VictorJuiz/thesis huggingface dataset:
Crystallographic studies on 2-oxoglutarate dependent oxygenases
Keywords: protein structure
structural biology
inhibition

The Fe(II) and 2-oxoglutarate dependent oxygenases (2OG oxygenases) catalyse a broad range of oxidative reactions in various organisms. 2OG oxygenases use 2OG and molecular oxygen to catalyse the oxidation of a variety of substrates including small molecules, fatty acids, nucleic acids and proteins. Several human 2OG oxygenases are implicated in diseases. The fat mass and obesity associated protein (FTO) is linked to obesity, whilst collagen prolyl-4-hydroxylases (CPHs), the procollagen lysyl hydroxylases (PLODs), and the hypoxia inducible factor hydroxylases (PHDs) are linked to cancer. Therefore, structure-based inhibition studies on FTO, CPH and related 2OG oxygenases are of significant therapeutic interest.
The obesity-associated FTO is an mRNA N6-methyladenine (m6A) demethylase and a homologue of E. coli alkylated DNA repair protein (AlkB), a DNA repair enzyme that demethylates N1-methyladenine (m1A) and N3-methylcytosine (m3C) bases. Human AlkB homologue 5 (ALKBH5) has a similar substrate profile as FTO, i.e. ALKBH5 is another mRNA m6A demethylase, making it a target for structural and inhibition studies to improve inhibitor selectivity for FTO. The CPH and PLODs catalyse hydroxylation of collagen prolyl- and lysyl-residues; the resultant 4-hydroxyprolyl- and 4-hydroxylysyl-residues are important for the formation of the collagen triple helix and intermolecular crosslinks, respectively. Another 2OG oxygenase, the 2-oxoglutarate and iron-dependent oxygenase domain-containing protein 2 (OGFOD2), is related by sequence similarity to the PLODs but its biological role is unknown.
This thesis describes crystallographic, biochemical and inhibition studies on five 2OG oxygenases: AlkB, FTO, ALKBH5, OGFOD2 and CPH. Three AlkB-inhibitor complexes were determined; taken together, these structures serve as proof-of-principle that the AlkB subfamily 2OG oxygenases are amenable to structure-based inhibition studies. Several classes of inhibitors of FTO were then identified and their binding modes were investigated through the determination of 7 crystal structures of FTO-inhibitor complexes. Subsequently, a crystal structure of ALKBH5 was determined, which provided insights into its substrate recognition mechanisms. The ALKBH5 structure also serves as a template for inhibitor design. Preliminary structural and biochemical data were also obtained for OGFOD2 and CPH.
Overall, these results contribute to the development of a biophysical understanding of human 2OG oxygenases, and will help to enable the development of selective inhibitors of 2OG oxygenases involved in nucleic acid and collagen modifications.
Performing barbers, surgeons and barber-surgeons in early modern English literature
Keywords: Shakespeare
early modern theatre
early modern literature
English literature
medicine and literature

This study addresses the problem critics have faced in identifying contemporary perceptions of the barber, surgeon and barber-surgeon in early modernity by examining the literature, predominantly the drama, from the period. The name ‘barber-surgeon’ is not given formally to any character in extant early modern plays; only within the dialogue or during stage business is a character labelled the barber-surgeon. Barbers and surgeons are simultaneously separate and doubled-up characters. The differences and cross-pollinations between their practices play out across the literature and tell us not just about their cultural, civic and occupational histories but also about how we interpret patterns in language, onomastics, dramaturgy, materiality, acoustics and semiology. Accordingly, the argument in this study is structured thematically and focuses on the elements of performance, moving from discussions of names to discussions of settings and props, disguises, stage directions and semiotics, and from sound effects and music, to voices and rhetorical turns. In doing so, it questions what it means in early modernity to have a developed literary identity, or be deprived of one. The barber-surgeon is a trope in early modern literature because he has a tangible social impact and an historical meaning derived from his barbery and surgery roots, and consequently a richly allusive idiom which exerted attraction for audiences. But the figure of the barber-surgeon can also be a trope in investigating how representation works. An aesthetic of doubleness, which this study finds to be diversely constructed, prevails in barbers, surgeons’ and barber-surgeons’ literary conception, and the barber-surgeon in the popular imagination is created from opposing cultural stereotypes. The literature from the period demonstrates why a guild union of barbers and surgeons was never harmonious: they are opposing dramaturgical as well as medical figures. This study has a wide-ranging literary corpus, including early modern play texts, ballads, pamphlets, guild records, dictionaries, inventories, medical treatises and archaeological material, and contributes to the critical endeavours of the medical humanities, cultural materialists, theatre historians and linguists.
Topologically close-packed phase prediction in Ni-based superalloys: phenomenological structure maps and bond-order potential theory
Keywords: Ni-base superalloys
Bond-order potentials
topologically close-packed phases
Tight-binding

