VictorJuiz/thesis huggingface dataset:
Visual recognition of human communication

The objective of this work is visual recognition of speech and gestures. Solving this problem opens up a host of applications, such as transcribing archival silent films, or resolving multi- talker simultaneous speech, but most importantly it helps to advance the state of the art in speech recognition by enabling machines to take advantage of the multi-modal nature of human communications. However, visual recognition of speech and gestures is a challenging problem, in part due to the lack of annotations and datasets, but also due to the inter- and intra-personal variations, and in the case of visual speech, ambiguities arising from homophones.
Training a deep learning algorithm requires a lot of training data. We propose a method to automatically collect, process and generate a large-scale audio-visual corpus from television videos temporally aligned with the transcript. To build such dataset, it is essential to know 'who' is speaking 'when'. We develop a ConvNet model that learns joint embedding of the sound and the mouth images from unlabelled data, and apply this network to the tasks of audio-to-video synchronisation and active speaker detection. Not only does this play a crucial role in building the dataset that forms the basis of much of the research done in this thesis, the method learns powerful representations of the visual and auditory inputs which can be used for related tasks such as lip reading. We also show that the methods developed here can be extended to the problem of generating talking faces from audio and still images.
We then propose a number of deep learning models that are able to recognise visual speech at word and sentence level. In both scenarios, we also demonstrate recognition performance that exceeds the state of the art on public datasets; and in the case of the latter, the lip reading performance beats a professional lip reader on videos from BBC television. We also demonstrate that if audio is available, then visual information helps to improve speech recognition performance.
Next, we present a method to recognise and localise short temporal signals in image time series, where strong supervision is not available for training. We propose image encodings and ConvNet-based architectures to first recognise the signal, and then to localise the signal using back-propagation. The method is demonstrated for localising spoken words in audio, and for localising signed gestures in British Sign Language (BSL) videos.
Finally, we explore the problem of speaker recognition. Whereas previous works for speaker identification have been limited to constrained conditions, here we build a new large-scale speaker recognition dataset collected from 'in the wild' videos using an automated pipeline. We propose a number of ConvNet architectures that outperforms traditional baselines on this dataset.

Advisor: Zisserman, A
Statistical mechanics of colloids and active matter in and out of equilibrium

Thermal and viscous forces compete for dominance at the microscopic length-scales which govern the behaviour of many soft or biological systems. We study three systems of increasing complexity with the central goal of understanding the statistical or hydrodynamic nature of their mechanics.
First we study experiments that have been conducted on ferromagnetic colloidal rods. At equilibrium, the magnetically pinned rod is observed to randomly flip between two orientational states, which our theoretical analysis shows is due to a competition between entropic and Hamiltonian forces. We show analytically how entropic forces can arise by considering the coupling between observed and unobserved variables of a system.
Experiments in which a rod is driven out of equilibrium by a rotating field display three phases of steady-state behaviour as a function of driving frequency. Using Brownian dynamics simulations we match the lower critical frequency to the experimentally obtained values, showing that thermal fluctuations play an important role in this regime and propose a simple argument to demonstrate that hydrodynamic interactions between the substrate and rod affect the upper critical frequency.
We then turn to the biophysical topic of cell locomotion in viscoelastic media. In order to study how bacterial flagella interact with similarly-sized polymers in their environment, we construct a Stokesian dynamics model of a helical filament and bead--spring polymer. Simulating their interaction first for a pinned--rotating helix, then for a swimming helix, we demonstrate that large polymers become hydrodynamically entrained by the flagellum and coil around it, causing both pinned and swimming flagella to expend more work. For the swimming helix, this results in a reduction of swimming speed on average.
Finally, we consider an active nematic fluid confined to a channel and show that the inclusion of a passive colloid induces a global state of coherent flow maintained by the intrinsic activity of the system. This flow is persistent, and transports the colloid with it along the channel. By this mechanism, a passive colloid is able to spontaneously induce its own transport through an otherwise quiescent fluid.

