O modelo a ser apresentado consiste em um jogo de preço e localização entre duas firmas. Utiliza-se o pressuposto de que os consumidores têm sua utilidade positivamente afetada por um efeito de rede, ou seja, são diretamente influenciados pela tamanho da demanda do bem. Dispondo os consumidores uniformemente distribuídos dentro de um intervalo linear [0, 1], buscamos encontrar os equilíbrios de preço e localização do jogo proposto. Verificamos que, dados os pressupostos do modelo, existem equilíbrios de Nash para cada subjogo e dependerão da força dos efeitos de rede. Quando os efeitos de rede são fortes o suficiente, os preços praticados serão inicialmente reduzidos até que o monopólio seja alcançado por uma das firmas, quando o preço será elevado e a outra firma passará a cobrar um preço nulo. No subjogo de localizações foi possível identificar que, no caso em que o poder do efeito de rede está acima de um determinado nível, as firmas não irão diferenciar seus produtos e se localizarão em algum ponto dentro do intervalo fechado [1/4 , 3/4] / The model to be presented is a price-location game between two firms. The assumption is that consumers\' utility is positively affected by a network effect, i.e. it is directly influenced by the size of demand. Distributing consumers uniformly in a linear interval [0, 1] we seek the price and location equilibrium of the proposed game. We found that, given the model assumptions, there are Nash equilibria for each subset that depend on the strength of network effects. When network effects are strong enough, prices are initially reduced until the monopoly is reached by one of the firms, then the price rises and the other firm shall charge a null price. In the subgame of locations, when the power of the network effect is above a certain level, the firms will not differentiate their products and will be located at any point within the closed interval [1/4 , 3/4]

O câncer é um dos principais problemas de saúde pública no mundo. Dentre as neoplasias primárias que acometem o fígado, o carcinoma hepatocelular (HCC) é a mais frequente. Diversos fatores de risco predispõem ao HCC, entre eles a doença hepática gordurosa não alcóolica (NAFLD). Segundo estudos prévios do grupo, a &#946-ionona (BI), apresenta potencial quimiopreventivo na hepatocarcinogênese, promovendo redução de lesões preneoplásicas (LPN). Assim pretendeu-se investigar se a NAFLD potencializaria o desenvolvimento de LPN em ratos Wistar submetidos ao modelo do hepatócito resistente (RH) na etapa de iniciação/promoção inicial da hepatocarcinogênese e se a BI apresenta efeito quimiopreventivo nesse contexto. Para tanto, os animais foram distribuídos em 4 grupos experimentais: grupo não-tratado (NT), grupo submetido ao RH (RH), grupo submetido ao RH e ao modelo de NAFLD, que consiste na administração de emulsão hiperlipídica, (AS) e grupo AS tratado com BI (AS + BI). Em uma primeira instância, 5 animais pertencentes aos grupos NT, AS,AS + BI foram eutanasiados após 6 semanas de administração de emulsão hiperlipídica, antes da aplicação do modelo RH, para se confirmar o desenvolvimento da NAFLD. Foi possível observar que a administração de emulsão hiperlipídica durante 6 semanas foi suficiente para o desenvolvimento de esteatose hepática. Após as 6 semanas foi introduzido o modelo do RH concomitante à administração da emulsão hipercalipídica até o fim do experimento na 13a semana . Após 13 semanas o grupo AS apresentou maiores (p<0,05) valores de focos de inflamação, hepatócitos balonizados e grau de esteatose hepática em relação ao grupo AS+BI, assim como maiores (p<0,05) níveis séricos de triacilgliceróis, colesterol, HDL, LDL, VLDL, e maior (p<0,05) valor de MDA em relação ao grupo RH embora sem diferença estatística. O grupo AS