VictorJuiz/thesis huggingface dataset:
The role of genetic variation in glucokinase and glucokinase regulatory protein in diabetes and related traits
Keywords: glucokinase
genetics
monogenic disease
glucokinase regulatory protein
diabetes
metabolism

The rising prevalence of type 2 diabetes (T2D) is a global problem, and suggests that we need better therapeutic strategies against this disease. The glycolytic enzyme glucokinase (GCK) catalyses the phosphorylation of glucose, and is a well-established T2D drug target. Rare GCK mutations cause monogenic beta-cell dysfunction, whilst common genetic variants within GCK are associated with fasting plasma glucose (FPG) levels and T2D risk. Since GCK is expressed in both the pancreas and liver, pharmacological GCK activation provides the promise of a two-pronged attack on hyperglycaemia.
In vivo, GCK activity is modulated by the hepatic inhibitor glucokinase regulatory protein (GKRP, gene GCKR). GKRP negatively regulates GCK activity competitively with respect to glucose, and is controlled by fructose 6- and fructose 1-phosphate (F6P and F1P), which compete with each other for binding and enhance or diminish GCK inhibition respectively. GKRP also sequesters GCK in the nucleus and paradoxically stabilises the enzyme.
As GCK and its regulatory protein are fundamental to glucose homeostasis, we aimed to investigate the role of genetic variation in both GCK and GCKR to further our understanding of these important T2D drug targets in a system that would be relevant to man.
I demonstrated that two novel GCK mutations (T103S and V389L) identified in patients with hyperinsulinaemic hypoglycaemia were kinetically activating and through structural modelling identified a novel regulatory site for GCK activation by small molecular activators.
Genome-wide association studies (GWAS) identified GCKR as a regulator of FPG and triglyceride levels, and showed a role for GKRP in T2D risk. Unlike most GWAS hits, this signal included a non-synonymous variant within GCKR (P446L), thus facilitating functional studies. P446L-GKRP was characterised kinetically and at the cellular sequestration-level. This variant showed diminished F6P-mediated modulation, which was proposed to reduce hepatic GCK inhibition, increase glycolytic flux (decreasing FPG), and feed metabolites into liver pathways (elevating triglycerides). As GCKR was not expressed at functional levels within human islets, this phenotype was thought to be driven by the liver. Preliminary analysis at the cellular level was inconclusive, with optimisation required to study human P446L-GKRP in this cellular system.
Finally, I showed that mutations within GCKR are not a common cause of “GCK-Like” phenotypes in man, despite the regulatory protein directly modulating GCK activity.
These data provide further insight as to the pathogenic consequences of perturbing GCK activity. This must be considered if this enzyme is to be the subject of therapeutic intervention in T2D.
'Marry - stitch - die - or do worse'?:  female self-employment and small business proprietorship in London c.1740 - 1880.
Keywords: social history
history of entrepreneurship
women's history
business history
history of the family
economic history

'Marry - Stitch - Die - or Do Worse' ran a Times newspaper leader in 1857. Yet a significant proportion of the adult female population at this time were surviving without a husband, particularly in London. This thesis focuses on the activities of such women who never married, were deserted or became widowed. Sometimes labelled 'redundant', 'distressed' or 'failed' by their contemporaries, they were frequently unsupported.
In the face of substantial barriers to paid employment, this thesis argues that self-employment and small business proprietorship was often a viable option. The evidence presented suggests a somewhat different picture to that often generalised for all middle and upper class women in the nineteenth century - that of retreat into the private sphere of home to become the ‘angel in the house’. A wide variety of sources have been drawn upon to examine women's use of small business proprietorship as a strategy in nineteenth century London, including published diaries, trade cards, opinion pieces, trade directories and insurance records.
In addition, it is argued that it is only by following the female proprietor home that we can begin to understand the role of proprietorship in women's work-life strategies. Record linkage has been used to obtain more detailed and consistent information on the families and household's of female proprietors than that available from trade directories or newspaper advertisements. Common stereotypes of women in business in this period relating to age, marital status and so on have been assessed in the light of this evidence.
This research has revealed that these stereotypes have some truth in their application to women engaged in the production and typically 'male' trades but that such trades represent only a small fraction of the experience and activities of female proprietors.
Étale homotopy sections of algebraic varieties
Keywords: arithmetic geometry
higher-category theory
homotopy theory

