VictorJuiz/thesis huggingface dataset:
Development of novel hyperpolarized magnetic resonance techniques for metabolic imaging of the heart

The advent of hyperpolarized magnetic resonance (MR) has provided new potential for real-time visualization of in vivo metabolic processes. The aim of the work in this thesis was to use hyperpolarized substrates to study rapid metabolic processes occurring in the healthy and diseased rat heart. Initial work, described in Chapter 2, optimized the hyperpolarization process to reproducibly generate tracers. Chapter 3 describes use of hyperpolarized 1-13C-pyruvate to investigate in vivo flux through the regulatory enzyme pyruvate dehydrogenase (PDH). Cardiac PDH activity was altered in several physiological and pathological states, namely fasting, type 1 diabetes, and high-fat feeding, and in vivo flux through PDH was measured using hyperpolarized MR. These measurements correlated with measurements of in vitro PDH activity obtained using a validated biochemical assay. The work in Chapter 4 investigated the physiological interaction between hyperpolarized tracer and cardiac tissue. The effect of hyperpolarized 1-13C-pyruvate concentration on its in vivo metabolism was analyzed using modified Michaelis-Menten kinetics. It was found that hyperpolarized MR could non-invasively follow mechanisms of metabolic regulation, in addition to reporting enzyme activity. In Chapter 5, hyperpolarized MR was incorporated into the isolated perfused rat heart. 1-13C-pyruvate in normal and ischaemic hearts revealed significant differences in lactate metabolism, and provided the foundation for a novel intracellular pH probe. Infusion of 2-13C-pyruvate in the isolated rat heart enabled the first real-time visualization of Krebs cycle intermediates. In summary, the work in this thesis has highlighted the potential of hyperpolarized MR to reveal novel information on heart disease.

Keywords: magnetic resonance imaging
hyperpolarisation
energy metabolism
dynamic nuclear polarisation
Advisor: Clarke, K
Tyler, DJ
Three-dimensional analysis of tunnelling effects on structures to develop design methods

The subject of this thesis is the verification of a three-dimensional numerical modelling approach for the prediction of settlement damage to masonry buildings due to tunnelling in soft ground. The modelling approach was developed by previous researchers at Oxford, and was applied to three sites, representative of a range of practical configurations. The first involved the excavation of a shaft close to the corner of an eighteenth century church in London. The second involved tunnelling with very low cover beneath the foundations of a terrace of cottages at Ramsgate, Kent. The third was the relatively well-known case of tunnelling beneath the Mansion House, London, for construction of the extension to the Docklands Light Railway in the late 1980’s. The overall conclusion of the project is that the modelling procedures are suitable for application to the detailed assessment of the response of buildings to tunnelling. Particular features of the procedures are that the building is modelled together with the ground and a representation of the tunnel excavation, and in three dimensions. It has been confirmed that all these features are necessary to model the building response, which may include a combination of shear deformation, arching and bending behaviour. Further lessons have been learned concerning the importance of the self-weight of the building in determining overall settlements, how to model openings such as doors and windows in façades, and whether it is necessary to model the building foundation. It has not proved possible, through lack of time, to model the advance of tunnels beneath buildings within this thesis. This, however, is observed to be an important effect in the field, particularly in causing damage to internal walls. It is recommended that further research be carried out in this area. This project made use of large-scale non-linear finite element analysis. The demand on computing resources was high, stimulating many enhancements to the software, the most important of which was parallelisation of the analysis program for use on the Oxford Supercomputer. To obtain optimum results, larger model sizes are required. The computing resources to enable this should become more commonly available within the next few years, enabling the modelling techniques to be used routinely.