também apresentou maior (p<0,05) incidência, número total e multiplicidade de nódulos, além de maior (p<0,05) número e tamanho de LPN persistentes (pLPN) e índice de proliferação quando comparado aos grupos RH e AS+BI. O grupo AS + BI, por sua vez, demonstrou menores (p<0,05) valores de escore de células ovais e menores valores de comprimentos de cometa e danos no DNA quando comparado ao grupo AS, embora sem diferença estatista para este último parâmetro. Em relação à expressão gênica, o grupo AS apresentou menores (p<0,05) valores de expressão do gene Hmgcr em relação ao grupo RH e maiores (p<0,05) valores dos genes Insig 1 e Thy 1 quando comparados ao grupo AS+BI. Portanto, no contexto de esteatose hepática associada ao modelo do RH, a administração de BI durante a etapa de iniciação/promoção em ratos Wistar resultou em atividade quimiopreventiva que se deu pela diminuição de pLNP, redução da proliferação celular e do número de células ovais, consideradas potenciais alvos para o desenvolvimento da hepatocarcinogênese, entretanto os genes analisados parecem não serem modulados pela BI. / Cancer is a major public health problem in the world. Among the primary neoplasms affecting the liver, hepatocellular carcinoma (HCC) is the most frequent. Several risk factors predispose to HCC, including the nonalcoholic fatty liver disease (NAFLD). According to previous studies of the group, the &#946-ionone (BI), has potential chemopreventive in hepatocarcinogenesis, promoting reduction of preneoplastic lesions (LPN). Thus we investigated whether NAFLD would increase the development of LPN in Wistar rats resistant hepatocyte model (RH) at the stage of initiation / promotion of hepatocarcinogenesis and if BI has chemopreventive effect in this context. Therefore, the animals were divided into 4 groups: non-treated group (NT), the group submitted to HR (HR), the group submitted to HR and NAFLD model, consisting of the fatty emulsion administration (AS) and AS group treated with BI (AS + BI). In a first point, 5 animals belonging to the groups NT, AS, AS + BI were euthanized after 6 weeks of administration of fat emulsion prior to application of the HR model, to confirm the development of NAFLD. It was observed that the administration of fatty emulsion for 6 weeks was sufficient to the development of hepatic steatosis. After 6 weeks it was introduced into the model HR the concomitant administration of fatty emulsion until the end of the experiment at 13 weeks. In the endpoint, the AS group had higher (p <0.05) of serum triacylglycerols, cholesterol, HDL, LDL, VLDL although no statistical difference inrelation to RH group, and increased (p <0.05) amount of MDA in relation to the group RH. The AS group also had higher (p <0.05) incidence, multiplicity and total number of nodes and greater (p <0.05) number and size of persistent LPN (pLPN) and proliferation index when compared to HR groups and AS + BI. AS + BI group. It was observed in AS+BI group lower (p <0.05) cell oval score values compared to AS group. In addition the AS+BI group showed lower values of the comet length and DNA damage compared to the AS group, although no statistical differences. In relation to gene expression, the AS group showed lower(p <0.05) HMGCR gene expression values in relation to HR group and higher (p <0.05) expression of Insig genes 1 and Thy 1 compared to group AS + BI.Therefore, in the context of hepatic steatosis associated with HR model BI for administration to the stage of initiation / promotion in rats resulted in chemopreventive activity was due to decrease in area of pLNP, reducing cell proliferation, and the number of oval cells, as potential targets for the development of hepatocarcinogenesis, however the genes do not seem to be modulated analyzed by BI.

