VictorJuiz/thesis huggingface dataset:
The monetary circulation of Moesia Inferior from the beginning of the 2nd century AD to the end of the 3rd century AD

This thesis intends to gather and analyse all coin hoards and the majority of the single finds found on the territory of Moesia Inferior, dated between AD 100 and 300. The study will demonstrate how coins, through their existence as archaeological objects, offer profound insights not only into the matters of economy, state organization, and monetary supply but also into the local history of the cities which operated as mints. This study attempts to build a new and detailed framework for studying and interpreting coin assemblages in this area of Europe. A major aim is to create a fundamental basis for future research in the province so every new hoard or stray find can be added to the database which will allow large-scale analysis; this database will facilitate the incorporation of Lower Moesia into the numismatic map of the Roman Empire.

Advisor: Howgego, C
Structural and functional analysis of serine-ADP-ribosylation

ADP-ribosylation is a protein post-translational modification involved in several biological pathways, including the DNA damage response. PARP1, one of the primary sensors of DNA breaks, and the main enzyme responsible for ADP-ribosylation has been the subject of study for several years. Despite the revelations from previous studies, we still lack a full understanding behind PARP1 regulation and activity. In this thesis, I will describe the identification and characterisation of a novel interactor/regulator of the PARP1 cycle, which we named Histone Parylation Factor 1 (HPF1), with particular emphasis of its role in DNA repair. In the second chapter, I will show a structural and biochemical characterisation of HPF1 and the discovery of HPF1 as a specificity factor inducing a novel post-translational modification named serine-ADP-ribosylation. In the third chapter, I will show that serine-ADP-ribosylation induced by HPF1 is a reversible post-translational modification. Further, I will show that the only human enzyme able to reverse serine-ADP-ribosylation is the previously poorly characterised glycohydrolase ARH3, and show an overall biochemical characterisation of ARH3. Finally, in the fourth and last experimental chapter, I will show that serine-ADP-ribosylation is a post-translational modification present also in the model organism Drosophila melanogaster. However, I’ll show that in Drosophila the enzyme responsible for its removal is DmParg, as Drosophila do not possess an ARH3 homolog. Finally, I will show a biochemical characterisation of DmParg and preliminary data for its structural characterisation.

Advisor: Ahel, I
Inhibition and mechanistic studies of FTO

The Fat Mass and Obesity Associated protein (FTO) is a nucleic acid demethylase that belongs to the 2-oxoglutarate dependent oxygenase superfamily (2OG oxygenases). Like other 2OG oxygenases, FTO uses Fe(II), 2-oxoglutarate (2OG) and molecular oxygen (O2) to catalyse oxidation of its substrates. Mutation of the gene encoding for FTO have been linked to obesity, type II diabetes, cancer, and Alzheimer’s disease. One aspect of the work described in this thesis aimed at developing small molecule inhibitors of FTO. An NMR binding assay was developed using 2OG as a reporter ligand. The inhibitors developed in this thesis exhibit high potency and selectivity for FTO (the lead inhibitor has an IC50 value of 1.32 μM).
The work also aimed at the synthesis of N6-methyladenosine (m6A) phosphoramidite with the aim of synthesising single stranded RNA (ss-RNA) oligonucleotide containing m6A. Apart from the literature reported substrates, work also focussed on the investigations of other nucleosides as natural and unnatural substrates of FTO. During the study, new synthetic routes to the m6A phosphoramidite, ethanoadenosine, ethylethanoadenosine and methylethanoadenosine were developed. The iodouridine phosphoramidite was also synthesised with the future aim of synthesising a ss-RNA substrate crosslinked to FTO.
The reaction of formaldehyde (the FTO co-product) with canonical and non-canonical nucleotides was then investigated using NMR. Various nucleotide/HCHO adducts were identified, including multiple novel species. Among the canonical nucleosides, TMP and UMP reacted the fastest followed by dCMP, dGMP and lastly dAMP. However, dAMP was observed to form the most stable adduct with formaldehyde, while the adducts of TMP and UMP were dynamically favoured. Comparing cytidine, 5-methyldeoxycytidine (5mdC) and 5-hydroxymethyldeoxycytidine (5hmdC) revealed that 5mdC reacts the fastest. Among m6A, N1-methyladenosine (m1A) and adenosine, the initial rate of reaction with formaldehyde was fastest with adenosine.
Finally, the FTO and AlkB catalysed oxidative demethylation of substrates was investigated by NMR using [13C] labelled substrates (e.g., N6-[13C]-methyladenosine ([13C]-m6A), N3-[13C]-methythymidine ([13C]-m3T) or N1-methyladenosine ([13C]-m1A)) as probes. The studies reveal the first direct evidence, using NMR, for the formation of N6-hydroxymethyladenosine as an intermediate of FTO- catalysed oxidative demethylation of m6A. The results also confirmed the formation of formaldehyde. The observation of formaldehyde in AlkB-catalysed oxidative demethylation of m1A led to the invalidation of the previously reported hypothesis that a phosphate group attached to a nucleoside is the minimum requirement for AlkB substrates.
Overall, the work described in this thesis suggests new approaches to the inhibition of FTO, helps to define the range of substrates for FTO, reassign the requirement for AlkB-catalysed oxidative demethylation, and informs on the reaction of the FTO-catalysed reaction co-product, HCHO, with nucleosides.

