Zusammenfassung 1) Fragestellung und zentrale Untersuchung Unter der Hypothese, dass die Transportrate des Glukosetransporters Typ 3 (GLUT3) abhängig von der Kopienanzahl (CNV) des für ihn kodierenden Gens SLC2A3 ist, wurden Zelllinien mit drei Kopien (Duplikation) mit Kontroll-Zelllinien mit nur zwei Kopien bezüglich ihrer Glukoseaufnahme miteinander verglichen (n=2; N=9). Hierzu wurde die zelluläre Glukoseaufnahme mittels radioaktiv markierter 2-Desoxyglukose in via Eppstein-Barr-Virus immortalisierten lymphoblastoiden Zelllinien (EBV-LCLs) gemessen. In den initialen Untersuchungen zeigt sich, dass das Protokoll an manchen Stellen zu viel Spielraum lässt. Die Methode wird daraufhin standardisiert und bezüglich einiger Parameter angepasst: g-Zentrifugeneinstellung, Mischen/Aliquotieren, Zellanzahl, Replikatanzahl, Inkubationszeit/-intervalle und Durchführungsdauer. 2) Wichtigste Ergebnisse Die funktionelle Untersuchung zur Duplikation des SLC2A3-Gens in Patienten mit Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung (ADHS) zeigt schließlich im dynamischen Aushungerungsversuch der EBV-LCLs über vier Tage (Vergleich t2 zu t1) statistisch für die Gruppen eine deutliche Differenz mit mittlerer Effektstärke (Lineares Gemischtes Modell; p = 0,06; Cohens d = 0,37). Zum zweiten Messzeitpunkt (t2) zeigt sich statistisch zwischen den Gruppen eine sehr signifikante Differenz mit hoher Effektstärke (Lineares Gemischtes Modell; p < 0,006; Cohens d = 0,55). Damit konnte in dieser Arbeit nachgewiesen werden, dass die SLC2A3-Duplikation neben dem Gendosiseffekt auf mRNA-Ebene auch hypermorph funktionelle Veränderungen auf zellulärer Ebene nach sich zieht. Nachfolgende Untersuchungen sollten vor diesem Hintergrund mögliche Kofaktoren investigieren und auf Alterationen in nachgeschalteten Signalwegen abzielen. / 5.1 Research question and central investigation Under the hypothesis that the transport rate of the glucose transporter type 3 (GLUT3) is dependent on the copy number (CNV) of the gene encoding it, SLC2A3, cell lines with three copies (duplication) were compared with control cell lines with only two copies with respect to their glucose uptake (n=2; N=9). For this purpose, cellular glucose uptake was measured using radiolabeled 2-deoxyglucose in lymphoblastoid cell lines (EBV-LCLs) immortalized via Eppstein-Barr virus. The initial studies show that the protocol leaves too much leeway at some maneuvers. The method is then standardized and adapted with regard to the following parameters: g-centrifuge setting, mixing/aliquoting, cell number, replicate number, incubation time/intervals and execution time. 5.2 Main results The functional investigation for the duplication of the SLC2A3 gene in patients with attention-deficit/hyperactivity disorder (ADHD) finally shows in the dynamic starvation test of EBV-LCLs over four days (comparison t2 to t1) statistically for the groups a significant difference with a mean effect size (Linear Mixed model; p = 0.06; Cohen's d = 0.37). At the second measurement time point (t2), there is statistically a very significant difference with a high effect size (Linear Mixed Model; p < 0.006; Cohen's d = 0.55). Thus, this work demonstrated that the SLC2A3 duplication in addition to the gene dosage effect at the mRNA level, also induces hypermorphic functional changes at the cellular level. Subsequent studies should investigate possible cofactors and target alterations in downstream signaling pathways.

