Cette thèse veut réactualiser les Séminaires dirigés par C. G. Jung de 1935 à 1939 sur la lecture de l'œuvre maîtresse de Nietzsche, Ainsi parlait Zarathoustra. Nous présentons, comme élément préalable d'investigation, un examen des méthodes des deux auteurs concernés. Le lecteur sera à même de saisir à quel point il est opportun de prolonger dans la psychologie analytique de Jung le projet initié par Nietzsche, ce dernier admettant lui-même être guidé par l'investigation psychologique, si ce n'est avoir écrit le Zarathoustra sous la pression des archétypes. Notre recherche nous amène à réévaluer le projet réformateur de Nietzsche à la lumière de ce qui se présente au départ comme une projection de l'homme/Nietzsche dans la figure du dieu/Zarathoustra. Nous établissons dans quelle mesure le concept de spiritualisation devient plus fondamental que celui d'esthétique lorsqu'il s'agit d'interpréter le fond de l'intention philosophique de Nietzsche; puis nous voyons comment s'associe l'ensemble du système nietzschéen à la perspective jungienne du quaternion, ce qui révélera le rôle essentiel que joue le corps dans un ensemble qui veut dépasser une tradition philosophique dominée par l'idée chrétienne de trinité. Cette réflexion éclairera ce qu'il convient d'appeler la pensée la plus abyssale de Nietzsche, soit l'Éternel retour, dans la dynamique des manifestations de l'inconscient. Nous résumons l'essentiel des volumineux Séminaires et présentons, en annexe, un lexique des concepts philosophiques importants qui s'y trouvent ainsi qu'une description contextuelle des symboles utilisés par Nietzsche, travail essentiel d'investigation de Jung qui se laisse porter par cette "rivière de figures" qu'est le Zarathoustra. À travers la lecture de Nietzsche, nous découvrons certaines motivations obscures que peut cacher l'intention philosophique. Nous verrons en quoi l'essentiel du processus d'identification entre Nietzsche, Zarathoustra et le Surhomme fait état de la présence irrépressible de la figure du Vieil homme sage; et comment la recherche du "sens de la Terre", chez Nietzsche, intègre une dimension "numineuse" caractéristique qui rend si complexe l'idée de "dépassement de la métaphysique" et la tenue d'un discours moralisateur, entendu l'ambivalence de la psyché humaine, notamment en situation de crise.

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Le présent mémoire de maîtrise a pour but d'expliciter l'idée de Volonté de Puissance chez Friedrich Nietzsche. Pour ce faire, le livre Ainsi parlait Zarathoustra sera au centre de l'étude sur la Volonté de Puissance. Dans un premier temps, nous introduirons la notion du Surhomme. Ensuite, le lecteur sera amené à travers les différentes formes du nihilisme telles que développées dans le Zarathoustra. Ces trois formes du nihilisme sont : le nihilisme réactif de l'homme; le Dernier Homme; l'Homme Supérieur. La compréhension du nihilisme est très importante car il fait obstacle à l'accomplissement de la Volonté de Puissance, c'est-à-dire à vouloir la vie sincèrement. Enfin, après une maîtrise de l'idée du nihilisme, les notions d'Éternel Retour et de Volonté de Puissance seront expliquées.

Some 5 million people were classified as internally displaced in Colombia at the end of 2012, which represented about 10 per cent of the population and the highest number in the world at the time. Colombia differs from other countries with high levels of displacement in that it is comparatively politically stable, has effective national institutions, a relatively strong formal economy, and can by no means be described as a ‘failed’ or ‘failing’ state. The displacement literature tends to characterise the phenomenon as a humanitarian crisis and a side effect of the long-running civil war. But Colombians continue to be displaced in very large numbers despite the formal demobilization of the paramilitaries in 2006 and the diminished military capacity and engagement of the guerrillas since about the same period: the same groups that are widely regarded as being the main perpetrators of displacement. This thesis contends that displacement of the civilian population in Colombia is frequently not a consequence of violence, but rather the primary objective, where violence plays a facilitatory role. Moreover, the thesis asserts that these massive levels of displacement are substantively linked to predominantly economically-motivated logics and are regionally specific. By examining an agricultural commodity that has significantly expanded relatively recently in Colombia - African palm oil - this research examines if and how expanded cultivation may be linked to displacement. Using a political economy framework of analysis combined with empirical fieldwork, it explores the ‘localised displacement logics’ whereby land is coercively acquired by powerful local groups. The thesis concludes that the abandonment and dispossession of land from poor and marginalised groups constitutes part of an ongoing process of capitalist expansion and statebuilding in Colombia. Contrary to assertions that it is the intra-state conflict that constitutes the central obstacle to development, Colombia’s current trajectory of capitalist development may actually be a central obstacle to sustainable peace and not lead to an end to displacement.

