VictorJuiz/thesis huggingface dataset:
The role of histone modification in DNA double-strand break repair in Schizosaccharomyces pombe
Keywords: DNA repair

DNA double-strand breaks (DSBs) are highly genotoxic lesions, which when incorrectly repaired can lead to gross chromosomal rearrangements and tumourigenesis through oncogene activation or loss of heterozygosity at tumour suppressor loci. Chromatin structure and therefore histone modification can play a key role in the repair of these lesions through affecting the access of repair machinery to the break. To identify novel histone-modifying enzymes involved in DSB repair, nineteen histone-modifying mutants from an S. pombe deletion library were screened for altered DSB repair. Eleven genes were identified as required for normal DSB repair: set1⁺, set2⁺, mst2⁺, sir2⁺, set3⁺, set11⁺, hat1⁺, set13⁺, clr4⁺, gcn5⁺ and elp3⁺. Two genes, hat1⁺ and set13⁺ are required for efficient homologous recombination (HR). In addition, four genes set1⁺, set2⁺, set3⁺ and mst2⁺ are required for non-homologous end-joining (NHEJ). Analysis of set1Δ, set2Δ, set3Δ and mst2Δ deletion mutants showed impaired NHEJ was associated with significantly increased levels of repair by HR, supporting the existence of a competitive relationship between these mechanisms of repair.
Further work focused on Set2, a H3K36 methyltransferase. In addition to a role for Set2 in NHEJ, a role for Set2 in promoting efficient DNA replication was identified. This is likely through regulation of MBF-dependent genes. However, this altered progression of DNA replication was not responsible for the repair phenotype seen. The methyltransferase activity of Set2 was required for its role in NHEJ and DNA replication. Further analysis of a H3K36R mutant identified an additional role for H3K36 in DSB repair. Results indicate that H3K36 is also acetylated by Gcn5; quantitative analysis of DSB repair in a gcn5Δ mutant, identified a role for Gcn5 in promoting HR repair. Modification of H3K36 by methylation and acetylation is mutually exclusive, and preliminary analysis of the levels of these modifications suggests that they are cell cycle controlled. The findings presented here support a model whereby differential modification of H3K36 by Gcn5 and Set2 defines the DNA repair mechanism utilised. Methylation of H3K36 by Set2, which peaks in G1, promotes NHEJ whereas acetylation of H3K36 by Gcn5, which peaks in S phase, promotes HR.
Multiple sequence analysis in the presence of alignment uncertainty
Keywords: Markov chain Monte Carlo
structural alignment
stochastic context-free grammars
graphical models
globin evolution
multiple sequence alignment
statistical alignment
sequence annotation
Bayesian phylogenetics
alignment uncertainty
directed acyclic graphs
hidden Markov models
RNA secondary structure

Sequence alignment is one of the most intensely studied problems in bioinformatics, and is an important step in a wide range of analyses. An issue that has gained much attention in recent years is the fact that downstream analyses are often highly sensitive to the specific choice of alignment.
One way to address this is to jointly sample alignments along with other parameters of interest. In order to extend the range of applicability of this approach, the first chapter of this thesis introduces a probabilistic evolutionary model for protein structures on a phylogenetic tree; since protein structures typically diverge much more slowly than sequences, this allows for more reliable detection of remote homologies, improving the accuracy of the resulting alignments and trees, and reducing sensitivity of the results to the choice of dataset. In order to carry out inference under such a model, a number of new Markov chain Monte Carlo approaches are developed, allowing for more efficient convergence and mixing on the high-dimensional parameter space.
The second part of the thesis presents a directed acyclic graph (DAG)-based approach for representing a collection of sampled alignments. This DAG representation allows the initial collection of samples to be used to generate a larger set of alignments under the same approximate distribution, enabling posterior alignment probabilities to be estimated reliably from a reasonable number of samples. If desired, summary alignments can then be generated as maximum-weight paths through the DAG, under various types of loss or scoring functions.
The acyclic nature of the graph also permits various other types of algorithms to be easily adapted to operate on the entire set of alignments in the DAG. In the final part of this work, methodology is introduced for alignment-DAG-based sequence annotation using hidden Markov models, and RNA secondary structure prediction using stochastic context-free grammars. Results on test datasets indicate that the additional information contained within the DAG allows for improved predictions, resulting in substantial gains over simply analysing a set of alignments one by one.
The Role of Hypoxia-Regulated MicroRNA in Cancer
Keywords: microRNA
hypoxia
renal cancer