Keywords: Cell swimming
Active Matter
Statistical Mechanics
Nematic liquid crystals
Biophysics
Advisor: Yeomans, J
Myofibroblast migration and signaling in in vitro colorectal cancer models

Colorectal cancer is one of the most prevalent, and one of the deadliest, types of cancer in the world. The colonic epithelium is positioned atop a subepithelial structure consisting of extracellular matrix and stromal cells, and colorectal tumors closely interact with this tissue. Myofibroblasts make up the primary cellular component of the subepithelial stroma in the colon, and play important roles in the maintenance of the normal colonic stem cell niche. Increased recruitment of local myofibroblasts into the tumor bulk is a feature of some primary and metastatic colorectal cancers, and is associated with poor prognosis.
The first aim of this thesis was to probe the nature of the bidirectional interaction between colorectal cancer cells and colonic myofibroblasts. Two in vitro assays integrating myofibroblasts, colorectal cancer cells, and extracellular matrix were devised to mimic the in vivo arrangement and communication between these cells. Using these assays, it was shown that myofibroblast-derived hepatocyte growth factor reduces differentiation in a subset of colorectal cancer cell lines (Chapter 3). Additionally, colorectal cancer cells were shown to recruit myofibroblasts by secreting ligands of the platelet-derived growth factor family (Chapter 4).
A secondary aim of the project was to develop an analytical technique to robustly categorize colorectal cancer gene expression profiles in an unsupervised manner. Gaussian Mixture Modeling was used to generate categorized expression data for an in-house colorectal cancer cell line panel, as well as a publically available dataset from primary tumors (Chapter 5). 2x2 statistical analyses on the categorized data confirmed known genetic associations in the cancer cells, and also uncovered characteristic gene expression signatures corresponding to intratumoral heterogeneity and stromal contamination (Chapter 6).
This project identifies several mechanisms responsible for the heterogeneity observed in colorectal cancer behaviors, and provides tools to probe these characteristics further both experimentally and analytically.

Advisor: Bodmer, W
Investigation into the relationship between PARPs in DNA repair and synthetic lethality with homologous recombination deficiency

The genome of each cell is under constant threat from various forms of DNA damage. In order to protect themselves from this danger, cells possess a number of pathways able to resolve DNA lesions. The addition of poly(ADPribose) is a post-translational modification produced by attaching successive ADP-ribose moieties to a protein acceptor, forming long chains. Enzymes called poly(ADP-ribose) polymerases (PARPs) catalyse the production of these modifications, and a number of different PARPs have been linked to the process of DNA repair, including PARP1, PARP2 and PARP3. How these enzymes might function together to facilitate the repair of different lesions is unclear. Furthermore, inhibitors that target these enzymes are in clinical use for their ability to kill homologous recombination deficient tumour cells, through a mechanism of synthetic lethality. Which subset of PARPs is necessary to inhibit to achieve maximum efficacy of these agents has not been assessed.
I use genome editing to generate cells disrupted for these PARPs in different combinations. Whilst loss of PARP1 compromises cellular tolerance to homologous recombination deficiency, this is independent of the status of PARP2 and PARP3, indicating the development of PARP1-specific inhibitors may hold therapeutic potential. In contrast to these observations, I uncover strong redundancy between PARP1 and PARP2 in the repair of damaged DNA bases through the base excision repair (BER) pathway. I also identify BER independent roles of both PARP1 and PARP2 in resolving replication forks that have collided with BER-intermediates, through promoting the stability of Rad51 nucleofilaments via an Fbh1-dependent mechanism. Thus PARP1 and PARP2 perform two closely-linked functions in response to cellular base damage promoting resolution of these lesions directly through BER, and stabilising replication forks which have encountered BER intermediates.

Keywords: DNA Repair
PARP
Genome Stability
Advisor: Lakin, N
Characterising the rhomboid-like protein TMEM115

The rhomboid-like superfamily of proteins comprises transmembrane proteins with an ancient evolutionary origin. They include both intramembrane serine proteases and inactive pseudoproteases, and they have diverse cellular and pathophysiological functions. These include regulation of growth factor signalling, protein quality control, trafficking, and mitochondrial dynamics. TMEM115, a recently recognised enzymatically inactive member of the rhomboid-like superfamily (confirmed in this thesis), is conserved from yeast to human and is ubiquitously expressed in all tissues. The absence of TMEM115 in both Drosophila and mice causes severe phenotypes. These compelling preliminary data indicate that TMEM115 has important cellular functions. To capitalise on these preliminary observations, the overall aim of my PhD project was to characterise the mammalian TMEM115 both structurally and functionally.
Structurally, I performed a topology study for TMEM115, and with a combination of bioinformatic and experimental analysis, proved that TMEM115 indeed has a six TMD structure. Using the HHpred and Phyre algorithms, which identify structural similarity among proteins, a high degree of homology was identified between the TMD regions of TMEM115 and other rhomboid-like proteins. The above analysis together with the topology of TMEM115 definitively positions TMEM115 in the rhomboid-like superfamily.
To elucidate the biological role of TMEM115, I started with a proteomic approach, a BioID proximity screen, to identify novel interactors for TMEM115 under different physiologically relevant conditions. A number of binding partners were identified in the BioID screen and validated with co-immunoprecipitation. These indicate intriguing possible functions of TMEM115, including regulating lipid biology, protein trafficking, protein degradation and ion channels. Given that several candidates are involved in protein trafficking, I used a secretome profile analysis method, the SPECS, for identifying TMEM115 dependent secreted proteins.
A role of TMEM115 in regulating the fundamental de novo lipogenesis pathway, the SCAP-SREBP pathway (Freeman lab unpublished data), had been identified during the course of my project. Pursuing this, I investigated the possible relationship between TMEM115, SCAP and the novel interactor, p62; the results suggest that TMEM115 may be involved in regulating lipid homeostasis by modulating SCAP levels through the proteasomal degradation machinery.