Un cadre d'optimisation multi-Objectif pour les pales d'hélicoptère est développé en utilisant des modèles de simulation de haute fidélité. Des fonctions objectives caractérisant la performance de l'hélicoptère en vol stationnaire et d'avancement sont retenues. Deux solveurs sont utilisés afin de prédire la performance du rotor: le code général HOST et le solveur CFD elsA. Le premier axe de recherche porte sur la caractérisation de la précision des méthodes de prédiction. L'influence de la prise en compte de la souplesse de la pale, du trim rotor et/ou de l'utilisation de modélisations aérodynamiques simplifiées est caractérisée pour chaque cas de vol en utilisant des mesures en soufflerie. Un cadre numérique adapté à l'optimisation est développé. Le deuxième axe de recherche porte sur des techniques d'optimisation multi-Objectif de pales en vol stationnaire et d'avancement. Deux algorithmes novateurs basés sur la compétition (Jeux de Nash) et la coopération (Descente à Gradients Multiples) sont présentés comme des alternatives aux approches traditionnelles pour traiter le problème multi-Objectif. Afin de réduire le coût des simulations, un cadre de simulation basé sur des métamodèles est développé y compris une stratégie multi-Fidélité pour prédire la performance du rotor en vol d'avancement. Ces techniques sont appliquées à un cas réaliste de rotor, en utilisant des simulations CFD trimmées avec pale souple pour le cas du vol d'avancement et des simulations CFD avec pale rigide en vol stationnaire. Les résultats sont ensuite analysés, démontrant le potentiel de ces techniques pour l'obtention de conceptions réalistes représentant des bons compromis entre les objectifs. / This work addresses the development of a multi-Objective optimization framework for helicopter rotor blades using high-Fidelity simulation models. In particular, objective functions corresponding to hover and forward flight are considered. Two solvers are used to predict the rotor performance: the comprehensive rotor code HOST and the Computational Fluid Dynamics (CFD) solver elsA. The first research axis of this work is the characterization of the accuracy of each available prediction method. The influence of considering the blade elasticity, the rotor trim and/or simplified aerodynamics is characterized for each flight case using wind-Tunnel data. As a result, a numerical framework adapted to the optimization is developed. The second part of this work concerns the formulation and development of techniques adapted to the multi-Objective optimization of rotor blades in hover and in forward flight. Innovative algorithms based on competition (Nash Games) and cooperation (Multi-Gradient Descent) are presented as alternatives to traditional multi-Objective approaches. In order to reduce the simulation costs, a surrogate-Based framework is developed, including a multi-Fidelity strategy to predict the rotor performance in forward flight. These techniques are finally applied to a realistic rotor, considering trimmed elastic CFD computations in the forward flight case and rigid blade CFD computations in the hover case. The results are subsequently analyzed, demonstrating the potential of these techniques to obtain realistic designs realizing interesting trade-Offs.

Ce travail se concentre sur l'étude de jeux joués sur des graphes finis, parun nombre arbitraire de joueurs, dont les objectifs ne sont pas antagonistes.Chaque joueur représente un agent, c'est-à-dire un programme, un processus,ou un périphérique, qui interagit avec les autres joueurs et leurenvironnement commun dans le but de satisfaire au mieux son objectifindividuel.Des concepts telsque les équilibres de Nash, permettant d'exprimer l'optimalité des stratégiesdes joueurs, ont été étudiés dans un cadre déterministe, et l'existencede tels équilibres n'est pas assurée, même lorsque les objectifs des joueurssont de simples conditions d'accessibilité ou de sûreté. En effet, lorsqueles joueurs jouent de manière déterministe, le système évolue en conservantune certaine symmétrie, ce qui nous motive à considérer un modèle stochastiqueoù les joueurs et l'environnement sont sources d'aléa. Dans le premier cas,nous montrons que les concepts classiques d'équilibres de Nash ne peuventêtre calculés, et introduisons des notions approchées d'équilibrescalculables. Dans le deuxième cas, nous nous intéressons à l'analyse desystèmes composés d'un nombre arbitraires de processus, dont l'éxécutionest déterminée par un ordonnanceur, c'est-à-dire l'environnement,probabiliste. / We study games played on graphs by an arbitrary number of players withnon-zero sum objectives. The players representagents (programs, processes or devices) that can interact to achieve their ownobjectives as much as possible. Solution concepts, as Nash Equilibrium, forsuch optimal plays,need not exist when restricting topure deterministic strategies, even with simple reachability or safetyobjectives. The symmetry induced by deterministic behavioursmotivates the studies where eitherthe players or the environment can use randomization. In the first case, weshow that classical concepts are undecidable with a fixednumber of agents and propose computable approximations.In the second case, we studyrandomization as a reasonable policy for scheduling an arbitrary number ofprocesses.