MicroRNAs (miRNAs) are short, non-coding RNA sequences which regulate gene expression. Regulation is mediated primarily through binding to complementary sites in their un-translated regions which leads to mRNA degradation or translational repression. Hypoxia is a known feature of many tumours, and increased hypoxia is associated with poor prognosis. Hypoxia leads to the up-regulation of many genes involved in a variety of functions including angiogenesis, a shift to glycolytic metabolism, and cell proliferation. This is mediated by the heterodimeric transcription factor HIF (hypoxia inducible factor), which is stabilised in hypoxia. In normoxia, the von-Hippel Lindau protein (VHL) targets HIF for degradation. Mutation in the VHL gene, as is frequently seen in clear cell renal cell cancer (CCRCC), results in constitutive over-expression of HIF and its gene targets, leading to a pro-angiogenic and pro-tumourigenic state.
This thesis examined the expression of hypoxia-regulated miRNAs in cancer. The principal aims were to determine gene targets of miR-210, and to explore the effects of its over-expression and knock-down, both in vitro and in vivo. The expression of hypoxia-regulated miRNAs was examined in clinical renal tumour samples with matched normal tissue controls, and correlated with VHL mutation status.
It was found that miR-210 targeted the iron sulphur cluster homologue (ISCU) gene, and was responsible for much of its down-regulation in hypoxia. Knock-down of ISCU had consequences on cell metabolism, in particular involving mitochondrial function and iron metabolism. miR-210 was found to be highly over-expressed in clear cell renal tumours (CCRCC), with greater expression seen in tumours with VHL mutations. miR-210 over-expression was also observed in papillary renal tumours, but to a lesser extent than in CCRCCs. miR-210 expression appeared to be correlated with reduced stage and grade, and improved survival. ISCU protein expression in CCRCCs was determined by immunohistochemistry, which showed that its expression correlated negatively with miR-210 expression, suggesting a functional role of miR-210 in vivo.
The morphology and semantics of expressive affixes
Keywords: semantics
typology
morphology
pragmatics
expressives

This dissertation focuses on two aspects of expressive affixes: their morphological/typological properties and their semantics. With regard to the former, it shows that the expressive morphology of many languages (including Bantu, West Atlantic, Walman, Sanskrit, English, Romance, Slavic, and others), has the following properties: 1) it is systematically anomalous when compared to plain morphology, or the ordinary processes of word-formation and inflection. From this, it follows that many familiar morphological arguments that adduce the data of expressive morphology ought to be reconsidered; and 2) it is far more pervasive than has been traditionally thought. For example, the Sanskrit preverb, and the Indo-European aspectual prefix/particle generally, are shown to have systematically expressive functions.
With respect to the semantics of expressive affixes, it develops a novel multidimensional account, in the sense of Potts (2005, 2007), of Spanish "connotative affixes," which can simultaneously convey descriptive and expressive meaning. It shows that their descriptive meaning is that of a gradable adjective, viewed as a degree relation which includes a measure function, in the sense of Kennedy (1997). The expressive meanings of connotative affixes, and expressives generally, arise as they manipulate the middle coordinate, I, of expressive indices which, it is proposed, is inherently specified on all lexical items and canonically set to "neutral." It introduces a new mechanism, AFF, which is an algebraic operation for manipulating I, and which accounts for the well-known, and seemingly "contradictory," range of meanings that expressive affixes can express. Whereas prior work assumes that expressive affixes are inherently polysemous, this approach derives their many attested meanings and functions (e.g., "small," "young," "bad," deprecation, appreciation, hypocorism, intensification/exactness, and attenuation/approximation, as well as pragmatic effects like illocutionary mitigation) compositionally, from the interactions of their multidimensionality with the meanings of the roots to which they attach.
Materialising kinship, constructing relatedness: kin group display and commemoration in First Intermediate Period and Middle Kingdom Egypt (ca 2150–1650 BCE)
Keywords: agency
Egyptology
kinship
households
stelae
archaeology
social structure
developmental cycle
Abydos
memory
material studies
kin groups
anthropology of kinship
families