Advisor: Freeman, M
Greeks, Jews, heretics, and the Church of God

The following study seeks to explore the subjects of Christianisation and Christian identity during the transitional period of the fourth century from an ecclesiological perspective, and argues that the very question of Christian identity is, indeed, an ecclesiological one. It approaches the subject through the writings of Cyril of Jerusalem, specifically his Catechetical Lectures, the earliest complete catechetical programme that has come down to us, making it an invaluable resource for anyone hoping to understand the Catholic Church’s efforts to preserve and construct its identity in the wake of Constantine’s formal conversion to its faith. Moreover, Cyril, who became bishop of the Holy City around 350, affords us a unique perspective on the question at hand, teaching as he did from the “very centre of the earth”, following the creation of a Christian holy land and pilgrimage centre in the midst of what remained a largely pagan province, and in a city still central to Judaism. The ability to possess the sites and relics associated with the life of Christ and the Prophets for the first time in Christian history not only made the drama of salvation tangible in Jerusalem like nowhere else, but raised new and important questions around the extent to which this sacred topography was compatible with Christianity's departure from the temple-centred worship of the Old Testament. It also provides valuable insight into the relationship between the local and the universal as regards notions of the Church’s catholicity, Cyril's definition of καθολική in his eighteenth lecture arguably being the earliest.
Membership of the Church, and therefore Christian identity, is for Cyril primarily ontological, defined and effected through mysteriological participation, with baptism — the believer's death, rebirth, and union with Christ — representing the dividing line between insider and outsider, a fact enforced by the so-called Disciplina Arcani, by which all knowledge of the Church's sacraments were jealously guarded from the unbaptised. The thesis explores how this notion of ontological membership underpins and informs Cyril's dealings with the various groups against which he sought to define his own community — the Greeks, Jews, and heretics — while also looking at the ecclesiological significance of the baptismal act itself.

Keywords: Catholicity
Late Antiquity
Disciplina Arcani
Christianization
Orthodoxy
Catechesis
Ecclesiology
Baptism
Advisor: Edwards, M
Depot-specific mechanisms determining human fat distribution

Body fat distribution is a strong determinant of human metabolic health but the mechanisms underpinning regional deposition of white adipose tissue (WAT) remain poorly understood. WAT also exhibits striking depot-specific functional properties. The aim of this project was to investigate the potential role of specific candidate genes implicated in regulating WAT development and/or function in a depot-specific manner. Cartilage oligomeric matrix protein (COMP) is an extracellular matrix protein that is highly differentially expressed between subcutaneous abdominal and gluteal WAT but has primarily been studied in the context of bone biology. WAT COMP expression was found to be significantly up-regulated in obesity; COMP expression in preadipocytes was increased by glucocorticoids; and COMP promoted adipogenesis in (immortalised) subcutaneous abdominal and gluteal preadipocytes.
Building on a finding during the COMP study, bone morphogenetic protein (BMP)-2 was identified as another candidate. BMP2 exerts positive adipogenic effects in murine models and a recent genome-wide association study meta-analysis identified a significant association between BMP2 and body fat distribution. BMP2 was found to exert a pro-adipogenic effect specifically in subcutaneous abdominal preadipocytes, with this effect requiring activation of SMAD1/5/8 signalling via type 1 BMP receptors. These data identify BMP2 as a novel depot-specific regulator of human adipogenesis.
Particularly lipid-laden cells were formed when conventional adipogenic medium was supplemented with fatty acids; these cells were captured, de-differentiated (DFAT) and expanded to generate immortalised abdominal and gluteal DFAT cells. These DFAT cells exhibit a greatly enhanced adipogenic potential compared to the mixed stromovascular (SVF) population from which they derive and retained an intrinsic memory of their anatomical origin. The use of DFAT cells is likely to represent a valid and enhanced model system to study various depot-specific aspects of WAT biology such as adipogenesis. Overall, the data from this thesis emphasise the striking depot-specific biology exhibited by WAT and provide novel insights into the mechanisms governing the regional distribution of WAT in humans.