We define and study the fundamental pro-finite 2-groupoid of varieties X defined over a field k. This is a higher algebraic invariant of a scheme X, analogous to the higher fundamental path 2-groupoids as defined for topological spaces. This invariant is related to previously defined invariants, for example the absolute Galois group of a field, and Grothendieck’s étale fundamental group.
The special case of Brauer-Severi varieties is considered, in which case a “sections conjecture” type theorem is proved. It is shown that a Brauer-Severi variety X has a rational point if and only if its étale fundamental 2-groupoid has a special sort of section.
Utility-based pricing of stochastic income
Keywords: stochastic income
marginal utility-based price
distortion solution
stochastic volatility
indifference pricing
utility maximisation

In this thesis we investigate an optimal investment problem for an investor who also receives an unhedegable stochastic income stream. We extend the log-Brownian model of Henderson to a stochastic volatility model where the underlying market is incomplete and the income is a function of the stock volatility. With exponential preferences, explicit solutions to the primal and dual problems are possible using extensions of the distortion power solution of Zariphopoulou and Henderson. We derive expressions for the utility indifference price and the associated marginal utility-based price of the stochastic income stream.
Even in the absence of stochastic income the market is incomplete and the optimal dual measure is the minimal entropy measure ℚE. We show how this horizon dependent measure serves as a pricing measure in the utility indifference valuation scheme. This is in contrast to Henderson [18] where the underlying market is a Black-Scholes model and the optimal dual measure, without the income, is the minimal martingale measure ℚM. The horizon dependence of the pricing kernel in the stochastic volatility model can potentially lead to inconsistencies in the pricing of claims with multiple payment dates. We carefully construct a forward utility function which restores the minimal martingale measure as the dual minimiser for the model without the claim, thus removing the horizon dependence.
Some aspects of complex statistical dependencies
Keywords: statistics

In the first part parametric models for which the likelihood is intractable are discussed. A method for fitting such models when simulation from the model is possible is presented, which gives estimates that are linear functions of a possibly large set of candidate features. A combination of simulations based on a fractional design and sets of discriminant analyses is used to find an optimal estimate of the parameter vector and its covariance matrix. The procedure is an alternative to Approximate Bayesian Computation and Indirect Inference methods. A way of assessing goodness of fit is briefly described.
In the second part the aim is to give a relationship between the effect of one or more explanatory variables on the response when adjusting for an intermediate variable and when not. This relationship is examined mainly for the cases in which the response depends on the two variables via a logistic regression or a proportional hazards model. Some of the theoretical results are illustrated using a set of data on prostate cancer. Then matched pairs with binary outcomes are discussed, for which two methods of analysis are described and compared.
Equality and global justice
Keywords: distributive justice
global justice
equality

This dissertation aims to defend an egalitarian conception of global distributive justice. Many hold that the scope of egalitarian justice should be defined by membership of a single political community but my dissertation will challenge this view. I begin by considering three distinctive arguments against the ideal of global equality. They maintain that egalitarian obligations of justice apply only to those people who are subject to the same sovereign authority which coerces them to abide by its rules; or to those who contribute to the preservation of each other’s autonomy through collectively sustaining a state; or to those who belong to the same nation. The first three chapters deal with these arguments respectively. Central to these arguments is the assumption that the domestic and the global contexts are different in some morally relevant way so egalitarian principles of justice apply to the former but not the latter. After rebutting these anti-egalitarian arguments I turn to the more constructive task of developing a form of global egalitarianism that is grounded in the value of equality as a normative ideal of how human relations should be conducted. I argue in Chapter 4 that relational equality—that is, standing in relations of equality to one another (rather than relations characterized by domination or exploitation)—is a demand of justice in the global context. This ideal of relational equality has distributive implications. In Chapter 5 I try to spell out these implications by defending a set of principles of global distributive justice that would follow from our commitment to global relational equality. In the sixth and final chapter, I discuss what responsibilities we have in relation to global injustice, how to distribute the burdens associated with these responsibilities, and whether they are excessively demanding on complying agents.
Multidimensional In Vivo NMR
Keywords: Vigabatrin
In Vivo
ISIS
COSY
brain
NMR
JRES
Nuclear Magnetic Resonance
GABA