Keywords: enzymatic assays
FTO
formaldehyde
Advisor: Schofield, C
Self-supervised learning using motion and visualizing convolutional neural networks

We propose a novel method for learning convolutional image representations without manual supervision. We use motion in the form of optical-flow, to supervise representations of static images. Training a network to predict flow from a single image can be needlessly difficult due to intrinsic ambiguities in this prediction task. We instead propose two simpler learning goals: (a) embed pixels such that the similarity between their embeddings matches that between their optical-flow vectors (CPFS), or (b) segment the image such that optical-flow within segments constitutes coherent motion (S3-CNN). At test time, the learned deep network can be used without access to video or flow information and transferred to various computer vision tasks such as image classification, detection, and segmentation. Our CPFS model achieves state-of-the-art results in self-supervision using motion cues, as demonstrated on standard transfer learning benchmarks.
Despite high transfer learning performance, we feel the need to visualize the representation learned by our self-supervised CPFS model. With that motivation we develop a suite of visualization methods and study several landmark representations, both shallow and deep. These visualizations are based on the concept of “natural pre-image”, that is a natural-looking image whose representation has some notable property. We study three such visualizations: inversion, in which the aim is to reconstruct an image from its representation, activation maximization, in which we search for patterns that maximally stimulate a representation component, and caricaturization, in which the visual patterns that a representation detects in an image are exaggerated. We formulate these into a regularized energy-minimization framework and demonstrate its effectiveness. We show that our method can invert HOG features more accurately than recent alternatives while being applicable to CNNs too. We apply these visualization techniques to our self-supervised CPFS model and contrast it with visualizations of a fully supervised AlexNet and a randomly initialized one.

Keywords: Convolutional Neural Networks
Deep Learning
Advisor: Vedaldi, A
Evolutionary modelling of biological structures

Many naturally occurring biological molecules, such as nucleic acids or proteins, are evolutionary related, having evolved from a common ancestor via a process of sequence mutation. Mutations undergo a process of selection, with combinations of mutations that preserve or improve a molecule's fitness having a higher probability of being maintained. Mutations that modify structure are expected to particularly impact fitness, and often detectably influence observed patterns of mutations.
Nucleotide coevolution is one such example, whereby pairs of nucleotides within biologically functional nucleic acid secondary structures exhibit evidence of coevolution that is consistent with the maintenance of canonical base-pairing. PINNACLE, the first of two models developed in this dissertation, is a sequence evolution model that assesses the rates of mutation associated with base-paired sites in alignments of DNA or RNA sequences. PINNACLE is able to fully account for an unknown secondary structure, and in doing so can be used to predict a secondary structure shared amongst an alignment of sequences. PINNACLE was used to infer rates of coevolution associated with GC, AU (AT in DNA), and GU (GT in DNA) dinucleotides in non-coding RNA alignments, and single-stranded RNA and DNA virus alignments. Strong evidence was found for GU dinucleotides being selectively favoured at base-paired sites in non-coding RNA and RNA virus alignments, with slight evidence for GT dinucleotides being selectively favoured at base-paired sites in DNA virus alignments. The strength of coevolution at base-paired sites in a SHAPE-MaP-determined HIV-1 NL4-3 RNA secondary structure and a corresponding alignment containing large numbers of HIV group 1M sequences was also measured, finding statistically significant correlations between the experimentally-determined SHAPE-MaP pairing scores and the inferred degrees of coevolution.
The second model developed in this dissertation, ETDBN, differs from typical evolutionary models in that it models the structural evolution of proteins in addition to their sequence evolution. ETDBN uses a dihedral angle representation of protein structure, and models the evolutionary trajectory between a pair of protein structures using an angular diffusion process on the two-dimensional torus. ETDBN is trained on a large database of proteins, and is parameterised such that it can learn the dependencies between sequence and structural evolution. The model has interpretable parameters, and is comparatively more realistic than previous stochastic models of protein structure evolution. Using the trained model, we were able to identify apparent sequence-structure evolutionary motifs present in numerous homologous protein pairs. The generative nature of our model enabled us to evaluate its validity and to infer various quantities, such as protein structures or alignments from sequences of amino acids, dihedral angles, secondary structure labels, or any combination thereof.

