VictorJuiz/thesis huggingface dataset:
Studies on metabolism in macrophages

A general metabolic profile of macrophages was established by measurement of maximum catalytic activities of enzymes in energy-producing pathways and rates of utilisation of glucose, glutamine, fatty acids and ketone bodies under various conditions. It was found that glucose, glutamine and fatty acids can be used to satisfy the energy requirement of the cell. Although a significant proportion of utilised glutamine or fatty acid was converted to C02 by the macrophage, most glucose was not oxidised and was converted, almost stoichiometrically, to lactate. Utilised fatty acids were not only oxidised by the macrophage, but were incorporated into cellular lipid (mainly triacylglycerol and phospholipid). The triacylglycerol rich macrophage was shown to be able to release fatty acids into the culture medium.
The importance of glutamine in macrophages was indicated from the high activity of phosphate-dependent glutaminase. Glutamine is probably metabolised by the following enzymes in macrophages: phosphate-dependent glutaminase, aspartate aminotransferase (or other amino acid aminotransferases), oxoglutarate dehydrogenase followed by enzymes of the TCA cycle and metabolism of oxaloacetate by phosphoenolpyruvate carboxykinase. Pyruvate derived via this pathway may be metabolised via pyruvate dehydrogenase or pyruvate carboxylase. A study of the sub-cellular distribution of some of these enzymes suggested that phosphate-dependent glutaminase has a cytosolic as well as a mitochondrial localisation. Further characterisation suggested that the non-mitochondrial activity could be associated with the plasma membrane. To the author's knowledge, this is the first report of a non-mitochondrial localisation for phosphate-dependent glutaminase. Glutaminase was shown to be activated by phosphate and inhibited by glutamate and 2-oxoglutarate. Significant inhibition of glutaminase occurred only at high concentrations of these compounds.
Glucose and glutamine were utilised at very high rates by the macrophage, but were not fully oxidised even though the cells were incubated in aerobic conditions. The significance of these high rates of utilisation to the macrophage is discussed.

Advisor: Newsholme, E
Optimising the quality and effectiveness of risk: benefit appraisal methodologies utilised in randomised control trials

This investigation systematically assesses the quality and effectiveness of risk:benefit appraisal methodologies implemented in the analysis of published randomised controlled trials for pre-licensure biomedical innovations – therapeutics, devices and surgical procedures. The key finding is that, to date, reported applications of risk:benefit methodologies are highly heterogeneous and poorly reflective of the stakeholder needs assessed in the investigation.
[Abstract continues in thesis]

Keywords: risk
Randomised control trials
Advisor: Carr, A
Bell, J
Number representation in the parietal lobes

This thesis considers the importance of the inferior parietal lobe for calculation and Arabic number comparison. The first experiment demonstrates that repetitive Transcranial Magnetic Stimulation (rTMS) can be used on normal subjects to replicate findings from studies of patients whose ability to calculate after brain injury was impaired. While subjects were solving addition tasks, rTMS was applied over anterior and posterior areas of the inferior parietal lobule and the adjoining intraparietal sulcus (aIPL+S, pIPL+S). In line with results from patient studies, magnetic stimulation showed a disruptive effect only over left IPL+S. It had no disruptive effect when delivered over right inferior parietal lobule and the adjoining intraparietal sulcus.
To investigate the representation of number magnitude in the human brain rTMS was subsequently applied to the same inferior parietal regions while subjects performed a number comparison task. With numbers between 31 and 99, repetitive TMS over the pIPL+S disrupted organisation of the putative "number line". rTMS had no disruptive effect when delivered over aIPL+S, in either the left or right hemisphere. With numbers between 1 and 9, however, TMS over the pIPL+S did not impair task performance. Here, TMS had a disruptive effect when delivered over aIPL+S, in either the left or right hemisphere, thus suggesting that areas in the inferior parietal lobes might be specialised for certain number sizes.
The idea of a spatial mental number line was further investigated in a detailed single-case description of a person with an automatic mental number line. In the last experiment, functional Magnetic Resonance Imaging (fMRI) was used to investigate number comparison. The fMRI study gave some indication that small numbers might be represented in the aIPL+S region. In general, the fMRI results suggest that parietal cortical contribution to number magnitude representation is intimately related to its role in basic sensorimotor processes.

