No description available.

One mechanism of plasticity within the adult mammalian brain is the dynamic process of adult neurogenesis that is functionally important in physiological and pathological conditions. During this process, neurons develop from adult neural stem cells (NSCs) via intermediate neural progenitors (NPCs) through several processes including proliferation, survival, differentiation, migration and integration. Despite neurogenesis during development sharing these same processes, there is growing evidence highlighting unique mechanisms that regulate adult versus embryonic neurogenesis. The studies in this thesis test the cell-intrinsic function of genes that have defined roles in embryonic neurogenesis and undefined roles in adult hippocampal neurogenesis using a combination of transgenic inducible mice and in vivo retroviral techniques. The first study examines the microtubule associated protein Doublecortin (DCX), which is transiently expressed by NPCs and is critical for neuronal migration. Our results show that, in the context of adult hippocampal neurogenesis, DCX is not required for the survival or differentiation of the NPCs within the subgranular zone (SGZ). The second study examines the functional role of the autophagy-associated gene 5 (Atg5) which is critical for embryonic neurogenesis and survival. Our findings demonstrate that the intracellular recycling process of autophagy is active throughout maturation of adult hippocampal NPCs and that ablation of Atg5 produces a drastic reduction in NPC survival, without altering the neuronal fate of these cells. The third study examines the requirement of the familial-Alzheimer’s disease associated genes, presenilin 1 and presenilin 2 (PS1 & PS2), which are critical for embryonic NSC maintenance and differentiation. Similar to the findings with DCX, our results demonstrate that presenilins are dispensable for adult neurogenesis. Altogether, these studies add to the growing evidence suggesting differences in the regulation of adult versus embryonic neurogenesis, and highlight autophagy as a novel regulator of survival for adult generated granule neurons in the hippocampus.

Given the high salinity, prevailing annual high temperatures, and ultra-oligotrophic conditions in the Red Sea isolation and characterization of important microbial groups thriving in this environment is important in understanding the ecological significance and metabolic capabilities of these communities. By using a high-­throughput cultivation technique in natural seawater amended with minute amounts of nutrients, members of the rare biosphere (PS1), methylotrophic Betaproteobacteria (OM43), and the ubiquitous and abundant SAR11 group (Pelagibacterales), were isolated in pure culture. Phylogenetic analyses of Red Sea isolates along with comparative genomics with close representatives from disparate provinces revealed ecotypes and genomic differentiation among the groups. Firstly, the PS1 alphaproteobacterial clade was found to be present in very low abundance in several metagenomic datasets form divergent environments. While strain RS24 (Red Sea) harbored genomic islands involved in polymer degradation, IMCC14465 (East (Japan) Sea) contained unique genes for degradation of aromatic compounds. Secondly, methylotrophic OM43 bacteria from the Red Sea (F5, G12 and H7) showed higher similarities with KB13 isolate from Hawaii, forming a ‘H-­RS’ (Hawaii-­Red Sea) cluster separate from HTCC2181 (Oregon isolate). HTCC2181 members were shown to prevail in cold, productive coastal environments and had an nqrA-­F system for energy generation by sodium motive force. On the contrary, H-­RS cluster members may be better adapted to warm and oligotrophic environments, and seem to generate energy by using a proton-­translocating NADH:Quinone oxidoreductase (complex I; nuoA-­N subunits). Moreover, F5, G12, and H7 had unique proteins related to resistance to UV, temperature and salinity, in addition to a heavy metal ‘resistance island’ as adaptive traits to cope with the environmental conditions in the Red Sea. Finally, description of the Red Sea Pelagibacterales isolates from the Ia (RS39) and Ib (RS40) subgroups, principally revealed unique putative systems for iron uptake and myo-inositol utilization in RS39, and a potential phosphonates biosynthetic pathway present in RS40. The findings presented here reflect how environments influence the genomic repertoire of microbial communities and shows novel metabolisms and putative pathways as unique adaptive qualities in diverse microbes encompassing from rare to predominant bacterioplankton groups from the Red Sea.

No description available.

