VictorJuiz/thesis huggingface dataset:
The effect of farnesylated prelamin A accumulation on nuclear morphology and function
Keywords: nucleoplasmic retciulum
nuclear morphology
HIV protease inhibitor
laminopathies
metabolomics
lamin
prelamin A
lipoatrophy

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.
Malaria elimination modelling in the context of antimalarial drug resistance
Keywords: eradication
malaria
Bangladesh
artemisinin
elimination
artesunate
resistance
falciparum
mathematical
modelling
Cambodia

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.
Selection in a spatially structured population
Keywords: branching
particle systems
spatial structure
Lambda Fleming Viot
population genetics
coalescence

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.
The role of peer rejection in adolescent depression: genetic, neural and cognitive correlates
Keywords: functional magnetic resonance imaging
cognitive bias modification
peer rejection
depression
adolescence
molecular genetics
ostracism

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.
Genetic susceptibility to endometrial cancer
Keywords: GWAS
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.
The evidence of evil
Keywords: Wykstra
evil
evidential argument
God
Bayesianism

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.
Enacting molecular complexity : data and health in the metabonomics laboratory
Keywords: bioinformatics
data
metabolomics
metabolism
statistics
post-genomic
laboratory
science and technology studies

In this dissertation, I examine how biological data practices enable researchers to interact with and enact biological life in statistical ways, and how this poses challenges to the use and integration of biological knowledge with clinical practices. Instead of considering data as a pre-existing cognitive representation of the world, I combine scholarship on the anthropology of science with scholarship from science and technology studies to consider data as a form of material practice. I consider, in other words, how data is intertwined with technologies, people, and values, such that data is used to make normative and naturalized claims about biology and disease.
To explore the generation, interpretation, and use of biological data, I focus on the field of “metabonomics”—the post-genomic study of metabolism—as it is carried out within the Biomolecular Medicine Laboratory (BMM) at Imperial College London. In doing so, I examine how metabonomics researchers use biochemical techniques and multivariate statistics to investigate metabolism and disease.
After providing an overview of the literature, central questions, and methodology that frame this dissertation, I examine how multivariate statistical practices are central to the historical identity and epistemic culture of metabonomics research at the BMM. From there, I demonstrate how multivariate statistics require and enable metabonomics to enact metabolism as an inherently complex entity. Consequently, I examine how researchers struggle to assign the categories of “normal” and “abnormal” to dynamic notions of metabolism and health. I then explore how the translation of metabonomics knowledge into clinical practices places value on multivariate forms and large volumes of information, eclipsing the importance of human interpretation and judgment. Finally, I examine how metabonomics research is used to develop personalized medicine, but in ways that make it difficult to address the health of individual patients.
Reclaiming experiment: geographies of experiment and experimental geographies
Keywords: research-creation
non-representational theory
experiment
cultural geography

This thesis investigates the injunction to experiment in the social sciences and, more specifically, geography. This is both a geography of certain ways of thinking experiment, and an exploration of how particular strands of geographical thinking are being re-imagined and reworked as experimental under the influence of ideas and practices from within and beyond the discipline. Against the backdrop of recent debates about the status of experiment, it poses a number of key questions about what it means to be experimental, how experimental practices emerge and travel, and how these processes are inflected by the organization and atmospheres of particular sites of experimentation. These questions are addressed through a form of attentive participation at four key sites: The SenseLab and the Topological Media Lab in Montreal, the Institut für Raumexperimente in Berlin, and FoAM in Brussels. Based upon these encounters, and drawing upon the work of a range of exemplary experimentalists, the thesis develops the argument that there are new spaces of experiment which are worthy of such examination as part of a renewal of experimentation within geographical thinking. As such, the thesis outlines the logics of these forms of experiment and proposes the notion of ecologies of experiment. It also speculates on the possibilities for re-imagining what constitutes a geographical experiment, foregrounding the necessity of reactivating experiment as an ongoing ethos that needs careful cultivation and tending.
Inventing the market. Smith, Hegel and political theory
Keywords: freedom
social justice
Smith
Hegel
capitalism
market