The aim of this thesis is to contribute to the understanding of ancient Egyptian kinship in the First Intermediate Period and Middle Kingdom (ca 2150–1650 BCE) by exploring how forms of relatedness were displayed in the monumental record. Kinship and marriage are contextually driven sociocultural phenomena that should be approached from the actors' perspective; such an approach can achieve some insight into emic notions of kinship, because monuments were integral to society and contributed to perpetuating and sustaining its fabric.
The introduction (chapter 1) presents the theoretical background on which the thesis is based, namely the notion of kinship as process, where relationships can be constructed and reconstructed throughout one’s life. In addition, it provides a working definition of 'kin group', an analytical category that is taken as the primary unit of social analysis that can encompass several ways of being related. Chapter 2 offers a discussion of kinship terminology in the First Intermediate Period and Middle Kingdom. The focus is less on basic kinship terms than on the little understood terminology for kin groups and how these were presented in the written record. Chapter 3 treats stelae, which constitute the core corpus of material for the thesis. Stelae present a variety of images of kin groups and, moreover, they should be considered within the larger units of which they were part. Many of these stelae are unprovenanced but have been attributed to Abydos. At this site, memorial chapels have been identified archaeologically, and some stelae have been found in association with them. Thus, the site offers a materialisation of constellations of relationships. Possible reconstructions of such chapels – one from Saqqara and two from Abydos – are presented in chapter 4, and the impact they may have had on the social memory of visitors is assessed. Display, presence, and performance were some of the ways in which the social role of those groups was communicated. Chapter 5 is concerned with how change and time may be represented in apparently static objects. On the basis of the model of the developmental cycle of domestic groups first introduced by Meyer Fortes, the dynamism of the social fabric is explored through three case studies of groups at different stages of their developmental cycle. The strategies of survival can be seen pervasively in the monumental record, allowing for a glimpse into time and change in kin groups. The conclusion (chapter 6) offers a holistic approach to the material presented in the thesis, emphasising the ways in which the different theoretical approaches proposed intertwine with the material.
Perfect and imperfect rights, duties and obligations: from Hugo Grotius to Immanuel Kant
Keywords: Immanuel Kant
Ethics
Philosophy of Law
Hugo Grotius
Modern Philosophy
Samuel Pufendorf

In this doctoral thesis, Kant's distinction between perfect and imperfect duties is examined. The thesis begins with an exploration of how the distinction originates and evolves in the writings of three of Kant's most prominent natural law predecessors: Hugo Grotius, Samuel von Pufendorf, and Christian Wolff. The thesis then moves on to Kant's own writings. It is argued that Kant draws the perfect-imperfect distinction in as many as twelve different ways, that these ways are not entirely consistent with one another, and that many of them, even taken by themselves, do not hold up to scrutiny. Furthermore, it is argued that Kant's claim that perfect duties always trump imperfect duties - which can be referred to as "the priority claim" - is not actually supported by any one of the ways in which Kant draws the perfect-imperfect distinction. After this critical reading of Kant's writings, the thesis then switches gears and a more "positive" project is attempted. It is argued that the perfect-imperfect distinction, even though it does not support the priority claim, is not altogether normatively neutral or uninteresting. In particular, for some of the ways in which the distinction is drawn, it is shown that the distinction yields the following normative implication: Sometimes perfect duties override imperfect duties and all other times there is no priority one way or the other. Finally, it is explained that this normative implication - which can be referred to as the "privilege claim" - translates into the following practical directive: When there is a conflict between a perfect duty and an imperfect duty, sometimes one must act in conformity with the former duty and all other times one is free to choose which of the two duties to act in conformity with. This practical directive represents the ultimate finding of this thesis.
The logic of political conflict in the late Middle Ages: a comparative study of urban political conflicts in Italy and the southern Low Countries, c. 1370-1440 
Keywords: politics and government
France
cities and towns
conflict
Belgium
Italy

