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Une mémoire émotionnelle normale se base sur la sélection de stimuli prédictifs d’un événement important pour l’individu. Cependant, ce processus de sélection peut être compromis en situation de forte intensité émotionnelle. En particulier, la sélection d’un élément saillant non nécessairement prédictif, associée à une amnésie de type déclaratif pour les éléments contextuels, caractérise les altérations mnésiques de l’état de stress post-traumatique (ESPT). Les données de la littérature suggèrent que l’action de glucocorticoïdes dans l’hippocampe serait l’une des causes possibles du développement de troubles mnésiques de type ESPT. Nos travaux ont porté sur les conditions dans lesquelles les glucocorticoïdes dans l’hippocampe peuvent altérer les fonctions mnésiques chez la souris.En utilisant des procédures de conditionnement classique aversif, nous montrons que l’injection post-apprentissage de corticostérone dans l’hippocampe dorsal, en situation de forte intensité émotionnelle, conduit (1) à une sélection incorrecte du stimulus saillant non prédictif du choc électrique au détriment des éléments contextuels (2) et à des dysfonctionnements d’activité neuronale au sein du circuit hippocampo-amygdalien (expression de c-Fos). De façon intéressante, par une action sur le même type de récepteurs (aux glucocorticoïdes, GR), l’injection de corticostérone dans l’hippocampe ventral conduit également à un processus incorrect de sélection du stimulus prédictif mais en faveur des éléments contextuels. Enfin, un apprentissage en labyrinthe radiaire révèle que l’injection de corticostérone dans l’hippocampe dorsal altère spécifiquement la mémoire relationnelle, analogue de la mémoire déclarative humaine, uniquement chez les animaux ayant été au préalable exposés à un stress.L’ensemble de nos données révèlent qu’un excès de glucocorticoïdes dans l’hippocampe contribue (1) à des déficits de mémoires émotionnelle et relationnelle, (2) à la sélection inadaptée de stimuli non prédictifs d’un événement aversif (3) reposant sur des dysfonctionnements du circuit hippocampo-amygdalien, le tout, correspondant à des altérations mnésiques de type ESPT. / Normal emotional memory is based on the selection of cues predicting threatening events. However, exposure to extreme threatening situation can compromise the selection of the correct cues. In particular, selection of a salient not necessarily predictive cue, associated with declarative amnesia for peritraumatic contextual cues, characterizes the memory disturbances of posttraumatic stress disorder (PTSD). Accumulating evidence suggest that action of glucocorticoids into the hippocampus could be a potential mechanism for PTSD-related memory disturbances. Hence, we studied the conditions for which glucocorticoids into the hippocampus can alter memory functions in mice.Using Pavlovian fear conditioning, we showed that post-training infusion of glucocorticoids in the dorsal hippocampus, in stressful situation, resulted in (1) selection of a salient non predictive cue instead of contextual cues and in (2) dysfunctions of neural activity of the hippocampal-amygdalar circuit (c-Fos expression). Interestingly, via action on the same receptor subtype (glucocorticoid receptors, GR), infusion of glucocorticoids in the ventral hippocampus also resulted in incorrect selection of predictive cue but in favor of contextual cues. Finally, using radial-maze task, we showed that infusion of glucocorticoids in the dorsal hippocampus specifically impaired relational declarative-like memory, only in mice previously exposed to stress.Altogether, our findings reveal that excess glucocorticoids in the hippocampus contributes to (1) deficits in emotional and relational memories, (2) incorrect selection of predictive cues (3) based to dysfunctions of the hippocampal-amygdalar circuit, all, corresponding to PTSD-related memory disturbances.

