VictorJuiz/thesis huggingface dataset:
Information structure in Japanese: scrambling, topicalization and passives

The main purpose of this thesis is to shed new light on Japanese grammar under the framework of the Givónian approach, with special attention to OSV word orders and by-passives: scrambling (OACCSV), topicalization (OTOPSV), ni-passive (S NPNI V), and niyotte-passive (S NPNiyotte V). This approach measures the discourse status of a referent by utilizing anaphoric and cataphoric co-referencing relationships within the texts. However, it is conceivable that OSV word orders and by-passives are also influenced by multiple factors other than information structure. Specifically, previous studies point out the possibility that heaviness and animacy are relevant to this issue. Therefore, the present study performs the corpus analysis, taking three factors into consideration: heaviness, animacy, and information structure.
First, OSV word orders have proven to be influenced by information structure and heaviness. In terms of information structure, scrambling correlates 'topic shift' from the referent of the scrambled object to that of the subject. In contrast, topicalization interrelates with 'continuing topic' realized as the referent of the subject. In terms of heaviness, the direct object tends to be longer than the subject in OSV word orders. Yet, animacy has no influence on the choice of word orders.
Second, by-passives are affected by information structure and animacy. In terms of information structure, the ni- and niyotte-passives are selected in order to maintain the topic continuity by promoting the topical logical object to the grammatical subject. However, the ni-passive is relevant to global topic whereas the niyotte-passive is related to local topic. In terms of animacy, the ni-passive prefers animate subjects while the niyotte-passive tends to select inanimate subjects. Yet, heaviness is unrelated to the use of by-passives in Japanese.
In conclusion, the thesis provides a functional analysis of OSV orders and by-passives from a descriptive and empirical point of view by using a written Japanese corpus. The new data reported contribute to elucidating the argument encoding system of Japanese.

Keywords: Corpus analysis
Discourse analysis
Word order
Givo´nian approach
Particles
mTOR signalling and the regulation of Hoxp3 expression

Regulatory T-cells (Treg) are essential for the establishment of self-tolerance and they can be identified by the expression of FOXP3, the "master" transcription factor for the development of Treg. A number of essential signals, namely TCR engagement, TGFβ, as well as the inhibition of the kinase mTOR, have been shown to be crucial for the induction of FOXP3 in the peripheral immune system. Despite recent progress, the molecular mechanisms for induction of FOXP3 remains elusive due, at least in part, to the lack of a cell line that mimics the behavior of primary CD4+ T-cells.
Here we report the isolation of a clone B02 from the mouse lymphoma line EL4 that can be induced to express high levels of FOXP3 in up to 50% of the cells. Pharmacological inhibition of mTOR and EAA depletion synergized with TGFβ in the induction, and led to reduced activity of both mTORC1 and mTORC2, which seemed to independently contribute to the enhanced FOXP3 expression. Luciferase reporter assays using Foxp3 promoter and enhancer sequences indicated that the mTOR inhibition-mediated increase in FOXP3 expression resulted primarily from enhanced transcriptional activity.
In addition to the enhancement of FOXP3 induction, mTOR inhibition reduced the levels of IL-17A, presumably by SOCS-mediated inactivation of STAT3, which could also have accounted for increased Foxp3 transcription. Although the precise targets of mTOR inhibition involved in the regulation of FOXP3 expression have yet to be identified, both luciferase assays and mass spectrometry-based quantitative phospho-proteomics using SILAC labelled B02 cells, have identified promising candidates. This unique EL4 clone could represent a special resource for investigating the signaling events leading to the induction of FOXP3 as well as events downstream of FOXP3 expression.

Keywords: mTOR
FOXP3
metabolism
Immunology
T cell
Advisor: Waldmann, H
Cobbold, S
A comparative analysis of depictions of female beauty in the Hebrew Bible and the Jewish Apocrypha and Pseudepigrapha

