional hierarchies of class, race and morality. The thesis explores the process of ‘shifting latitude’, a form of social mobility that is eroding and re-constituting social hierarchies in home communities.

Keywords: migration
religion
transnationalism
Dominican Republic
occupations
music
transnational migration
Analysis of buoy measurements in the laboratory and field

Wave following buoys, which are widely deployed across the oceans, offer the potential to measure various wave properties. However, some aspects of buoy measurements are still not fully studied. Knowing the accuracy of buoy measurements and affecting factors of accuracy is essential. This thesis first assesses the accuracy of directional spreading estimates made using buoy measurements. The influence moorings may have on buoy measurements was then investigated.
In the first part of the thesis, directional spreading estimates are compared based on experimentally obtained buoy and wave gauge measurements. Experiments with both following (unimodal in direction) and crossing (bimodal in direction) sea states are examined. In addition to this, synthetic wave data are used to investigate the effects of wave generation and nonlinearity on spreading estimates. The results show that while directional estimates produced using buoy measurements are reasonably accurate in following sea states, they struggle to identify distinct directional peaks in crossing sea states.
The second part of the thesis looks at the effects moorings may have on buoy measurements made in the field. Sea states with similar statistics have been collected and investigated. It is found find that while moorings have no observable effects on buoy measurements for the majority of parameters, they may affect the directional spreading estimates.

Keywords: Mooring
Directional Spreading
Wave Buoys
Ocean Waces
Surface Gravity Waves
Wave Measurement
Advisor: Adcock, T
McAllister, M
Quantification of gait and time perception in Parkinson’s disease

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by motor dysfunctions because of death of dopaminergic cells in the basal ganglia (BG). It is usually treated with the dopamine precursor levodopa and/or deep brain stimulation (DBS) where electrical stimulus pulses are delivered to parts of the BG.
Despite much research into potential biomarkers, current diagnosis and disease staging remain reliant on the clinical assessment of motor symptoms using rating scales. This causes several problems: assessments are subject to inter-observer variability; rating scales are nonlinear; and the scales only enter their working range once more than half of the dopamine producing cells in the brain have died.
New treatments, and in particular disease modifying drugs (DMDs), are desperately needed. Only around one in 10 newly developed drugs survives rigorous assessment in trials, which are both time consuming and very costly. Failures must be recognized quickly so that resources can be transferred to the next candidate agent. When evaluating DMDs investigators are usually looking for small changes in disease trajectory. The more sensitive a biomarker, and the less affected it is by noise, the sooner a difference will be seen after treatment commences. A sensitive and noise resistant measure is therefore critical to minimizing resource consumption in the evaluation of doomed drugs. An additional problem arises when the measurement is affected by background symptomatic medication, which the great majority of PD patients are treated with. Symptomatic treatment can obscure progression in motor scales almost completely, rendering them completely insensitive to changes in disease trajectory.
Thanks to novel technology we are now able to quantify motor disturbances rapidly, accurately, noninvasively, and objectively using wearable sensors. Due to its portable and easily operable nature, wearable sensors are replacing motion detection systems and force plates to give quick clinical measurements. This thesis examines the usefulness of precise measurements of gait and balance as a means of quantifying PD. The aim is to identify and characterize features that change significantly over periods of months rather than years, are not noisy, and are relatively unaffected by the presence of symptomatic medication. Gait measurements will be taken from both PD patients and age-match controls every three months for two years. In addition, cross-sectional studies will be conducted to examine gait in patients’ on- and off- medication and DBS states to allow rapid evaluation of which features show the greatest change and thus warrant the closest examination from inducing abrupt shifts in parkinsonian state.

Keywords: progression marker
Parkinson's disease
deep brain stimulation
biomarkers
gait
time perception
Advisor: Antoniades, C
Fitzgerald, JJ
Constitutional courts in hybrid regimes

Democratic backsliding and the resurgence of authoritarianism have led to the prevalence of hybrid regimes in the twenty-first century. This ambiguous kind of authoritarian regime has complicated the traditional democracy-versus-pure-authoritarian-regime divide. Hybrid regime is the new game in town, but can constitutional courts promote democracy in these contexts? And if so, how? Cautiously optimistic about the potential of constitutional courts, the thesis argues that this is not an empty wish. Constitutional courts are not effective substitutions of the political process. Nevertheless, they have a modest but meaningful role to play in advancing democratic norms in a hybrid regime. The thesis provides a valuable examination of hybrid regimes and constitutional courts, and offers theories and tools that aim to guide democratically committed judges in hybrid regimes. These prescriptions are not limited to the adjudicative context, and cover what judges as social actors can and should do as well. While normative theoretical in substance, the thesis is informed by comparative insights and empirical studies, and draws heavily on a wide range of disciplines including law, political theory and science, sociology and psychology. The thesis hopes to illuminate and inspire judges who are operating in politically challenging environments.