Esta tese tem como objetivo apresentar uma reflexão de um espaço público aberto com o intuito de despertar novos modos de olhar e compreender a cidade a partir da imagem. Imagem esta, que amplia o universo do conhecimento sobre o lugar, enquanto dimensão simbólica trans-histórica, cuja articulação com outras imagens constrói referências de memória. Esta pesquisa pauta-se em dois momentos: um primeiro, onde a percepção atua como protagonista do processo de reconhecimento da cidade por meio da deambulação, que resultou no recorte espacial e na escolha de um espaço público aberto presente no eixo monumental da cidade de Maringá-PR; e um segundo momento, onde utiliza-se a associação de imagens como deflagrador de novas possibilidades de compreensão do espaço urbano. Nesse sentido, adota-se aproximações metodológicas de Aby Warburg (1866-1929), hoje reconhecido como o pai da iconologia moderna. Historiador das artes, desenvolveu um Atlas de imagens - Mnemosyne - uma História de Arte sem palavras. As aproximações metodológicas deste processo propõem apresentar um ensaio Mnemosyne. Uma ferramenta perceptiva de falar de imagens por imagens, utilizando apenas painéis, com combinações imagéticas feitas entre elas, dispensando o uso da linguagem escrita; e as relações estabelecidas entre as imagens se articulam e produzem modos de leitura de forma a não revelar as suas inter-relações. Desta forma, os leitores que tiverem acesso a estes painéis, possam criar novos vínculos e levantar discussões, sem estabelecer conexões fechadas. Isso permite que novos resultados de leituras, a cada novo contato do leitor, sejam estabelecidos, permitindo novas experiências e novas leituras por meio do painel de imagens. As relações visuais existentes no painel atlas não se estruturam apenas por leituras históricas, se organizam de forma a estabelecer descobertas e discussões por meio das imagens, não sendo apenas um modo de transmitir informações. O painel atlas permite considerações de um processo inicial, impulsionado e dirigido por imagens, que possibilitou, acima de tudo, criar novas decifrações de leituras frente ao espaço urbano em questão, tanto com base na memória histórica individual e coletiva, tanto por meio do significado de cada representação imagética. Assim, esta tese pretende verificar novas possibilidades de aproximações metodológicas, por meio da ferramenta atlas -, de análises dos espaços da cidade viabilizando um aprofundamento em questões até então, discutidas, mas pouco fundamentadas, de modo a despertar o processo criativo e de instigar debates, revelados por meio das imagens e de suas associações. Associações que representam uma variedade de concepções e contribuições, que em algum momento, a história possa ter deixado de contar, como a idealização dos espaços urbanos da cidade e das relações possíveis estabelecidas com o sujeito. Ainda como resultado desse processo associativo, observa-se as indicações subjetivas de características visuais e plásticas, com aproximações conceituais relativas às primeiras construções arquitetônicas neolíticas, referente a demarcações territoriais e de cunho religioso, representando força, coletividade, autoridade e poder. Associações que vislumbram a glorificação dos corpos em forma de admiração, expressão, exibição de força, saúde e beleza e em contrapartida também conduzem a um pensamento social hostil relativo a supremacia masculina. Essas associações transmitem algumas das possíveis relações e discursos estabelecidos pelo atlas de imagens e que contribuem para os novos modos de ver, ler e compreender a cidade de Maringá-PR. / This thesis aims to present a reflection of an open public space in order to awaken new ways of looking at and understanding the city from the image. This image enlarges the universe of knowledge about the place as a trans historical symbolic dimension, whose articulation with other images builds references of memory. This research is based on two moments: a first, where the perception acts as protagonist of the process of recognition of the city through ambulation, which resulted in the spatial clipping and the choice of an open public space present in the monumental axis of the city of Maringá -PR; and a second moment, where the association of images is used as a trigger for new possibilities of understanding the urban space. In this sense, methodological approaches of Aby Warburg (1866-1929), now recognized as the father of modern iconology, are adopted. Historian of the arts, he developed an Atlas