This thesis analyses the constructions of the market in the thought of Adam Smith and Georg Wilhelm Friedrich Hegel and their relevance for contemporary political philosophy. Combining the history of ideas with systematic analysis, it contrasts Smith’s view of the market as a benevolently designed ‘contrivance of nature’ with Hegel’s view of the market as a ‘relic of the state of nature.’ In two interpretative chapters these two constructions of the market are discussed within the contexts of Smith’s and Hegel’s thought. In three systematic chapters, the relevance of these different constructions for the problems of identity and community, social justice, and different notions and dimensions of freedom is discussed. The first of these chapters argues that the conceptualization of the labour market as a market place for human capital or as a locus for the development of a professional ethos has a deep impact on how one thinks about the relation between individual and community, cutting across the debate between liberals and communitarians. The second systematic chapter shows that the market can be seen either as an instrument for addressing issues of social justice or as an institution against which social justice needs to be realized: for Smith, who thinks that free markets reward virtue and equalize income, it is the former, whereas for Hegel, who holds that free markets lead to unpredictable results and exacerbate social differences, it is the latter. The third systematic chapter addresses the relation between different aspects of liberty and the market. It shows that the market offers both chances and risks for liberty in the sense of individual autonomy, and analyses the relations of the market to positive liberty in a political sense. The concluding chapter draws some broader methodological lessons, arguing for a closer integration of economic and political theory at a ‘less-ideal’ level.
Prediction of NMR J-coupling in condensed matter
Keywords: pseudopotentials
nuclear magnetic resonance
special relativity
density functional theory

Nuclear magnetic resonance (NMR) is a popular spectroscopic method and has widespread use in many fields. Recent developments in solid-state NMR have increased interest in experiment and, alongside simultaneous developments in computational theory, have led to the field dubbed 'NMR crystallography.' This is a suite of methodologies, complementing the capabilities of other crystallographic methods in the determination of atomic structure, especially when large crystals cannot be made and when exploring materials with phenomena such as compositional, positional and dynamic disorder. NMR J-coupling is the indirect coupling between nuclear spins, which, when measured, can reveal a wealth of information about structure and bonding.
This thesis develops and applies the method of Joyce for the prediction of NMR J-coupling in condensed matter systems using plane-wave pseudopotential density-functional theory, an important requirement for efficient treatment of finite and infinite periodic systems. It describes the first-ever method for the use of ultrasoft pseudopotentials and inclusion of special relativistic effects in J-coupling prediction, allowing for the treatment of a wider range of materials systems and overall greater user friendliness, thus making the method more accessible and attractive to the wider scientific community.
Theology and identity of the Egyptian Jewish diaspora in Septuagint of Isaiah
Keywords: Hellenistic Jewish literature
Temple of Onias
Old Testament
Isaiah
Septuagint

The Old Greek version of the Book of Isaiah (hereafter LXX-Is) should be studied not only as a translation but also as an interpretation reflecting the theology of the translator or translator’s community in Egypt. ‘Free’ translation in LXX-Is usually appears not to originate from any misunderstanding of the probable Hebrew Vorlage or from a different Vorlage, but deliberately and consciously. Also it is important that these Greek renderings should be dealt with in a broader context, not merely verse by verse; because the Septuagint seems to have been regarded as a religious text in itself, circulating among Jews in Egypt. The most conspicuous theme in Septuagint Isaiah is a bold declaration concerning their identity. According to this, the Jewish diaspora in Egypt is the true remnant, and their residence in Egypt should be regarded as due to God’s initiative, thus “Eisodos” instead of “Exodus” is emphasized. Such ideas may be understood as displaying an apologetic concern of the Jewish diaspora to defend their continued residence in Egypt, whereas the Bible states firmly that Jews are not to go down there. Judgments against Egypt appear more strongly than MT, and this is another expression of their identity. LXX-Is supplies a bold translation in 19:18: a temple in Egypt, called the ‘city of righteousness’. The writings of Josephus testify to the existence of the Temple of Onias in Heliopolis under the reign of Ptolemy Philometor who apparently showed great favour towards the Jews. The temple’s significance should be considered as more than a temporary shrine for local Jewish mercenaries. Rather, it aimed to be a new Jerusalem under a lawful Zadokite priest. In addition to this, LXX-Is shares some interesting and distinctive ideas with Hellenistic Jewish literature, including views on priests and sacrifice, and an attitude towards foreign kings shared by Hellenistic Jewish literature of the period. To conclude, through comparing with MT and investigating LXX-Is as it stands, this work shows that LXX-Is is not just a translation but a Hellenistic Jewish document reflecting a particular theology of at least some Jews in Egypt. LXX-Is is shown to have its place within Jewish Hellenistic literature.