VictorJuiz/thesis huggingface dataset:
The end of the Psalter

"The End of the Psalter" argues, based on original text-critical and intertextual research, that Psalms 146-150 are originally separate texts, contrary to current Psalms research viewing them to be written partly as an originally coherent end of the Psalter.
Firstly, rather than focussing on the Masoretic Text only, all three oldest text forms of each Psalm are interpreted separately: the Hebrew Masoretic Text as the oldest complete text form of the Hebrew Bible in its original language, and the older sources of the Hebrew Dead Sea Scrolls and the Greek Septuagint. The thesis highlights considerable differences in these three sources which call the supposed original coherence of Psalms 146-150 into question.
Secondly, rather than merely listing other texts similar in their words or ideas, possible intertextual references are assessed using clear criteria and explicating consequences for the interpretation. The thesis demonstrates that intertextual references differ between each of the Psalms and between the sources, leading to shifts in aspects of content and to a lack of original connection of Psalms 146-150.
Thirdly, rather than presupposing Psalms 146-150 as one originally coherent group, each Psalm is examined on its own. The thesis demonstrates that the individual Psalms 146-150 cannot originally be seen as one group, and that differences in the content of each individual Psalm should not be smoothed out.
The thesis provides a new historical-critical commentary and intertextual analysis of Psalms 146, 147, 148, 149, and 150, each in all three different oldest text forms. It includes fresh translations and detailed comments on form, intertextuality, content, genre, and date, combined with a comparison of the different Psalms and text forms and an extensive evaluation of previous interpretations.

Keywords: Psalter
Textual Criticism
Old Testament / Hebrew Bible
Dead Sea scrolls
Septuagint
Psalms
Intertextuality
Masoretic Text
Advisor: Barton, J
Meningococcal genome dynamics: an allele based, population approach to define lineage structure

Advances in genome sequencing technologies have rapidly expanded the number of bacterial genome sequences available for study, permitting the emergence of the discipline of population genomics. Bioinformatics platforms were used to exploit this resource by the provision of data in an easily accessible and uniform format.
The de novo assembly, combined with gene-by-gene annotation, generated high quality draft genomes in which the majority of protein-encoding genes were present with high accuracy. The approach catalogued diversity efficiently and was a practical approach to interpreting whole genome sequence data for a large bacterial population.
The hyperinvasive meningococcal Lineage 3 core and accessory genome was described and mobile genetic elements and undescribed proteins were found to be influencing the shape of the lineages evolution and population structure.
Commensal carriage of the meningococcus was examined using temporally paired isolates. Long-term carriage was found and the comparison of the genomes pairs found a highly conserved set of core genes.
The methods used generated novel insights into the biology of the meningococcus and improved our understanding of the whole population structure, not just disease causing lineages. This work contributes to knowledge of genomic evolution of bacteria and population structure within a species.

Advisor: Maiden, M
Interlocked halogen bonding host systems for anion recognition

This thesis describes the synthesis and anion recognition properties of acyclic and mechanically interlocked anion receptors containing either the 3,5-bis-iodotriazole pyridinium or pyridine-N-oxide motifs.
Chapter One introduces the field of supramolecular chemistry, highlighting areas of particular relevance to this thesis, viz. anion coordination, recognition, templation, halogen bonding and synthesis of interlocked structural frameworks.
Chapter Two describes the synthesis of acyclic, [2]catenane and water-soluble [2]rotaxane anion receptors containing the novel 3,5-bis-iodotriazole pyridinium motif and details their anion recognition properties. X-ray crystal structures of the [2]catenane bearing this motif are provided in support of the anion binding results. X-ray Absorption Spectroscopy is used to probe the nature, and quantify the degree of covalency, of halogen-bonding interactions.
Chapter Three details further work incorporating the 3,5-bis-iodotriazole pyridinium motif into elaborate symmetric and asymmetric [2]rotaxane anion hosts designed for nitrate binding in competitive aqueous solvent media. Moreover, the synthesis of an analogous water-soluble [2]rotaxane is presented and its anion recognition properties investigated.
Chapter Four focuses on the synthesis of acyclic and symmetric interlocked anion receptors bearing the novel neutral 3,5-bis-iodotriazole pyridine-N-oxide motif. The anion recognition properties of these hosts are presented with an emphasis on [2]rotaxane species capable of binding chloride and nitrate in competitive aqueous solvent media.
Chapter Five provides a summary of the major conclusions of this thesis.
Chapter Six furnishes procedures pertaining to chemicals, instrumentation, data handling and analytical protocols, as well as detailing synthetic methods and characterisation of novel compounds.
Chapter Seven provides the references cited within Chapters One to Six.
Full crystallographic information and details of molecular modeling experiments are provided in Digital Appendices on an enclosed DVD.