of images - Mnemosyne - \"a History of Art without words\". The methodological approaches of this process propose to present a Mnemosyne assay. A perceptive tool to speak of images by images, using only panels, with combinations of images made between them, without the use of written language; and the relations established between the images articulate and produce modes of reading so as not to reveal their interrelationships. In this way, readers who have access to these panels can create new links and raise discussions without establishing closed connections. This allows new reading results, with each new reader contact, to be established, allowing for new experiences and new readings through the imaging panel. The visual relationships existing in the atlas panel are not only structured by historical readings, they organize in order to establish discoveries and discussions through the images, not being just a way of transmitting information. The atlas panel allows considerations of an initial process, driven and driven by images, which made it possible, above all, to create new deciphers of readings in front of the urban space in question, both based on individual and collective historical memory, both through meaning of each imagery representation. Thus, this thesis intends to verify new possibilities of methodological approaches, through the atlas tool - of analyzes of the spaces of the city, allowing a deepening in questions until then, discussed but not well founded, in order to awaken the creative process and instigate debates, revealed through images and their associations. Associations that represent a variety of conceptions and contributions, which at some point, history may have failed to tell, such as the idealization of the urban spaces of the city and the possible relations established with the subject. Also as a result of this associative process, one observes the subjective indications of visual and plastic characteristics, with conceptual approximations related to the first neolithic architectural constructions, referring to territorial and religious boundaries, representing strength, collectivity, authority and power. Associations that glimpse the glorification of bodies in the form of admiration, expression, display of strength, health and beauty, and in turn also lead to a hostile social thought concerning male supremacy. These associations transmit some of the possible relations and discourses established by the atlas of images and that contribute to the new ways of seeing, reading and understanding the city of Maringá-PR.

Le métabolisme cellulaire est la source principale d’énergie et les cellules cancéreuses ont un métabolisme différent des cellules non transformées. La cellule tumorale a tendance à éviter l’activité mitochondriale et ainsi la phosphorylation oxydative, pour lui préférer la voie de la glycolyse pour la production d’énergie (Effet Warburg). Cette altération du métabolisme est si bénéfique pour les cellules en croissance que cela favorise la croissance tumorale et supprime la réponse immunitaire anticancéreuse. La spécificité de ce métabolisme en fait une cible intéressante pour le développement de thérapies anticancéreuses. Mon travail de thèse comporte deux parties. La première partie décrit que lorsque les cellules cancéreuses sont forcées à utiliser la voie mitochondriale comme source d’énergie à travers l’oxydation phosphorylative, elles initient un mécanisme antioxydant pour tolérer les effets délétères des espèces oxygénées réactives (EOR ou ROS pour reactive oxygene species) produites au cours de l’activité mitochondriale. La stimulation mitochondriale entraîne l’activation de la voie de signalisation ERK5-MEF2, et cette dernière engendre un mécanisme antioxydant de deux façons.Initialement, nous avons observé que MEF2 régule positivement l’expression de miR23a, et ce dernier inhibe l’expression de KEAP1. Cette protéine est responsable de la dégradation ubiquitine dépendante de NRF2, un régulateur clé de la réponse antioxydante cellulaire. L’inhibition de KEAP1 empêche la dégradation cytoplasmique de NRF2. Consécutivement à cela la concentration cytoplasmique en NRF2 augmente ce qui engendre sa translocation dans le noyau où il se lie à une séquence élément de réponse antioxydant (ARE) dans la région promotrice de nombreux gènes antioxydants, initiant ainsi leur transcription. Plus tard nous avons observé que l’activation de la voie ERK5-MEF2 induisait directement la synthèse de novo de NRF2, induisant sa