VictorJuiz/thesis huggingface dataset:
Genomic regulation and molecular pathways of X chromosome inactivation
Keywords: polycomb
Xist
genomics
gene silencing
X chromosome inactivation
gene regulation
chromatin
long non-coding RNA

X chromosome inactivation (XCI) is a process by which one X chromosome in female mammals is silenced to equalise the dosage of X-linked gene expression between XX females and XY males. XCI is initiated by a long non-coding RNA (lncRNA), Xist, expressed from the future inactive X chromosome (Xi) during embryonic development. Xist spreads in cis to coat the chromosome and recruits molecular pathways which modify the underlying chromatin from an active to a repressive state, leading to complete transcriptional silencing of almost all genes on Xi. XCI is an important paradigm for lncRNA-directed gene repression and its study can inform our understanding of mechanisms of chromatin regulation more widely.
This thesis presents an experimental characterisation of iXist-ChrX, a cellular model that recapitulates the establishment of XCI during early mouse development. I perform quantitative, high-resolution and allele-specific genomic analyses of Xist-mediated changes to chromatin over time courses of Xist induction, providing novel insights into the cis-regulatory features that influence variable silencing dynamics on a gene-by-gene basis. A key finding from these analyses is that slow-silencing genes and genes which escape complete inactivation are marked by binding motifs for the transcription factor YY1. I also document a pilot scRNA-seq experiment to address questions of cellular heterogeneity in Xist-mediated gene silencing and lay the foundations for future investigations at single-cell resolution.
In further experiments, I use CRISPR-Cas9 genome editing to interrogate two key molecular pathways acting downstream of Xist. By disrupting SPEN and Polycomb pathways individually and in combination in iXist-ChrX cells, I dissect the relative contributions of each pathway and demonstrate that they act in parallel, through distinct mechanisms of chromatin modification, and additively to silence X-linked genes. These experiments also reveal that both SPEN and PCGF3/5-PRC1 have secondary roles in ensuring correct localisation of Xist RNA over Xi, and highlight an interplay with cellular differentiation important for the complete establishment of silencing during the later stages of XCI.
Identifying and exploiting structures for reliable deep learning
Keywords: regularisation
encyrpted prediction
calibration
generalisation
benign overfitting
adversarial robustness
label noise
machine learning

Deep learning research has recently witnessed an impressively fast-paced progress in a wide range of tasks including computer vision, natural language processing, and reinforcement learning. The extraordinary performance of these systems often gives the impression that they can be used to revolutionise our lives for the better. However, as recent works point out, these systems suffer from several issues that make them unreliable for use in the real world, including vulnerability to adversarial attacks (Szegedy et al. [243]), tendency to memorise noise (Zhang et al. [286]), being over-confident on incorrect predictions (miscalibration) (Guo et al. [99]), and unsuitability for handling private data (Gilad-Bachrach et al. [88]). In this the- sis, we look at each of these issues in detail, investigate their causes, and propose computationally cheap algorithms for mitigating them in practice.
To do this, we identify structures in deep neural networks that can be exploited to mitigate the above causes of unreliability of deep learning algorithms. In Chapter 4, we show that minimising a property of matrices, called stable rank, for individual weight matrix in a neural network reduces the tendency of the network to memorise noise without sacrificing its performance on noiseless data.
In Chapter 5, we prove that memorising label noise or doing improper representation learning makes achieving adversarial robustness impossible. Chapter 6 shows that a low-rank prior on the representation space of neural networks increases the robustness of neural networks to adversarial perturbations without inducing any tradeoff with accuracy in practice.
In Chapter 7, we highlight the use of focal loss, which weights loss components from individual samples differentially by how well the neural network classifies each of them, as an alternative loss function to cross-entropy for minimising miscalibration in neural networks.
In Chapter 8, we first define a new framework called Encrypted Prediction As A Service (EPAAS) along with a set of computational and privacy constraints. Then we propose the use of a Fully Homomorphic Encryption [84] scheme which can be used with a Binary neural network [61], along with a set of algebraic and computational tricks, to satisfy all our conditions for EPAAS while being computationally efficient.
‘Voices of all the nations’: Strauss, Saint-Saëns, Scriabin, and the American concert tour at the Fin de Siècle
Keywords: Americanist musicology
Concert tour
Reception history
Bildungsroman
Gilded Age
Richard Strauss
Fin de Siècle
Alexander Scriabin
Musicology
Feminist musicology
Camille Saint-Saëns
Newspaper criticism
Progressive Era
American studies
Cosmopolitanism