Advisor: Beer, P
Biochemical and functional studies of the histone demethylases

Histone lysine methylation is an important post-translational modification (PTM), directing the regulation of gene expression in eukaryotic genomes. Methylation states are dynamically altered by the activity of methyl-transferases and demethylases, including the JmjC 2OG oxygenase Lysine Demethylases (KDMs). KDMs have been associated with perturbed chromatin methylation profiles seen in several pathologies, including cancer and developmental disorders. There is much interest in elucidating both the substrate profile of the KDMs and the full biological functions of KDMs. For this reason, "chemical probes" for KDMs are of particular interest. Selective and potent inhibitors of these enzymes will help to identify the extent to which KDMs drive disease states, and whether they can be targeted as drug candidates in specific contexts.
This thesis presents a systematic study on the sequence and methylation state selectivity specific demethylation of the isolated catalytic domains of the JmjC-domain containing oxygenases, all assigned as KDMs in the literature, using histone H3 synthetic peptide arrays. Demethylation activity was monitored at H3K4, K9, K27, K36 and K79. Results clarify the lysine position and methylation specific demethylation activities of the catalytic domain of the histone demethylases in vitro. Unexpected demethylation profiles were observed for the KDM4 subfamily, showing both demethylation at K4 and K27, as well as K9 and K36 (for KDM4A-C).
Several novel substrates were identified and further biochemical characterisation was performed using kinetic and structural analyses. Demethylation activities were quantified for KDM4A and E at tri-methyl K27, while K4 demethylation activity was repeatedly too low to analyse, suggesting it is not a catalytically productive substrate. Structural analyses confirm H3K27me3 binds in the active site of KDM4A in a similar conformation to characterised substrates. Experiments exploring the potential for KDM4A to demethylate in vivo showed full length KDM4A to demethylate at K27, suggesting that the novel activity is not just an artefact of the catalytic domain.
With an interest to design specific chemical probes for the KDMs and 2OG oxygenases, I developed an mRNA-display peptide screen and identified potential cyclic peptides inhibitors for the prolyl hydroxylase PHD2. The results from this work are preliminary, but point to wider cellular functions of PHD2 in metabolism and oxygen sensing.

Keywords: Histone
Substrate
Demethylase
Advisor: Kawamura, A
Schofield, C
Structure and inhibition of the human SNM1a and SNM1b/Apollo DNA repair exonucleases

The human SNM1A and SNM1B enzymes are 5'-3' exonucleases implicated in DNA interstrand crosslink (ICL) repair. Cells deficient in SNM1A or SNM1B show increased sensitivity to clinically important crosslinking drugs such as mitomycin C (MMC). Moreover, purified SNM1A and SNM1B have been shown to resect cross-linked DNA past the site of cross-links. Consequently, inhibitors of these enzymes may be useful in potentiating the effects of ICL agents in cancer chemotherapy.
Since key residues at the active sites of SNM1A and SNM1B are conserved with those on bacterial metallo-β-lactamases (MBLs), compounds that inhibit bacterial MBLs were included in a screen for inhibitors of SNM1A and SNM1B. A real-time fluorescence assay was developed for a high-throughput screen for inhibitors of SNM1A/B. It produced 22 hit compounds with 4 different scaffolds. Since these compounds are either the natural substrates of MBLs or mimics of these substrates, it is not surprising that most of these compounds are reversible competitive inhibitors of hSNM1A and SNM1B.
Crystal structures of SNM1A and SNM1B were solved and they show that, while their active sites are near-identical, the charges on the surface of these proteins were very different. Biochemical studies of the putative DNA binding groove identified amino acid residues that could be involved in DNA binding.
Therefore, this current study helps elucidate the structural properties of SNM1A and SNM1B, and show that inhibitors to these enzymes can be developed and potentially sensitise cancer cells to ICL-inducing chemotherapeutics.