Keywords: Constitutional theory
Courts
Hybrid regime
Advisor: Barber, N
Biological applications of chemically modified recombinant histones

In eukaryotes, DNA is packaged into repeating units called nucleosomes, which consist of ~150 base pairs of DNA wrapped around eight proteins called histones. These histones are often laden with post-translational modifications (PTMs), and while many PTMs have been shown to have profound effects on gene expression and chromatin organization, most remain uncharacterized. This thesis strives to elucidate the functions of PTM containing histones. Chapter 1 describes a light-driven reaction that site-specifically inserts sidechains of interest into histones via radical addition to previously installed dehydroalanine residues, with a scope encompassing many native and PTM containing sidechains, as well as several reactive functional groups. Chapter 2 utilizes the reaction from Chapter 1, as well as others from our group, in several independent applications: The enzymatic removal of installed histone PTMs is tested, histone methylation and phosphorylation are assessed in the structural context of a nucleosome, PTM processing on fluorinated histone sidechains is tracked by 19F-NMR, and interaction partners are crosslinked to histones bearing electrophilic sidechains. Chapter 3 studies histones in more complex, living systems. The understudied ability of histones to penetrate cell membranes is investigated, revealing the incorporation of extracellular histones into the chromatin of nearby cells, provoking a strong inflammatory and immune response. Furthermore, several light-driven histone modification reactions are attempted in the translucent model organism, the zebrafish. In conclusion, this thesis describes powerful tools for modifying histones and applies them to relevant problems in epigenetics, revealing unknown roles and functions of histones and their PTMs.

Keywords: epigenetics
protein modification
chromatin
histone
post-translational modification
Advisor: Davis, B
Oppermann, U
In-situ polymerization of diacetylene ligands for applications in quantum dot solar cells

Improving the efficiency of next-generation solar cells is crucial to their commercialization. This thesis presents a novel approach to coupled organic-inorganic nanostructures through in-situ polymerization of a ligand, creating an extended, delocalized sp2 environment surrounding lead sulfide (PbS) quantum dots in a thin film.
Through the design of this novel, in-situ polymerizing ligand, ligand exchange dynamics are explored by looking at terminal alkynes, primary amines, and carboxylic acids as anchoring moieties. Using Fourier Transform Infrared Spectroscopy (FTIR) and X-ray Photoelectron Spectroscopy (XPS), it is shown that terminal alkynes and primary amines do not coordinate to PbS quantum dots, and that ligands containing sp-hybridized bonds can influence the band position of thin films through successful coordination via a carboxylic acid coordinating group. A proof-of concept diacetylene ligand, dodeca-5,7-diynedioic acid (D57DDA) is synthesized and coordinated to PbS quantum dots, confirmed through the use of XPS. In-situ polymerization of the diacetylene ligand is confirmed using FTIR and XPS. Finally, solar cells incorporating the novel D57DDA ligand are fabricated and compared to PbS quantum dot control devices. Devices using the coupled organic-inorganic nanostructure as the hole-transport layer show comparable device efficiencies to control devices at 4%, with performance improving with increased UV exposure. This is hypothesized to be due to the polymer’s band alignment with the quantum dots leading to efficient charge transfer of holes and increased mobility through the hole-transport layer. Impurities, believed to be chloride ions introduced in the ligand synthetic isolation, are shown to improve device performance with their absence reducing short circuit current.

Keywords: photonic
alkyne
polymerization
quantum dot
FTIR
XPS
nanomaterial
diacetylene
photovoltaic
solar cell
ligand
Advisor: Watt, A
Assender, H
Quasi-trees and product set growth

In this thesis we investigate the geometric properties of quasi-trees, and study product set growth in groups with acylindrical actions on quasi-trees and hyperbolic spaces.
The main tool we use when considering quasi-trees is the end-approximating tree, which is a tree that we can construct from a geodesic space while preserving its space of ends. We use this construction to prove that every quasi-tree is (1,C)-quasi-isometric to a simplicial tree, one consequence of which is that having a cobounded quasi-action on a simplicial tree is equivalent to having a quasi-conjugate (1,C)-quasi-action on a simplicial tree. The end-approximating tree can also be used to show that the boundary of a quasi-tree is isometric to the boundary of its approximating tree under a certain choice of visual metric, and that this gives us a natural extension of the standard construction of a visual metric on the boundary of a tree.
As another consequence, we are able to show that Gromov's Tree Approximation Lemma for hyperbolic spaces can be improved in the case of quasi-trees to give a uniform approximation for any set of points, independent of cardinality. From this we show that having uniform tree approximation for finite subsets is equivalent to being able to uniformly approximate the entire space by a tree.
This uniform version of Gromov's Tree Approximation Lemma has an application to Delzant and Steenbock's work on product set growth in acylindrically hyperbolic groups. In particular, we are able to show that for any group G that acts acylindrically on a quasi-tree, there exists α>0 such that for any finite U ⊂ G that has large enough displacement in the quasi-tree, and is not contained in a virtually cyclic subgroup, we have that |Un|⩾(α|U|)⸤n+1/2⸥. By a result of Balasubramanya, this theorem applies to every acylindrically hyperbolic group.
We also study growth in acylindrically hyperbolic groups directly from their actions on hyperbolic spaces, which allows us to get a dichotomy on the finitely generated subgroups of mapping class groups, at the cost of working only with symmetric subsets. Specifically, we show that for every surface S of finite type, there exist α, β > 0 such that for any finite symmetric subset U of the mapping class group MCG(S) we have that |Un|⩾(α|U|)βn, so long as no finite index pure subgroup of h 〈U〉 has an infinite order central element.
As right-angled Artin groups embed as subgroups of mapping class groups, a similar dichotomy also applies in this case. We separately prove that we can quickly generate loxodromic elements in right-angled Artin groups, which by a result of Fujiwara shows that the set of growth rates for many of their subgroups are well-ordered.

Keywords: Mapping class groups
Right-angled Artin groups
Group growth
Acylindrically hyperbolic groups
Quasi-trees
Hyperbolic geometry
Advisor: Drutu badea, C