VictorJuiz/thesis huggingface dataset:
Learning with multimodal self-supervision

Deep learning has fueled an explosion of applications, yet training deep neural networks usually requires expensive human annotations. In this thesis we explore alternatives to avoid the substantial reliance on manual annotated examples when training deep neural networks. Specifically, we do so by either adapting self-supervised methods to automatically correct freely obtained data labels, or by completely abandoning the use of human labels and instead utilizing the natural co-occurrence of audio and visual information to learn object representations in videos.

Growing collections of digital data often provide noisy labels that can be exploited to supervise the learning process. Conventional data pre-processing includes correcting/cleaning them before training recognition models, but this can require infeasible amounts of manual effort. We consider correcting the annotation noise automatically, and hence eschew the need for costly manual annotation. We build and extend recent breakthroughs with a consistency loss which enables training even without ground truth, and an spatial memory map that provides flexible instance-level registration, leading to greater generalization.

We further explore multimodal sensory streams to provide self-supervision to the model by utilizing modality redundancy, i.e. the overlapping information between modalities. Representations are learned by harnessing different modalities without using any human-annotated labels. We demonstrate this technique using three different applications. First, we automatically curate a large-scale audio dataset, VGG-Sound, with more than 200k videos collected using visual guidance, training on which yields state-of-the-art models for audio recognition. Second, we present a method to improve and extend recent sound source localization techniques by introducing a mechanism to mine hard samples and add them to a contrastive learning formulation automatically. Finally, unlike existing audio-visual synchronization tasks performed on one specific domain, we propose to solve the synchronization problem in open world settings by exploring the use of several transformer-based architectures. With these models, we achieve state-of-the-art results in challenging speech datasets and show excellent generalization in a general sound dataset.

Keywords: convolutional neural network
self-supervision
multimodal
datasets
Advisor: Vedaldi, A
Zisserman, A
Estimates for small eigenvalues of the Laplacian and conformal Laplacian on closed manifolds

A central and well-established theme in geometry is eigenvalue estimates for geometric operators on manifolds. In this thesis we obtain new estimates for small eigenvalues of the Laplacian and conformal Laplacian respectively, in two distinct geometric contexts.

In the first part of this thesis we consider eigenvalues of the Laplacian on closed hyperbolic surfaces. It is known that for such surfaces degenerating by the collapse of a single simple closed geodesic, the first eigenvalue to highest order depends only on the length of that geodesic and the topology of the limiting surface. We consider the behaviour of the eigenvalues in the more general case of surfaces degenerating by the collapse of multiple simple closed geodesics. We exploit the fact that the geometry of a closed hyperbolic surface of fixed genus depends on a finite number of parameters (up to pullback by diffeomorphisms), the Fenchel-Nielsen coordinates. We prove new local energy estimates for the eigenfunctions of small eigenvalues and use these to obtain estimates for the derivatives of the eigenvalues with respect to the Fenchel-Nielsen coordinates. These are then used to prove that in the case of multiple collapsing geodesics, the small eigenvalues of the Laplacian again to first order depend only on the lengths of the collapsing disconnecting geodesics nd the topology.

In the second part of the thesis, we consider the behaviour of the first eigenvalue of the conformal Laplacian for particular families of metrics on closed manifolds of dimension at least three. It is known that the volume-normalised first positive eigenvalue of the conformal Laplacian is not bounded on any conformal class of metrics, contrasting with the behaviour of the Laplacian eigenvalues. We initiate an exploration of this difference in behaviour by proving sharp estimates for the first eigenvalue of the conformal Laplacian for particular families of conformal metrics, which we call asymptotically conical. We also obtain sharp estimates for the behaviour of the volume- and diameter-normalised eigenvalues for these metrics, giving new examples of conformal families of metrics for which the volume-normalised eigenvalues are unbounded.

