VictorJuiz/thesis huggingface dataset:
Time-varying source reconstruction

The human brain is a highly dynamical system. One way of imaging neural activity is through electrophysiological techniques such as magnetoencephalography and electroencephalography (M/EEG). However, for these data to be truly useful, the ill-posed inverse problem must first be tackled.
A fundamental step in solving this problem involves the introduction of assumptions about the data (and noise) covariance. To date, the majority of source localisation algorithms employ static approximations to the data covariance matrix.
Here we make the argument that researchers should consider a Temporally Adaptive SourcE Reconstruction (TASER) approach to solving the inverse problem. We achieve this by introducing a novel machine learning unsupervised recurrent neural network (RNN) based algorithm. Our model does not make restrictive assumptions about the temporal processes generating the data (i.e. it is not Markovian), nor does it assume that data originate from a set of mutually exclusive states. Instead, we model the data as a continuous mixture of temporally evolving modes or elements.
This algorithm, which we call VRAD, lets us add a temporal extension onto preexisting M/EEG source reconstruction approaches. In this thesis we develop and explore the concepts of temporally adaptive spatial filters (beamformers) and generative model-based reconstruction procedures (e.g. multiple sparse priors). This is motivated first by simulations which show an improvement in source reconstruction accuracy when a time-varying beamformer is used, and the ground truth source space data has a dynamic covariance profile. We then validate the algorithm on a previously published MEG head cast dataset Barratt et al. (2018). Our results show an improvement upon existing static techniques, and we are able to spatially distinguish activation on the order of a few millimetres between pinky and index finger movement. Despite never being exposed to the underlying task-structure, we show that VRAD is capable of learning physiologically plausible latent descriptions of the data. We further assess the philosophy of TASER on a more generic multi-modal multi-subject openly available M/EEG dataset published by Wakeman and Henson. We show that using multiple source reconstruction weights is not detrimental to the reconstruction of neural waveforms, and that dynamic techniques have benefits of static reconstruction algorithms.

Keywords: MEG
machine learning
source reconstruction
inverse problems
Advisor: Quinn, A
Woolrich, M
Smith, S
Investigating the effects of D-alanine on pituitary intracellular signalling: a comparison with D-serine

The D-amino acid, D-alanine, is a co-agonist of the N-methyl-D-Aspartate receptor (NMDAR), and an agonist of the glycine receptor (GlyR). In the rat, D-alanine is highly concentrated in the pituitary gland, where it is localized to adrenocorticotropic hormone (ACTH) containing cells. This suggests that D-alanine may influence the release of ACTH, and ultimately the secretion of the stress hormone, corticosterone. Previous studies have shown that ACTH secretion from pituitary cells involves CREB and ERK1/2 signalling. We have, therefore, investigated the influence of D-alanine on the levels of these signalling proteins (western blot) and ACTH (ELISA) in cultures of the AtT-20 mouse pituitary tumour cell-line. For comparison, the effect of D-serine, a co-agonist of central NMDARs, but not GlyRs, was also examined.
AtT-20 cells were incubated with D-alanine or D-serine, CRH, dexamethasone (DEX) and MK-801 (NMDAR antagonist) in different combinations. Data was expressed as ratios of total/phosphorylated protein, where tCREB is CREB/β-actin and pERK1/2 is pERK/ERK, and subjected to one-way ANOVA statistics.
Compared to controls, the levels of tCREB and ACTH expressed by AtT20 cells were significantly greater when incubated with 500 µM of D-alanine (+35%, p=0.011 and +12%, p=0.028 respectively) or D-serine (+29%, p= 0.028 and +13%, p=0.043 respectively) for 24 hours. The level of tCREB and ACTH in AtT20 cells was significantly lower when incubated with D-alanine and DEX for 24 hours (-30%, p= 0.019 and -44%, p=0.030 respectively), but significantly greater for pERK/ERK and ACTH in cells treated with D-serine and DEX for 24 hours compared to controls (+38%, p = 0.039 and +16%, p=0.038 respectively).
The current data show that D-alanine and D-serine differentially modulate stress hormone-mediated negative feedback signalling in AtT-20 cells. Based on our findings, the changes suggest that D-alanine might augment the inhibition of ACTH, whereas Dserine may attenuate negative feedback, and release ACTH. The elevation of both ERK (with DEX and D-serine), and CREB (with both D-amino acids alone) implies NMDAR activation. The combination of DEX and D-alanine, suggests the possible involvement of GlyRs.