Keywords: Adipose
Advisor: Karpe, F
Pinnick, K
Trade, development and resilience: an archaeology of contemporary livelihoods in Turkana, northern Kenya

The recent history of the Turkana of northern Kenya has rarely been explored in detail, a fact that corresponds with, and to a large extent facilitates, their regular portrayal in the popular press as passive, unchanging and therefore vulnerable in the face of ongoing and ensuing socio-economic transformations. Such visions of the Turkana and the region in which they live have, via their manifestation in the policies and practices of development-orientated interventions, actively inhibited (although never fully arrested) the fulfilment of various local desires and aspirations over the years. In addressing these topics, this thesis provides some hitherto largely unexplored and unrecognised historical context to the many socio-economic and political issues surrounding Turkana’s ongoing development. It discusses interdisciplinary research which combined archaeological and ethnographic techniques and was undertaken amongst communities engaged in the most prominent livelihoods that have historically underlain the Turkana pastoral economy: fishing (akichem), cultivation (akitare), herding (akiyok) and raiding (aremor). In doing so, it draws attention to some of the ways in which these communities have actively and dynamically negotiated broad economic, environmental and political transformations over the last century and beyond, thereby providing a picture of social change and long-term continuity that might serve as a means for a more critical assessment of regional development over the coming years.
By weaving together a series of historical narratives that emerge from a consideration of the changing production, use and exchange of material culture, the thesis builds an understanding of Turkana’s history that diverges from more standard, implicitly accepted notions of recent change in such regions of the world that envisage globalisation purely as a process of convergence or homogenisation. Its central argument, which it demonstrates using various examples, is that seemingly disruptive transformations in daily practices, social institutions, livelihoods and systems of livelihood interaction can be envisaged as articulations of longer-term continuities, emerging from a set of durable yet open-ended dispositions within Turkana society and culture. Moreover, rather than being built on a stable, passive repertoire of cultural knowledge, the thesis shows that this capacity for change is established upon a dynamic generative process where value systems and institutions are reconfigured to the same extent as daily practices and skills, as knowledge is continually reconstituted and recast in relation to the shifting constraints and possibilities of daily life. It thus characterises this process as a form of resilience that is deeply rooted in and determinant of the Turkana pastoral economy.

Keywords: Kenya
Turkana
fishing
farming
herding
anthropology
development
pastoralism
trade
raiding
ethnography
contemporary archaeology
pastoralist history
history
Africa
archaeology
resilience
pastoral economy
Advisor: Mitchell, P
Hicks, D
Application of engineered T cell receptors to investigate the failure of cytotoxic T lymphocytes to eliminate the HIV reservoir

HIV establishes a reservoir comprising long lived, latently infected CD4+ T cells and monocytic cells early during primary infection. This population represents a major barrier to an HIV cure. This thesis aimed to investigate the role of the immunological synapse in the failure of cytotoxic T lymphocytes (CTLs) to eliminate the HIV reservoir and the potential for engineered bispecific Immune-mobilising monoclonal T cell receptors Against Viruses (ImmTAV) to overcome this by redirecting fully functional CD8+ T cells against viral targets.
A primary cell model of latency was used to investigate the expression of HIV Gag on latently infected cells and their susceptibility to ImmTAV-mediated elimination. A subset of cells expressed low levels of Gag without spreading infection and ImmTAV-redirected healthy donor CD8+ T cells were able to eliminate up to 40% of infected cells without latency reversal. CD8+ T cells from chronic HIV infected (CHI) donors showed impaired antiviral activity even with ImmTAV redirection.
To investigate this further, confocal microscopy was used to study immunological synapse formation using primary CD8+ T cells from HIV-negative and CHI donors. CD8+ T cells from CHI donors were able to form conjugates with virus-infected cells but exhibited impaired synapse maturation, indicated by reduced Zap70 localisation, delayed microtubule-organising centre polarisation and impaired perforin recruitment to the synapse. ImmTAV redirection partially overcame these defects.
Finally, the impact of antiretroviral agents on T cell mitochondrial function was explored. Exposure to zidovudine increased mitochondrial reactive oxygen species production and susceptibility to apoptosis. However, there was no evidence of impaired mitophagy.
These data show that defects in CD4+/CD8+ T cell synapse maturation contribute to HIV persistence but nevertheless suggest that a subset of HIV reservoir cells may be susceptible to ImmTAV-mediated elimination. The therapeutic potential of ImmTAVs may depend in part on correction of CD8+ T cell exhaustion.

Keywords: HIV
Reservoir
Immunology
T cells
Advisor: Dorrell, L
Chojnacki, J