Advisor: Rushworth, M
Rushworth, V
Investigating carbon nanotube - polymer blends for organic solar cell applications

This thesis describes studies on nanohybrid systems consisting of single-walled carbon nanotubes (SWNTs) with monolayer coatings of semiconducting polymers. Steady-state and time-resolved optical and high-resolution microscopy experiments were used to investigate the blends. These materials show promise for use in organic photovoltaics (OPVs) owing to the high carrier mobilities and large aspect ratios of SWNTs, the controllable solubilisation of tubes with various polymers and the broad light-harvesting abilities of organic polymers.
Chapters 1 and 2 introduce the theory and background behind the work and present a literature review of previous work utilising carbon nanotubes in OPV devices, revealing poor performances to date. The experimental methods used during the thesis are detailed in Chapter 3 and the solution processing techniques used to prepare the polymer–nanotube blend samples are described in Chapter 4.
Chapter 5 describes a study on a nanotube blend with a thiophene polymer, a system previously unsuccessfully implemented into OPV devices. Ultrafast spectroscopic measurements showed that electrons can transfer on a 400 fs time scale from the polymer to nanotubes and the conditions to allow long-lived free charges to be produced were found. The study is extended in Chapter 6 to show that nanostructures consisting of a nanotube coated in one polymer can then be coated by a second polymer and that these nano-engineered structures could be implemented into OPV devices. The use of a competition binding process to isolate purely semiconducting nanotubes dispersed with any desired polymer is then described in Chapter 7. Finally, Chapter 8 introduces systems consisting of chains of porphyrin units, nature’s light-harvesting systems, bound to nanotubes and the blends were found to exhibit the required electronic alignment for use in OPVs.
The work described in this thesis provides an explanation for the poor device behaviour of nanotube–polymer blends to date and, in particular, demonstrates several nanohybrid systems that show particular promise for improved OPV applications.

Keywords: ultrafast
organic photovoltaics
carbon nanotubes
polymers
organic solar cells
charge transfer
Advisor: Nicholas, R
Johnston, M
Tudor Abingdon

This thesis is an early modern urban study that focuses both on national trends and events but also acknowledges the distinctive nature of the individual town. It takes a holistic approach to economic, administrative and socio-cultural changes and developments in a small but significant Berkshire town. The years after the dissolution of Abingdon abbey in 1538 were a critical time of losses, problems and opportunities for Abingdon. In the light of the town's successful development later in the century how serious were the challenges that it faced and what factors contributed to its survival? After a historiographical introduction and discussion of sources, two chapters investigate the town's medieval development under monastic lordship. The central chapters explore different aspects of change in Abingdon during the reformation period. In practical administrative terms the town's response was opportunistic and positive, due to a happy convergence of government policy and the continuity of local elite leadership. Economic and social strength and diversity gave stability, and a detailed rental survey demonstrates how the acquisition of public and private property benefited the town's elite. However, cultural and religious changes had some ill effects. Chapters 8 and 9 discuss Abingdon's successful administrative, economic and social development under the new institutions of the borough and Christ's Hospital established in the 1550s. Experienced leading men were supported by a thriving middling group of tradesmen. A brief discussion about the relationship between civic culture, civil discipline and puritanism later in the 1500s follows. The thesis concludes that Abingdon's resilience and survival was based on its diversified economic development and on social and cultural continuities. Abingdon's richly documented experience of reformation change demonstrates the need for continuing research into individual towns and offers an important contribution to our understanding of the age of reformation in English urban history.

Advisor: Archer, I
Rosen, A
Dr. Ian Archer, A
The effect of farnesylated prelamin A accumulation on nuclear morphology and function

Failure to process prelamin A, by the enzyme ZMPSTE24, leads to the build up of farnesylated prelamin A, which has been implicated in causing the symptoms experienced in laminopathies and HIV therapy. A common feature to these conditions is the development of an irregular nuclear boundary, often including deep invaginations that form a nucleoplasmic reticulum. Additionally, dysregulated lipid synthesis is frequently associated with improper lamin A processing and I set out to address the molecular mechanisms behind these two features that could explain lipoatrophy experienced in patients. By using siRNA targeted against Zmpste24 I utilised an array of biochemical, molecular and imaging techniques to uncover a mechanism that leads to the production of a nucleoplasmic reticulum that was dependent on both the farnesylated tail of prelamin A and the phosphatidylcholine synthesising enzyme CCTα. The morphology of this structure consisted of an invagination of both the inner and outer nuclear membranes with a cytoplasmic core or just invagination of the inner nuclear membrane. Serial section dual axis electron tomography provided a new insight into the ultrastructural changes at the nuclear periphery that revealed novel structural features. The dysregulation of lipid synthesis was assessed by investigating the effects farnesylated prelamin A has on the distribution and dynamics of the transcription factor SREBP-1 and assessment of the downstream consequences this has on its targets that regulate adipocyte differentiation potential. Finally, the metabolomic profile of an HIV protease inhibitor that leads to prelamin A build up was generated and revealed increases in lipolysis, glycolysis and mediators of inflammation. The research presented offers a new insight into the development of a convoluted nuclear boundary and nucleoplasmic reticulum, in the context of lamin A mutants and how dysregulated lipid synthesis, caused by farnesylated prelamin A, leads to lipoatrophy.