Orientador: Manoel Ferreira Borges Neto / Banca: Sandra Regina Monteiro Masalskiene / Banca: Antonio Luís Venezuela / Resumo: O presente trabalho tem por objetivo abordar aspectos fundamentais da teoria de imersão proposta por John Nash em 1954, na qual foi mostrado que uma variedade continua com derivada continuação nua C1, pode ser imersa em espaços euclidianos de 2n dimensões. Faz-se importante citar que ao longo do trabalho serão destacados aspectos inovadores do Teorema de Nash, tais como a não necessidade da hipótese de analitici-dade conforme havia sido usada anteriormente por Janet-Cartan, além do aspecto da perturbação que permite construir qualquer outra variedade imersa por uma sequência de deformações infinitesimais. São discutidos também extensões do Teorema de Nash, sobretudo os trabalhos de Greene e de Gunther, e aplicações do método perturbativo de Nash nas Teorias unificadoras da física. / Abstract: The present work has for objective to approach basic aspects of the immersion theory proposal for John Nash in 1954, in which it was shown that a continuous variety with continuous derivative C1, can be immersed in Euclidean spaces of 2n dimensions. One becomes important to cite that throughout the work innovative aspects of the The- orem of Nash will be detached, such as the necessity of the hypothesis of in agreement analiticidade had not been used previously for Janet-Cartan, beyond the aspect of the disturbance that allows to construct any another immersed variety for a sequência of infinitesimal deformations. Extensions of the Theorem of Nash are also argued, over all the works of Greene and Gunther, and applications of the perturbativo method of Nash in the unifying Theories of the physics. / Mestre

Denna kandidatuppsats bemöter frågan om väljarbeteende i allmänna val; huruvida strategiskt röstande (taktikröstning) är ett förekommande fenomen i val till svenska kommunfullmäktige eller ej och i så fall vilka faktorer som ligger bakom strategiskt röstande. En underförstådd tes bakom väljarbeteende är att röstberättigade röstar i enlighet med deras partipreferens utifrån en rad underliggande orsaker, såsom sakpolitik, partifärg, ideologi och organisationsstruktur. Dock har viss forskning uppstått som tyder på att somliga väljare agerar konsekvent och röstar utifrån bästa möjliga utdelning (payoff), snarare än direkta skäl. Dessa indirekta skäl kan röra sig om partiernas valallianser med övriga partier, något som alltid inte uppskattas av väljarna. Under senare halvan av 1900-talet har studier kring väljarbeteende uppmärksammats av statsvetare och beteendevetare. En av de mest omnämnda publikationerna inom vetenskapen är undertecknad den amerikanska ekonomen Anthony Downs som genom sin bok An Economic Theory of Democracy (1957) har undersökt relationen mellan politiska kandidater och väljare. Uppsatsen kommer presentera för läsaren tidigare studier inom detta specifika forskningsområde samt en nutidshistorisk överblick i s.k. oheliga allianser. Resultatet kommer visa på partisamverkans tydliggjorda betydelse i hur kommunmedborgarna röstar i allmänna val.

In the generalized Nash equilibrium problem not only the cost function of a player depends on the rival players' decisions, but also his constraints. This thesis presents different iterative methods for the numerical computation of a generalized Nash equilibrium, some of them globally, others locally superlinearly convergent. These methods are based on either reformulations of the generalized Nash equilibrium problem as an optimization problem, or on a fixed point formulation. The key tool for these reformulations is the Nikaido-Isoda function. Numerical results for various problem from the literature are given. / Das verallgemeinerte Nash-Gleichgewichtsproblem ist ein Lösungskonzept für Spiele, in denen neben der Kostenfunktion eines Spielers auch dessen Strategiemenge von den Entscheidungen der anderen Spieler abhängt. In dieser Arbeit werden global konvergente und lokal superlinear konvergente Verfahren zur numerischen Berechnung eines verallgemeinerten Nash-Gleichgewichts vorgestellt. Die Verfahren basieren entweder auf einer Umformulierung des verallgemeinerten Nash-Gleichgewichtsproblems als Optimierungsproblem oder als Fixpunktproblem. Für diese Umformulierungen wird die Nikaido-Isoda Funktion verwendet. Es werden numerische Ergebenisse für einige Probleme aus der Literatur widergegeben.

