Thesis (Ph.D.) -- University of Texas Southwestern Medical Center at Dallas, 2005. / Embargoed. Vita. Bibliography: 118-133.

Accumulation of misfolded proteins and alterations in calcium homeostasis induces endoplasmic reticulum (ER) stress, leading to apoptosis. In this study, we tested the hypothesis that β-AR stimulation induces ER stress, and induction of ER stress plays a pro-apoptotic role in cardiac myocytes. Using thapsigargin and brefeldin A, we demonstrate that ER stress induces apoptosis in adult rat ventricular myocytes (ARVMs). β-AR-stimulation (isoproterenol; 3h) significantly increased expression of ER stress proteins, such as GRP-78, Gadd-153, and Gadd-34, while activating caspase-12 in ARVMs. In most parts, these effects were mimicked by thapsigargin. β-AR stimulation for 15 min increased PERK and eIF-2α phosphorylation. PERK phosphorylation remained higher, while eIF-2α phosphorylation declined thereafter, reaching to ∼50% below basal levels at 3 h after β-AR stimulation. This decline in eIF-2a phosphorylation was prevented by β1-AR, not by β2-AR antagonist. Forskolin, adenylyl cyclase activator, simulated the effects of ISO on eIF-2α phosphorylation. Salubrinal (SAL), an ER stress inhibitor, maintained eIF-2α phosphorylation and inhibited β-ARstimulated apoptosis. Furthermore, inhibition of caspase-12 using z-ATAD inhibited β-AR-stimulated and thapsigargininduced apoptosis. In vivo, β-AR stimulation induced ER stress in the mouse heart as evidenced by increased expression of GRP-78 and Gadd-153, activation of caspase-12, and dephosphorylation of eIF-2α. SAL maintained phosphorylation of eIF-2α, inhibited activation of caspase-12, and decreased β-AR-stimulated apoptosis in the heart. Thus, β-AR stimulation induces ER stress in cardiac myocytes and in the heart, and induction of ER stress plays a pro-apoptotic role.

Innovation and entrepreneurship are buzzwords that fit any policy discussion on economic development. In this sense, innovation is not only a category of analysis employed by (social) scientists to circumscribe a defined set of economic practices for analytical purposes. Innovation is simultaneously a category of practice employed by practitioners and academics with their own, sometimes concealed, political agendas. Providing a situated sketch for a socio-spatially more attuned definition of innovation as a category of analysis, the article primarily asks what kind of innovation practices are imagined and / or enacted by both academic and policy circles. Thus, the article aims at scrutinizing the politics involved in thinking, doing, and relating innovation in the context of Armenia’s and Georgia’s quest for viable economic trajectories. We assess the legal and organizational framework in both countries and funding patterns of Georgia’s Innovation and Technology Agency (GITA) and Armenia’s Enterprise Incubator Foundation (EIF). Locational analysis of grant holders suggests company concentration within metropolitan areas of Tbilisi and Yerevan. Analysis of selection criteria of funding program allows for the assertion that a developmentalist project is advanced. Rather than reifying the actors’ language of innovation, we wish to highlight that current imaginations and practices of innovation are analytically better understood through the concept of “internationalized developmentalist agglomeration project”.

Las enfermedades de etiología viral destacan por ser el principal factor limitante de las hortalizas. La estrategia más eficaz para el control consiste en la identificación de genes de resistencia y el posterior desarrollo de variedades resistentes. El principal objetivo de esta tesis se centra en el aprovechamiento y la caracterización de la variabilidad genética de las especies cultivadas del género Capsicum (C. annuum, C. chinense, C. frutescens, C. baccatum y C. pubescens). Se ha puesto a punto una plataforma de EcoTILLING que permite un cribado eficiente de la colección de entradas de Capsicum del Banco de Germoplasma del COMAV. Esta plataforma se exploró para la búsqueda de variantes alélicas de los genes eIF4E y eIF(iso)4E, implicados en la resistencia a virosis. Una colección de 31 entradas que representan distintas combinaciones de los alelos eIF4E y eIF(iso)4E se inocularon mecánicamente con el Potato virus Y (PVY) y el Tobacco etch virus (TEV). Cinco nuevas variantes del gen eIF4E (pvr210, pvr211, pvr212, pvr213, pvr214) están relacionadas con la respuesta de resistencia al PVY y al TEV. Diez microsatélites y cuatro combinaciones de AFLPs se utilizaron para caracterizar 260 entradas del género Capsicum. Se detectó la existencia de cierta estructuración intraespecífica relacionada geográficamente. C. baccatum y C. pubescens muestran un par de grupos genéticos, por un lado están las entradas procedentes de Bolivia y por el otro las entradas de Ecuador y Perú. Además, las entradas de C. chinense procedentes de Perú pudieron ser diferenciadas del resto. En este estudio las entradas de Ecuador y Perú han mostrado una diversidad elevada y similar a las de Bolivia, el cual es un importante centro de diversidad del género Capsicum. Por tanto, las entradas procedentes de estos países podrán constituir fuentes importantes de variación para ser utilizadas en los programas de mejora del pimiento. / Ibiza Gimeno, VP. (2011). Nuevas herramientas en la lucha contra las virosis del pimiento [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/11549