This thesis examines urban political conflict in the late Middle Ages (c. 1370-1440) in Europe’s most heavily urbanised regions, Italy and the Southern Low Countries. Conflicts have frequently been viewed in the context of an emerging state-controlled political order, and have been interpreted either as forms of disruptive disorder, or as affirmations of political processes shaped by states. This thesis suggests that urban conflict should be studied not in the context of a state-controlled political order, but within the political framework provided by the numerous semi-autonomous jurisdictional institutions inside and outside cities (such as guilds, parishes or contending outside powers). This pluralistic order of politics gave rise to a form of political order sui generis which expressed itself in two ways. According to a general logic of conflict (Part One), particular rationales for justifying conflict (Chapter One) and specific political practices ranging from concealed protest to urban warfare (Chapter Two) were embedded in this multi-faceted and shifting political framework. Action groups could be negotiated and renegotiated around the resources provided by the city’s multiple legitimating institutions (Chapter Three). At the same time, such political institutions were configured differently in different cities, and this also generated a particular logic which lay at the basis of different systems of conflict (Part Two). Levels of conflict could, in fact, vary greatly between Bologna and Liège (Chapter Four), Florence and Tournai (Chapter Five), and Lille and Verona (Chapter Six), where, on the basis of different underlying political institutions, diverse practices of conflict and forms of association prevailed. The pluralistic order of politics itself was, therefore, a form of political organisation which crystallised around conflict. It gave rise to a logic which put conflict at the centre of the political order of late medieval cities.
The study of soil-reinforcement interaction by means of large scale laboratory tests
Keywords: soil reinforcement

This thesis presents the results of an investigation into soil-reinforcement interaction by means of direct shear and pull-out tests. Scale and other factors affecting test results were studied; for this purpose an apparatus able to contain a 1 cu.m sample of sand was designed by the author in order to perform large scale tests. Plastic and metal sheet and grid reinforcements were used in conjunction with Leighton Buzzard sand. Direct Shear tests on unreinforced sand samples showed that soil strength parameters were not affected by the test scale, although the post peak behaviour and the shear band thickness at the centre of the sample were significantly affected by the scale of the test. The presence of a reinforcement layer inclined to the central plane of the box had a marked effect on the strength and behaviour of the sample. The reinforcement increased the vertical stress and inhibited the shear strain development in the central region of the sample. The behaviour of the reinforced sample was found to depend on the type and form of the reinforcement as well as its mechanical properties. Pull-out test results can be severely affected by boundary conditions, in particular by the friction on the front wall of the box. The results obtained in the series of tests showed that interference between grid bearing members is the main factor conditioning the pull-out resistance of a grid reinforcement. The intensity of such interference was quantified on the basis of results obtained in tests using single isolated bearing members and grids with different geometric characteristics. An expression for the bond coefficient between soil and grid, taking into account the degree of interference, was suggested. It was also observed that the maximum bearing pressure exhibited by a bearing member depends on the ratio of the member diameter to the mean particle size.
A theory of national application of the European Convention on Human Rights
Keywords: ECHR; domestic courts' application of international law; comparative public law