The subject of this thesis are mathematical programs with complementarity conditions (MPCC). At first, an economic example of this problem class is analyzed, the problem of effort maximization in asymmetric n-person contest games. While an analytical solution for this special problem could be derived, this is not possible in general for MPCCs. Therefore, optimality conditions which might be used for numerical approaches where considered next. More precisely, a Fritz-John result for MPCCs with stronger properties than those known so far was derived together with some new constraint qualifications and subsequently used to prove an exact penalty result. Finally, to solve MPCCs numerically, the so called relaxation approach was used. Besides improving the results for existing relaxation methods, a new relaxation with strong convergence properties was suggested and a numerical comparison of all methods based on the MacMPEC collection conducted. / Das Thema dieser Dissertation sind mathematische Programme mit Komplementaritätsrestriktionen (MPCC). Zunächst wurde eine ökonomische Anwendung dieses Problemklasse betrachtet, das sogenannte Wettbewerbsdesignproblem. Während es für dieses spezielle Problem möglich war eine analytische Lösung herzuleiten, ist dies im Allgemeinen nicht möglich. Daher wurden anschließend Optimalitätsbedingungen, die für eine numerische Lösung verwendet werden können, betrachtet. Genauer wurde ein stärkeres Fritz-John Resultat als die bisher bekannten zusammen mit neuen Constraint Qualifications hergeleitet und anschließend zum Beweis eines exakten Penaltyresultates benutzt. Schließlich wurden zur numerischen Lösung von MPCCs sogenannte Relaxationsverfahren betrachtet. Zusätzlich zur Verbesserung der Resultate für bekannte Verfahren wurde eine neue Relaxierung mit starken Konvergenzeigenschaften vorgeschlagen und ein numerischer Vergleich aller Verfahren auf Basis der MacMPEC Testsammlung durchgeführt.

A teoria da evolução de Darwin - como introduzida em teoria de jogos por Maynard Smith - não é o único aspecto evolucionário importante a ser considerado em uma dinâmica evolucionária, uma vez que as complexas interdependências, competição, e o crescimento podem ser modelados por, por exemplo, aspectos reativos. No jogo do ultimato, a reciprocidade e a partição meio-a-meio parecem ser um desvio do comportamento racional dos jogadores sob a luz do Equilíbrio de Nash. Tal equilíbrio emerge, por exemplo, da punição do respondedor que geralmente tende a refutar propostas injustas. Na versão iterada do jogo do ultimato, os proponentes são capazes de melhorar suas propostas por adicionar um valor a elas tornando-as mais justas. Tais aspectos evolucionários não são propriamente Darwinianos, mas eles são dotados de um aspecto fundamental: eles retêm suas ações de acordo com suas ofertas. Recentemente, uma versão reativa do jogo do ultimato onde a aceitação ocorre com probabilidade fixa foi proposta. Na primeira parte desta tese, exploramos esta versão reativa do jogo do ultimato onde a aceitação pelos jogadores depende da oferta. A fim de realizar tal procedimento, analisamos duas situações: (i) campo médio e (ii) consideramos jogadores inseridos em redes com coordenação arbitrária. Assim, mostramos então que o aspecto reativo aqui estudado, não amplamente estudado, de acordo com o nosso conhecimento, na teoria evolucionária de jogos da literatura pode desvendar um aspecto essencial para a convergência da divisão fifty-fifty. Além disso, nós também analisamos populações sobre quatro diferentes politicas que variavam de uma altamente conservadora até uma moderada, com respeito a decisão de mudar as propostas baseadas na quantidade de aceitações recebidas. Mostramos que a ideia de ganhar menos, mais vezes, adicionada a reciprocidade dos jogadores, concomitantemente ao lema do \dando mais pra receber mais" , é altamente relevante para o conceito de populações economicamente saudáveis que barganham. Finalmente, para completar nossos estudos no jogo do ultimato reativo, adicionamos a mobilidade aos jogadores. Neste caso, realizamos algumas mudanças levando em consideração então a seleção natural (cópia Darwiniana). Mostramos que a mobilidade lidera a menores ofertas médias e também elaboramos um estudo complementar que mostra os valores médios das densidades de ofertas e estratégias/politicas mediadas em intervalos finais para grandes tempos de evolução temporal. Nossos resultados sugerem que apesar de uma coexistência temporária, a política/estratégia III (só oferece menos se todos aceitarem) deve prevalecer em relação a todas as outras em redes quadradas considerando apenas 4 vizinhos sob os efeitos de mobilidade. Finalmente, na segunda parte desta tese, continuamos a estudar os efeitos de mobilidade, no entanto, em outro paradigma da teoria de jogos, mais precisamente no que tange aos dilemas sociais relacionados