Single crystal nickel-based superalloys are used in modern gas turbines because of their remarkable resistance to creep deformation at elevated temperatures, which is ensured by the addition of significant amounts of refractory elements. Too high concentrations of refractory elements can lead to the formation of topologically-close packed (TCP) phases during exposure to conditions of high temperature and stress which result in the degradation of the creep properties. The traditional methods for predicting the occurrence of TCP phases in Ni-based superalloys have been based on the PHACOMP and newPHACOMP methodologies which are well-known to fail with respect to new generations of alloys. In this work a novel two-dimensional structure map (Nbar, deltaV/V) for TCP phases where Nbar is the valence-electron count and deltaV/V is a compositional dependent size factor. This map is found to separate the experimental data on the TCP phases of binary, ternary and multi-component TCP phases into well-defined regions corresponding to different structure types such as A15, sigma, chi, delta, P, R, mu, and Laves. In particular, increasing size factor separates the A15, sigma and chi phases from the delta, P, R, mu phases. The structure map is then also used in conjunction with CALPHAD computations of sigma phase stability to show that the predictive power of newPHACOMP for the seven component Ni–Co–Cr–Ta–W–Re–Al system is indeed poor.
In order to gain a microscopic understanding of the observed structural trends, namely the differences between the two groups of TCP structures with increasing deltaV/V and the trend from A15 to sigma to chi with increasing Nbar, the electronic structure is coarse-grained from density functional theory (DFT) to tight-binding to bond-order potentials (BOPs). First, DFT is used to calculate the structural energy differences across the elemental 4d and 5d transition metal series and the heats of formation of the binary alloys Mo-Re, Mo-Ru, Nb-Re, and Nb-Ru. These calculations show that the valence electron concentration stabilizes A15, sigma and chi but destablizes mu and Laves phases. The latter are shown to be stabilized instead by relative size difference. Second, a simple canonical TB model and in combination with the structural energy difference theorem is found to qualitatively reproduce the energy differences predicted by the elemental DFT calculations. The structural energy difference theorem rationalizes the importance of the size factor for the stability of the mu and Laves binary phases as observed in the structure map and DFT heats of formation. Finally, analytic BOP theory, is employed to identify the structural origins of the energetic differences between TCP structure-types that lead to the trends found within the two-dimensional structure map.
Mises en scène de la favorite dans la littérature du "Grand Siècle" (1665-1715)
Keywords: favorite
Louis XIV
France
favourite
royal mistresses

This study enquires into the construction of a cultural fantasy, the favorite (or royal mistress), in the reign of Louis XIV (1661-1715), and aims to explore the kinds of narrative, the 'scénario pour l’imaginaire', articulated around this figure.
A process of crystallization in respect of the favorite, both as word and as literary figure, develops across the late seventeenth century. This process is on the one hand fuelled by the increasing prominence of female favouritism as a political practice during the period, and on the other facilitated by the emergence of new privileged media such as the novel and the 'nouvelle historique'. The favorite, as a new incarnation of the ‘femme forte’, becomes a trope by which anxieties can be expressed: about female power, but also about the monarchy in general.
This thesis advances by way of close readings and studies of vast corpora of texts; it alternates – both within and between chapters – between analysis and synthesis. Following the introduction, the first chapter introduces a set of mental landmarks, both semantic and axiological, and explores the dictionaries, treatises and courtly manuals of the time in search of the favorite. The second chapter focuses on the fiction of the 1660s and 1670s, and questions the way in which these texts established elements of definition and recurrent issues related to the staging of the favorite in this period.
The third chapter considers the representation of Louis XIV's mistresses, principally through a study of the ballets, poems, letters, memoirs, satires and pamphlets concerned with the Sun King's loves. Its object is to show how the favorite is inserted into the royal mythology. The fourth chapter is dedicated to the first text explicitly and exclusively devoted to the favorite: the Histoire des Favorites (1697) by Anne de La Roche-Guilhen. This chapter attempts to bring to light the tensions underlying the text, while interrogating the determining role of this collection in the process of crystallization explored throughout the thesis.
The fifth chapter sketches out the afterlife of the favorite under Louis XV and Louis XVI, and describes the principal evolutions which ensured her survival in the collective imagination.
Historical assembly of seasonally dry tropical forest diversity in the tropical Andes
Keywords: molecular dating
species diversification
Neotropics
taxonomy
seasonally dry tropical forests
phylogenetics