Yes / A key aim of Alzheimer disease research is to develop efficient therapies to prevent and/or delay the irreversible progression of cognitive impairments. Early deficits in long-term potentiation (LTP) are associated with the accumulation of amyloid beta in rodent models of the disease; however, less is known about how mGluR-mediated long-term depression (mGluR-LTD) is affected. In this study, we have found that mGluR-LTD is enhanced in the APPswe /PS1dE9 mouse at 7 but returns to wild-type levels at 13 months of age. This transient over-activation of mGluR signalling is coupled with impaired LTP and shifts the dynamic range of synapses towards depression. These alterations in synaptic plasticity are associated with an inability to utilize cues in a spatial learning task. The transient dysregulation of plasticity can be prevented by genetic deletion of the MAP kinase-activated protein kinase 2 (MK2), a substrate of p38 MAPK, demonstrating that manipulating the mGluR-p38 MAPK-MK2 cascade at 7 months can prevent the shift in synapse dynamic range. Our work reveals the MK2 cascade as a potential pharmacological target to correct the over-activation of mGluR signalling. / Wellcome Trust, Grant/Award Number: 200646/Z/16/Z

Depuis quelques années, les oligomères du peptide Aβ sont identifiés comme étant responsables du déclenchement de la pathologie alors que les dépôts amyloïdes sont des conséquences aggravantes de la pathologie. Cependant, les formes oligomériques d’Aβ impliquées dans la pathologie ainsi que l’origine de ces peptides sont toujours débattues. Notre objectif principal était d’identifier des signatures Aβ oligomériques cérébrales et vasculaires et de déterminer si nous pouvions interférer avec ces signatures pour modifier le décours de la pathologie. Nous avons réalisé des analyses biochimiques qualitative des formes d’Aβ dans des échantillons de cerveau et de vaisseaux issus de patients atteints de la MA et de souris transgéniques modèle de la MA. Nous avons montré qu’une même forme Aβ oligomérique (17-18 kDa) est impliquée dans le développement de la pathologie cognitive chez l’homme et chez la souris APP/PS1. Une signature Aβ oligomérique vasculaire spécifique a été observée dans les vaisseaux périphériques et plus particulièrement la veine porte hépatique des souris APP/PS1. De plus, un traitement pharmacologique ciblant l’expression des protéines de transport de l’Aβ a permis de restaurer les profils Aβ oligomériques contrôles dans le cerveau des souris APP/PS1 tout en « chargeant » la veine porte des mêmes souris en Aβ oligomérique. Ces résultats montrent que les signatures Aβ vasculaires et cérébrales sont intimement liées. De plus, nos travaux mettent l’accent sur une possible intervention thérapeutique agissant sur les formes Aβ cérébrales et vasculaires. / Alzheimer's disease (AD) is a complex disorder of the central nervous system that affects an increasing number of people worldwide due to the overall aging of the human population. Vascular factors and mechanisms have emerged as an area of key importance. Accumulating evidence indicates that pre-fibrillar aggregates, specifically the low-molecular weight oligomers of Aβ peptide, are responsible for the synaptic dysfunction and neuronal loss that occur in AD pathology. But, these oligomeric forms implicated in the pathology are currently under debate. Our primary goal was to identify cerebral and vascular oligomeric signatures. Secondly, we try to interfere with these signatures in order to modify the evolution of AD. We realize qualitative analyses of cerebral and vascular oligomers Aβ by western-blot. Vascular and cerebral tissues were extracted from AD patients and from a transgenicmouse model of AD. We demonstrate that the same oligomer Aβ (17-18 kDa) is implicated in the cognitive impairment for patients and APP/PS1 mouse. A specific vascular signature of oligomer Aβ was detected in peripheral vessels and particularly in portal vein from liver of APP/PS1 mouse. Moreover, pharmacological treatment targeting clearance of soluble Aβ restored the control signature of oligomer Aβ in the brain of APP/PS1 mouse. This configurational change was associated with an increase of oligomer Aβ in portal vein from liver. These results show that cerebral and vascular oligomeric signatures were closely linked. Finally, our work emphasizes potential therapeutic strategies for AD by targeting cerebrals and vasculars oligomers Aβ.