Advisor: Schofield, C
Mchugh, P
Computational study of lithium-ion mobility in stoichiometric solid-state systems

Lithium-ion mobility in solid-state systems is an important field with significance for a range of technological interests, especially in the field of energy materials. The binary lithium compounds Li2O and Li3N have been studied using modern computational techniques to elucidate their diffusion properties. The macroscopic diffusion coefficients have been calculated and the underlying microscopic diffusion processes elucidated using molecular-dynamics-based techniques. In both systems studied the diffusion has been modelled over a wider temperature range than previously attempted. The agreement between the calculated diffusion coefficients and the best available experimental data surpasses previous computational studies. The level of agreement achieved is due to the use of force-field non-equilibrium molecular dynamics (FF-NEMD). This method, which has only recently been applied to solid-state diffusion, allows rates of diffusion that are typically too low to be studied with equilibrium molecular dynamics to be modelled. NEMD uses a fictitious external field to increase the frequency of the rare diffusion events in a predictable manner without changing the nature of the diffusion mechanisms. In the case of Li2O the transition from the non-superionic to the superionic regime has been modelled. The dominant mechanism in each regime has been determined: in the non-superionic regime a concerted mechanism dominates and in the superionic regime an interstitial-mediated mechanism dominates. For Li3N the anisotropic nature of the lithium diffusion coefficient has been modelled. The diffusion mechanisms dominant for different directions have also been elucidated. The rapid diffusion in the (001) plane of the hexagonal structure has been explained by the presence of vacancies on the in-plane Li sites, both in this thesis and in previous works. Previous studies have explained this by the presence of contaminants leading to non-stoichiometric Li3N. However, in this thesis the under occupation of these sites has been explained by the formation of Li2 dumbbells, or site sharing, largely about the interlayer Li sites, but also about the in-plane Li sites. The existence of these dumbbells explains the experimental diffusion coefficients of stoichiometric Li3N.

Keywords: Solid State Modelling
Litihum-ion Diffusion
Advisor: Battle, P
David, W
Conjugation class from Latin to Romance: heteroclisis in diachrony and synchrony

This thesis investigates the origins and behaviour of the non-canonical morphological phenomenon of heteroclisis in the verb paradigms of Latin and the Romance languages. Heteroclisis is the coexistence, within a single paradigm, of forms which pattern according to different inflectional classes existing otherwise in the language: a heteroclite lexeme can thus be seen as 'mixed' or 'undecided' as to its inflectional identity. I begin by examining the development of the theoretical concept of heteroclisis and approaches to the idea of inflectional class in general, before situating heteroclisis in typological space in comparison with better-known instances of non-canonical morphology such as deponency and suppletion; heteroclisis exists at a different level of generalization from these, because its identification presupposes the existence of inflectional classes, themselves generalizations over the behaviour of individual lexemes. I also consider two recent theoretical treatments of the phenomenon and survey recent linguistic studies making use of the notion. I then look at the synchronic and diachronic behaviour of heteroclisis in Latin and Romance verbs: the great time depth of our attestations of these languages gives us the chance to witness the development of successive examples of heteroclisis, and their subsequent treatment within the morphological system, in the history of a single family. Focusing chiefly on data from Latin, Romanian and Romansh, I find that the principal (though not the only) source for new instances of heteroclisis in Latin/Romance lies in regular sound change, and find that speakers can treat these synchronically anomalous patterns as robust models of inflectional behaviour to be extended over the lexicon or brought into line with pre-existing types of paradigm-internal alternation. These findings concur with previous demonstrations that speakers make use of non-canonical phenomena as markers of the internal structure of inflectional paradigms.