Keywords: Bayesian
Evolution
RNA structure
Probabilistic
Protein structure
Phylogenetics
Advisor: Hein, J
The liberal myth. Foreigners’ property rights and the making of modern world politics

The thesis conceptualizes a new approach to the historical study of the global legal order. Instead of following an influential contextual approach focusing on understanding the works of great legal theorists, I analyze the relationship between legal thought and the global legal practices that constituted actually existing patterns of social order. The usual idea of legal practice needs however first be reimagined. A focus on the ‘profession of international law’ is too narrow. As often the most influential actors in legal practice were not lawyers but for example parliamentarians and diplomats. Second the conventional idea of a legal text needs to be reconceptualised. Drawing on literary theory, I argue that the historical significance of a legal text is constituted not only by the context of its writing but also through its reception and use by later practitioners. Moreover, legal texts are not constant but are often modified, even after the death of the original author, by later editors seeking to make the work useful for contemporary practitioners. This insight highlights a neglected and important alternative dynamic of legal change that first takes place through legal practice and is introduced to doctrine only afterwards. In this practice story, legal change predominantly takes place through practitioners pursuing their interests within broad bounds set by normative expectations rather than with the novel speculations of great thinkers.
I have applied the new method to the case of foreigners’ property rights. These rights are crucial as the legal frameworks that have enabled the growth of a global liberal economy through transnational trade and investment. The study of these rights has allowed me to challenge the conventional interpretation that Britain and the United States, as leading liberal democracies drawing on the liberal political thought of Locke, created a liberal international order through multilateral treaty making.
Stein's method for functional approximations

We extend the ideas of Barbour's paper from 1990 and adapt Stein's method for distributional approximation to infinite-dimensional distributions. Hence, we obtain theoretical results bounding the rate of functional convergence of certain classes of stochastic processes to diffusions. Those are applied to examples coming from queuing theory, random-graph theory, statistics and combinatorics.
We firstly look at the motivation for this thesis and an overview of Stein's method. Then we present our original work, contained in four articles. The first one is a collaboration with Andrew Duncan and Sebastian Vollmer, published in the Electronic Communications in Probability and the other ones, for which I am the sole author, are currently under consideration for publication. The first paper corrects a mistake in Barbour's seminal work from 1990.
The second paper considers the approximation of a time-changed Poisson process by a time-changed Brownian motion for time changes independent of the processes they are applied to. As an application, we study the M/M/1 queue and a time-changed Brownian Motion and bound a distance between the two.
The third paper studies the asymptotic behaviour of scaled sums of random vectors having different dependence structures. As an application, a bound on the distance between scaled non-degenerate U-statistics and Brownian Motion is proved. Moreover, we prove a quantitative functional limit theorem for exceedances in the m-scans process.
In the fourth paper, we adapt the exchangeable-pair approach to Stein's method to approximations by infinite-dimensional laws. It is used to provide the rate of convergence in a functional combinatorial central limit theorem, extending the result of Barbour and Janson from 2009. We further apply this approach to study the asymptotics of edge and two-star counts in a certain graph-valued process.
The final part of the thesis presents the conclusions and suggestions for future work.

Advisor: Reinert, G
The role of demographic and monetary factors in the late medieval economies of England, Scotland and the southern Low Countries (1351–1530)