This thesis proposes a collection of analytical and computational methods for inferring an underlying social structure of a given population, observed only via timestamped occurrences of its members across a range of locations. It shows that such data streams have a modular and temporally-focused structure, neither fully ordered nor completely random, with individuals appearing in "gathering events". By exploiting such structure, the thesis proposes an appropriate mapping of those spatio-temporal data streams to a social network, based on the co-occurrences of agents across gathering events, while capturing the uncertainty over social ties via the use of probability distributions. Given the extracted graphs mentioned above, an approach is proposed for studying their community organisation. The method considers communities as explanatory variables for the observed interactions, producing overlapping partitions and node membership scores to groups. The aforementioned models are motivated by a large ongoing experiment at Wytham woods, Oxford, where a population of Parus major wild birds is tagged with RFID devices and a grid of feeding locations generates thousands of spatio-temporal records each year. The methods proposed are applied on such data set to demonstrate how they can be used to explore wild bird sociality, reveal its internal organisation across a variety of different scales and provide insights into important biological processes relating to mating pair formation.

Covalent modifications of histone tails play essential roles in mediating chromatin structure and epigenetic regulation. JmjD3 is a JumonjiC domain containing histone demethylase, belongs to the KDM6 subfamily, and catalyses the removal of methyl groups on methylated lysine 27 on histone 3 (H3K27), a critical mark to promote polycomb mediated repression and gene silencing. The importance of JmjD3 has been implicated in development, cancer biology and immunology. In this thesis, I report the recombinant production of active human JmjD3, development of two in vitro screening assays, a cell-based assay, and structural determination of JmjD3 in complex with the inhibitor 8-hydroxy-5-carboxyquinoline (8HQ). A highly selective and potent small molecule inhibitor GSK-J1 was subsequently identified. The inhibitor is active in HeLa cells and promotes a dose-dependent increase of global H3K27 methylation. The inhibitor GSK-J1 was used in two different cell assay systems related to inflammation and differentiation, to understand how H3K27 demethylation controls cellular functions. By inhibiting H3K27me3 demethylation, it is demonstrated that tumor necrosis factor (TNF) and other pro-inflammatory cytokines are regulated by H3K27 demethylase inhibition in M1- type macrophages derived from healthy volunteers and rheumatoid arthritis patients. It is also shown that inhibition of H3K27me3 demethylation abrogates cellular fusion of M2- type macrophages. During RANKL induced osteoclast differentiation, JmjD3 is up-regulated and promotes the expression of the key transcription factor NFATc1. By inhibiting JmjD3, NFATc1 expression is reduced and osteoclastogenesis is inhibited. This mechanism demonstrates a novel anti-resorptive principle of potential utility in conditions of excess bone resorption such as osteoporosis, bone erosion in inflammatory arthritis or cancer of the bone. These experiments further resolve the ambiguity between scaffold and catalytic function associ- ated with the H3K27 demethylase in these biological systems, and demonstrate that its enzymatic activity is crucial for epigenetic regulation of macrophage and osteoclast function.

An individual's Human Leukocyte Antigen (HLA) type is an essential immunogenetic parameter, influencing susceptibility to a variety of autoimmune and infectious diseases, to certain types of cancer and the likelihood of adverse drug reactions. I present and evaluate two models for the accurate statistical determination of HLA types for single-population and multi-population studies, based on SNP genotypes. Importantly, SNP genotypes are already available for many studies, so that the application of the statistical methods presented here does not incur any extra cost besides computing time. HLA*IMP:01 is based on a parallelized and modified version of LDMhc (Leslie et al., 2008), enabling the processing of large reference panels and improving call rates. In a homogeneous single-population imputation scenario on a mainly British dataset, it achieves accuracies (posterior predictive values) and call rates >=88% at all classical HLA loci (HLA-A, HLA-B, HLA-C, HLA-DQA1, HLA-DQB1, HLA-DRB1) at 4-digit HLA type resolution. HLA*IMP:02 is specifically designed to deal with multi-population heterogeneous reference panels and based on a new algorithm to construct haplotype graph models that takes into account haplotype estimate uncertainty, allows for missing data and enables the inclusion of prior knowledge on linkage disequilibrium. It works as well as HLA*IMP:01 on homogeneous panels and substantially outperforms it in more heterogeneous scenarios. In a cross-European validation experiment, even without setting a call threshold, HLA*IMP:02 achieves an average accuracy of 96% at 4-digit resolution (>=91% for all loci, which is achieved at HLA-DRB1). HLA*IMP:02 can accurately predict structural variation (DRB paralogs), can (to an extent) detect errors in the reference panel and is highly tolerant of missing data. I demonstrate that a good match between imputation and reference panels in terms of principal components and reference panel size are essential determinants of high imputation accuracy under HLA*IMP:02.