Keywords: settlement
tunnelling
Advisor: Houlsby, G
Ideal beauty in late eighteenth- and early nineteenth-century french art and art criticism with special reference to the role of drapery and costume

Scholarly attention to late eighteenth- and early nineteenth-century French art has focused on the importance that Johann Joachim Winckelmann attributed to the male nude figure in his definition of ideal beauty, and the impact of his work on debates over the 'beau idéal' in French art and art criticism. In contrast, Winckelmann's extensive interest in the detail of ancient costume, the folds of drapery, and the teleological and aesthetic significance that he ascribed to them, has been underplayed. The role played by costume and drapery as components of the 'beau idéal' in French art and aesthetics has also not been fully explored. This thesis examines the way in which costume and drapery formed an important component and embodiment of ideal beauty in the work of Winckelmann and in late eighteenth- and early nineteenth-century French artistic circles, providing new insights into the arguments over the meanings of Truth, Beauty and Nature in this period.
The thesis proposes that ideal beauty in late eighteenth- and early nineteenth- century France was conveyed in works of art through the accurate rendering of costume and the expressive qualities of drapery in combination with the perfect form and contour of the nude body. The first part of the thesis sets up a proposition that costume and drapery formed part of the definition of ideal beauty in the work of Winckelmann. Highlighting the significance of Winckelmann's work on costume and drapery in French art theory, it demonstrates how the definition of ideal beauty in France also incorporated the accurate rendering of costume and the aesthetic impact of drapery. In demonstrating the significance of costume and drapery to both Winckelmann and French theorists it is proposed that the application of a meta-historical approach of costume and drapery to French art theory can provide new understandings and readings of the definition of ideal beauty, the hierarchy of the genres and the broader aesthetic concerns of late eighteenth- and early nineteenth- century French art.
The second part of the thesis applies the proposed hermeneutic of costume and drapery to a small selection of theoretical work on the nature of ideal beauty and on a significant collection of Salon criticism. With this approach to the primary material this thesis demonstrates how French artists were able to express the 'beau idéal' within the traditional academic conventions and hierarchies, and negotiate the sense of public unease over the use of nudity in contemporary art.

Keywords: Ideal Beauty
Quatremere de Quincy
Art Dictionaries
Drapery
Emeric-David
Costume
Pierre Chaussard
Salon Criticism
Winckelmann
Costume Dictionaries
Beauty
Grace
Advisor: Whiteley, J
Wright, A
Compression behaviour and shear strength characteristics of a natural silty clay sedimented in the laboratory

The compression behaviour, shear strength characteristics, and material properties of dense slurries and soft settled beds of natural fine-grained sediments were studied experimentally. Slurries of varying initial density, initial height, and pore fluid salinity were settled one-dimensionally, by self-weight, in the laboratory. Settling behaviour was studied in terms of slurry appearance, particle segregation, height of surface versus time, sediment surface and element settlement rates, and the redistribution of sediment with respect to height and time. Consolidation behaviour was studied in terms of sediment compressibility and pore fluid flow. Shear strength was examined "in situ" and elated to the parameters effective stress and specific volume. Instruments and techniques were developed to facilitate the measurement of low effective stresses, low strengths, and high specific volumes. A small scale sediment sampler was developed and used in an attempt to study the arrangement of particles within soft sensitive beds. The experimental results revealed numerous fundamental reasons why theoretical models of settling and consolidation are unsatisfactory when applied to dense flocculated slurries and beds of high specific volume, respectively. For the sediment studied, well-defined compressibility and shear strength relationships were observed. Pore fluid flow relationships were non-unique at high specific volumes. The compression behaviour of slurries was found to have a rational basis in terms of electrochemical forces and degrees of particle association. The experimental results are relevant to engineering practice. Recommendations are made regarding future research.

Keywords: clay
consolidation
shear strength
Advisor: Sills, G
Positional cloning of an X;8 translocation (p22.13;q22.1) associated with multiple exostoses and autism