The narrative of the post-Black Death English economy has been shaped by two contrasting interpretations: whether England’s economy was one of economic decline or prosperity; and whether its economy was largely driven by demographic or monetary factors. These two debates, which both appear to be irreconcilable, are the result of a persistent Anglo-centric approach to the late medieval English economy. My thesis puts the economy of England into the context of Scotland and the southern Low Countries, using comparison to shed new light on these debates. With the addition of both new mint output data from Scotland and annual population estimates for Flanders and Brabant, I employ regression analysis to quantitatively test the extent to which demographic and monetary factors were able to play a determining role in the long-term trends of prices, rents and wages. Thus, my work offers a more rounded approach than previous studies of the impact of money and population on prices, rents and wages. This comparative approach and use of statistical methods offers a number of striking conclusions. First, England’s post-Black Death economy was atypical when compared with her trading partners—the currency was unusually stable and the population was unique in its slow recovery. Prices in England remained flatter than elsewhere and appear to have been driven more clearly by demographic factors, though there are caveats to this conclusion. Second, relative to the periods of monetary shortage and undulating prices seen in the southern Low Countries and Scotland, while England’s fifteenth-century economy might have lacked the prosperity of the late fourteenth century, it appears to have survived the bullion famine and mid fifteenth-century ‘slump’ better than elsewhere. England’s balance of trade remained positive, and sluggish population recovery after the Black Death kept the per capita money stock buoyant enough to prevent the dramatic price depression seen in the southern Low Countries during the mid fifteenth century. Such conclusions only manifest themselves through my unique combination of triple comparison and statistical analysis.

Advisor: Mayhew, N
Watts, J
Mapping the ubiquitin ligase interaction landscape at the endoplasmic reticulum membrane

The Endoplasmic Reticulum (ER) is the entry-point of the secretory pathway and is responsible for coordinating essential cellular functions, including ER-associated degradation, calcium flux and sterol homeostasis. These processes are regulated by a common post-translational mechanism: the ubiquitination of target substrates by RING-domain E3 ubiquitin ligases (E3s) resident in the ER membrane. At least 25 different transmembrane domain-containing E3s are reported to be ER-localised. However, despite the indication that select E3s control specific ER and cellular functions, few have been extensively characterised. Since E3 function is determined by the complexes it forms with specific cofactors, as well as interactions with the substrates it regulates, the primary objective of this project was to map the interaction networks of these E3 ligases. To this aim, mass spectrometry coupled with comparative proteomic profiling was employed to identify high-confidence interacting proteins (HCIPs) for the ER-resident E3 family. Using this approach, 226 HCIPs were discovered for 21 E3s, which represent novel potential cofactors and substrates, and implicate the ER-resident E3s in multiple homeostatic, metabolic and regulatory processes. A subset of HCIPs were validated as bona fide E3 interactors, including the RNF26 interactors TMEM43, TMED1 and ENDOD1. These largely uncharacterised membrane-embedded proteins were found to contribute to the role of RNF26 in regulating STING-dependent innate immune signalling, which orchestrates a protective response against pathogenic DNA viruses. Therefore, these data provide a comprehensive collection of E3 interaction networks at the ER membrane, which serves as a discovery platform to enable the characterisation of ER-resident E3 complexes and their functions.

Advisor: Christianson, J
Probing nuclear effects in neutrino-nucleus scattering at the T2K off-axis near detector using transverse kinematic imbalances

The precise characterisation of neutrino oscillations offers a range of auspicious opportunities in the search for physics beyond the standard model. In particular T2K and NOvA, as the current generation of accelerator-based long-baseline neutrino oscillation experiments, are just beginning to provide the first measurements of the complex phase that gives rise to CP-violation in the neutrino sector within the PMNS description of neutrino oscillations. However, the limiting systematic uncertainty in making such precision measurements of neutrino oscillations - and soon, for some measurements, the largest of all uncertainties - stems from a naivety of relevant O(GeV) neutrino-nucleus interactions. These interactions are particularly difficult to understand since the bare neutrino-nucleon scatter is often obfuscated by a variety of poorly-understood `nuclear effects', such as nucleon-nucleon correlations and hadronic re-interactions, which distort the outgoing particle kinematics. A better understanding of these nuclear effects is therefore essential to constrain the principle systematics associated with neutrino oscillation measurements.
This thesis details how the T2K experiment's off-axis near detector is used to provide a novel characterisation of nuclear effects. This is achieved through the first measurement of differential neutrino-nucleus scattering cross sections as a function of kinematic imbalances in the plane transverse to an incoming neutrino beam. The use of transverse kinematic imbalances are motivated by a series of recent phenomenological studies, which this thesis further develops, that illustrate how these observables can provide a new examination of nuclear effects at T2K. In order to extract the cross sections with minimal input model bias, a new cross-section extraction procedure, which minimises the use of the input model and facilitates a data-driven regularisation, is developed, validated and applied. Extensive comparison of the results to the predictions of a variety of neutrino-nucleus interaction simulations then enables a unique probe, and partial isolation, of some nuclear effects. This probe is expected to play a significant role in future neutrino-nucleus interaction model development, whilst also facilitating new constraints on the principle systematic uncertainties associated with neutrino oscillation measurements.

Advisor: Weber, A