The development of safe and efficient gene delivery systems in pluripotent human embryonic stem cells (hESc) is essential to realising their full potential for basic and clinical research. The purpose of this study was to develop an efficient, non-integrating gene expression system in pluripotent hESc using human artificial chromosomes (HAC). Similar to endogenous chromosomes, HAC are capable of gene expression, replication and segregation during cell division. Unlike retroviral-mediated gene delivery vectors, HAC do not integrate into the host genome and can encompass large genomic regions for the delivery of multiple genes. Despite the advantages HAC offer, their use has been limited due to laborious cloning procedures and poor transfection efficiencies, and thus only studied in immortalised and tumour-derived human cell lines. In this study, the high transduction efficiency of herpes simplex virus type-1 (HSV-1) amplicons was utilised to overcome the described difficulties and delivered HAC vectors into pluripotent hESc. Analysis of stable hESc clones showed that de novo gene-expressing HAC were present at high frequencies ranging from 10-70% of metaphases analysed, without integrating into the genome. The established HAC contained an active centromere, and were stably maintained without integration or loss in the absence of selection for 90 days. Stable HAC-containing hESc clones retained their pluripotency as demonstrated by neuronal differentiation, in vitro germ layer and teratoma formation assays. HAC gene expression persisted, with some variation, post-differentiation in the various deriving cell types. This is the first report of successful de novo HAC formation in hESc for gene expression studies. These findings show potential for delivering high-capacity genomic constructs safely and efficiently into pluripotent cells for the purpose of genetic manipulation and ultimately patient-specific somatic gene therapy.

The past five years has seen the discovery of a wealth of genetics variants associated with an incredible range of diseases and traits that have been identified in genome- wide association studies (GWAS). These GWAS have typically been performed in in- dividuals of European descent, prompting a call for such studies to be conducted over a more diverse range of populations. These include groups such as African Ameri- cans and Latinos as they are recognised as bearing a disproportionately large burden of disease in the U.S. population. The variation in ancestry among such groups must be correctly accounted for in association studies to avoid spurious hits arising due to differences in ancestry between cases and controls. Such ancestral variation is not all problematic as it may also be exploited to uncover loci associated with disease in an approach known as admixture mapping, or to estimate recombination rates in admixed individuals. Many models have been proposed to infer genetic ancestry and they differ in their accuracy, the type of data they employ, their computational efficiency, and whether or not they can handle multi-way admixture. Despite the number of existing models, there is an unfulfilled requirement for a model that performs well even when the ancestral populations are closely related, is extendible to multi-way admixture scenarios, and can handle whole- genome data while remaining computationally efficient. In this thesis we present a novel method of ancestry estimation named MULTIMIX that satisfies these criteria. The underlying model we propose uses a multivariate nor- mal to approximate the distribution of a haplotype at a window of contiguous SNPs given the ancestral origin of that part of the genome. The observed allele types and the ancestry states that we aim to infer are incorporated in to a hidden Markov model to capture the correlations in ancestry that we expect to exist between neighbouring sites. We show via simulation studies that its performance on two-way and three-way admixture is competitive with state-of-the-art methods, and apply it to several real admixed samples of the International HapMap Project and the 1000 Genomes Project.

Hypoxia-inducible factor (HIF) is the master regulator of genes involved in adaptation to hypoxia. The stability and transcriptional activity of HIF are regulated by post-translational hydroxylations: prolyl hydroxylation by the prolyl hydroxylase domain-containing enzymes PHD1 – 3 earmarks HIF for proteasomal degradation, whilst asparaginyl hydroxylation by factor inhibiting HIF (FIH) blocks the interaction of HIF with the transcriptional coactivators p300/CBP. The PHDs and FIH hydroxylate HIF directly from molecular oxygen and are therefore oxygen sensors. Recent literature shows that FIH also hydroxylates a number of proteins containing an ankyrin-repeat domain (ARD). Together with reports suggesting that the PHDs are involved in HIF-independent pathways, this suggests that the HIF hydroxylases may have a wide range of non-HIF targets. This thesis describes my investigations into novel substrates of the HIF hydroxylases. This work has characterized the FIH-dependent hydroxylation of the ARD-containing protein Notch1, and defined a consensus sequence for hydroxylation that corresponds to the ankyrin-repeat consensus. Using this consensus potential sites of hydroxylation in a novel ARD FIH substrate, myosin phosphatase targeting subunit 1 (MYPT1), were identified then subsequently confirmed and characterized. Notch1 competes with HIF for FIH hydroxylation. My experiments show that this occurs because Notch1 is a more efficient substrate than HIF, whilst studies on MYPT1 and other proteins indicate that competitive inhibition of FIH may be a general property of ARDs. There are more than 300 ARD proteins in the human genome, and this thesis demonstrates that FIH may hydroxylate a significant percentage of these. In addition to the analysis of ARD hydroxylation a proteomic investigation into novel PHD3 substrates has identified two candidate proteins, suggesting that the PHDs may also have multiple targets. These results have important implications for oxygen sensing, and indicate that post-translational hydroxylation is likely to be a widespread modification in cell biology.