translocation nucléaire et un mécanisme antioxydant. L’inhibition de la voie ERK5-MEF2 altère la réponse antioxydante, sensibilisant ainsi les cellules au stress oxydant.La seconde partie de mon travail a exploré les mécanismes à l’origine des effets hypolipémiants du dichloroacétate (DCA). Le DCA est une petite molécule qui inhibe la PDK1 et permet au pyruvate d’entrer dans la mitochondrie. Il a été utilisé en clinique dans le passé pour baisser les taux plasmatiques de cholestérol mais le mécanisme n’était pas clair et nous l’avons décris. Le DCA force les cellules à entrer en oxydation phosphorylative ce qui active la voie ERK5-MEF2. Cette voie augmente directement l’expression du LDLR (Low Density Lipoprotein Receptor ; récepteur aux lipoprotéines de basse densité) qui permet l’endocytose des LDL riches en cholestérol qui sont responsables de la plupart des maladies cardiovasculaires. L’inhibition de cette voie supprime l’afflux de lipides et par conséquent serait une cible intéressante pour de futures recherches puisque de hauts taux de cholestérols sont directement corrélés avec une augmentation du risque d’athérosclérose et de toutes les complications mortelles qu’il entraine.Notre prochain objectif est d’explorer les autres mécanismes cellulaires régulés par la voie ERK5-MEF2. Sur la base de nos résultats préliminaires, nous proposons que cette voie non seulement régule l’expression du LDLR mais aussi celle de nombreux autres gènes qui sont impliqués directement ou indirectement dans le métabolisme des lipides. / Cellular metabolism is the main source of energy and cancer cells has different metabolism than non-transformed cells. Tumor cell tends to avoid mitochondrial activity and oxidative phosphorylation (OXPHOS) and prefer glycolysis for energy production (Warburg effect). This alteration in metabolism is beneficial for growing cells in many ways that promote tumor growth and suppress the anti-cancer immune response. This specific metabolism is an auspicious target for the better development of cancers chemotherapies.My thesis work comprises two parts. The first portion describes that when cancer cells are forced to utilize their mitochondria in order to obtain the energy from OXPHOS they initiate an antioxidant mechanism to cope with the deleterious effects of reactive oxygen species (ROS) produced during mitochondrial activity. Mitochondrial stimulation leads to activation of ERK5-MEF2 signaling pathway, which triggers the antioxidant mechanism by at least two ways.Initially we observed that MEF2 up regulates the expression of miR23a, which inhibits KEAP1 expression. This protein is responsible for ubiquitinational degradation of NRF2, a master regulator of the antioxidant response in cells. The inhibition of KEAP1 prevents the NRF2 cytoplasmic degradation. This results in high built up of NRF2 in cytoplasm that translocates to nucleus where it binds to ARE (antioxidant response element) in the upstream promoter region of many antioxidant genes hence initiates their transcription. Latter we observed that activation of ERK5-MEF2 pathway directly results in de novo synthesis of NRF2, resulting in nuclear translocation and triggering of the antioxidative mechanism. Inhibition of ERK5-MEF2 pathway impairs the cellular antioxidant response, thus sensitizing cells towards oxidative stress.The second part of my work explored the mechanism behind the lipid lowering effects of dichloroacetate (DCA). DCA is a small molecule, which inhibits the PDK1 and enables pyruvate to enter the mitochondria. It was used clinically in past to lower the plasma cholesterol level but the underlying mechanism was not clear and we describe it here. DCA forces cells to perform OXPHOS, which activate the ERK5-MEF2 pathway. This pathway directly up-regulates the expression of Low Density Lipoprotein Receptors (LDLR) that are mainly involved in the endocytosis of cholesterol-rich low density lipoproteins, which are responsible for the majority of cardiovascular diseases. Inhibition of this pathway suppresses lipid influx and hence, it would be an interesting target of future investigation since high cholesterol level is the main cause of various life threatening diseases and the development of atherosclerosis.Our next goal is to exploit other possible cellular mechanism regulated by ERK5-MEF2 pathway. Based on our preliminary data, we propose that this pathway not only regulate the LDLR expression but many other genes, which are directly or indirectly involved in lipid metabolism.