L'arrivée de Hitler au pouvoir et la mise en œuvre de la politique du IIIème Reich provoquent l'arrivée en France de plusieurs vagues successives de réfugiés provenant d'Allemagne et de tous les pays nouvellement conquis par le nazisme. Lyon, véritablecitadelle contre l'obscurantisme, allait s'élever comme un rempart pour les protéger et venir en aide aux nouveaux arrivants, parmi lesquels les Juifs.Le 26 août 1942, 1016 juifs étrangers, entrés en France après le 1er janvier 1936, des dix départements de la Région de Lyon, situés en zone dite libre, avaient été arrêtés et dirigés au camp de Vénissieux, situé dans la proche banlieue de Lyon, par les forces de police et de gendarmerie françaises afin d'être livrés par Vichy à l'occupant nazi. En utilisant la couverture de l'Amitié Chrétienne et grâce au soutien des membres résistants des services de Vichy, des combattants sans armes et de toutes obédiences, qui avaient déjà entrepris d'autres actions de sauvetage et qui se connaissaient, participèrent au travail de la commission de criblage de Vénissieux afin de plaider chaque dossier des internés dans un sens favorables aux exemptions.Trois jours plus tard, le 29 août 1942, 545 d'entre eux ont été conduits à la gare de St Priest pour être livrés à l'occupant en vue de leur déportation à Auschwitz tandis que les 470 restants viennent d'être libérés dont une centaine d'enfants, et prennent le chemin de la liberté. Ceux que nous avons pu retrouver nous livrent le récit de cet épisode tragique.L'affaire emblématique de Vénissieux restera dans l'histoire de la Shoah en France comme la plus grande opération de sauvetage entreprise dans un camp en France. Elle a été le résultat d'une conjonction d'éléments favorables saisis avec brio par les meilleurs du sauvetage, des résistants sans arme membres des œuvres charitables de toutes confessions qui agirent de concert avec Gilbert LESAGE du Service des Etrangers (SSE) et sous le couvert de l'Amitié Chrétienne avec l’appui du Service Social d'Aide aux Etrangers (SSAE), en coopération avec des membres de l'œuvre de Secours aux Enfants (OSE) et avec le soutien des Eclaireurs Israélites de France (EIF), du Consistoire, des rabbins. / The arrival of Hitler to power and the installation of the policy of the 3rd Reich lead to the arrival in France of several successive waves of refugees coming from Germany and all the countries conquered by the Nazis. Lyon, a real citadel against obscurantism , was going to rise like a rampart to protect them and come to the rescue of the newcomers, among them the Jews.On August 26th, 1942, 1016 foreign Jews, who arrived in France after January 1st, 1936, of the ten departments of the area of Lyon, located in the so called "free zone", had been arrested by the French police and sent to the Vénissieux camp, located in the outskirts of Lyon, in order to be handed over to the nazi occupant.Under the cover of the Christian Friendship and thanks to the help of the resistant members inside the Vichy regime, fighters without weapons and of all denominations, who had already undertaken other rescue actions and who knew each other, took part in the screening commission in Vénissieux, in order to save as many internees as possible. Three days later, on August 29th, 1942, 545 prisoners where led to the train station of St Priest, handed over to the occupant and deported to Auschwitz, while 470 others, among which 100 children, and set off to freedom.The survivors we could find after the war, gave us the account of this epic. Still, the emblematic case of Vénissieux, will remain in the history of the Shoah in France. It was the result of an environment of favourable elements seized with brilliance by the best of the rescuers, unarmed partisans, members of charitable organisations of all faiths who acted in liaison with Gilbert LESAGE from the SSE ( Service des Etrangers ) and under the cover of the Christian Frienship together with the SSAE (Service Sociald’Aide aux Etrangers), in cooperation with members of the OSE (Oeuvre de Secours aux Enfants ) and the help of the Eclaireurs Israélites de France, the Consistoire and rabbis.