This thesis compares the motif of female beauty in the Hebrew Bible and in the Apocrypha and Pseudepigrapha, contending that although these sets of texts share affinities, overall there is a marked divergence between them. Scholars have argued that the condemnatory characterisations of women in the intertestamental era are inherited from the biblical tradition and are the product of increasingly negative depictions of women during the Second Temple era (Archer: 1987; 1990). I argue that in contrast to the bleaker depictions of female beauty prevalent in the later literature, the Hebrew Bible offers more diverse and balanced perspectives. Rather than seeing the apocryphal and pseudepigraphical beauty-texts as the predictable outworking of biblical Hebrew thought, I argue that the primary explanations for these critical presentations of female beauty should be sought elsewhere.
Scholars have written extensively on the subject of sexuality in the Hebrew Bible and later Jewish literature. Significantly less has been written about human beauty (Augustin (1988) is one notable exception). I focus on female beauty in Hebrew literature, which has received little attention as a topic in its own right.
In chapter two, I argue that in the Apocrypha and Pseudepigrapha beautiful women are presented as seductresses undermining patriarchal control, whereas in the Hebrew Bible beautiful Israelite women are not seductresses, and foreign seductresses are not beautiful. In chapter three, I analyse the depiction of beauty as vanity. In chapter four, I assess biblical depictions of abused beautiful women. In chapter five, I consider positive associations between beauty and character. In chapter six, I summarise the comparisons, arguing that the differences between the literatures outweigh the similarities. I then assess Archer's explanation for the negative presentation of women in the post-exilic era, recommending a revised explanation that takes greater account of Hellenistic influences on Second Temple Judaism.

Advisor: Gillingham, S
Enhancement of lentiviral vector production through alteration of virus-cell interactions

Gene therapy is the introduction or alteration of genetic material with the intention to treat disease. To support this aim, viruses have been modified, with elements linked to viral pathogenicity removed from their genome and replaced by the genetic material to be delivered. Gene therapy vectors based on lentiviruses have many advantages, such as the ability to transduce non-dividing cells and to target specific cell types via pseudotyping. They have been successfully used in ex vivo clinical trials for several haematopoietic stem cell disorders. Lentiviral vectors, however, suffer from substantially lower titres than the more popular adeno-associated virus (AAV)-based vectors and therefore have limited applicability for in vivo gene therapy which requires much greater quantities of virus.
The main aim of this thesis was to investigate strategies to improve lentiviral vector productivity during manufacture, in order to increase the likelihood of lentiviruses being adopted for disease treatment.
Initial experiments were based on the lentiviral vector manufacturing process currently being developed by the United Kingdom Cystic Fibrosis Gene Therapy Consortium for the generation of highly concentrated, purified lentivirus for clinical use. Supplementation of FreeStyle 293 Expression Medium used during upstream processing was attempted, but none of the assessed supplements led to significant increases in lentiviral vector production. Investigation into intrinsic immunity to viral infection indicated that over-expression of the protein kinase RNA-activated (PKR) led to lower production titres, but over-expression of its inhibitors was not successful at increasing titres. The focus then shifted to reducing, or 'knocking-down', inhibitory factors present in the host cells, which could adversely affect viral titres. Investigation of the published HIV-1 literature revealed a possible 152 candidate inhibitory factors described as having a negative impact on HIV-1 replication in the late stages of the life cycle of the virus. A novel siRNA screen was developed to assess the effect of ‘knock-down’ of inhibitory factors on lentiviral vector titre. Application of the screen to 89 candidate inhibitory factors identified nine genes which, when knocked-down, resulted in increased lentiviral vector production by more than 40%.
Further work will be necessary to understand the role of the inhibitory factors in lentiviral vector production, but novel cell lines in which genes encoding these factors have been permanently deleted from producer cells could lead to higher titres, reducing costs in the manufacture of lentiviral vectors and making in vivo gene therapy more feasible from a health economics perspective.

Keywords: lentiviral vector
lentivirus
HIV
gene therapy
production
Advisor: Gill, D
Hyde, S
Molecular mechanisms underlying haplotypespecific regulation of gene expression at the microtubule associated protein tau locus

Genome wide association studies (GWAS) have identified the H1 microtubule associated protein tau (MAPT) haplotype single nucleotide polymorphisms as leading common risk variants for Parkinson's disease (PD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Gene expression studies have demonstrated haplotype-specific increases in expression of MAPT exon 3-containing transcripts from the protective H2 allele compared to the H1. The difference in alternative splicing between the haplotypes likely contributes risk or protection in the absence of protein coding variants.
Here, we investigate the regulation of MAPT exon 3 alternative splicing by common, risk-associated, non-coding, haplotype-specific single nucleotide polymorphisms (SNPs) through a combination of in silico analysis of the MAPT locus, in vitro gene expression and biochemistry studies. Comparative sequence analysis of whole-locus genomic H1 and H2 MAPT (143 kb) vectors showed they capture over 86% of the MAPT sequence diversity. We generated and expressed haplotype-hybrid H1 and H2 MAPT vectors in a human neuroblastoma cell culture model and demonstrated that a functional SNP rs17651213 near the exon 3 5' splice site regulates exon 3 inclusion in a haplotype-specific manner. Using RNA-electrophoretic mobility shift assays (RNA-EMSA), we showed differential RNA-protein complex formation at the H1 and H2 sequence variants of SNP rs17651213. We further identified candidate trans-acting splicing factors interacting with functional SNP rs17651213 sequences by RNA-protein pull-down experiment and mass spectrometry. Finally, gene knockdown of candidate splice factors identified by mass spectrometry demonstrated a role for hnRNP F and hnRNP Q in the haplotype-specific regulation of exon 3 inclusion.
In this study, we have dissected the MAPT locus to identify sequences regulating the allele-specific alternative splicing of exon 3 and provided mechanistic insights into how common non-coding H1/H2 MAPT haplotype-specific SNPs may contribute to the risk/protection of neurodegeneration at a complex genetic locus.