Keywords: D-alanine
D-serine
CREB
ACTH
ERK
Epigenetics of osteoblast differentiation within an inflammatory environment


Rheumatoid arthritis (RA) is a debilitating autoimmune disease. Symptoms can be characterised by the inflammation of the synovium and irreversible articular bone erosion. Inflammatory cytokines, transforming growth factor β1 (TGF-β1) and tumour necrosis factor α (TNFα) are enriched in the synovial fluid of RA patients and play a critical role in bone formation. We hypothesise these cytokines are involved in the epigenetic regulation of osteoblast differentiation. Thus, the effects of TNFα and TGF-β1 were characterised and inflammatory osteogenesis models were formed. We observed that prolonged TNFα treatment in human mesenchymal stem cells (hMSCs) promoted osteoblast differentiation and mineralisation. Through the screening of epigenetic probes in the model, we discovered 18 statistically significant hits, which regulated alkaline phosphatase (ALP) activity (a marker of osteogenic differentiation).
TGF-β1 treatment during osteogenic differentiation completely inhibited mineralisation and strongly repressed ALP activity in hMSCs. The screening of epigenetic probes revealed inhibitors for three specific epigenetic protein families regulated ALP activity. Bromodomain extra terminal protein inhibitors repressed ALP activity, whilst histone deacetylase and lysine demethylase (KDM5) inhibitors promoted ALP activity in a dose dependent manner. TGF-β1 treatment upregulated the expression of the KDM5 isoforms. Moreover, shRNA knockdown of KDM5 promoted ALP activity. Through RNA sequencing, we observed profound changes in genes that regulate the PI3K-AKT pathway, a pathway critical for osteogenesis. We observed the downregulation of expression of PI3K-AKT pathway signalling components following TGF-β1 treatment. Furthermore, we observed the promotion of expression of the pathway components after KDM5 inhibitor treatment. In summary, this study demonstrated the important effects of RA cytokines on osteoblast differentiation with epigenetic regulators closely involved in this process. In addition, KDM5 plays an important role in TGF-β1 mediated bone dysfunction diseases.

Keywords: epigenetics
genetics
mesenchymal stem cells
inflammation
osteoblast
bone
biology
Advisor: Philpott, M
Oppermann, U
Dunford, J
The elusive divide between tacit collusion and concerted practices

Sellers in oligopolistic markets can cooperate in ways that diverge from the orthodox vision of competition. It is a bigger issue, however, that there are also deviations in vision between competition law and economics on some basic categories. Foremost among these is the grey zone between two of the practices this thesis studies: tacit collusion and concerted practices. The two disciplines’ divergent interpretations of the interaction between sellers permeate the canon of enforcement practice, case law, and academic thinking. In more clear-cut instances, like cartels, this underlying divergence is inconsequential. However, the more ambivalent the practice, the more glaring the divergence becomes. Blind spots ensue because the two disciplines look at the problem from different angles. Using the prism of natural and artifical transparency, this thesis explores these blind spots, which feature throughout the history of competition law but appear to be expanding as technology and the means of interaction evolve from human intution to artificial intelligence (“AI”). Novel forms of coordination may expand the scope of tacit collusion. Here, the competition toolkit will likely prove adaptable. Yet, as long as human actors remain involved in the process, certain social codes and mutual perceptions of the market and will continue to enhance transparency in ways that competition law struggles to categorise. These social and economic vagaries of human interaction necessarily elude clean binary categorisations between the permissible and the impermissible.