A proton nuclear magnetic resonance spectrum of the brain in vivo contains peaks from every proton-containing molecule in the brain. Sensitivity limitations mean that only those molecules present at concentrations of at least a few millimolar are detectable in a reasonable period of time; this still leaves many important molecules such as amino acids and other small metabolites. Most of their resonance frequencies fall in the region between 1.0 and 4.5 p.p.m.. A typical linewidth in vivo is about 0.05 p.p.m., so the number of distinct peaks observable is restricted. The use of two-dimensional NMR techniques such as COSY can spread peaks out into a second dimension enabling otherwise overlapping peaks to be resolved. This thesis describes the development, testing and application of two such 2D NMR pulse sequences, dubbed ISIS-COSY and ISIS-JRES. They are based on an existing magnetisation localisation sequence and excite detected magnetisation in a manner analogous to the high-resolution sequences COSY and 2D J-resolved spectroscopy. A method for quantifying the metabolites visible in an ISIS-COSY spectrum from their cross-peak intensities is described, and results presented from both control rat brains and those of animals treated with vigabatrin, an inhibitor of GABA-transaminase that has the effect of increasing brain γ-amino butyric acid (GABA) levels. Further applications mentioned are in the study of neutrophil-infiltrated rat brain and adaptation of the ISIS-COSY technique for human use.
Spectral analysis of breast ultrasound data with application to mass sizing and characterization
Keywords: ultrasound medical imaging
breast cancer
spectral analysis
ultrasonic tissue characterization

Ultrasound is a commonly used imaging modality in diagnosis and pre-operative assessment of breast masses. However, radiologists often find it very difficult to correctly size masses using conventional ultrasound images. Consequently, there exists a strong need for more accurate sizing tools to avoid either the removal of an over-estimated amount of tissue or a second surgical procedure to remove margins involved by tumour not removed in the primary operation.
In this thesis, we propose a new method of processing the backscattered ultrasound signals from breast tissue (based on the Fourier spectral analysis) to better estimate the degree of echogenicity and generate parametric images where the visibility of breast mass boundaries is improved (SPV parametric image). Moreover, an algorithm is proposed to recover some anatomical structures (particularly, Cooper’s ligaments) which are shadowed during the image acquisition process (LWSPV parametric image). The information from both algorithms is combined to generate a final SPV+LWSPV parametric image.
A 20-case pilot study was conducted on clinical data, which showed that the SPV+LWSPV parametric image added useful information to the B-mode image for clinical assessment in 85% of the cases (increase in diagnostic confidence in at least one boundary). Moreover, in 35% of the cases, the SPV+LWSPV parametric image provided a better definition of the entire boundary. Note that the radiologist knew the final diagnosis from histopathology.
In addition, the SPV+LWSPV method has the advantage that it uses the I/Q data from a standard ultrasound equipment without the need for additional hardware.
On the basis of these facts, we believe there to be a case for further investigation of the SPV+LWSPV imaging as a useful clinical tool in the pre-operative assessment of breast mass boundaries.
Stem and progenitor cells in wound healing
Keywords: STEM CELLS
UMBILICAL CORD BLOOD
ADIPOSE TISSUE
BURNS.
PROGENITOR CELLS
WOUND HEALING