From the 1880s to the First World War, some of Europe’s most eminent composers were invited to the United States to conduct and perform. Almost invariably, American audiences, critics, and musicians experienced these visits as major cultural events, influencing contemporary discussion about the future of art, the nature of American concert life, and its relationship to that in Europe. In defining their relationship to a musical Other, American critics helped fashion a national musical Self.
This dissertation documents, for the first time, the tours of Strauss (1904), Saint- Saëns (1906), and Scriabin (1907), and adds to the growing literature on music economics and the changing social status of performers. The critical reception of these tours also demonstrates a complex American understanding of its European heritage, adapted by commentators to their own ends. The success of Strauss intersects with the end of Gilded-Age aestheticism and, I argue, a deliberate ‘re-masculinisation’ of the artistic sphere. To understand Saint-Saëns’s visit, I explore evolutionary methodologies in music history and a national enthusiasm for cultural acquisition. In discussing the relative failure of Scriabin, I address enduring racial and gendered prejudice. Each tour introduces a variety of critical issues. Considered together, they demonstrate how Americans, reckoning with their European heritage, treated that relationship as a way of articulating the Self. Critics saw America’s future in its synthesis of the best elements of the Old World. In affirming the virtues of European art, critics deliberately positioned American music as its eventual heir.
TARG1 protects against DNA ADP-ribosylation stress
Keywords: ADP-ribosylation
DNA damage response

ADP-ribosylation is a modification that can target a variety of macromolecules and can regulate an array of important cellular processes. ADP-ribosylation is catalysed by ADP-ribosyltransferases that use NAD+ as a cosubstrate to transfer ADP-ribose onto target molecules. The resulting modification can be recognised by ADP-ribose binding domains and can also be removed by enzymes collectively known as ADP-ribosylhydrolases. Recently, a toxin termed DarT from bacteria was shown to modify thymidine bases on single-stranded DNA. The antitoxin of DarT is DarG, which shows striking structural homology to the human ADP-ribosylhydrolase TARG1. Here, we show that TARG1 can directly reverse thymidine-linked ADP-ribosylation like DarG. We also use DarT as a genotoxin to induce DNA ADP-ribosylation stress in human cells. We sought to examine how human cells respond to DNA ADP-ribosylation stress and to determine if TARG1 is involved in the response of this form of DNA damage. We find that wild-type cells expressing DarT show no sensitivity to DNA ADP-ribosylation. However, in the absence of TARG1, cells show elevated levels of DNA damage and cytotoxicity. This sensitivity to DNA ADP-ribosylation is rescued with TARG1 wild-type overexpression but not for a catalytically inactive form of TARG1. The damage inflicted by DarT-mediated DNA ADP-ribosylation occurs within replicating cells and co-localises with sites of DNA synthesis. Furthermore, we demonstrate the first detection of reversible ADP-ribosylated genomic DNA in vivo from bacterial and human cells. We also examine sensitivity of TARG1-deficient cells to an inhibitor of PARG, another ADP-ribosylhydrolase. PARG inhibitor treated TARG1-deficient cells show signs of replication stress and elevated levels of ADP-ribosylation that is dependent on PARP1-2 activity. We consider if TARG1 and PARG have a shared substrate, perhaps in the form of a nucleic acid. Collectively, our results elucidate the impact of DNA ADP-ribosylation stress in human cells and provides the molecular toolkit for future studies of this largely unknown facet of ADP-ribosylation.
Studying protein interaction and glycosylation with chemical proteomics
Keywords: glycoproteomics
monoclonal antibody
protein crosslinking
synthetic histones
chemical mutagenesis
O-GlcNAc
chemical biology
stepped collision energy
proteomics
protein glycosylation
de-novo sequencing
H2B-S36