Les lésions hépatiques observées au cours de l'obésité (NAFLD, stéatopathie non alcoolique) s'étendent de la stéatose isolée à la stéatohépatite (NASH, stéatohépatitie non alcoolique), la fibrose, la cirrhose et au carcinome hépatocellulaire. L'identification des mécanismes de recrutement des cellules immunitaires par le foie stéatosique est une étape clé dans la compréhension du déclenchement de l'inflammation hépatique et la recherche de nouvelles cibles thérapeutiques. Au cours de l’obésité, la stéatose sensibilise le foie au lipopolysaccharide (LPS), qui active la voie pro-inflammatoire NFκB. Nous avons récemment montré que: 1) la stéatose induisait une augmentation du recrutement lymphocytaire (TCD4+, TCD8+ et B) vers le foie mais également une augmentation de la réponse des lymphocytes TCD4+ à la chimiokine CXCL12 (SDF-1α), dont le récepteur est CXCR4 ; 2) GILZ (Glucocorticoid-Induced Leucine Zipper), une protéine induite par les glucocorticoïdes (GCs), inhibait la voie NFkB et jouait un rôle clé dans l’inflammation hépatique au cours de la consommation excessive d’alcool.Le but de ce travail était d’étudier les mécanismes de l’inflammation hépatique liée à l’obésité. Au cours de mon travail, nous avons montré que le chimiotactisme des lymphocytes TCD4+ à la chimiokine CXCL12 était augmenté non seulement chez les souris obèses mais également chez des patients ayant une NASH. L’augmentation de l’effet chimiotactique de CXCL12 était due à une augmentation de l’affinité de CXCL12 à son récepteur CXCR4. La migration anormale des lymphocytes T CD4+ vers le foie stéatosique était réversible pharmacologiquement en inhibant la liaison de CXCL12 à CXCR4 par AMD3100 (antagoniste deCXCR4). Le déficit d’expression et l’altération de l’induction du facteur anti-inflammatoire GILZ dans les cellules des Kupffer des souris obèses étaient responsables de la sensibilisation de ces cellules au LPS. Cette altération était liée à la diminution de l’expression du récepteur aux glucocorticoïdes (GR) dans les cellules de Kupffer des souris obèses. La surexpression de GILZ dans l’obésité en utilisant des souris trangéniques restaurait la tolérance hépatique au LPS. Ces anomalies des lymphocytes TCD4+ et de l’expression de GILZ dans les cellules de Kupffer participent au déclenchement d’une inflammation hépatique sur un foie stéatosique et pourraient représenter de nouvelles cibles thérapeutiques / Non alcoholic fatty liver disease (NAFLD) includes a spectrum ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma. The identification of the mechanisms involved in the recruitment of immunity cells by the fatty liver is a key in the comprehension of the onset of liver and the finding of new therapeutic targets. In obesity, steatosis sensitizes the liver to the lipopolysaccharide (LPS) from the gastrointestinal tract and the NFkB pro-inflammatory pathway is activated. We recently showed that: 1) the steatosis led to an increase recruitment of lymphocytes (TCD4+, TCD8+ and B) by the liver but also an hyperresponsive of CD4+T cells to CXCL12 (SDF-1"), the ligand of CXCR4; 2) GILZ(Glucocorticoid-Induced Leucine Zipper), a protein induced by glucocorticoids (GCs), inhibits the nuclear factor kB pathway and plays a key role in alcoholic hepatitis.This aim of my work was to study the mechanisms involved in obesity-related liver inflammation.I demonstrated that the chemotaxis of CD4+T cells to CXCL12 was increased not only in obese mice but also in patients with NASH. This increased chemotactisme of CXCL12 was due to an increase of the affinity ofCXCL12 to its receptor. The abnormal migration of CD4+T lymphocytes to the fatty liver was reversible by pharmacologically inhibiting the binding of CXCL12 to CXCR4 using AMD3100.The decreased expression and the impairment of the induction of the anti-inflammatory factor GILZ in Kupffer cells from obese mice was responsible for a sensitization of these cells to LPS. This impairment was due to a decrease of the glucocorticoid receptor (GR) expression in Kupffer cells from obese mice. The overexpression of GILZ level in obese transgenic mice restored the liver tolerance to LPS. These abnormalities of CD4+T lymphocytes and the GILZ expression in Kupffer cells contribute to the onset of liver inflammation in obesity and may represent new therapeutic targets.