aos conitos entre cooperação e interesses próprios de indivíduos em grandes populações, uma vez que a emergência da cooperação e sua manutenção é a chave para o entendimento dos conceitos fundamentais sobre a evolução das espécies. A fim de entender os mecanismos envolvidos neste contexto, aqui estudamos o jogo de bem público opcional com foco nos efeitos dos aspectos difusivos nos padrões emergentes de dominância cíclica entre as diferentes estratégias. Diferentemente de outros trabalhos, mostramos que os padrões de pedra-papel-tesoura (RPS, em inglês, rock-paper-scissors) ocorrem por introduzir no jogo um tipo simples de mobilidade aleatória em uma rede esparsadamente ocupada. Tal padrão tem se revelado muito importante na conservação das espécies em ambientes ecológicos e sociais. Uma das mais importantes contribuições desta tese é mostrar que não precisamos de esquemas mais elaborados para construção da vizinhança no jogo para observar padrões de RPS como sugerido na literatura. Como um interessante resultado adicional, propomos um método alternativo para quantificar a densidade de RPS em um contexto quantitativo da teoria de jogos que torna possível realizar um estudo de tamanho finito. Tal abordagem pode ser muito interessante para ser aplicada em outros jogos genericamente. / Darwin's theory of evolution - as introduced in game theory by Maynard Smith - is not the only important evolutionary aspect in evolutionary dynamics, since complex interdependencies, competition, and growth should be modeled by, for example, reactive aspects. In the ultimatum game, the reciprocity and the fty- fty partition seems to be a deviation from rational behaviour of the players under the light of Nash equilibrium. Such equilibrium emerges, for example, from the punishment of the responder who generally tends to refuse unfair proposals. In the iterated version of the game, the proposers are able to improve their proposals by adding a value thus making fairer proposals. Such evolutionary aspects are not properly Darwinian-motivated, but they are endowed with a fundamental aspect: they re ect their actions according to value of the o ers. Recently, a reactive version of the ultimatum game where acceptance occurs with xed probability was proposed. In the rst part of this thesis, we aim at exploring this reactive version of the ultimatum game where the acceptance by players depends on the o er. In order to do so, we analyse two situations: (i) mean eld and (ii) we consider players inserted within the networks with arbitrary coordination. We then show that the reactive aspect, here studied, thus far not analysed in the evolutionary game theory literature can unveil an essential feature for the convergence to fty- fty split. Moreover we also analyse populations under four di erent polices ranging from a highly conservative to a moderate one, with respect to the decision in changing the proposal based on acceptances. We show that the idea of gaining less more times added to the reciprocity of the players is highly relevant to the concept of "healthy"societies population bargaining. Finally by completing our studies in the reactive ultimatum game, we added mobility to the players. In this case, we performed some changes taking into account the natural selection (Darwinian copy). We show that mobility leads to lower average o ers and we also elaborated color maps for all occupation and mobility values show the density of o ers and strategies/polices which suggests a temporary coexistence. Finally, in the second part of this thesis, we explore the mobility e ects which are very important in social dilemmas that concern a natural con ict between cooperation and self interests among individuals in large populations. The emergence of cooperation and its maintenance is the key for the understanding of fundamental concepts about the evolution of species. In order to understand the mechanisms involved in this framework, here we study the Optional Public Good Games with focus on the e ects of di usive aspects in the emergent patterns of cyclic dominance between the strategies. Di erently from other works, we showed that rock-paper-scissors (RPS) patterns occur by introducing a simple kind of random mobility in a lattice sparsely occupied. Such pattern has been revealed to be very important in the conservation of the species in ecological and social environments. The goal of this paper is to show that we do not need more elaborated schemes for construction of the neighbourhood in the game to observe RPS patterns as suggested in the literature. As an interesting additional result, in this contribution we also propose an alternative method to quantify the RPS density in a quantitative context of the game theory which becomes possible to perform a nite size scaling study. Such approach can be very interesting to be applied in other games generically.