Autism is characterized by qualitative impairments in communication and reciprocal social interaction. About 3 in 10,000 in the general population suffer from this neurodevelopmental disorder. The majority of patients also manifest mental retardation and about 20-45% epilepsy.
Multiple exostoses is the commonest form of all skeletal dysplasias, affecting 1 in 50,000 live births. The condition, characterized by cartilaginous protuberances at the ends of the diaphyses, affects the extremities causing skeletal deformities and short stature.
Autism and multiple exostoses are considered to be inherited disorders, but the underlying biochemical defects of the disorders are unknown. Both of these conditions allow for survival but considerably diminish the quality of life.
An X;8 translocation was identified in a female patient, ML, with autism and multiple exostoses. Her phenotypic manifestations are likely due to the chromosomal abnormality.
A positional candidate cloning strategy was used to investigate the genes involved in the translocation. The translocation breakpoint was first isolated in Yeast Artificial Chromosomes (YACs), then in cosmid and plasmid clones. The translocation was reciprocal within a 5'-GGCA-3' sequence found on both X and 8 chromosomes without gain or loss of a single nucleotide. The translocation breakpoint on the X chromosome occurred in the first intron of the gastrin releasing peptide receptor (GRPR) gene and on chromosome 8 approximately 30 kb distal to the 3' end of the Syndecan-2 gene (SDC2), also known as human heparan sulfate proteoglycan or fibroglycan.
Although the GRPR gene was shown to escape X-inactivation and the coding region of the SDC2 gene was not disrupted, a dosage effect of the GRPR gene and a position effect of the SDC2 gene may, however, have contributed to the phenotype observed in this patient. The orientation of these genes with respect to the translocation was incompatible with the formation of a fusion gene.
The GRPR and SDC2 genes may provide insight into the biochemical nature of autism and multiple exostoses. Investigation of mutations in these two genes in unrelated patients with either autism or multiple exostoses as well as linkage and association studies are needed to validate them as candidate genes.
Membrane transport abnormalities in patients with renal failure

The possibility that changes in membrane transport systems may contribute to the pathophysiology of the uraeraic syndrome has not been extensively studied.
This thesis presents a study of eight erythrocyte membrane transport systems, namely the Na/K pump, the amino acid systems y+, ASC, gly, L and T, the nucleoside and choline transporters.
The results indicate that, compared to normal controls, K+ flux through the Na/K pump was reduced in chronic renal failure patients (CRF), on haemodialysis (HD), and on continuous ambulatory peritoneal dialysis (CAPD), but was normal in functional transplant (FT) patients' erythrocytes. The number of Na/K pumps per erythrocyte was decreased in CRF and CAPD but showed no differences between HD, FT and Normal controls. The mean turnover rate per pump site was reduced in patients on HD, whereas other groups were not significantly different from controls.
Cross-incubation experiments suggest that the lowered pump flux seen in the HD group was due to plasma factors since reversibility of the defect was achieved when those cells were incubated in normal plasma. The defect was completely reversed with a successful transplant.
Erythrocytes from haemodialysis patients exhibited an increased uptake of L-lysine through the y+ system. The uptake of L-serine was decreased and the affinity of the ASC system for L-serine was increased in these patients compared with controls. The glycine transporter showed a significant increase in affinity for glycine. The flux of L-leucine and L-tryptophan showed no differences from control cells.
Erythrocyte membrane transport of uridine was similar in normal control cells and in those obtained from uraemic patients.
Choline influx rates were significantly increased and affinity of the transporter for choline reduced in dialysis patients' erythrocytes. Renal transplant and CRF patients showed variable influx rates which gave a significant negative correlation with creatinine clearance.
These results show that there are selective abnormalities in some membrane transport system of the erythrocyte in patients with renal failure. The mechanism and possible significance of these changes are discussed.

Advisor: Ellory, J
Ellory, C
Functional analysis of cancer-causing FBXW7 mutations