A pesquisa aborda o movimento dos espaços alternativos de arte contemporânea observado em Nova Iorque (EUA), nas décadas de 1960 e 1970, com foco no PS1 lnstitute of Contemporary Ar/, inaugurado em 1976. Embora sua criação abarque características latentes do modelo dos espaços alternativos, logo indicou uma progressão inevitável rumo à institucionalização desses espaços, cujos padrões administrativos se afastaram de suas concepções e ideias mais experimentais. Ainda que alguns autores classifiquem o PS1 como antimuseu\", não tardou para que este centro de arte contemporânea fosse incorporado ao tradicional Museu de Arte Moderna de Nova Iorque - MoMA-NY. Com isso, o PS1 adentra o mainstream da arte sob o título de MoMA-PS1, oficialmente em 2010. A abordagem discorre sobre o objeto de estudo como resultado de manifestações artísticas que contribuem na mudança de convenções estabelecidas no sistema da arte. Essas manifestações incluem a prática de apropriação da arquitetura como tema da criação artística. Assim, este trabalho contribui para fomentar novas interpretações na análise crítica do projeto de arquitetura para espaços expositivos de arte, instalados em edifícios não projetados para um fim museológico. / The research addresses the movement of alternative spaces for contemporary art seen in New York (USA), in the 1960s and 1970s, focusing on the PS11nstitute of Contemporary Art, opened in 1976. Though his creation comprises /atent characteristics of the model of the alternative spaces, soon it indicated an inevitable progresswn bound for the institutionalization of these spaces, whose administrative standards have drifted away from their conceptions and more experimental ideas. Even though some authors c!assify the PS1 as \"antimuseum \", soon this contemporary art center was incorporated into the traditional Museum of Modem Art of New York- MoMA-NY. Thus, the PS 1 enters the mainstream of art under the title of MoMA-PS1, officially in 201 O. The approach discusses the object of study as a result of artistic events that contribute to the change of conventions established in the art system. These events include the practice of architecture appropriation as theme for artistic creation. 7his work contributes to fostering new interpretations on critica/ analysis of the architectural project for exhibition spaces of art instal/ed in buildings not designed for Museum purpose.

A pesquisa aborda o movimento dos espaços alternativos de arte contemporânea observado em Nova Iorque (EUA), nas décadas de 1960 e 1970, com foco no PS1 lnstitute of Contemporary Ar/, inaugurado em 1976. Embora sua criação abarque características latentes do modelo dos espaços alternativos, logo indicou uma progressão inevitável rumo à institucionalização desses espaços, cujos padrões administrativos se afastaram de suas concepções e ideias mais experimentais. Ainda que alguns autores classifiquem o PS1 como antimuseu\", não tardou para que este centro de arte contemporânea fosse incorporado ao tradicional Museu de Arte Moderna de Nova Iorque - MoMA-NY. Com isso, o PS1 adentra o mainstream da arte sob o título de MoMA-PS1, oficialmente em 2010. A abordagem discorre sobre o objeto de estudo como resultado de manifestações artísticas que contribuem na mudança de convenções estabelecidas no sistema da arte. Essas manifestações incluem a prática de apropriação da arquitetura como tema da criação artística. Assim, este trabalho contribui para fomentar novas interpretações na análise crítica do projeto de arquitetura para espaços expositivos de arte, instalados em edifícios não projetados para um fim museológico. / The research addresses the movement of alternative spaces for contemporary art seen in New York (USA), in the 1960s and 1970s, focusing on the PS11nstitute of Contemporary Art, opened in 1976. Though his creation comprises /atent characteristics of the model of the alternative spaces, soon it indicated an inevitable progresswn bound for the institutionalization of these spaces, whose administrative standards have drifted away from their conceptions and more experimental ideas. Even though some authors c!assify the PS1 as \"antimuseum \", soon this contemporary art center was incorporated into the traditional Museum of Modem Art of New York- MoMA-NY. Thus, the PS 1 enters the mainstream of art under the title of MoMA-PS1, officially in 201 O. The approach discusses the object of study as a result of artistic events that contribute to the change of conventions established in the art system. These events include the practice of architecture appropriation as theme for artistic creation. 7his work contributes to fostering new interpretations on critica/ analysis of the architectural project for exhibition spaces of art instal/ed in buildings not designed for Museum purpose.