As more patients with large body surface area burns are surviving and requiring reconstructive surgery, there is a necessity for advances in the provision of bioengineered alternatives to autologous skin cover. The aims of this Thesis are to identify feasible source tissues of Endothelial Colony Forming Cells and Mesenchymal Stem/Stromal Cells for microvascular network formation in vitro with three-dimensional dermal substitute scaffolds. The working hypothesis is that pre-vascularised dermal scaffolds will result in better quality scarring when used with split thickness skin grafts.
Human umbilical cord blood, peripheral blood and adipose tissue were collected and processed with ethical approval and informed consent. Samples were cultured to form endothelial outgrowth colonies and confluent Mesenchymal Stem/Stromal Cells, which were characterised using flow cytometry and expanded in vitro. Mesenchymal Stem/Stromal Cell multipotency was confirmed with tri-lineage mesenchymal differentiation. Primary cells were tested in a two-dimensional tubule formation co-culture assay and differences assessed using a proangiogenic antibody array. Tubule formation was tested in four different acellular dermal substitute scaffolds; Integra® Dermal Regeneration Template, Matriderm®, Neuskin-F® and De-cellularised Human Cadaveric Dermis.
Umbilical cord blood was the most reliable source of Endothelial Colony Forming Cells, the yield of which could be predicted from placental weight. Microvasculature dissected free from adipose tissue was a reliable source of Mesenchymal Stem/Stromal Cells which supported significantly more tubule formation than Mesenchymal Stem/Stromal Cells from whole adipose tissue. Microvasculature Mesenchymal Stem/Stromal Cells secreted significantly higher levels of the proangiogenic hormone leptin, and addition of exogenous leptin to the tubule formation assay resulted in significantly increased tubule formation. Microvasculature was cultured in all four of the scaffolds tested, but depth of penetration was limited to 100µm. The artificial oxygen carrier perfluorocarbon was shown to increase two-dimensional tubule formation and may be useful in further three-dimensional scaffolds studies to improve microvascular penetration.
The regulation of stem cell engraftment
Keywords: CD164
Stem Cell Engraftment
Bone marrow transplantation
umbilical cord blood
Migration
Chemotaxis
Endolyn
Haemopoietic Stem/progenitor Cells
haemopoietic cell expansion

The engraftment of haemopoietic stem/progenitor cells (HSPCs) from umbilical cord blood (UCB) into adult recipients, although advantageous in terms of sourcing units, the decreased need to match donor and recipient and reduced risk of graft versus host disease (GvHD), is delayed compared to grafts using HSPCs from mobilised peripheral blood (MPB) or bone marrow (BM). One reason for this is the limited number of HSPCs (CD34+/CD133+ cells) in a unit of UCB compared to MPB or BM. The CXCR4-CXCL12 axis is widely recognised as a key player in the bone marrow homing, retention, and engraftment of HSPCs. The aim of this thesis was to investigate whether the engraftment of HSPCs from UCB into the bone marrow could be improved. Firstly, a novel in vitro 3D time-lapse chemotaxis assay to assess the homing capacity of human UCB CD133+ HSPCs, towards the chemokine CXCL12 was developed. One advantage of this assay was that it distinguished cell chemotaxis from chemokinesis and allowed these parameters to be quantified. Human UCB CD133+ HSPC chemotaxis towards CXCL12 was inhibited by the CXCR4 antagonist, AMD3100. Importantly, the presence of CXCL12 or AMD3100 had no affect on cell chemokinesis. To complement the in vitro chemotaxis assay, a short term in vivo homing assay in NSG mice was successfully established. The effect of siRNA silencing of the CXCR4 co-receptor, CD164, which is also expressed on CD133+ HSPCs, on cell migratory and homing ability was investigated. CD164 knock-down using siRNA in human UCB CD133+ HSPCs did not demonstrate an effect on homing to NSG bone marrow in vivo or chemotaxis to CXCL12 in vitro. However, homing to NSG mouse spleen was significantly reduced in cells silenced for CD164. Following this, an 8 day HSPC expansion system using nanofibre scaffolds (Nanex) and differing cytokines was investigated. These serum and feeder free conditions yielded a significant expansion of cells that retained CD133+CD34+ expression and their in vitro chemotactic ability to CXCL12. Time constraints did not permit the engrafting ability of these cells to be analysed in an in vivo HSC reconstitution assay that was initiated. However these studies will provide the basis to support future related research in this laboratory.
New methods for the construction of C-18F bonds
Keywords: PET
Radiochemistry
18F-DOPA
Organic synthesis
Fluorine-18