Keywords: tacit collusion
oligopoly
competition law
concerted practices
Advisor: Ezrachi, A
A court in transition: the literary culture of the English court, c. 1590-1612

The accession of James I in 1603 transformed the English court, altering its personnel, formal organisation, and protocols. This interdisciplinary thesis examines how these changes affected and were addressed in the court’s literary culture.
Most previous investigations of early Jacobean English court culture have focused on a limited number of texts, especially court masques. By contrast, this thesis provides the first sustained study of a broad range of literary texts written, read and performed by courtiers, who carried out a variety of roles at the court. It examines forms of court literature that have previously been neglected by scholars, including chivalric entertainments, verse libels, and vernacular and neo-Latin poetry by Scottish courtiers. By analysing such texts, this thesis deepens scholars’ understanding of, and revises assumptions about, the English court and its culture during an important period of transition. It illuminates the contributions made by Scottish courtiers both before and after 1603, and demonstrates that courtiers routinely expressed reservations, and even criticisms, about changes to the court.
The Introduction justifies the distinctive range of sources examined in the thesis, and summarises the major institutional changes to the court that followed James’s accession and how they affected court politics. Chapter One uses the baptism of Prince Henry of Scotland in 1594 as a case study to reveal what English courtiers knew of Scottish court culture before 1603. Chapter Two demonstrates the vibrancy and political significance of the court’s chivalric culture, arguing that chivalric pageantry and ceremonial was used (with varied success) to foster amity between courtiers. Chapter Three examines how the changes at court were addressed in court sermons: although preachers helped to smooth James’s accession, they also expressed reservations about new personnel and protocols at court. Chapter Four analyses poetry by Scottish courtiers, revealing their distinctive interpretations of James’s accession, their contributions to court culture, and their criticisms of court life. Chapter Five examines the career and writings of Sir Fulke Greville to show how the changes at court effected and were analysed critically by a former Elizabethan courtier. Chapter Six analyses an overlooked form of court literature, in which changes at court were depicted most unsparingly: verse libels. The Conclusion evaluates the thesis’s revisionary account of early Jacobean English court culture, and discusses how its approach could be used to study other courts in transition.

Keywords: King James I
court culture
King James VI
Advisor: Gajda, A
Kewes, P
Nonparametric independence testing and regression for time-to-event data

The main goal of this thesis is to develop statistical methods for non-parametric independence testing and regression between a covariate and a right-censored event-time. First, we study tests of independence that use reproducing kernel Hilbert spaces (RKHSs) to quantify the dependence in a dataset. In particular we study permutation tests with the Hilbert Schmidt independence criterion (HSIC) as the test-statistic. We show such tests are pointswise consistent, which means that, for each fixed alternative hypothesis, the probability the null hypothesis is rejected con-verges to 1 as the sample size converges to infinity. This shows that kernel-based permutation tests of independence are able to detect every type of independence. Second, we propose two nonparametric tests of independence between a covariate and right-censored time. The first of these tests, termed optHSIC, consists of a two-step procedure: first the censored dataset is transformed into an uncensored one using optimal transport, after which a standard permutation test with test statistic HSIC is applied to the uncensored dataset. The second proposed test is the kernel-logrank test. This test uses a supremum of scores over an RKHS as the test-statistic, and uses wild-bootstrap to test for significance. We show that these tests are able to detect a wider range of dependencies between covariates and event-times than existing methods. Lastly, we study scoring rules for right-censored regression models. We show that several often-used scoring rules are not proper, meaning that the true distribution may score worse than inaccurate distributions. Since this does not hold for the right-censored log-likelihood scoring rule, we then propose a method, termed SuMo-net, that uses neural networks to optimize the right-censored log-likelihood. SuMo-net models the cumulative distribution function and the density of a right-censored event-time jointly using partially monotonic neural networks and achieves competitive performance on a range of datasets.