The current thesis investigated a potential relationship between Alzheimer disease and type-2 diabetes mellitus by analysing early gene expression related to insulin receptor signalling in the hippocampus as well as glucose metabolism in APP/PS1 mice, a model of familial Alzheimer disease. Compared to wild-type animals, a reduction in hippocampal insulin receptor and insulin-receptor substrate 2 transcripts in APP/PS1 mice three-month old as well as an increase in insulin-like growth factor 2 transcripts after six months was detected using real-time polymerase chain reaction. The alterations in hippocampal insulin signalling were accompanied by perturbation of glucose metabolism analysed by intraperitoneal glucose tolerance test. At the age of six months APP/PS1 mice developed glucose intolerance. Learning and recognition memory in APP/PS1 mice were tested using the Novel Object Recognition Test. Cognitive decline became evident in APP/PS1 mice at six months of age. Degradation of both insulin and amyloid β is mediated through insulin-degrading enzyme. However, expression of insulin-degrading enzyme in APP/PS1 mice was notdifferent from wild-type littermates. Changes in hippocampal phosphorylation of the tau phosphoepitopes serine 199, threonine 205, serine 396 and serine 404 were investigated using Western blot. Levels of three phosphoepitopes were increased significantly at either age.IV Protein expression of the phosphorylated form of glycogen synthase kinase 3β remained unchanged indicating an alternative pathway of tau phosphorylation in the APP/PS1 mouse model of familial Alzheimer disease. The current results demonstrate an increase in cyclin-dependant kinase 5 phosphoralyted at tyrosine 15 in APP/PS1 mice at three and six months of age. The correlation between elevated levels of phosphorylated tau and cyclin-dependant kinase 5 suggests that cyclin-dependant kinase 5 might contribute to tau phosphorylation in APP/PS1 mice. In general, this work corroborates common pathologic features in Alzheimer disease and diabetes mellitus. A significant cognitive decline in APP/PS1 mice was associated with changes in early gene expression of insulin-related molecules and perturbations in glucose metabolism. Cyclin-dependant kinase 5 is considered to coregulate tau phosphorylation in APP/PS1 mice, and to be part of a pathway contributing to pathology in Alzheimer disease

Prostate cancer is the most common cancer in men, with the incidence rapidly increasing in Europe over the past two decades. Reliable biomarkers for prostate cancer are currently unavailable. Thus, there is an urgent need for improved biomarkers to diagnose prostate cancer at an early stage and to determine the best treatment options. Higher expression of transforming growth factor-β (TGFβ) has been reported in patients with aggressive cancer. TGFβ is a multifunctional cytokine that acts as a tumor suppressor during early tumor development, and as a tumor promoter at later stages of cancer. TGFβ signals through the canonical Smad or non-Smad cascade via TGFβ type II and type I receptors. The TGFβ signaling cascade is regulated by various post-translational modifications of its key components. The present investigation aimed to identify a potential function of TRAF6 in TGFβ-induced responses in prostate cancer. The first two articles of this thesis unveil the proteolytic cleavage of TGFβ type I receptor (TβRI), and the biological importance of the liberated TβRI intracellular domain (TβRI-ICD) in the nucleus. We found that tumor necrosis factor receptor-associated factor 6 (TRAF6) polyubiquitinates TβRI, which leads to cleavage of TβRI by tumor necrosis factor alpha converting enzyme (TACE) in a protein kinase C zeta (PKCζ)-dependent manner. Following ectodomain shedding, TβRI undergoes a second cleavage by presenilin 1 (PS1), which liberates TβRI-ICD. TβRI-ICD translocates to the nucleus, where it regulates its own expression as well as expression of the pro-invasive gene Snail1, thereby promoting invasion. We further found that TβRI-ICD associates with Notch intracellular domain (NICD) to drive expression of the pro-invasive gene Snail1, as well as Notch1 ligand Jag1. The third article provides evidence that TRAF6 promotes Lys63-linked polyubiquitination of TβRI at Lys178 in a TGFβ-dependent manner. TβRI polyubiquitination was found to be a prerequisite for TβRI nuclear translocation, and thus for regulation of the genes involved in cell cycle, differentiation, and invasion of prostate cancer cells. In the fourth article we investigated the role of the pro-invasive gene Snail1 in TGFβ-induced epithelial-to-mesenchymal transition (EMT) in prostate cancer cells.