Phosphorylation of the alpha-subunit of the eukaryotic initiation factor 2 (eIF2alpha) on Serine 51 (Ser51) is an early event associated with downregulation of protein synthesis at the level of translation and constitutes a potent mechanism to overcome various stress conditions. In mammals, four eIF2alpha-kinases PERK, PKR, HRI and GCN2, activated following specific stresses, have been involved in this process. Our laboratory has previously demonstrated that the adaptor protein Nck, composed only of Src homology domains and classically implicated in cell signaling by activated plasma membrane receptor tyrosine kinases, modulates translation through its interaction with the beta-subunit of the eukaryotic initiation factor 2 (eIF2beta). Moreover, we reported that Nck-1 overexpression antagonizes the inhibition of translation in endoplasmic reticulum stress condition and prevents the PERK-mediated phosphorylation of the alpha-subunit of eIF2 on Ser51. In this thesis, I demonstrate that the adaptor protein Nck-1 modulates eIF2alpha-kinase-mediated eIF2alphaSer51 phosphorylation in a specific manner. More particularly, I show that Nck-1 overexpression reduces eIF2alpha phosphorylation in conditions activating PKR or HRI as described previously for PERK. In contrast, I observe that overexpression of Nck-1 in mammalian cells fails to attenuate eIF2alphaSer51 phosphorylation in response to amino acid starvation, a stress condition activating GCN2. I further confirm this observation by showing that Nck-1 fails to alter eIF2alphaSer51 phosphorylation in Saccharomyces cerevisiae, for which the sole eIF2alpha-kinase is GCN2. In addition, I report that Nck-1 reduces PKR activation in response to dsRNA. I also find that Nck-1 reduces dsRNA-induced activation of p38 MAPK, a PKR-downstream substrate, and cell death. Finally, I show that Nck-1 interacts exclusively with the inactivated form of PKR in a Src homology domain independent manner. All together these data uncover the existence of a novel mechanism regulating phosphorylation of eIF2alphaSer51 under various stress conditions and identifies Nck-1 as a modulator of the tumor suppressor and antiviral protein kinase PKR.

No description available.

No description available.

No presente estudo, foram selecionados 33 pacientes infectados com HCV genótipo 3a, tratados com IFN e Ribavirina, incluindo pacientes cirróticos (C) e não-cirróticos (NC), respondedores (R) e não-respondedores (NR). Foi realizado o seqüenciamento das regiões E2 e NS5A do genoma do HCV. As seqüências geradas foram analisadas quanto a presença de mutações para correlacionarmos com a resposta virológica sustentada ao tratamento e com a presença de cirrose. Na análise estatística as mutações na região E2 não apresentaram diferença significante. As mutações conservadoras encontradas nas regiões NLS e V3 da NS5A apresentaram diferença significante. Estudos funcionais envolvendo a proteína NS5A são necessários para que possamos avaliar o valor preditivo das mutações conservadoras e não-conservadoras encontradas na NS5A / The aim of this study was to analyse the sequences of fragments of E2 and NS5A regions from 33 outpatients infected with HCV genotype 3, including cirrhotic (C) and non-cirrhotic (NC) patients that have responded (R) or not (NR) to treatment. In the E2 region, we did observe few amino acids changes between patients without statistical significance. In the NLS region and in V3 domain, we found conservatives mutations with statistical significance. In conclusion, our results confirm that the ISDR domain is not predictive for treatment success in patients infected with HCV genotype 3. The carboxy-terminal region and especifically V3 domain region showed most of variations. Structure-function studies are required to identify precisely how NS5A and IFN interact

No presente estudo, foram selecionados 33 pacientes infectados com HCV genótipo 3a, tratados com IFN e Ribavirina, incluindo pacientes cirróticos (C) e não-cirróticos (NC), respondedores (R) e não-respondedores (NR). Foi realizado o seqüenciamento das regiões E2 e NS5A do genoma do HCV. As seqüências geradas foram analisadas quanto a presença de mutações para correlacionarmos com a resposta virológica sustentada ao tratamento e com a presença de cirrose. Na análise estatística as mutações na região E2 não apresentaram diferença significante. As mutações conservadoras encontradas nas regiões NLS e V3 da NS5A apresentaram diferença significante. Estudos funcionais envolvendo a proteína NS5A são necessários para que possamos avaliar o valor preditivo das mutações conservadoras e não-conservadoras encontradas na NS5A / The aim of this study was to analyse the sequences of fragments of E2 and NS5A regions from 33 outpatients infected with HCV genotype 3, including cirrhotic (C) and non-cirrhotic (NC) patients that have responded (R) or not (NR) to treatment. In the E2 region, we did observe few amino acids changes between patients without statistical significance. In the NLS region and in V3 domain, we found conservatives mutations with statistical significance. In conclusion, our results confirm that the ISDR domain is not predictive for treatment success in patients infected with HCV genotype 3. The carboxy-terminal region and especifically V3 domain region showed most of variations. Structure-function studies are required to identify precisely how NS5A and IFN interact