Keywords: spectral geometry
hyperbolic geometry
Riemannian geometry
eigenvalue estimates
differential geometry
conformal Laplacian
Advisor: Rupflin, M
Nguyen, L
Enhancing protective efficacy of avian influenza vaccines through targeted delivery of protective antigens to chicken immune cells

Avian influenza viruses (AIVs) are highly contagious viruses that are widespread in birds. Wild aquatic birds (e.g., waterfowls, gulls, and shorebirds) are their natural hosts. However, they can be easily transmitted between different bird species and infect gallinaceous poultry including chickens, quails, and turkeys, resulting in severe economic losses. AIVs also pose a significant zoonotic and pandemic threats. Most of the commercially available avian influenza vaccines for poultry are inactivated whole virus vaccines that have several drawbacks including sub-optimal immunogenicity, need for multiple dose administration and interference from maternally derived antibodies (MDAs). Here, the immunogenicity and protective efficacy of recombinant subunit poultry AIV vaccine were enhanced by selective delivery of antigens to the professional antigen presenting cells (APCs) like dendritic cells and macrophages. This led us to the development of targeted antigen delivery vaccines whereby the haemagglutinin (HA) protein of H9N2 AIV was fused to single chain fragment variable antibodies (scFv) specific to chicken Dec205, CD11c and CD83 receptors. Out of the three targeted antigens tested, CD83 targeting induced higher serum haemagglutinin inhibition and virus neutralising antibodies compared to the untargeted H9HA and inactivated H9N2 vaccine. Furthermore, chickens vaccinated with CD83 targeted H9HA showed a reduced virus shedding post challenge compared to the untargeted H9HA, as well as a reduced interference from H9HA-specific MDAs. Overall, CD83 targeted H9HA was able to generate antibodies that were cross-reactive against different heterologous H9N2 viruses. Following on, the recombinant Herpesvirus of Turkey (rHVT) was also assessed for its use as a viral vector for in vivo expression of secreted and native membrane bound forms of H9HA antigen. The antibody titres generated by rHVT expressing native membrane bound H9HA was higher than any of the secreted forms.
Overall, these results will assist in developing the next generation vaccines for preventing animal and human infectious diseases.

Keywords: scFv antibodies
avian influenza virus
targeted antigen delivery vaccines (TADV)
immunogenicity
protective efficacy
viral vector
herpes virus of Turkey (HVT)
maternally derived antibodies (MDAs)
Advisor: Iqbal, M
Van Hulten, M
Smith, A
Strategies for increasing frataxin expression in Friedreich's ataxia: modulation of the epigenome and proteome

Friedreich's ataxia is a rare and fatal childhood neurodegenerative disease that causes shrinkage of the spinocerebellar tracts and the progressive loss of neurons in the dorsal root ganglia. This leads to awkward, unsteady movements and impaired sensory function, leaving sufferers wheelchair bound. It is caused by the expansion of a trinucleotide repeat region within the first intron of the FXN gene, leading to reduced production of the essential mitochondrial protein frataxin. The average life expectancy of sufferers is 37 years old, and there is currently no available treatment.

Reduced frataxin production is thought to be the result of a host of epigenetic changes at the FXN locus that cause heterochromatin-induced gene silencing. Recently, the histone lysine methyltransferase SUV4-20 has been implicated in heterochromatin formation. Pharmacological inhibition with SUV4-20 chemical probe A-196 leads to an increase in frataxin production, however its substantial metabolic instability precludes its use in vivo. This thesis describes attempts to design and synthesise analogues of A-196 with improved metabolic stability, enabling their testing in animal disease models and continued preclinical development. It also examines the development of a novel approach to disease treatment through the use of a heterobifunctional molecule to induce frataxin stabilisation.

Chapter 1 evaluates the challenges facing drug discoverers in the context of rare disease treatment and provides an overview of Friedreich’s ataxia. It also examines key pharmacokinetic concepts and strategies for their modulation. Chapter 2 describes the design and synthesis of analogues of A-196, culminating in the development of a compound with a nine-fold improvement in stability that will permit its evaluation in vivo. Chapter 3 describes the conceptualisation and efforts towards the development of a novel, heterobifunctional small molecule for induced frataxin stabilisation via deubiquitination.