This study seeks to flesh out a theory of national application of the European Convention on Human Rights (ECHR). It does so by seeking to provide an answer to the research question, ‘what is the proper role of the domestic courts in the application of the European Convention?’ By relying upon the examples of French, German, and UK law, the study argues that it is not true in descriptive terms, nor desirable in normative terms, that the domestic courts take an approach to the ECHR based upon friction and assertion of sovereignty. This study argues instead that domestic application of the ECHR is built on the attainment of certain aims. These aims are inferred, in the main, from the domestic courts’ jurisprudence, such as it relates to four central ECHR doctrines, and they are: the doctrines of evolutionary interpretation; proportionality; the margin of appreciation; and autonomous concepts. On the basis of an analysis of this jurisprudence, the four aims are identified as being, first, honouring the principle of pacta sunt servanda; secondly, the safeguarding of human rights based upon the insight that human rights are a paramount good to be pursued; thirdly, the aim of positive, as opposed to negative, rights diversity; and, fourthly, the aim that conclusions reached on the domestic level of one state must be capable of being universalized. The approach of the domestic courts to the application of the ECHR can be explained on the basis of the domestic courts’ wish to attain these four aims. The proper role played by the domestic courts, the study argues, is one in which they are willing to give a lead to Strasbourg as well as to be led, in both, to use the wording of the Preamble of the ECHR, ‘the maintenance’ and in the ‘further realisation’ of the Convention rights.
Stratagems for effective function evaluation in computational chemistry
Keywords: genetic algorithms
early rejection
active sites
computational chemistry
shape descriptors
PASTRY
molecular structure
parallel processing
virtual screening
lazy evaluation
machine learning
pocket detection
PIES
computational geometry
spatial reasoning
drug discovery
protein-ligand docking
quaternions

In recent years, the potential benefits of high-throughput virtual screening to the drug discovery community have been recognized, bringing an increase in the number of tools developed for this purpose. These programs have to process large quantities of data, searching for an optimal solution in a vast combinatorial range. This is particularly the case for protein-ligand docking, since proteins are sophisticated structures with complicated interactions for which either molecule might reshape itself. Even the very limited flexibility model to be considered here, using ligand conformation ensembles, requires six dimensions of exploration - three translations and three rotations - per rigid conformation. The functions for evaluating pose suitability can also be complex to calculate. Consequently, the programs being written for these biochemical simulations are extremely resource-intensive. This work introduces a pure computer science approach to the field, developing techniques to improve the effectiveness of such tools. Their architecture is generalized to an abstract pattern of nested layers for discussion, covering scoring functions, search methods, and screening overall. Based on this, new stratagems for molecular docking software design are described, including lazy or partial evaluation, geometric analysis, and parallel processing implementation. In addition, a range of novel algorithms are presented for applications such as active site detection with linear complexity (PIES) and small molecule shape description (PASTRY) for pre-alignment of ligands. The various stratagems are assessed individually and in combination, using several modified versions of an existing docking program, to demonstrate their benefit to virtual screening in practical contexts. In particular, the importance of appropriate precision in calculations is highlighted.
Revelations of a modern mystic: the life and legacy of Kun bzang bde chen gling pa 1928-2006
Keywords: Tibet
gTer ma

This study traces the development of Tibetan ‘treasure’ texts and practices in contemporary times via the life-story and scriptural revelations of the Tibetan ‘treasure revealer’ (gter ston) Kun bzang bde chen gling pa (1928-2006). It examines how his revelations (gter ma) rooted in the historic spirituality of Tibet, continue and adapt into the twenty first century.
The study is important in order to understand the ways this Asian religious concept develops and coalesces in North America. With the dramatic advances in communication through digital technology, it examines how gter ma texts and practices reach a modern audience. Also discussed are the implications of centuries old debates surrounding Buddhist lineage, transmission and ‘authenticity’ as well as concepts such as liberty, equality and authority. All of which are culture-specific constructions that differ radically when seen from a variety of perspectives.
The main conclusion drawn from this research is that as a Western Vajrayāna ‘tradition’ emerges and intersects with older Tibetan forms, both must attempt to find a middle path between their differing applications and interpretations if they are to avoid drifting into an arena of extensive commercialisation, dilution and distortion.