Protein glycosylation is present in all kingdoms of life, from small virus particles to complex living organisms. It is the most abundant and diverse form of post-translational modification, ranging from the attachment of a single monosaccharide to entire sugar chains onto cellular proteins. This modification affects the recognition and interaction of proteins with their interaction partners, altering their role in health and diseases. Despite its importance, the study of protein glycosylation has lacked behind other biomolecules and post-translational modifications, partly because of absence of available tools and methods. This doctoral thesis aims at expanding existing analytical approaches and developing new technologies to study the different types of protein glycosylation using tandem mass spectrometry.
The second chapter demonstrates de novo determination of the sequence and protein N-glycosylation of the anti- H2AX monoclonal antibody, enabling structural modelling of the antigen recognition and laying the groundwork for further development of this diagnostic reagent for DNA damage in cancers. Chapter 3 focusses on improving analysis of protein O-glycosylation using tandem mass spectrometry. The use of low-energy stepped collision energy (SCE) methods is described for improved characterisation of the glycan part and site-localisation of protein O-glycosylation. SCE-HCD methods such as 10-20% of normalised collision energy (NCE) show the formation of valuable fragment ions enabling a more accurate identification of O-glycopeptides.
The O-GlcNAc modification is a particular form of O-glycosylation, consisting in the attachment of a single N-acetylglucosamine sugar to proteins. In chapter 4, the role of O-GlcNAc as an epigenetic mark on H2B-S36 is investigated. Homogeneously GlcNAcylated histones and nucleosomes were synthesised and used in pull-down ex- periments to enrich putative interaction partners for the H2B-S36-GlcNAc modifica- tion. Mass spectrometry-based quantitative interaction proteomics revealed a direct interaction between H2B-S36-O-GlcNAcylated nucleosomes and the TCF20 transcrip- tion factor, suggesting a possible signalling role for the O-GlcNAc modification. Lastly, chapter 5 shows that synthetic histones with reactive side chains can be used to co- valently trap interaction partners in a native context, identifying their binding site by crosslinking mass spectrometry with amino-acid resolution inside the interaction.
Wall-crossing and orientations for invariants counting coherent sheaves on CY fourfolds
Keywords: Invariants
Donaldson--Thomas theory
Orientations
Hilbert schemes
Counting sheaves
Gauge theory
Wall-crossing
Vertex algebras
Moduli problems

Borisov–Joyce and Oh–Thomas defined virtual invariants counting sheaves on Calabi–Yau fourfolds. Similarly to Donaldson invariants, these depend on existence and choice of orientations on moduli spaces of coherent sheaves. The first part of the thesis addresses this question for quasi-projective Calabi–Yau fourfolds, generalizing the work of Cao– Gross–Joyce. The orientations on compactly supported perfect complexes are expressed in terms of a pull-back of gauge-theoretic ones which live on the classifying space CcsX of compactly supported K-theory. The proof relies on a choice of a compactification, which allows us to directly obtain orientability of moduli spaces of stable pairs. In the second part of the thesis, we study the conjectural wall-crossing formulae of Gross– Joyce–Tanaka. We begin, by addressing the conjecture of Cao–Kool , which expresses the virtual integrals of a tautological line bundle L[n] on the Hilbert scheme of points Hilbn (X) in terms of the MacMahon function. We also obtain a prediction for the K-theoretic refinement of this invariant proposed by Nekrasov, which coincides with the expectations from the result for C 4 . Studying the invariants further, we find a universal transformation relating them to integrals on Hilbert schemes of points for elliptic surfaces. To understand this, we recover the previously known results for Quot-schemes on elliptic surfaces using similar wallcrossing arguments. We will further study this in to recover and generalize the full result of Arbesfeld–Johnson–Lim–Oprea–Pandharipande for surfaces including divisor contributions.
Chasing the dream—defying the odds: exploring the professional identity development of women in comedy
Keywords: Identity play
Identity claiming
Claiming risks
Identity work
Women in comedy
Professional identity
Odds-defying aspirations
Female comedians
Identity threat
Professional identity development
Comedy
Identity