Keywords: histone methyltransferase
epigenetics
Friedreich's ataxia
Advisor: Brennan, P
State-switching models of human brain activity using recurrent neural networks

It has been shown that spatiotemporal dynamics of neuronal activity can be well described using state-related behaviour, comprising a discrete set of reoccurring quasi-stable states associated with distinct patterns of spatial and functional connectivity. Most methods of analysis will either assume stationarity of these states, as in ICA; or constrain the dynamics to be Markovian, as in hidden Markov models (HMMs). These tools lack the capability to explicitly model the higher order temporal dependencies that can occur over timescales of various scales.

In this thesis, we introduce a model that combines probabilistic state-space models with recurrent neural networks (RNNs), enabling us to relax the Markovian constraint of HMMs and learn temporal features of the data occurring over longer timescales. The model takes the form of a recurrent state-switching network, which models the uncertainty in time-varying state labels via discrete random variables. We introduce a variational Bayesian framework for computationally efficient inference of the model that also generalises to a variety of time series models.

Using simulations, data taken from the resting state magnetoencephalography (MEG) scans of 55 participants, and data taken from the MEG recordings of a face-viewing task undertaken by 19 participants, we demonstrate that we can reliably infer a set of states that fits the data better than where the Markovian constraint is enforced, however we do not see significantly different temporal behaviour emerging. We additionally demonstrate that unlike the Markovian model, the recurrent model can internally represent the temporal dynamics of the data.

Keywords: RNN
variational inference
functional connectivity
MEG
Advisor: Woolrich, M
Remy de Gourmont and the crisis of erotic idealism

This thesis explores the relationship between erotic desire and philosophical idealism in the work of Remy de Gourmont (1858-1915). Tracing a discourse of ‘erotic idealism’ through the chronological evolution of Gourmont’s novels and theatre, it also incorporates essays as well as select short fiction and poetry.
Through close readings of fiction and drama, I examine how Gourmont pursued a double-sided question: how does erotic desire shape our experience in the world of phenomenal appearances, and how is the experience of erotic desire shaped in turn? In pursuing this question, two of Gourmont’s most prominent concerns – idealism and erotic desire – continually transform one another in the course of his work, influencing his thought at large, yet constitute a distinct discourse from the critical and theoretical writings to which his intellectual development is most often attributed. I explore how Gourmont’s erotic idealism underpinned the major aesthetic and intellectual manoeuvres of his career, particularly his negotiation with Symbolist values, mysticism and the occult and, later, with the idea of Nature and the philosophy of materialism.
Where previous scholarship has understood Gourmont’s idealist worldview as essentially a tool of Symbolist aesthetic theory, I demonstrate how the riddle of erotic desire led Gourmont’s philosophy into different, often contradictory, territory. I argue that the interplay of idealism and erotic desire was a source of productive tension key to the evolution and maturity of Gourmont’s work.

Keywords: eroticism
idealist
idealism
Eros
decadence
Remy de Gourmont
French literature
sexuality
symbolism
Advisor: McGuinness, P
Evolved P450 mutants as general oxidation catalysts