Keywords: nucleoplasmic retciulum
nuclear morphology
HIV protease inhibitor
laminopathies
metabolomics
lamin
prelamin A
lipoatrophy
Advisor: Vaux, D
Malaria elimination modelling in the context of antimalarial drug resistance

Introduction
Antimalarial resistance, particularly artemisinin resistance, is a major threat to P. falciparum malaria elimination efforts worldwide. Urgent intervention is required to tackle artemisinin resistance but field data on which to base planning of strategies are limited. The aims were to collect available field data and develop population level mathematical models of P. falciparum malaria treatment and artemisinin resistance in order to determine the optimal strategies for elimination of artemisinin resistant malaria in Cambodia and treatment of pre-hospital and severe malaria in Cambodia and Bangladesh.
Methods
Malaria incidence and parasite clearance data from Cambodia and Bangladesh were collected and analysed and modelling parameters derived. Population dynamic mathematical models of P. falciparum malaria were produced.
Results
The modelling demonstrated that elimination of artemisinin resistant P. falciparum malaria would be achievable in Cambodia in the context of artemisinin resistance using high coverages with ACT treatment, ideally combined with LLITNs and adjunctive single dose primaquine. Sustained efforts would be necessary to achieve elimination and effective surveillance is essential, both to identify the baseline malaria burden and to monitor parasite prevalence as interventions are implemented. A modelled policy change to rectal and intravenous artesunate in the context of pre-existing artemisinin resistance would not compromise the efficacy of ACT for malaria elimination.
Conclusions
By being developed rapidly in response to specific questions the models presented here are helping to inform planning efforts to combat artemisinin resistance. As further field data become available, their planned on-going development will produce increasingly realistic and informative models which can be expected to play a central role in planning efforts for years to come.

Keywords: eradication
malaria
Bangladesh
artemisinin
elimination
artesunate
resistance
falciparum
mathematical
modelling
Cambodia
Advisor: Day, N
White, L
Dondorp, A
Selection in a spatially structured population

This thesis focus on the effect that selection has on the ancestry of a spatially structured population. In the absence of selection, the ancestry of a sample from the population behaves as a system of random walks that coalesce upon meeting. Backwards in time, each ancestral lineage jumps, at the time of its birth, to the location of its parent, and whenever two ancestral lineages have the same parent they jump to the same location and coalesce. Introducing selective forces to the evolution of a population translates into branching when we follow ancestral lineages, a by-product of biased sampling forwards in time.
We study populations that evolve according to the Spatial Lambda-Fleming-Viot process with selection. In order to assess whether the picture under selection differs from the neutral case we must consider the timescale dictated by the neutral mutation rate Theta. Thus we look at the rescaled dual process with n=1/Theta.
Our goal is to find a non-trivial rescaling limit for the system of branching and coalescing random walks that describe the ancestral process of a population. We show that the strength of selection (relative to the mutation rate) required to do so depends on the dimension; in one and two dimensions selection needs to be stronger in order to leave a detectable trace in the population.
The main results in this thesis can be summarised as follows. In dimensions three and higher we take the selection coefficient to be proportional to 1/n, in dimension two we take it to be proportional to log(n)/n and finally, in dimension one we take the selection coefficient to be proportional to 1/sqrt(n). We then proceed to prove that in two and higher dimensions the ancestral process of a sample of the population converges to branching Brownian motion. In one dimension, provided we do not allow ancestral lineages to jump over each other, the ancestral process converges to a subset of the Brownian net.
We also provide numerical results that show that the non-crossing restriction in one dimension cannot be lifted without a qualitative change in the behaviour of the process. Finally, through simulations, we study the rate of convergence in the two-dimensional case.