Thesis (Ph.D. (Space Physics)--North-West University, Potchefstroom Campus, 2008.

Thesis (Ph.D. (Space Physics)--North-West University, Potchefstroom Campus, 2008.

Thesis (Ph.D. (Space Physics)--North-West University, Potchefstroom Campus, 2008.

Made available in DSpace on 2015-03-03T15:28:32Z (GMT). No. of bitstreams: 1 ManassesPN_DISSERT.pdf: 2146671 bytes, checksum: a562634d1e686680a598403ed93762dd (MD5) Previous issue date: 2010-05-17 / Two-level factorial designs are widely used in industrial experimentation. However, many factors in such a design require a large number of runs to perform the experiment, and too many replications of the treatments may not be feasible, considering limitations of resources and of time, making it expensive. In these cases, unreplicated designs are used. But, with only one replicate, there is no internal estimate of experimental error to make judgments about the significance of the observed efects. One of the possible solutions for this problem is to use normal plots or half-normal plots of the efects. Many experimenters use the normal plot, while others prefer the half-normal plot and, often, for both cases, without justification. The controversy about the use of these two graphical techniques motivates this work, once there is no register of formal procedure or statistical test that indicates \which one is best". The choice between the two plots seems to be a subjective issue. The central objective of this master's thesis is, then, to perform an experimental comparative study of the normal plot and half-normal plot in the context of the analysis of the 2k unreplicated factorial experiments. This study involves the construction of simulated scenarios, in which the graphics performance to detect significant efects and to identify outliers is evaluated in order to verify the following questions: Can be a plot better than other? In which situations? What kind of information does a plot increase to the analysis of the experiment that might complement those provided by the other plot? What are the restrictions on the use of graphics? Herewith, this work intends to confront these two techniques; to examine them simultaneously in order to identify similarities, diferences or relationships that contribute to the construction of a theoretical reference to justify or to aid in the experimenter's decision about which of the two graphical techniques to use and the reason for this use. The simulation results show that the half-normal plot is better to assist in the judgement of the efects, while the normal plot is recommended to detect outliers in the data / Os experimentos fatoriais 2k s?o muito utilizados na experimenta??o industrial. Contudo, quanto maior o n?mero de fatores considerados maior ser? a quantidade de provas necess?rias para a execu??o de um experimento, e realizar replica??es dos tratamentos pode ser invi?vel, considerando as limita??es de recursos e de tempo, tornando tal experimento dispendioso. Nestes casos, s~ao utilizados os fatoriais 2k n?o replicados. Mas, sem replica??oo, n?o ? poss?vel obter uma estimativa direta da variabilidade do erro experimental para se avaliar a signific^ancia dos efeitos. Uma das poss?veis solu??es para este problema ? utilizar os gr?fificos normal ou semi-normal dos efeitos. Muitos pesquisadores usam o gr?fifico normal, ao passo que outros preferem o semi-normal e, em muitas vezes, para ambos os casos, sem alguma justificativa. A controv?rsia sobre o uso destas duas t?cnicas gr?ficas ? o que motiva a realiza??o do presente trabalho, uma vez que n?o h? registro de procedimento formal ou teste estat?stico que indique \qual delas ? melhor". A escolha entre os