Keywords: Latin
Romanian
Autonomous morphology
Historical linguistics
Romansh
Morphological theory
Advisor: Maiden, M
Chromatin regulation of lifespan in C. elegans

The biological basis of lifespan regulation is a subject of intense interest, and epigenetic control of gene expression is thought to play an important role in the ageing process. A library of RNAi clones against chromatin factors was used to screen for their effects on lifespan in C.elegans, utilising microscopic examination of lipofuscin accumulation as a primary biomarker of ageing. A secondary RNAi screen involving full lifespan monitoring confirmed knock-downs of four genes, isw-1, cbp-1, mes-2 and jmjd-3.2, results in extension of lifespan. The use of mutant alleles of these genes also resulted in statistically significant lifespan extension. Intriguingly, three of those genes encode H3K27 modifiers: cbp-1 is an acetyl transferase, whilst mes-2 and jmjd-3.2 are H3K27 methyltransferase and demethylase respectively.
Mutation in another gene of the jmjd-3.2 family, utx-1, is also known to have a lifespan prolonging effects by increasing H3K27 methylation on the daf-2 promoter (Jin et al, 2012). In addition to its lifespan effects, utx-1 is also an essential developmental gene. Its role in development has, however, been confirmed to be independent of its demethylase activity (Vandamme et al. 2012) raising questions about the biological significance of UTX-1- mediated H3K27 demethylation. I used a demethylase-dead form of UTX-1 to demonstrate that enzymatic activity is absolutely required for UTX-1 function in lifespan regulation.
Intriguingly, it is not just utx-1 loss of function that causes lifespan extension; overexpression of utx-1 from a transgenic array is associated with even more dramatic lifespan extension. Moreover, mes-2 and jmjd-3.2 overexpression also increases the lifespan of transgenic animals. Interestingly, however, lifespan extension driven by overexpression of jmjd-3.2 is not dependent on its demethylase function, suggesting a different mode of action to utx-1. Epistasis analysis suggests that the insulin signalling pathway is a crucial target of regulation for all the factors I identified, but ChIP analysis implies that lifespan extension driven by utx-1 overexpression may involve a different pathway from H3K27me3 regulation at the daf-2 locus.
Overall, this work pinpoints H3K27 modifications at key target genes as critical determinants of longevity, and furthermore identifies the crucial importance of the fine balance of factors controlling H3K27 methylation status.

Keywords: C. elegans
epigenetics
chromatin
Advisor: Woollard, A
Mellor, J
Pathogenic immune responses in Spondyloarthritis

Immune dysfunction in spondyloarthritis (SpA) causes significant morbidity to a large number of patients. An understanding of the underlying pathological processes involved in causing the disease is essential for the development and better targeting of therapies.
I have shown for the first time in patients with SpA an overall expansion of peripheral blood and synovial fluid T cells producing GM-CSF and an expansion of GM-CSF positive Th17 cells. In addition, I have shown GM-CSF to be a major effector cytokine of joint-derived innate lymphoid cells. Surface phenotyping and transcriptional analysis of the IL-17A/GM-CSF double positive cells showed that whilst they are related to classic Th17 cells, they also have a uniquely activated transcriptional profile.
Additionally, I have shown IL-7 to be a promoter of GM-CSF production by CD4 T lymphocytes in vitro. However, my data shows that polymorphisms of the IL7R, which have been shown to be associated with AS in genome-wide association studies, play a functional role through cell surface expression of the IL7R on CD14 monocytes. This genotypic expression of the IL7R on monocytes is only seen after activation with LPS or TNFα. I further show CD14 monocytes expressing IL7R to be present in SpA joints.
My data shows that RORγt, the master transcription factor of Th17 cells, can be therapeutically targeted using small molecule inhibitors in-vitro. These inhibitors lead to a specific suppression of both polyfunctional and IL-17A single positive Th17 cells.
The work in this thesis has highlighted several areas of novel immune biology with potential therapeutic applications in SpA and across the spectrum of related inflammatory diseases.