The relative contributions of biome history and geological setting to historical assembly of species richness in biodiversity hotspots remain poorly understood. The tropical Andes is one of the world’s top biodiversity hotspots, and with its diverse biomes and the relatively recent but dramatic uplift, the Andes provides an ideal study system to address these questions. To gain insights into the historical species assembly of the tropical Andes, this study focuses on investigating patterns of plant species diversification in the Andean seasonally dry tropical forest (SDTF) biome.
Three plant genera are used as study groups: Amicia (Leguminosae, Papilionoideae), Tecoma (Bignoniaceae), and Mimosa (Leguminosae, Mimosoideae). Species limits are re-evaluated to enable dense sampling of species and intraspecific diversity for phylogeny reconstruction for each group. Time-calibrated phylogenies for Amicia and Mimosa are presented and used to determine patterns of species diversification in time and space. For Tecoma, incongruence between nuclear and chloroplast gene trees precludes straightforward estimation of a species tree and this incongruence is attributed to possible reticulation caused by hybridization.
Divergence time estimates and patterns of diversification for Amicia and Mimosa are compared with other Andean SDTF groups (Cyathostegia, Coursetia, Poissonia; Leguminosae) using isolation by distance and phylogenetic geographic structure analyses. Consistently deep divergences between sister species and high geographic structure across all five groups suggest that Andean SDTF lineages have persisted over the past 10 million years (My) with high endemism driven by dispersal limitation, caused by geographic isolation, following the most recent episode of rapid mountain uplift 5-10 My ago. This prolonged stasis of the Andean SDTF biome is in line with Miocene fossil and paleoclimate evidence. Finally, wider analyses of the contrasting evolutionary timescales of older SDTF and more recent high-altitude grassland diversity suggest that the exceptional plant species diversity in the Andes is the outcome of highly heterogeneous evolutionary histories reflecting the physiographical heterogeneity of the Andean biodiversity hotspot.
Sub-hertz optical frequency metrology using a single ion of 171Yb+
Keywords: spectroscopy
metrology
atomic clock

Optical frequency standards offer the possibility of a step improvement of up to two orders of magnitude in the accuracy with which the SI second can be realised. 171Yb+ possesses two dipole-forbidden optical transitions that are promising candidates for a redefinition of the second. In this thesis, absolute frequency measurements of these two transitions are presented.
A number of experimental upgrades have been implemented, which have resulted in a large reduction in both the statistical and systematic uncertainties associated with the measurements and have improved both the reliability and simplicity of the experimental setup. In particular, the replacement of two frequency-doubled Ar+-pumped Ti:sapphire lasers with extended cavity diode lasers has eliminated the downtime associated with their maintenance. Additionally, the introduction of polarisation modulation on the cooling light has allowed the residual bias magnetic field required for laser cooling to be reduced by a factor of thirty.
The first measurement at the National Physical Laboratory (NPL) of the frequency of the 2S1/2 (F = 0) → 2D3/2 (F′ = 2) electric quadrupole (E2) transition at 436 nm is presented. The transition frequency was measured against a hydrogen maser using a femtosecond optical frequency comb, and was determined with a relative standard uncertainty of 1.3 × 10−14.
A commercial diode-based laser system was then implemented in order to drive the 2S1/2 (F = 0) → 2F7/2 (F′ = 3) electric octupole (E3) transition at 467 nm. The laser frequency was actively stabilised to the ultra-narrow atomic absorption with a resolved linewidth of 11 Hz, allowing the acquisition of ninety hours of frequency data measured relative to the NPL’s primary frequency standard CsF2. Combined with a thorough evaluation of the systematic perturbations, the total fractional uncertainty in the absolute frequency of the transition has been reduced by a factor of twenty to 1 × 10−15. Recent complementary results from Physikalisch-Technische Bundesanstalt (PTB) show that the E3 transition in 171Yb+ has the potential to be a highly accurate and reproducible optical frequency standard, and to date these measurements demonstrate the best international agreement between trapped ion optical frequency standards.
Spatial analysis of exposure coefficients with applications to stomach cancer
Keywords: H. pylori
stomach cancer
spatial analysis
regression mixtures
Portugal
spatially varying regressions
clustering models
varying exposure coefficients