Keywords: biostatistics
neural networks
time-to-event data
survival analysis
statistics
Advisor: Sejdinovic, D
Steinsaltz, D
Constructing praise: the poetics of monumentality in Statius' Silvae

This thesis examines the interaction between the literary motif of the ‘monument poem’, and the poetic description (ecphrasis) of material monuments, in the Flavian poet Statius’ collection of occasional praise poetry, the Siluae. It explores the close relationship between poetic and material commemorative practices, and the theme of the poet’s and patron’s aspirations for immortality, within the dynamic and volatile political context of the Domitianic regime. A central concern of this thesis is the interaction between the Siluae’s complex poetic programme and the material world with which it engages, and the connection between the cultural capital of the poet and the social capital of which the patron is custodian. Scholarship tends to oscillate between formalist and historicist interpretations of the Siluae, focusing either on the ways in which Statius’ poetry can serve to ‘mystify’ and lend symbolic capital to the material conditions of his patrons or, on the other hand, to focus on the cultural and historical import of the poems, to the detriment of the Siluae’s poetic value. The following study focuses on the issues that arise when the traditional tropes of Roman poetic discourse and literary history which Statius uses are reshaped through material referents of the monuments described.
This is to be clarified by looking at how ‘Statius’ monuments’ illuminate the connection between poetics and politics in the Siluae. Statius’ descriptions of monuments provide opportunities to heavily politicise the aesthetics of the Siluae. Domitian’s monuments are used by Statius as analogies for the Siluae’s poetic programme, resulting in a deliberate interchange between poet and princeps. This theme is further complicated through Domitian’s own complex representation as a poet in Flavian literature, a point often overlooked. Crucial to my reading is the underlying presence of Nero in the Siluae, whose monumental footprint in Rome, and status as an emperor-poet, were both obstacles and opportunities for Domitian. Just as Domitian’s monuments work to reshape the memory of Nero in Rome, Statius’ Siluae deconstruct Neronian literature and rehabilitate it to suit a Flavian agenda.

Keywords: monument
Silvae
ecphrasis
memory studies
Statius
Flavian poetry
Advisor: Morgan, L
Tradigital knowledge? Indigenous video games, intellectual property law and the protection of traditional knowledge

Using intellectual property law and video games made by, for, and with Indigenous communities, this thesis examines the challenges and opportunities for the protection of Indigenous traditional knowledges in digital spaces. Existing scholarship addresses the inability the various categories of intellectual property (IP) law (particularly copyright) as they currently exist, to provide adequate protection for Indigenous traditional knowledges. Digital media poses a similar challenge to IP law. These two categories of “challenges”—sometimes dichotomized as the ‘very old’ and the ‘very new’—are often discussed in opposition to one another, the former associated with demands for increased protections and limited access, the latter with demands for increased access to information and diminished IP protection This dichotomy of ‘old’ and ‘new’ is likely based on an assumed incompatibility between Indigenous traditional knowledge and technological innovation. By situating Indigenous video games and the traditional knowledges they hold within an historical context of continual development and (ex)change, this thesis demonstrates that change and innovation do not contradict tradition as the discourse often suggests. The video games presented in this thesis emerge from traditional, local, and historical contexts, and demonstrate the ways in which forms of traditional knowledge such as storytelling, mythology, song and language, exist digitally. Through the lens of Indigenously determined game design, this research argues for the validity of what I have termed ‘tradigital’ knowledges — that is, the traditional knowledge in and of digital environments. It suggests that meaningful protection extends beyond the bounds of Western law and must include the support of intergenerational knowledge-exchange, skill-sharing and capacity-building which ensure the continued relevance, responsiveness and resilience of traditional knowledges.

Keywords: indigenous
traditional knowledge
intellectual property
tradigital knowledge
video games
Advisor: Gosden, C
Homo europaeus: identity, bureaucracy and belonging in Brussels

This thesis is an ethnographic study of identity, belonging and bureaucracy among permanent officials in and around the European Union civil service. Drawing on fieldwork carried out in the European Quarter of Brussels over 18 months, its focus encompasses two central research queries. The first seeks to capture a shifting institutional ethos inside the European Commission, investigating how policymakers see their roles as Union officials and embody, negotiate and problematize a particular administrative identity. The second analyzes how Europeanness as a recognition of selfhood, a mode of belonging and a way of life is enacted and performed within these spaces. Data was collected primarily through semi-structured, in-person interviews with current and former officials working in 16 policy directorates and services. The study pays special consideration to the aspects, norms and formalities of ‘work-life’, defined as the dimensions of experience pertaining to one’s occupation. It argues that Brussels-based European identity is not a delimited category anchored in specific points in time and space but an ‘elective identity’ that is a steppingstone to a global cosmopolitan manner of being in and interacting with the world. Its findings speak to an anthropological understanding of the conditions and possibilities for being European and belonging to Europe, where Europeanness emerges as an assertion of systemic integration in a turbulent geopolitical context marked by overlapping crises and enduring fragmentation.