Keywords: single nucleotide polymorphisms
microtubule associated protein tau
allele specific splicing
parkinson's disease
gene expression
Advisor: Wade-Martins, R
Caffrey, T
Rare genetic variants and susceptibility to severe bacterial diseases

Infectious diseases are a major cause of morbidity and mortality worldwide. Streptococcus pneumoniae
and Neisseria meningitidis are major causes of severe bacterial disease which can manifest as invasive disease such as bacteraemia and meningitis. Exposure to these pathogens is relatively widespread, yet only a minority of individuals develop invasive disease. A host genetic component to infectious disease susceptibility has been implied from twin and adoptee studies. A role for rare large effect genetic variants in predisposition to infection has been demonstrated through the study of individuals with primary immunodeficiencies. However, a majority of these studies have been undertaken in individuals with a history of recurrent disease or in multi-case families. The relative role of rare genetic variants of moderate to large effect at the population level has not been widely explored. This thesis presents effort made using next generation sequencing methods to identify rare genetic variants that lead to increased susceptibility to bacterial disease focussing on meningococcal disease, pleural infection(empyema), pneumococcal disease and sepsis phenotypes.
Using an exome sequencing approach in 13 cases with invasive meningococcal disease, a novel mutation leading to a complement deficiency and increased risk of meningococcal infection was identified and functionally validated in one individual. This mutation in the CFP gene was demonstrated as leading to impaired properdin secretion. Further analysis implicated loss of function mutations in CD4 and ZAP70 as novel loci for meningococcal disease susceptibility.
A case control association analysis for sepsis susceptibility highlighted the possible role for small Rho GTPases in sepsis pathology. By aggregating all rare predicted deleterious mutations in a gene, four genes in this pathway, (ROCK2, ARHGAP18, FYN and CDC42BPG) were implicated as having an excess of rare deleterious variants in sepsis samples compared to population controls.
A similar approach identified low frequency genetic variants in the CD109 gene as predisposing to empyema susceptibility in children.
Finally, preliminary evidence from adult individuals with invasive pneumococcal disease points to a potential role of the RNASE7 gene in invasive pneumococcal disease susceptibility. This association was primarily due to a predicted deleterious missense mutation present in cases and absent in controls.
Taken together, these results have identified a number of potential loci with rare variants associated with susceptibility to severe phenotypes of bacterial diseases.

Keywords: Complex traits
Human genetics
Advisor: Chapman, S
Elliott, K
Thin-walled structures for energy absorption

This thesis considered three types of new and improved high-performance energy absorbing devices for either compression or bending applications. These improvements were achieved by only altering their initial geometries for desired failure modes. Three types of proposed energy absorbing structures are as follows.
First, origami initiators were added to tubes with concave cross-sections. This new type of geometries, named as origami concave tubes, successfully triggered a reliable progressive buckling failure, which is uncommon for tubes with concave cross-sections. Origami concave tubes achieved ultra-high energy absorption and relatively low peak force. A comprehensive numerical, experimental, and theoretical analysis was conducted on the square, traditional concave, and origami concave tubes, which showed origami concave tubes achieved 3.3 times of specific energy absorption of square tubes. Additional to the huge improvement, it was illustrated that origami concave tubes can approach the theoretical limit of energy absorption through progressive buckling failure.
Second, thin-walled tubes with corrugated cross-section instead of traditional circular tubes were proposed for inversion. Comparing to circular tubes, the introduction of corrugation not only increased specific buckling force and reduced imperfection-sensitivity of tubes, but also decreased load needed for inversion process. In consequence, thin corrugated tubes could be inverted significantly more reliably, and even allowed practical frictional contact and geometric imperfection, which was not achieved or claimed before for tube inversion. A comprehensive numerical, experimental, and theoretical analysis was carried out on thin circular and corrugated tubes inversion, and validated the effectiveness of the new design. Thin corrugated tube inversion also reaches the theoretical limit of energy absorption.
Third, a series of novel bending devices of beams, panels, arches, and shells using origami technique were developed. These bending devices can provide more constant bending resistance and overall higher energy absorption than conventional open-section beams. Numerical simulations and experiments were used to validate these designs, which showed that properly designed origami bending devices can achieve 23.0%-40.0% increase of energy absorption and 12.7%-20.7% lower load uniformity than those of a conventional beam.