dois gr?fificos parece ser uma quest~ao subjetiva. O objetivo central desta disserta??o ?, ent?o, realizar um estudo comparativo experimental dos gr?fificos normal e semi-normal no contexto da an?lise dos experimentos fatoriais 2k n?o replicados. Tal estudo consiste na constru??o de cen?rios simulados, nos quais o desempenho dos gr?fificos em detectar os efeitos significativos e identificar valores discrepantes ? avaliado com o intuito de verificar as seguintes quest?es: Um gr?fifico pode ser melhor que o outro? Em que situa??es? Que informa??es um gr?fifico acrescenta ? an?lise do experimento que possam complementar aquelas fornecidas pelo outro gr?fifico? Quais as restri??es no uso de cada gr?fifico? Com isso, prop?e-se confrontar estas duas t?cnicas; examin?-las simultaneamente a fim de conhecer semelhan?as, diferen?as ou rela??es que possam contribuir para a constru??o de um referencial te?rico que sirva como um subs?dio para justificar ou auxiliar na decis~ao do pesquisador sobre qual das duas t?cnicas gr?fificas utilizar e o porqu^e deste uso. Os resultados das simula??es mostram que o gr?fifico semi-normal ? melhor para auxiliar no julgamento dos efeitos, ao passo que o gr?fifico normal ? recomendado para detectar a presen?a de valores discrepantes nos dados

Submitted by Automa??o e Estat?stica (sst@bczm.ufrn.br) on 2018-03-12T18:58:57Z No. of bitstreams: 1 FidelHenriqueFernandes_DISSERT.pdf: 1091767 bytes, checksum: e62c7343dd6383ea93795ea06d1fe95d (MD5) / Approved for entry into archive by Arlan Eloi Leite Silva (eloihistoriador@yahoo.com.br) on 2018-03-16T14:34:02Z (GMT) No. of bitstreams: 1 FidelHenriqueFernandes_DISSERT.pdf: 1091767 bytes, checksum: e62c7343dd6383ea93795ea06d1fe95d (MD5) / Made available in DSpace on 2018-03-16T14:34:02Z (GMT). No. of bitstreams: 1 FidelHenriqueFernandes_DISSERT.pdf: 1091767 bytes, checksum: e62c7343dd6383ea93795ea06d1fe95d (MD5) Previous issue date: 2018-02-20 / A s?rie temporal ? uma cole??o de observa??es medidas sequencialmente ao longo do tempo, sendo estudadas com profunda notoriedade nos ?ltimos anos juntamente com o controle estat?stico de processo. O presente trabalho objetiva estudar o desempenho dos gr?ficos de controle CUSUM e Shewhart na detec??o de m?dias do processo com infla??o ou defla??o de zeros atrav?s do modelo autorregressivo de valores inteiros geom?trico zero modificado de primeira ordem [ZMGINAR(1)]. Nesse sentido, analisa-se ainda a sensibilidade atrav?s de simula??es, o n?mero m?dio de amostras que excedem o limite de controle (NMA), al?m disso, novos estimadores foram propostos afim de verificar, atrav?s do estudo de Monte Carlo, o comportamento dos estimadores atrav?s do erro quadr?tico m?dio (EQM) e vi?s em diferentes cen?rios, os estimadores propostos se mostraram mais eficazes. No que concerne a simula??o, os diferentes cen?rios apresentados com infla??o e defla??o de zeros, o CUSUM mostrou-se mais eficiente no cen?rio com defla??o de zeros e o de Shewhart com infla??o de zeros em determinados casos. Nessa inst?ncia, considerou-se duas aplica??es, uma com infla??o de zeros e outra com defla??o de zeros. Assim como na simula??o, o CUSUM ? melhor no cen?rio com defla??o de zeros e o Shewhart com infla??o de zeros. O grande diferencial deste trabalho ? a apari??o da defla??o de zeros modelada nos gr?ficos de controle, al?m disso o modelo a ser trabalhado possui distribui??o marginal conhecida diferentemente de outros modelos, o que ? uma vantagem na implementa??o e constru??o de novos estimadores, acrescido a isso, considera-se ainda as estimativas dos par?metros por diversos m?todos: M?xima Verossimilhan?a, Yule-Walker e o estimador baseado em Probabilidade.