Warburg Micro syndrome is a severe autosomal recessive condition characterised by abnormalities affecting the ocular, neurological and endocrine systems. Previous studies have identified causative loss-of-function mutations in four members of the RAB protein network; RAB3GAP1, RAB3GAP2, RAB18 and TBC1D20, causing clinically indistinguishable phenotypes. RAB3GAP1 and RAB3GAP2 form a heterodimeric complex specifically regulating the RAB3 family of proteins in calcium mediated exocytosis of hormones and neurotransmitters. Rab3gap1 deficient mice have previously been generated and showed altered short term plasticity in the hippocampus and inhibition of Ca2+ mediated exocytosis of glutamate from cortical synaptosomes, but failed to recapitulate the characteristic ocular or neurological features of Warburg Micro syndrome. Mutations in TBC1D20, a GTPase activating protein (GAP) for the RAB1 family, have recently been identified in Warburg Micro syndrome patients and the bs (blind sterile) mouse model; although this model recapitulated many ocular and endocrine abnormalities of the disease any neurological abnormalities have yet to be reported. The function and localisation of RAB18 remains to be fully elucidated and its role in disease pathogenesis is still unclear. Initially, I have confirmed previous reports co-localising RAB18 with the cis-Golgi, ER and lipid droplets in mouse embryonic fibroblasts and identified a novel localisation in neuronal processes of primary hippocampal neurons. To examine the role of RAB18 in vivo a novel Rab18 genetrap mouse was generated by MRC Harwell as part of the EUMODIC screen. In this study I describe detailed histopathological and neurological characterisation of the Rab18-/- mouse model. Rab18-/- mice were viable and fertile. At eye opening they presented with dense nuclear congenital cataracts and atonic pupils recapitulating major ocular features of Warburg Micro syndrome. Analysis of embryonic eye development revealed a delay in lens development in Rab18-/- mice as early as embryonic day 12.5. From three weeks of age Rab18-/- mice developed progressive hind limb weakness indicative of neurological dysfunction. I have undertaken detailed neuropathological analysis of the observed hind limb weakness and identified no abnormalities in synaptic vesicle recycling and no atrophy of peripheral muscles or aberrant development or stability of neuromuscular connectivity. However, loss of RAB18 resulted in gross accumulations of neurofilament and microtubule proteins at the neuromuscular junction and disorganisation of the cytoskeleton in peripheral nerves. Investigation of global proteomic profiling in peripheral nerve of Rab18-/- mice identified alterations in core pathways regulating the axonal cytoskeleton in neurons. In summary this thesis describes a novel Rab18-/- mouse model recapitulating the characteristic ocular and neurological features of Warburg Micro syndrome. I highlight a novel mechanistic insight into Warburg Micro syndrome disease pathogenesis and a role for RAB18 in regulating cytoskeletal dynamics in neurons.

[pt] Fundador da iconologia, Aby Warburg (1866-1929) apresentou em 1923 a conferência intitulada Imagens do Território dos Pueblos na América do Norte, texto mais tarde conhecido como o Ritual da Serpente: Desde sua viagem aos Estados Unidos, em 1896, que teve um papel determinante na sua vida, se sentia profundamente grato aos etnólogos americanos... Em grande parte, foi graças às experiências que Warburg recolheu nos territórios indígenas que se tornou o historiador das imagens simbólicas que o Velho Mundo criou e que se perpetuam na Europa moderna. O presente trabalho busca um sentido satisfatório para estas afirmações de Fritz Saxl, primeiro discípulo de Warburg. Problematizando historicamente uma relação objetiva das idéias de Warburg com a antropologia americana - sobretudo através de Franz Boas -, tenta-se demonstrar que o tríptico warburguiano viagem-experiência-obra tem sido insuficientemente explorado partindo de sua relação com as amplas sínteses vitalistas - uma delas a aventura, aqui proposta à luz das idéias de Georg Simmel. / [fr] Fondateur de l iconologie, Aby Warburg (1866-1929) a présenté en 1923 la conférence intitulée Récit d un voyage en pays Pueblo, texte connu plus tard sous le nom de le Rituel du Serpent: Depuis son voyage aux États-Unis, en 1896, qui joua un rôle déterminant dans sa vie, il se sentait de profondes obligations envers les ethnologues américains... Pour une large part, c est grâce aux expériences que Warburg recueillit dans les territoires indiens, qu il est devenu l historien des images symboliques que le Vieux Monde a créées et qui se perpétuent dans l Europe moderne. Dans ce travail, nous chercherons à donner un sens approprié à ces affirmations de Fritz Saxl, premier disciple de Warburg. Problématisant historiquement une relation objective des idées de Warburg avec l anthropologie américaine - principalement à travers de Franz Boas -, nous remarquerons que le triptyque warburgien, voyage-expérience-oeuvre, n a pas été suffisamment exploré en partant de ses relations avec les synthèses vitalistes - l une d entre elles l aventure, ici proposée à la lumière des idées de Georg Simmel.