Keywords: energy absorption
structures
origami
Advisor: You, Z
Nonlinear control of the Josephson plasma in superconducting cuprates

Femtosecond optical laser pulses have been comprehensively applied in the past to control the material properties of high critical temperature superconductors. However, since the superconducting gap is of the order of several millielectronvolts, optical photons have the potential to deplete the condensate by breaking Cooper-pairs.
This thesis takes a novel direction as it reports on the non-dissipative control of the Josephson plasma in the layered cuprate superconductor La1:84Sr0:16CuO4 using terahertz electromagnetic waves. To achieve sufficiently intense sub-millimetre radiation, two complementary experimental approaches are taken. First, the table-top tilted pulse front technique is employed as a source of microjoule broadband terahertz pulses. Second, a large-scale free electron laser is operated to achieve multi-cycle pulses of less than two percent relative bandwidth.
Using the tilted pulse front technique, out-of-plane superconducting transport in La1:84Sr0:16CuO4 is gated bi-directionally on ultrafast timescales. The applied electric field modulates the interlayer coupling, leading to picosecond oscillations between superconducting and resistive states. Thereby, the modulation frequency is determined by the electric field strength in spirit of the a. c. Josephson effect. Throughout the oscillations, in-plane properties remain unperturbed, revealing an exotic state in which the dimensionality of the superconductivity is time-dependent.
Using a free electron laser, it is shown that resonant terahertz excitation of nonlinear Josephson plasma waves in La1:84Sr0:16CuO4 creates a metastable state that is transparent over a narrow spectral region. This finding is interpreted as the result of disruptive quantum interference between the linear plasma modes of the cuprate and an optically injected Josephson vortex lattice, which features the periodicity of the driving field, giving rise to three-level quantum interference optical transparency.
Both observations demonstrate the potential of layered superconductors for quantum nonlinear optics and are of relevance for applications in ultrafast nanoelectronics.

Keywords: Atomic and laser physics
Advisor: Cavalleri, A
Boothroyd, A
Room temperature caesium quantum memory for quantum information applications

Quantum memories are key components in photonics-based quantum information processing networks. Their ability to store and retrieve information on demand makes repeat-until-success strategies scalable. Warm alkali-metal vapours are interesting candidates for the implementation of such memories, thanks to their very long storage times as well as their experimental simplicity and versatility. Operation with the Raman memory protocol enables high time-bandwidth products, which denote the number of possible storage trials within the memory lifetime. Since large time-bandwidth products enable multiple synchronisation trials of probabilistically operating quantum gates via memory-based temporal multiplexing, the Raman memory is a promising tool for such tasks. Particularly, the broad spectral bandwidth allows for direct and technologically simple interfacing with other photonic primitives, such as heralded single photon sources. Here, this kind of light-matter interface is implemented using a warm caesium vapour Raman memory. Firstly, we study the storage of polarisation-encoded quantum information, a common standard in quantum information processing. High quality polarisation preservation for bright coherent state input signals can be achieved, when operating the Raman memory in a dual-rail configuration inside a polarisation interferometer. Secondly, heralded single photons are stored in the memory. To this end, the memory is operated on-demand by feed-forward of source heralding events, which constitutes a key technological capability for applications in temporal multiplexing. Prior to storage, single photons are produced in a waveguide-based spontaneous parametric down conversion source, whose bespoke design spectrally tailors the heralded photons to the memory acceptance bandwidth. The faithful retrieval of stored single photons is found to be currently limited by noise in the memory, with a signal-to-noise ratio of approximately 0.3 in the memory output. Nevertheless, a clear influence of the quantum nature of an input photon is observed in the retrieved light by measuring the read-out signal's photon statistics via the g(2)-autocorrelation function. Here, we find a drop in g(2) by more than three standard deviations, from g(2) &Tilde; 1.69 to g(2) &Tilde; 1.59 upon changing the input signal from coherent states to heralded single photons. Finally, the memory noise processes and their scalings with the experimental parameters are examined in detail. Four-wave-mixing noise is determined as the sole important noise source for the Raman memory. These experimental results and their theoretical description point towards practical solutions for noise-free operation.

Keywords: Quantum optics
Quantum computing
Spontaneous parameteric down-conversion
Atomic vapour
Alkali atoms
Four wave mixing
Single photons
Pulsed lasers
Quantum information
Raman transitions
Caesium
Quantum memory
Quantum process tomography
Nonlinear optics
Advisor: Walmsley, I