FBXW7 encodes the substrate recognition component of an SCF E3 ubiquitin ligase complex. This complex regulates the degradation of multiple targets, such as Notch1, c-Jun, c-Myc and cyclin E, that function in critical developmental and cancer pathways. FBXW7 mutations are found in cancers of diverse tissue origins, with one of the highest mutation rates in the colorectrum. FBXW7 mutations are typically missense mutations that disrupt the substrate recognition domain at critical arginine propellor-tips. Mutations are often mono-allelic suggesting that FBXW7 is not a typical tumour supressor gene. Despite this, most of the evidence on FBXW7 function to date comes from null systems.
Several Fbxw7 -null mouse models have been generated and suffer homozygous embryonic lethality due to disrupted vascular development. Conditional Fbxw7-null mice have been created but do not in general reflect the mutation spectrum found in human tumours. In order to analyse the functional effects of Fbxw7 propellor-tip missense mutations, mice carrying a commonly-occurring Fbxw7 R482Q mutation were generated.
This propellor-tip mutation was knocked-in constitutively and whilst heterozygous mice developed normally in utero, they died perinatally due to defective lung development. Cleft palate and eyelid fusion defects were also observed with incomplete penetrance. Fbxw7 substrates were screened in embryonic lungs and significantly elevated protein levels of Klf5 and Tgif1 were observed.
The Fbxw7 R482Q mutation was also conditionally knocked-in in the gut. In the heterozygous state, large adenomas in the small intestine were observed at a low multiplicity, in approximately 30% of mice at an age greater than 300 days. Upregulation of Wnt signalling and Ctnnb1 mutations have been identified in a selection of these tumours. Breeding the Fbxw7R482Q allele onto Apc-mutant backgrounds led to accelerated morbidity, in which compound R482Q/Apc-mutant mice exhibited polyps of increased number and size. Elevated protein levels of Fbxw7 substrates Klf5 and Tgif1 were observed in adenoma and normal intestinal tissue from these mice.
In vitro work using epitope-tagged murine wildtype and propellor-tip mutant Fbxw7 proteins showed that they were capable of dimerising, opening the prospect of investigating a dominant negative mechanism of action.
To conclude, an Fbxw7 propellor-tip mutation studied in vivo resulted in both disrupted embryonic development and intestinal tumorigenesis and was distinct from Fbxw7 -null alleles.

Keywords: genetics
cancer
colorectal cancer
FBXW7
Advisor: Tomlinson, I
Killer immunoglobulin-like receptor polymorphism in a Chinese HIV-1 infection cohort

Genetic and functional studies have demonstrated that KIR gene polymorphism, including different haplotypes, allelic polymorphisms and different expression levels of KIRs, may all play a part in the association with HIV-1 infection outcome. Currently, there are very few studies focusing on the association between KIR and HIV in the Chinese population.
In this project, we started to look at the polymorphism of KIRs in a unique chronic HIV-1 infected cohort (SM cohort), evaluating the impact of KIR and KIR-HLA interactions in terms of HIV-1 infection progression. The SM cohort is unique because the major factors such as viral strain, transmission route and timing of infection, which could affect the natural history of HIV-1, have been narrowly controlled. Through comparison with a healthy control population, some genetic associations were identified. The frequency of KIR2DL3 was lower in the “slow progressors” group; the compound genotype of KIR3DS1+ Bw4 homozygotes was significantly lower in the “slow progressors” group; additionally, group B genotypes (multiple activating genes) were shown to be likely to mount a greater immune pressure on HIV-1. In terms of KIR footprints, several amino acid positions were identified for which the substitution of an amino acid may be ascribed to the immune response from KIR-modulated NK cells rather than from HLA restricted CTL immune pressure.
In Chapter 4, we report a novel method to sequence the entire locus of KIR3DL1/S1. Two specific pairs of primers have been successfully designed and tested to amplify KIR3DL1 and KIR3DS1 exclusively. Using this novel sequencing method, we showed the polymorphism of this locus at a 6-digit level. 8 new KIR3DS1 alleles, 12 new KIR3DL1 alleles, 1 new KIR3DL1 gene and 1 new KIR3DS1 gene have been identified in this study.
In Chapter 5, we used a valuable acute HIV-1 infection cohort to further study associations between KIRs and the clinical outcomes. It was interesting to find that the frequency of KIR3DS1 was significantly lower in the slow progressors group (31%) than in the acute group (40.7%), which implies that KIR3DS1 plays a role in HIV-1 disease progression. There are two other trends demonstrated in this study. One trend was that positive KIR2DL2 and/or KIR2DS2 (they are in strong linkage disequilibrium with each other) were associated with a higher set point viral load (at 3 month) (p=0.06). Another trend was that KIR3DS1 might have an association with disease progression (p=0.057).
Overall, in this study, the role of KIRs and KIR/HLA interactions were evaluated in acute and chronic HIV-1 infection, which has provided important information for further study.