Toxoplasma gondii is an obligate intracellular parasite, that is able to infect any nucleated cell. An important global pathogen, T. gondii can cycle between primary and secondary hosts, thus enabling widespread penetrance. Within its intracellular niche – a membrane-bound parasitophorous vacuole – T. gondii is nevertheless able to subvert a variety of host cell processes to allow its continued survival and replication. This includes modulation of host signalling processes as well as the scavenging of nutrient macromolecules. In recent years, microRNAs have emerged as important regulators of cellular processes including inflammation, tumorigenesis and metabolism, as well as development. It has become increasingly clear that this species of non-coding RNA is of great importance in ‘fine tuning’ many cellular responses. I hypothesise in this work that host cell miRNAs may be yet another means by which T. gondii manipulates its host upon infection. Using high-throughput-sequencing, I examine host cell transcriptional responses to infection both at the mRNA and microRNA level, using two strains of T. gondii at a variety of Multiplicities of Infection over a time course of 43 hours. Through these transcriptional analyses I identify a number of dysregulated pathways common in tumorigenesis, and contemplate the hypothesis that T. gondii may be behaving as an ‘intracellular tumour’, subverting host cell metabolic processes to mimic a long-known feature of cancer metabolism – that of aerobic glycolysis (the Warburg effect) – in order to satisfy its own energetic and metabolic needs.

Ductal carcinoma in situ (DCIS) has been shown to be a precursor to invasive ductal cancer (IDC). Though the progression of DCIS to IDC is believed to be an important aspect of tumor aggressiveness, prognosis and molecular markers that predict progression are poorly understood. Therefore, determining the mechanisms by which some DCIS progress is critical for future breast cancer diagnostics and treatment. Singleminded-2s (SIM2s) is a member of the bHLH/PAS family of transcription factors and a key regulator of differentiation. SIM2s is highly expressed in mammary epithelial cells and lost in breast cancer. Loss of Sim2s causes aberrant mouse mammary development with features suggestive of malignant transformation, whereas over-expression of Sim2s promotes precocious alveolar differentiation, suggesting that Sim2s is required for establishing and enhancing mammary gland differentiation. We hypothesize that SIM2s expression must be lost in premalignant lesions for breast cancer to develop. We first analyzed Sim2s in the involuting mammary gland, which is a highly tumorpromoting environment. Sim2s is down-regulated during involution, and forced expression delays involution. We then analyzed SIM2s expression in human breast cancer samples and found that SIM2s is lost with progression from DCIS to IDC, and this loss correlates with metastasis. SIM2s expression in DCIS promoted a differentiated phenotype and suppressed genes associated with de-differentiation. Furthermore, loss of SIM2s expression in DCIS xenografts increased metastasis likely due to an increase in hedgehog signaling and matrix metalloproteinase expression. Interestingly, we found metabolic shifts with gain and loss of SIM2s in not only DCIS cells, but also MCF7 and SUM159 cells. SIM2s expression decreased aerobic glycolysis and promoted oxidative phosphorylation through direct upregulation of CDKN1a and senescence. Loss of SIM2s, conversely, promotes mitochondrial dysfunction and induction of the Warburg effect. This is the first time CDKN1a and cellular senescence have been indicated as causative to metabolic shifts within cancer cells. These studies show a new role for SIM2s in metabolic homeostasis, and this regulation is lost during tumorigenesis. These data indicate SIM2s is at the apex where aging, metabolism, and disease meet – regulating the delicate relationship between the three.