Advisor: Powrie, F
Bowness, P
Computational and experimental study of intense shock-cavity interactions

This thesis presents a numerical and experimental study of the interaction of shock waves with air-filled cavities in a liquid. At the incident shock pressures studied, this process leads to the formation of high-speed jets which propagate across the cavities, causing them to collapse. This phenomenon is modelled numerically using a front-tracking approach, which enables explicit tracking of the gas-liquid interface. In arrays of multiple cavities, this method is used to show that inter-cavity effects can lead to intensification of the collapse process under certain conditions. A number of different arrangements are presented, demonstrating that in all cases the separation distance between the cavities and the relative radius of the cavities are of key importance. This result is highlighted with the study of an array of three cavities, in which it is shown that pressures over five times higher than the maximum pressure observed in the single cavity case may be achieved.
Experimentally, a single stage light-gas gun is utilised to create strong shock waves in hydrogel blocks, into which spherical cavities are cast. With this setup, high-speed imaging and optical diagnostics are used to show that cavities collapse as predicted numerically, and that light is emitted upon collapse. In the single cavity case, this light is formed initially at the position at which the high-speed jet strikes the far cavity wall, propagating out subsequently into a torus. The spectral intensity of the light emission increases consistently with increased incident shock pressure. In multiple cavity arrangements, the complex inter-cavity effects seen numerically are found to be substantiated by experimental results. The spectral intensity of the light emission is seen to vary significantly with the separation distance between the cavities, with order of magnitude increases observed for particular cases.

Keywords: multi-cavity
shock-cavity
cavity collapse
multi-bubble
Advisor: Ventikos, Y
Roy, R
Codicological evidence of reading in late medieval England, with particular reference to practical pastoral verse

This study advances and adds detail to our history of the reading of verse in England c.1350–1500. Scholarship has established major twelfth- and thirteenth-century changes in reading, and linked these changes to manuscripts containing the modern Middle English verse canon. Historians of early modern reading have also argued for distinctive changes in their own period. But the examination of reading between these two clusters of change has been limited. This study therefore asks how later medieval Middle English verse was read.
The surviving copies of The Prick of Conscience and Speculum Vitae, two hugely successful religious instructional poems, form the primary body of evidence. This body is augmented by reference to hundreds of other manuscripts containing Middle English verse. Together, these can reveal much about what was normal and abnormal in reading. They are also an important part of the context for the reading of more canonical Middle English verse. Manuscript studies often proceeds through case studies of individual books and unusual evidence such as marginalia. This thesis turns to codicology to understand more widespread evidence for reading, combining qualitative case studies with quantitative techniques borrowed and developed from continental scholarship.
The first chapter examines evidence of provenance, revealing that both The Prick of Conscience and Speculum Vitae were read by an impressive range of people and remained current into the sixteenth century. The second chapter considers the navigational aids used in copies of both poems. Reading in this period has been characterised as 'discontinuous', but it could be discontinuous in diverse ways, and readers also read continuously. The third chapter is a large-scale study of books' size and shape, showing how these features can reveal books' reading histories, sometimes in counterintuitive ways. The fourth chapter contends that readers in this period attended closely to rhyme and probably read for balanced rhyme structures. The fifth chapter uncovers the ways in which these poems were rewritten for new readers and investigates the composition of the Southern Recension of The Prick of Conscience, arguing that this new text was partly a formalist intervention. The conclusion summarises the new 'baseline' history of the reading of Middle English verse which is offered here, and gestures towards implications for our reading of the Middle English poems which are canonical today.

Keywords: Religious instructional verse
Codicology
History of reading
Manuscript studies
History of formalism
Advisor: Wakelin, D