Keywords: KIR
HIV
polymorphism
HLA
AIDS
sequencing
alleles
Advisor: Rowland-Jones, S
Dong, T
Borderline consciousness, phenomenal consciousness, and artificial consciousness: a unified approach 

Borderline conscious creatures are neither definitely conscious nor definitely not conscious. In this thesis, I explain what borderline consciousness is and why it poses a significant epistemological challenge to scientists who investigate phenomenal consciousness as a natural kind. When these scientists discover more than one overlapping kind in their samples of conscious creatures, how can they identify the kind to which all and only conscious creatures belong? After assessing three pessimistic responses, I argue that different groups of scientists can legitimately use the concept of phenomenal consciousness to refer to different kinds, in accord with their empirical interests. They can thereby resolve three related impasses on the status of borderline conscious creatures, the neural structure of phenomenal consciousness, and the possibility of artificial consciousness.
The thesis has three parts: First, I analyse the concept of borderline consciousness. My analysis counters several arguments which conclude that borderline consciousness is inconceivable. Then I explain how borderline consciousness produces the multiple kinds problem in consciousness science. Second, I assess three recent philosophical responses to this problem. One response urges scientists to eliminate the concept of consciousness, while another judges them to be irremediably ignorant of the nature of consciousness. The final response concludes that scientific progress is limited by the concept's referential indeterminacy. I argue that these responses are too pessimistic, though they point to a more promising approach. Third, I propose that empirically constrained stipulation can solve the multiple kinds problem. Biologists face the same problem because of their longstanding controversy over what counts as a species. Building on new arguments for stipulating the reference of species concepts, I demonstrate that this use of stipulation in biology is neither epistemologically complacent nor metaphysically capricious; it also need not sow semantic confusion. Then I defend its use in consciousness science. My approach is shown to be consistent with our understanding of natural kinds, borderline cases, and phenomenal consciousness.

Keywords: consciousness
natural kinds
consciousness science
vagueness
biological species
artificial consciousness
Advisor: Child, T
Bayne, T
Morris, K
Investigating molecular mechanisms of Dali, an intergenic chromatin-associated lincRNA regulating genes locally and neural differentiation genome-wide

Recently, long non-coding RNAs (lncRNAs) emerged as important regulators of many cellular functions. Many nuclear lncRNAs regulate the expression of geomically proximal or overlapping protein coding genes. Less clear is whether intergenic lncRNAs can regulate transcription by modulating chromatin at genomically distant loci in an RNA-dependent manner. This thesis investigated molecular functions of Dali, an intergenic central nervous system expressed lncRNA conserved in therian mammals. Dali is transcribed from a locus 50 kb downstream of the Pou3f3 transcription factor gene and performs both genomically local and distal RNA-dependent roles. Its depletion disrupts the differentiation of neuroblastoma cells. Locally, Dali regulates transcription of the Pou3f3 locus. Distally, it preferentially binds near to and regulates active promoters across the genome, including by physically associating with the POU3F3 transcription factor. Dali also interacts with the DNMT1 DNA methyltransferase in mouse and human and regulates CpG island-associated promoters by modulating their DNA methylation levels in trans. This work is the first to demonstrate that a lncRNA can regulate the DNA methylation of CpG island-associated promoters in trans and one of the first large scale studies to identify direct transcriptional targets of a lncRNA genome-wide. It also provides a more detailed molecular dissection of the extended Pou3f3 locus and a framework for the prioritisation and comprehensive functional characterisation of nuclear lncRNAs.

Keywords: RNA
DNA methylation
non-coding RNA
transcription
lncRNA
epigenetics
chromatin
Advisor: Ponting, C
Vance, K