The main electrophilic source used in radiolabelling is [18F]F2, which is highly reactive, toxic and requires specialist equipment for safe handling. The Gouverneur group has initiated a research programme focused on the preparation of new stable and easy-to-handle N-18F reagents. In the development of [18F]radiolabelling reactions it would be extremely valuable to develop a library of selective N-18F reagents possessing reactivity tailored to the desired chemical transformation. The aim of this thesis is to further assess the scope of electrophilic N- 18F reagents in new transformations for the construction of C-18F bonds.
The Vir Tricultus: an investigation of the classical, Jewish and Christian influences on Jerome's translation of the Psalter Iuxta Hebraeos
Keywords: Jerome
Old Testament
Hebrew
Iuxta Hebraeos

This thesis investigates the influences on Jerome's translation of the Psalter from the Hebrew (IH Psalter) that came from the three major socio-religious spheres with which Jerome was acquainted. It argues that the results offer insights into Jerome's conception of the nature of Hebrew text itself, of the relationship between it and the Christian faith, and of his role as translator.
The thesis argues and demonstrates that the language of the IH Psalter reveals influences that derive from Jerome's classical background, from his contact with rabbinic scholars in Palestine, and, especially, from his adopted Christian faith. These influences are subtle, but their combined effect is considerable.
Care is taken to demonstrate that Jerome was a competent translator, and that he deliberately intended the classical, Jewish or Christian nuances that are discussed. This is achieved, first, by comparing the IH Psalter with the Hebrew as an initial step, then with Jerome's translation of the Psalter from the Hexaplaric Septuagint, and with the various Greek versions where they are extant; and second, by evaluating the relationship between Jerome's translations and his exegetical material on the Psalter. The fact that Jerome is both translator and exegete of the Psalter allows clear insight into the impact of his understanding of the Psalms on his translation of them.
The Conclusion argues that the issues can be focussed on and find their resolution in Jerome's conception of the nature and function of the Hebrew text. By imputing to Jerome a belief in the divine inspiration of the Hebrew text, and a belief that the Hebrew text properly understood and properly translated reveals Jesus Christ, the character of the IH Psalter can best be explained. Jerome's translations often exploited available linguistic space, but they rarely went beyond what hebraica veritas could reasonably signify.
Evolutionary patterns derived from 150 million years of morphological and functional evolution in neopterygian fishes
Keywords: neopterygii
fossil fishes
neopterygian fishes
genome duplication

Neopterygian fishes represent over half of vertebrate richness in the Recent and display staggering phenotypic variety, yet little is known about the first 150 million years of their evolution. Furthermore, neopterygian richness and disparity is highly unevenly partitioned between teleost fishes, with ~29,000 species expressing a plethora of phenotypes, and holostean fishes, with 8 species and just two morphological styles. Fossil phenotypes have the unique ability to illuminate the assembly of neopterygian disparity, and can reveal the pattern by which the uneven partitioning of disparity arose.
Morphology and function were quantified with landmarks and six functional traits, respectively, for 356 neopterygian species known globally throughout the first 150 million years of their history. The main axes of morphological and functional variation were derived and used to examine a series of evolutionary questions. Pertinently, they revealed how disparity was accumulated for 60% of the neopterygian radiation; morphological disparity increased through time, whereas functional disparity remained stable.
The morphological dataset was expanded to include shape data for 398 species and size data for 471 species. Time scaled supertrees containing 671 mostly Mesozoic, but also living neopterygian species, were created. Together, the trees and traits were used to quantify evolutionary rates and innovation and test the predictions of genome duplication enhanced morphological diversification in teleosts, and the presence of 'living fossil' characteristics in holosteans. The analyses revealed higher rates and greater innovation in teleosts guaranteed to possess duplicated genomes, consistent with the predictions of genome duplication enhanced diversification. The only 'living fossil' characteristic of holosteans is their poor capacity for size innovation, yet they possess relatively high rates of shape evolution. However, estimates of rates and innovation are heavily influenced by timescale choice, emphasising the need for workers to perform their analyses on a variety of plausible timescales to determine the limits of their conclusions.