Non-alcoholic fatty liver disease (NAFLD) now affects around one in four adults in the human population and parallels the global increase in obesity. Within the spectrum of NAFLD, simple steatosis is associated with insulin resistance and type 2 diabetes while progression to steatohepatitis (NASH) is associated with an increased risk of liver cirrhosis and all-cause mortality. The molecular pathology of NAFLD is incompletely understood, however observational studies in human cohorts suggest the regulation of DNA methylation may play a role. 5-hydroxymethylcytosine (5hmC) is a cytosine modification generated from 5- methylcytosine (5mC) by the Ten eleven translocase isoenzymes (Tets) as part of a demethylation process. The aim of this project was to examine the role of Tet enzyme activity on the pathogenesis and progression of NAFLD. Detailed characterisation of two established murine dietary interventions allowed the selection of a NAFLD mouse model which broadly recapitulated the metabolic, histological and transcriptional features of human disease. Using DNA immunoprecipitation coupled with whole genome next generation sequencing and RNA micro expression arrays I examined the effect of high fat diet feeding (HFD) on hepatic DNA 5hmC levels within annotated gene regions. Whilst the global 5hmC profile was not altered by HFD, there was profound genic enrichment of 5hmC in upregulated mediators of cholesterol synthesis and transport (Lss, Sc4mol, Fdps, Hsd17b7, Cyp17a1, Mvd, Cyp1a2, Dhcr7 and Apoa4) with no enrichment in genes with other pathological functions (drug detoxification, inflammation, cell cycle regulation). Induced peaks of 5hmC enrichment were subsequently abolished following rescue of the NAFLD phenotype by conversion to control diet. Cross species validation was performed in vitro utilising embryonic stem cell derived hepatocytes challenged with a cocktail of high energy substrates. My in vivo findings were broadly replicated with specific 5hmC enrichment in genes synthesising lipotoxic molecules (PLIN2, CIDEC, APOA4, ACADVL, HMGCS2, APOA5, CYP2J2, IGFBP1, PPAP2C, ACSL1, APOC3, ANGPTL4, NRG1) with no enrichment in upregulated genes of alternative function. To determine whether or not the 5hmC enrichment seen is of functional relevance, I studied Tet1-/- C57BL/6J mice. Tet1-/- mice are grossly normal in appearance, however loss of Tet1 conferred a striking resistance to diet induced obesity with reduced body fat mass, improved insulin-sensitivity and near complete absence of NAFLD compared to wild type littermates. Furthermore, the HFD fed Tet1-/- liver transcriptome showed a ‘protective’ profile, with suppression of genes for lipid synthesis, inflammation and fibrosis. Thus, in multiple cross-species models of NAFLD, over nutrition induces genic hydroxymethylation specifically within activated genes driving the synthesis and transport of lipid molecules. Such changes are reversible with resolution of the NAFLD phenotype strengthening functional association. Tet1 deficiency conveys an obesity and NAFLD resistant phenotype. I therefore introduce Tet1 mediated hydroxymethylation as a novel mechanism for NAFLD pathogenesis.