Although in today’s world of work “the repertoire of potential professional identities [individuals] can envision for themselves seems limitless” (Obodaru, 2017: 523), our understanding of professional identity development is limited when it comes to those who attempt to defy the odds in who they become in their careers. This thesis aims to understand the professional identity development process for individuals with odds-defying aspirations—hoped-for professional identities that, by their own estimation, seem unlikely to come about. Using in-depth interviews with aspiring professional comedians who also ‘happen to be women’ (Kirkman, 2016: 220), I develop a grounded theoretical model showing how odds-defying aspirers recalibrate their ideas regarding what is possible in the world of work, regarding what it means to succeed in achieving their aspirations, and regarding what is at stake in their decision to give up or go on in pursuing their odds-defying aspirations. These changes to their aspirational assumptions are brought about through the process of enacting their desired professional identities and receiving and managing identity feedback—efforts that require them to carefully navigate the competing identity threats of trying and failing or else of failing to try, as well as the steep risks and costs inherent in attempting to achieve their odds-defying aspirations. These developmental efforts gradually enable individuals to alter their regulatory focus and to build up their motivational resolve—moving away from focusing on preventing the loss of their nascent professional identity to focusing on promoting its growth and overcoming motivational precarity with motivational resilience. The findings highlight how this professional identity development process is recursive and circular, often requiring odds-defying aspirers to repeat these efforts throughout their careers. This research contributes to the literatures surrounding identity threat and identity play in professional identity development and provides practical insights into the lived experiences of odds-defying aspirers.
Atomic study of defects in two-dimensional transition metal chalcogenides using electron microscopy
Keywords: Defects
Electron microscopy
Transition metal dichalcogenides

Two-dimensional (2D) transition metal dichalcogenides (TMDs) are layered semiconductors with unique electronic and optical properties which have shown immense potential in ultrathin (opto-)electronic devices. Structural defects that are ubiquitous in 2D materials have demonstrated to exert significant impacts on the materials’ properties. The in-depth comprehension of structural defects at the atomic level is vital for the rational exploration of their exceptional properties, which is the objective of my DPhil project.
By conducting advanced scanning transmission electron microscopy (STEM), this project resolves the structures and dynamics of defects with the atomic-scale clarity in 2D TMDs of different phases, and the use of in-situ heating holder in the STEM enables the direct visualization structural dynamics at elevated temperatures. The first part focuses on the grain boundary (GB)-involved defective structures in the typical 2H-phase MoS2/WS2 monolayers/bilayers at the thermal condition. For the monolayers, the high-temperature mechanism is elucidated for the dynamics of 60° GB-coupled large inversion domains. In the bilayers, the existence of dual localized GBs is demonstrated with high-temperature stability. This co-localization causes one layer to adopt novel dislocation cores, not found in monolayers, due to van der Waals strain of maintaining 2H and 3R interlayer stacking either side. Then, the defects and GB structures in TMDs of another significant phase, 1T phase, are also investigated systematically, taking the emerging1T-PtSe2 as the study object. The atomic structures and dynamics of point vacancies, 1D defects, GBs and dislocations exhibit distinct “1T-feature” that differs from those found in 2H-phase MoS22/WS2.
Apart from imaging the intrinsic defects, this project also explores the controlled in-situ structural modification methods by manipulating focused electron beam and the heating conditions in STEM with atomic-resolution monitoring of the process. The precise controllability is demonstrated in intentionally patterning 2D nanowell arrays at bilayer WS2 in terms of shapes, depth and locations, using the combination of convergent beam and the high temperature. Besides, the phase transformation is triggered by the controlled in-situ heating process for promoting Se loss from few-layered PdSe2, obtaining the novel phase 2D Pd2Se3 monolayers. The structural defects and their beam-driven behaviours in Pd2Se3 are visualized, which are sharply distinguished from those in the conventional TMDs.
Multigene metabolic engineering for the increase of photosynthetic efficiency
Keywords: photosynthesis
metabolic engineering
molecular biology
plant transformation
Nicotiana tabacum
transgenic
multigene
plant biotechnology