Chapter 1 introduces chemical methods for oxidation and noteworthy examples applied to total synthesis. Subsequently, a brief history of biocatalysis and enzymes as oxidation catalysts will be discussed, and cytochrome P450 monooxygenases and their applications will be introduced.
Chapter 2 describes the application of cytochrome P450 mutants as catalysts to affect the regio-, diastereo- and enantioselective hydroxylation of N-protected cycloalkylamines, cycloalkylcarboxamides and BCPAs. The derivatisation of these key building blocks into medicinally relevant structures will also be discussed. Furthermore, a first proof-of-principle of the kinetic resolution of sulfoxides will be reported.
Chapter 3 explores the synthetic efforts towards the natural product trigoxyphin L. Improvements to a previous synthetic route, two routes based on a C(sp2)–C(sp2) bond disconnection and a final route constructing the aryl ring via Robinson annulation will be discussed. New methodologies including an intramolecular Heck cross-coupling and a Lewis acid catalysed coupling of furfuryl alcohols with silyl enol ethers will be presented.
Chapter 4 focuses on the late-stage functionalisation of trigoxyphin-type core structures, yielding a range of natural product analogues from our library of P450BM3 mutants. This work describes an enzymatic platform for the diversity-oriented C–H hydroxylation of complex chemical scaffolds.

Advisor: Robertson, J
Wong, L
Scoring space in the open work and portfolio of original compositions

The central focus of this thesis is the elucidation and application of a new analytical framework, connecting existing discourses on sound, space, and place in late twentieth and early twenty-first century “open form” music, and sound installation art. It builds especially on Richard Sennett’s urban understanding of openness, which helps to generate a model for the analysis of musical open form beyond only the relationship between the performer and the score. At the same time, it explores the role of space and place in music performance, interrogating the manner in which the environment shapes different realisations of indeterminate musics. Whereas many existing accounts of the spaces in and of music performance focus predominantly on the technical or locative elements of spatial sound, this dissertation is informed by contemporary spatial and urban theory as well as architectural studies in its more generative and expansive understanding of space. This thesis constructs space beyond tectonics, incorporating and acknowledging social, political, corporeal, architectural, and acoustic factors that inform and transform our experience of sound. Methodologically speaking, this thesis references interviews with the composers, performers and audience members of sonic artworks in combination with more conventional musicological analysis of audiovisual media, seeking to emphasise incidents and sentiments that don’t fit grander conceptual or composer-centric narratives but help to draw out a more everyday, lived experience of sound. Substantial analyses of Lin Chi-Wei’s ongoing participatory composition Tape Music and Claudia Molitor’s locative audio work Sonorama help to illustrate the value of this framework across two large case studies.

Keywords: space
sound art
experimental music
graphic scores
spatiality
open form
Advisor: Harry, M
Ouzounian, G
Neoliberalism and Hindutva in the Actually Existing State: The case of Dholera smart city

In recent decades, countries around the world have witnessed the expansion of neoliberal policies, within which the concept of smart cities has been proffered as a panacea for ‘sustainable development’. Alongside economic changes, many countries have also seen the rise of right-wing nationalism, with leaders using policies of urbanisation and infrastructure building to take their agendas forward. What is often witnessed, although barely studied, is the coming together of these two ideologies – neoliberalism and right-wing nationalism – as they help one another to deeply influence state organisations. This dissertation studies the Dholera smart city project in the western Indian province of Gujarat. Launched and continuously promoted by India’s current Prime Minister and head of a right-wing Hindu nationalist party, Narendra Modi, since his days as Gujarat’s Chief Minister, Dholera has been a platform to reimagine the state and ideas of development.

The dissertation uses the state as an analytical lens to understand micro-practices of development in Dholera. Based on nine months of ethnography observing numerous actors across villages, corporations and the state, the dissertation explores how the everyday state functions in Dholera. The study finds that at various levels of government, the state constitutes and is simultaneously constituted by multiple intricate linkages between the actors and practices of neoliberalism and right-wing Hindu nationalism (or Hindutva). It shows how these linkages help to promote the cause of both ideologies, further entrenching them into institutions across state and society. In doing so, both neoliberalism and Hindutva, use strategies that display disjuncture between their foundational ideologies and practices, which help them further their cause. At the intersection of development, smart urbanism, and right-wing nationalism, the study is of topical significance to understand how the very idea of the state is being transformed in Gujarat and India – beyond recognition – with implications that are global.