Earlier ecological studies on the relation between H. pylori infection and stomach cancer have considered that the relation between these two variables, as estimated by the exposure coefficient, is constant. However, there is evidence to suggest that this relation changes geographically due to differences in strains of H. pylori. Since the prevalence of H. pylori varies with socio-economic status, the association between the latter and stomach cancer mortality may also vary geographically. This thesis studies stomach cancer by taking into account the geographical variability of the exposure coefficients. The study proposes the use of regression mixtures, clustering models and spatially varying regressions for the study of varying exposure coefficients. The effect of transformations of variables in these models appears to have been little considered. We provide new necessary conditions for invariance under transformations of variables for mixed effect models in general, and for the proposed models in particular. In addition, we show that varying exposure coefficients may induce a varying baseline risk. The regression mixtures and the clustering model are applied to a data set on stomach cancer incidence and H. pylori prevalence in 57 countries worldwide. We extend the clustering model to reflect any distance measure between the geographical units, including the Euclidean distance, in the formation of clusters. We also show that the clustering model performs better than the regression mixture model when the aim is to identify connected clusters and the observations present large variance. The results obtained with the clustering model supported the existence of three clusters where the interaction between the human and H. pylori populations have similar characteristics. Spatially varying regressions are applied to a data set of areal death counts of stomach cancer and spending power in 275 counties in continental Portugal. We provide an original strategy for implementing multivectorial intrinsic autoregressions as the distribution for the random effects. The results obtained with the application of this methodology were consistent with a varying exposure coefficient of spending power.
Statistical dynamical models of multivariate financial time series
Keywords: Signal processing
Financial time series analysis
Interaction measurement
Multivariate analysis
Causality

The last few years have witnessed an exponential increase in the availability and use of financial market data, which is sampled at increasingly high frequencies. Extracting useful information about the dependency structure of a system from these multivariate data streams has numerous practical applications and can aid in improving our understanding of the driving forces in the global financial markets. These large and noisy data sets are highly non-Gaussian in nature and require the use of efficient and accurate interaction measurement approaches for their analysis in a real-time environment. However, most frequently used measures of interaction have certain limitations to their practical use, such as the assumption of normality or computational complexity. This thesis has two major aims; firstly, to address this lack of availability of suitable methods by presenting a set of approaches to dynamically measure symmetric and asymmetric interactions, i.e. causality, in multivariate non-Gaussian signals in a computationally efficient (online) framework, and secondly, to make use of these approaches to analyse multivariate financial time series in order to extract interesting and practically useful information from financial data.
Most of our proposed approaches are primarily based on independent component analysis, a blind source separation method which makes use of higher-order statistics to capture information about the mixing process which gives rise to a set of observed signals. Knowledge about this information allows us to investigate the information coupling dynamics, as well as to study the asymmetric flow of information, in multivariate non-Gaussian data streams. We extend our multivariate interaction models, using a variety of statistical techniques, to study the scale-dependent nature of interactions and to analyse dependencies in high-dimensional systems using complex coupling networks. We carry out a detailed theoretical, analytical and empirical comparison of our proposed approaches with some other frequently used measures of interaction, and demonstrate their comparative utility, efficiency and accuracy using a set of practical financial case studies, focusing primarily on the foreign exchange spot market.
Fabians and 'Fabianism': a cultural history, 1884-1914
Keywords: Cultural history; British literature; literary history; British history; British socialism; Fabianism; Bernard Shaw; H. G. Wells; Edith Nesbit; history of British education; British drama; Russian emigres; Hubert Bland; Sidney Webb; turn of the century Britain; Pierre Bourdieu; literary modernism

This thesis is a cultural history of the early Fabian Society, focusing on the decades between 1884, the Society’s inaugural year, and 1914. The canonical view is that ‘Fabianism,’ which the Oxford English Dictionary defines as the ‘doctrine and principles of the Fabian Society,’ is synonymous with State socialism and bureaucratic ‘efficiency.’ By bringing the methods of cultural history to bear on the Society’s founding members and decades, this thesis reveals that ‘Fabianism’ was in fact used as a dynamic metonymy, not a fixed doctrine, which signified a range of cultural, and even literary, meanings for British commentators in the 1890s and 1900s (Part 1). Further, by expanding the scope of traditional histories of the Fabian Society, which conventionally operate within political and economic sub-fields and focus on the Society’s ‘official’ literature, to include a close examination of the broader discursive context in which ‘Fabianism’ came into being, this thesis sets out to recover the symbolic aspects of the Fabians’ efforts to negotiate what ‘Fabianism’ meant to the English reading public. The Fabians’ conspicuous leadership in the modern education debates and the liberal fight for a ‘free stage,’ and their solidarity with the international political émigrés living in London at the turn of the twentieth century all contribute to this revised perspective on who the founding Fabians were, what they saw themselves as trying to achieve, and where the Fabian Society belonged—and was perceived to belong—in relation to British politics, culture, and society (Part 2). The original contribution of this thesis is the argument that the Fabians explicitly and implicitly evoked Matthew Arnold as a precursor in their efforts to articulate a kind of Fabian—latterly social-democratic—liberalism and a public vocation that balanced English liberties and the duty of the State to provide the ‘best’ for its citizens in education and in culture, as in politics.