Keywords: branching
particle systems
spatial structure
Lambda Fleming Viot
population genetics
coalescence
Advisor: Etheridge, A
The role of peer rejection in adolescent depression: genetic, neural and cognitive correlates

Adolescent depression is a major public health problem, which is associated with educational problems, long-term psychiatric illness and suicide. One major source of stress during adolescence is peer rejection. In this thesis, I investigate the nature of the relationship between peer rejection and adolescent depression. In a review of longitudinal and experimental studies, I describe a bi-directional relationship between peer rejection and depressive symptoms. I then outline how genetic, cognitive and neural vulnerability may modify the effects of peer rejection on adolescent depression. Finally, I introduce five empirical chapters which test these hypotheses using different methodological approaches. The first study is a molecular genetic analysis of a sample of adolescents with and without a diagnosis of mood disorder. I report an interaction between diagnostic group, environmental stress (though not peer rejection specifically) and 5HTTLPR genotype on symptoms of anxiety, which supports the role of genetic factors in modifying the relationship between environmental stress and adolescent mood disorder. The second study is a behavioural study of negative attention biases in a typically developing sample of adolescents. I report a negative attention bias in adolescents with low (versus high) self-esteem. Although the data do not support a causal role for attention biases in adolescent depression, such biased cognitions could also moderate responses to peer rejection, maintaining affective symptoms. A final set of three fMRI datasets investigates how neural circuitry may influence depressed adolescents’ responses to peer rejection at three distinct stages: i) expectation of peer feedback, ii) the receipt of peer rejection, iii) emotion regulation of peer rejection. Data show distinct behavioural and neural differences between depressed patients and healthy controls during expectation and reappraisal of peer rejection, although heightened emotional reactivity immediately following the receipt of peer rejection did not differentiate behavioural or neural responses in adolescents with and without depression.

Keywords: functional magnetic resonance imaging
cognitive bias modification
peer rejection
depression
adolescence
molecular genetics
ostracism
Advisor: Lau, J
Murphy, S
Genetic susceptibility to endometrial cancer

Endometrial cancer (EC) is the fourth most common cancer affecting women in the UK. Those with a family history of EC have an increased risk compared with the general population. Highly penetrant germline mutations in mismatch repair (MMR) genes and DNA polymerases account for only a small proportion of the familial aggregation.
The aim of this thesis is to investigate the genetic susceptibility to EC in the general population using cases and controls of European ancestry. A GWAS meta-analysis totalling 7,737 EC cases and 37,144 controls yielded five novel EC risk loci of genome-wide significance (P < 5x10−8). In decreasing order of significance, these were at chromosomes 13q22.1 (rs11841589, near KLF5), 6q22.31 (rs13328298, in LOC643623 and near HEY2 and NCOA7), 8q24.21 (rs4733613, telomeric to MYC), 15q15.1 (rs937213, in EIF2AK4, near BMF) and 14q32.33 (rs2498796, in AKT1, near SIVA1). A second independent EC signal was found in the 8q24 locus.
The association found in a previous EC GWAS at HNF1B on chromosome 17 was replicated at a higher significance, with the most significant SNP being rs11263763. CYP19A1 SNPs have previously been associated with EC and higher circulating levels of oestrogen from candidate studies, but I confirmed this locus to be genome-wide significant for the first time.
Functional annotation and in vitro studies for the EC risk loci at the intergenic region of chromosome 13q22 suggested that the functional SNP sits within a transcriptional repressor for KLF5, with the higher-risk allele reducing repressor activity.
The propensity for germline MMR and DNA polymerase muations to cause both EC and colorectal cancer (CRC) prompted me to search for common variants associated with both cancer phenotypes. An EC CRC GWAS meta-analysis showed little evidence of shared susceptibility loci. However, this meta-analysis revealed a novel genome-wide significant risk locus: rs3184504, a missense SH2B3 SNP that has not previously been associated with either EC or CRC.
This thesis has enhanced the understanding of genetic susceptibility to sporadic EC and increased the number of genome-wide EC-associated variants to seven.

Keywords: GWAS
endometrial cancer
Advisor: Tomlinson, I
The evidence of evil

Does evil constitute any evidence against the existence of God? Stephen Wykstra argues that it does not, claiming that “if we have realized the magnitude of the theistic proposal, cognizance of suffering ... should not in the least reduce our confidence that it is true”. I argue that he is mistaken. I outline a framework for modelling the confidence we lend to propositions and assessing the rational propriety of such confidences both at a given time and over time, and apply this framework to the issue at hand by imagining a scenario in which a subject observes for the first time a terrible evil. I argue that no matter which one of us this subject is, he ought to undergo a reduction in confidence in the existence of God as a result of this observation. The bulk of this thesis is taken up with a defence of two central premises of this argument, the most controversial of which is, roughly speaking, that our subject ought to be more confident of the occurrence of the evil on the supposition that God does not exist than on the supposition that He does. In the course of a defence of this premise I seek to counter the challenge to evidential arguments from evil made by the 'Sceptical Theists' and the challenge, based on the claim that in deciding which evils to permit God may have to draw an arbitrary line, that van Inwagen issues.

Keywords: Wykstra
evil
evidential argument
God
Bayesianism
Advisor: Leftow, B