Improving photosynthesis is one of the most promising approaches to increase crop yield. To date, most efforts to enhance photosynthesis have focused on single-gene approaches. However, from a theoretical and experimental perspective, it is evident that multigene manipulations could lead to a greater impact. This DPhil project sets out to implement two innovative multigene metabolic engineering strategies for improved photosynthesis in Nicotiana tabacum. Firstly, combinatorial co-transformation was used with 12 transgenes, chosen to increase source leaf photosynthesis and downstream carbon metabolism. A library of metabolic phenotypes was recovered, from which five lines were selected for showing increased stem growth under high light conditions. This phenotype was not reproducible in subsequent experiments, but further characterisation of the selected lines suggested that their specific transgene combinations may not have been beneficial for growth due to transgene interference effects. Secondly, a diel flux balance analysis model of primary metabolism in Arabidopsis leaves was used to design a novel metabolic engineering strategy for improved leaf-energy efficiency and photosynthesis. A five-gene construct was generated that was predicted to result in increased mitochondrial ATP production, reduced chloroplast ATP export, and increased chloroplast NAD(P)H export. Contrary to the model predictions, transgene expression was found to correlate negatively with plant growth and photosynthesis. One possible explanation was a detrimental effect caused by the increased capacity of the chloroplast malate valve. This thesis constitutes one of the first investigations into the multigene engineering of photosynthesis and energy metabolism. Together, the results of this thesis highlight the complexity of manipulating plant central metabolism, particularly when targeting multiple transgenes, and suggests that further scrutiny of network behaviour and testing of transgene combinations will be needed to enhance photosynthesis and achieve the yield increases required to feed a growing population.
Cognitive and neural embodiment of artificial-arms in individuals with hand-absence
Keywords: Body representation
Motor control
Amputees
Visuomotor
Prosthetics
fMRI
Embodiment

In the typically developed brain, numerous networks and regions are involved in sensing, actuating and understanding hand functions. In this thesis I take a neurocognitive approach to provide a better understating of how prosthesis users harness hand-specific resources to support their prosthetic limb (embodiment). In a series of cognitive, motor and neural studies, I test two distinct populations: congenital one-handers who are born without a hand and acquired amputees who lost their hand in adulthood, to investigate the processes underlying upper-limb prosthesis use.
First, available hand-related resources were assessed in each of the tested populations using a visual hand laterality task. Congenital one-handers were less efficient than amputees in processing visual hand information, possibly due to atypical available motor hand resources. This finding reaffirms the notion of 'embodied cognition' – that our motor repertoire shapes visual perception and cognition. This was further supported by a significant relationship between amputees’ ability to move their phantom hand and their visual hand processing efficiency. Within the embodiment framework presented in this thesis, having different hand resources could potentially lead to different capabilities in prosthetic-limb use.
Next, using fMRI brain decoding analysis, I probed the neural representation of prostheses in relation to hands and tools, within the visual cortex. Increased levels of prosthesis use were associated with a formation of a novel neural visual ‘prosthesis’ category. This experience-dependent plasticity was observed in both congenital one-handers and amputees, pointing towards high levels of flexibility in occipitotemporal cortex. These findings challenge the naïve notion of neural embodiment, since prosthesis representation did not become more similar to hand representation.
Finally, the control dynamics of prosthetic-arms were assessed using several reaching and localisation tasks. Motor reaching accuracy with a prosthesis was found to depend on early life experience with a hand (either prosthetic or biological). Specifically, the ability to efficiently perform visually guided reaches with a prosthesis is impaired in the absence of early experience. These findings point towards a possible reliance of prosthesis use on neural hand-specific processes and provide evidence for a sensitive developmental period for sensorimotor control.
Taken together, this thesis provides a comprehensive overview of the multifaceted phenomenon of embodiment, shedding light on the underlying processes supporting human-machine interactions, and expanding our understanding of the development and plasticity of body representation.