Keywords: European Union institutions
European identity
bureaucratic culture
nationalism
elite ethnography
Advisor: Parkin, R
Lezaun, J
Targeting tumour-associated macrophages with locally-expressed T cell engagers

Tumour associated macrophages (TAMs) are implicated in cancer progression but can also exert anti-tumour activities. In this thesis, a strategy to redirect endogenous T cell cytotoxicity towards cancer supporting (M2-like) TAMs is explored. A panel of novel bi- and tri-valent T cell engagers (BiTEs/TriTEs) was generated, recognising CD3ε on T cells and M2-like macrophage markers CD206 or folate receptor β (FRβ). Primary human T cells activated by the BiTEs/TriTEs preferentially killed M2- over M1-polarised autologous macrophages, with EC50 values in the nanomolar range. This work represents the first to demonstrate the feasibility of redirecting T cells to kill macrophages.
To avoid on-target off-tumour toxicities, we propose localising BiTE/TriTE expression to the tumour with an engineered oncolytic virus. We confirmed the feasibility of this approach by modifying an oncolytic adenovirus in early-phase clinical trials for solid cancers, enadenotucirev (EnAd), to express the BiTEs. Critically, T cell engager-armed EnAd retained its oncolytic and replicative capacities, whilst mediating BiTE expression from infected cancer cells.
In immunosuppressive human malignant ascites samples, free and EnAd-encoded FRβ-targeting BiTEs (but not CD206-targeting T cell engagers) triggered endogenous T cell activation and IFN-γ production, leading to increased T cell numbers and a reduction in the number of CD11b+CD64+ ascites macrophages. Strikingly, surviving macrophages exhibited a general increase in M1-like marker expression, suggestive of a repolarisation of the microenvironment towards a more immune-responsive state. Taken together, this approach to deplete cancer-promoting TAMs in the context of the immune-stimulatory effects of BiTEs and oncolytic viruses offers a powerful new strategy for removing barriers to anti-tumour immunity in patients with cancer.

Keywords: BiTEs
tumour-associated macrophage
adenovirus
oncolytic virus
Advisor: Duffy, M
Seymour, L
Identification of novel DNA damage response mechanisms using SLiM proteomics

The repair of damaged DNA is essential for maintaining genome integrity. Accordingly, all known forms of life have evolved a complex repertoire of biochemical pathways to detect and repair such damage, collectively called the DNA damage response. Like all biological pathways, the DNA damage response is facilitated by a series of protein-protein interactions, but the mechanisms by which DNA repair protein complexes are assembled, disassembled and regulated by post-translational modifications are still poorly understood.
To address this issue, a combined bioinformatics and proteomics approach was developed to identify and characterize novel protein-protein interactions in DNA damage response proteins relying on Short Linear peptide Motifs (SLiMs). Using this approach, novel interactions have been identified between the DNA repair proteins: MDC1 and TOPBP1, TOPBP1 and CIP2A, AUNIP and CtIP, and between the BLM helicase complex and the single-stranded DNA binding protein RPA. Investigation of the functional relevance of the interaction between the BLM helicase complex and RPA demonstrated that RPA-binding is required for stable BLM recruitment to sites of DNA replication stress and replication fork restart.
To overcome the limitations of manually identifying SLiMs, a web-based tool was developed to predict SLiMs in DDR proteins automatically. This work forms the foundation for the development of a DNA repair interactome based on SLiMs, for a greater understanding of the diverse range of pathologies associated with mutations in DNA repair genes and the development of new therapies.

Advisor: Blackford, A