There exists a profound need for biomarkers that will allow for better screening and risk stratification for colorectal cancer (CRC). With the advent of the newly termed "metabolic syndrome", CRC prevalence is trending upwards even with much improved screening protocols and remains the second leading cause of cancer related morbidity. The "metabolic syndrome" refers to a range of environmental risk factors, including diabetes and obesity, thought to be increasing the prevalence of CRC. An altered metabolism is seen in metabolic syndrome, which affects cancer through changes in the relationship between glycolysis, the Krebs cycle, and mitochondrial oxidative phosphorylation (OXPHOS). Specifically, it has been observed that highly proliferative tumorigenic cells are undergoing a shift away from the energy efficient OXPHOS and toward aerobic glycolysis even under normoxic conditions. This effect has been termed, the Warburg Effect. As a consequence of endogenous (e.g. genetic, diabetes etc.) and exogenous (e.g. diet, smoking etc.) factors, alterations in cell proliferation/death have been shown to occur throughout the colon reflecting the diffuse "field of injury" (field carcinogenesis). Also due to high energy demands it is recognized that the hyper-proliferative mucosa contiguous to colonic tumors may be hyper-metabolic. Our group has been interested in elucidating the biological nature of field carcinogenesis and assesses expression of key metabolic markers in the rectal biopsies from patients who harbor neoplasia elsewhere in their colon. We found key indications of a glycolytic shift toward aerobic glycolysis with upregulation of glucose transporter (GLUT1) as well as pyruvate shunting away from OXPHOS via pyruvate kinase muscle 2 (PKM2). These changes were further corroborated by an increase in hypoxia inducible factor 1 alpha (HIF1alpha), which is normally seen to increase glycolytic function in hypoxic conditions. Along with these glycolytic changes we also found mitochondrial dysfunction in patients with adenomas. Specifically, mitochondrial mass was found to be increased, with increases in mtDNA as well as upregulation of mitochondrial fusion via optic atrophy 1 (OPA1). Uncoupling protein 2, which decouples OXPHOS from ATP synthesis in the mitochondria, was also found to be upregulated. These findings represent a novel panel of biomarkers for assessing CRC risk via analysis of metabolic dysfunction in the easily accessible rectal epithelium.

Seven genes involved in metabolism were tested as direct targets of the Notch signalling pathway. For each gene the occupancy of its enhancers by Su(H), its transcriptional response to Notch pathway and its biological functionality was verified in vitro and in vivo.

Dissertação (mestrado)—Universidade de Brasília, Instituto de Artes, Programa de Pós-Graduação em Arte, 2017. / Submitted by Raquel Almeida (raquel.df13@gmail.com) on 2017-08-14T16:48:59Z No. of bitstreams: 1 2017_AnaLúciaTaveira.pdf: 3126828 bytes, checksum: 4b6423448a884467aa7ccf3585a1eca0 (MD5) / Approved for entry into archive by Raquel Viana (raquelviana@bce.unb.br) on 2017-10-02T14:09:58Z (GMT) No. of bitstreams: 1 2017_AnaLúciaTaveira.pdf: 3126828 bytes, checksum: 4b6423448a884467aa7ccf3585a1eca0 (MD5) / Made available in DSpace on 2017-10-02T14:09:58Z (GMT). No. of bitstreams: 1 2017_AnaLúciaTaveira.pdf: 3126828 bytes, checksum: 4b6423448a884467aa7ccf3585a1eca0 (MD5) Previous issue date: 2017-10-02 / A realização desta pesquisa tem o propósito de formar uma antologia, por meio de um recorte intencional, de algumas fotografias da Coleção Joaquim Paiva, a maioria das quais presentes no Museu de Arte Moderna do Rio de Janeiro. O corpus escolhido se reúne à luz das vinculações entre fotografia e antropologia. Para tanto, consideramos os aspectos antropológicos da imagem, isto é, a carga simbólica da imagem que sobrevive ao tempo, que Aby Warburg nomeia Nachleben. Finalmente, pretendo que tal antologia fotográfica e de cunho antropológico possa adquirir potencial para uma exposição virtual, destinada a diversos perfis etnográficos, contribuindo assim para uma ampliação da pesquisa sobre a historiografia da fotografia brasileira. / The purpose of this research is to offer an anthology of some photographs of the Joaquim Paiva Collection, most of all from Rio de Janeiro’s Museum of Modern Art. The corpus was chosen because of the linkages between photography and anthropology. For this, we consider the anthropological aspects of the image, that is, the symbolic load of the image that survives to time, which Aby Warburg names Nachleben. Finally, I propose that this anthropological and photographic anthology can acquire the potential for a virtual exhibition, destined to several ethnographic profiles, contributing to a broader research on the historiography of Brazilian photography.