Keywords: eight-wing nationalism
smart cities
neoliberalism
urbanisation
Advisor: Sud, N
Structure, reactivity, and solid-gas catalysis in ligand-varied solid-state molecular organometallic systems

Chapter 1, Introduction: The concepts of solid-state organometallic chemistry; single-crystal to single-crystal (SC-SC) transformations; alkene isomerisation; continuous flow techniques; and para-hydrogen induced polarisation (PHIP) are introduced and given brief theoretical and practical backgrounds, each relevant to the following chapters.
Chapter 2: This chapter explores the successful application of P2-type Rh-containing SMOMs in the solid- gas catalytic isomerisation of 1-butene, and describes their deployment under both batch and continuous flow conditions, achieving non-thermodynamic selectivity. In an effort to explore the chemical space, a wide variety of ligand-varied SMOMs are deployed under flow conditions: the direct tunability of solid-gas catalysis is demonstrated through ligand (R-group and tether-length) modification.
Chapter 3: The SC-SC chemistry of two related systems are described: a PONOP-bound cationic Ir- containing SMOM (in collaboration with the Diamond Light Source) and a P2-type perfluorophenyl/Rh- containing SMOM. Remarkably, both of these systems undergo SC-SC transformations with shifts in periodic structure upon solid-state hydrogenation and desolvation respectively. These transformations are tracked with single-crystal X-ray diffractometry as well as solid-state NMR spectroscopy.
Chapter 4: This chapter explores the NMR batch-scale solid-gas catalytic hydrogenation-polarisation of unsaturated substrates with para-hydrogen by P2-type Rh-containing SMOMs. Conducted in collaboration with the Centre for Hyperpolarisation in Magnetic Resonance, York (CHyM), the tunability of solid-gas catalysis is again demonstrated through ligand modification, yielding vastly different activities and rates of deactivation. The solid-gas hydrogenation mechanisms are elucidated with the assistance of D2 gas.
Chapter 5, Experimental: The syntheses and characterisation of materials not already reported in the literature are provided, in addition to experimental methods.
Chapter 6, Future Directions: The possible future directions for these projects are described in a short epilogue.

Keywords: iridium
single crystal to single crystal
solid-gas catalysis
alkene isomerisation
rhodium
organometallics
butene
crystallography
para-hydrogen
PHIP
propene
Advisor: Weller, A
O'Hare, D
Regulation of the Fanconi anemia DNA repair pathway by phosphorylation of FANCD2

Living organisms have evolved multiple repair pathways that recognize and tackle different types of DNA damage. One such pathway is the Fanconi anemia DNA repair pathway which is able to repair DNA interstrand crosslinks (ICLs) – deleterious lesions arising by a covalent binding of the opposite DNA strands through a linker molecule. Of central importance to the ICL repair lies the FANCD2/FANCI heterodimer which is recruited to the site of the lesion and is subsequently monoubiquitinated by the Fanconi anemia core complex. These two steps are essential for the pathway to proceed and if they fail, so fails the entire repair. Due to its importance, FANCD2/FANCI is highly regulated by numerous post-translational modifications, phosphorylation being the best characterized.
In the work presented herein, I focus on FANCD2 phosphorylation and its linkage to ATR. In the first two chapters I have demonstrated that FANCD2 is activated by phosphorylation at multiple residues which enables its recruitment to ICLs as well as its monoubiquitination. This phosphorylation occurs in two steps. First, before its recruitment to ICLs, and subsequently between the recruitment and the monoubiquitination step. These data also suggest that FANCD2 recruitment and monoubiquitination are partially facilitated by ATR. In the third chapter I used a Single Particle Tracking technique to start characterising the kinetics of FANCD2 recruitment. It was shown that an increased number of FANCD2 molecules binds to chromatin after the introduction of ICLs. An increased number of bound FANCD2 was observed also in the unperturbed S phase cells, and depletion of FANCI nullifies this increase. Finally, the mean retention time of FANCD2 was determined to be approximately 30 seconds in unperturbed cells.

Advisor: Cohn, M