Dissertations / Theses on the topic 'Neuronal NOS'
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1
Papale, Davide. "Oxygen activation during neuronal NOS reaction." Thesis, University of Edinburgh, 2008. http://hdl.handle.net/1842/12755.
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Nitric oxide synthase (NOS) catalyzes nitric oxide (NO) production in a two step reaction. The first step involves L-arginine being oxidised to NG-hydroxy-L-arginine (NOHA) that remains bound to the enzyme before it is oxidised to NO and L-citrulline in the second step. The three mammalian isozymes are homodimeric enzymes and each subunit is composed of a reductase and an oxygenase domain. The oxygenase domain contains the arginine binding site, one cysteine ligated heme thiolate, and one H4B molecule ((6R)-5,6,7,8-Tetrahydrobiopterin). The enzyme’s substrates are O2, L-arginine (or NOHA) and NADPH. H4B is an essential cofactor for NO production by NOS and its roles are in dimerization and as redox cofactor. The mechanism of the reaction between L-arg and oxygen in the active site is currently uncertain. Therefore in order to alter the course of the reaction site-directed mutagenesis was conducted: Glycine 586 of nNOS was replaced by a serine residue (G586S nNOSoxy) and expressed and purified from E.coli. Stopped flow kinetic experiments showed the formation of a novel reaction intermediate during G586S nNOSoxy catalysis in the presence of H4B and substrate, subsequent to the formation of the oxy-ferrous compound. It is suggested that the new intermediate is formed as a transient along the path of the NO production reaction and has spectroscopic resemblance to the putative P450 active species, the oxy-ferryl compound. Crystals of the G586S mutant have been obtained and the solved x-ray structure shows the newly introduced serine residue pointing toward the guanidinium group of L-arg, reinforcing its involvement in the stabilization of a reaction intermediate.
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Sobolewska-Stawiarz, Anna. "Probing the dynamics and conformational landscape of neuronal nitric oxide synthase." Thesis, University of Manchester, 2014. https://www.research.manchester.ac.uk/portal/en/theses/probing-the-dynamics-and-conformational-landscape-of-neuronal-nitric-oxide-synthase(82903814-5474-42e3-9339-d9a7a98ead6d).html.
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Rat neuronal nitric oxide synthase (nNOS) is a flavo-hemoprotein that catalyses the NADPH and O2-dependent conversion of L-arginine (L-arg) to L-citrulline and nitric oxide (NO) via the intermediate N-hydroxyarginine. nNOS is a homodimer, where the subunits are modular and are comprised of an N-terminal oxygenase domain (nNOSoxy) that binds iron protoporphyrin IX (heme), (6R)-5,6,7,8-tetrahydro-biopterin (H4B) and L-arg, and a C-terminal flavoprotein or reductase domain (nNOSred) that binds NADPH, FAD and FMN. Regulation of NO biosynthesis by nNOS is primarily through control of interdomain electron transfer processes in NOS catalysis. The interdomain electrons transferred from the FMN to the heme domain are essential in the delivery of electrons required for O2 activation (which occurs in the heme domain) and the subsequent NO synthesis by NOS. Both spectroscopic and kinetic approaches have been used in studying the nature and control of interdomain electron transfer, reaction mechanism and structural changes during catalysis in WT and R1400E nNOS in both full length (FL) and nNOSred. Cytochrome c reduction activity of nNOS was used to determine kinetic parameters for NADPH for FL and nNOSred, WT and R1400E nNOS in the presence and absence of calmodulin (CaM). FL nNOS, where both domains (nNOSred and nNOSoxy) were present, was proven to be more stable and more catalytically efficient than nNOSred by itself. Additionally it was observed that R1400E is still promoting electron transfer despite being thought to lower the affinity of the enzyme to the substrate (NADPH); R1400E also showed lower catalytic efficiency and lower dependence on CaM/Ca2+ compared to the WT. The structure of the functional output state has not yet been determined. In the absence of crystallographic structural data for the NOS holoenzyme, it was important to experimentally determine conformational changes and distances between domains in nNOS. A pulsed EPR spectroscopy (PELDOR) approach has been utilised to gain important and unique information about the conformational energy landscape changes in nNOS. In the presence of CaM, PELDOR results for FL WT nNOS shows a complex energy landscape with multiple conformational states, while in the absence of CaM the interflavin distance distribution matches that exhibited by nNOSred CaM- in the presence of NADP+, suggesting that CaM binding affects some major large-scale conformational changes which are involved in internal electron transfer control in nNOS. A high-pressure stopped-flow technique was also used to perturb an equilibrium distribution of conformational states, to observe the effect of the pressure on the internal electron transfer and to study the kinetics of NADPH oxidation, flavin reduction by NADPH and NO formation. It was shown that high pressure is forcing major changes in the conformational energy landscape of the protein, affecting internal electron transfer. NO formation studies under pressure show that the R1400E mutation in FL nNOS may be affecting protein/NADPH affinity and flavin reduction, but it has no effect on the heme reduction step.
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Nardi, Geisson Marcos. "Óxido nitrico proveniente da isoforma neuronal da enzima óxido nítrico sintase (NOS-1)." Florianópolis, SC, 2011. http://repositorio.ufsc.br/xmlui/handle/123456789/95541.
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Tese (doutorado) - Universidade Federal de Santa Catarina, Centro de Ciências Biológicas, Programa de Pós-Graduação em Farmacologia, Florianópolis, 2011Made available in DSpace on 2012-10-26T03:11:53Z (GMT). No. of bitstreams: 1 295312.pdf: 1743921 bytes, checksum: 5721b330602424fbe65211dfbf890383 (MD5)
Vários estudos demonstraram que produção excessiva de NO, relacionada com o aumento da expressão da NOS-2, contribui para as alterações hemodinâmicas observadas durante a sepse. No entanto, alguns trabalhos mostram que a inibição desta enzima não reverte a hipotensão, a hiporeatividade a agentes vasoconstritores e não influencia na sobrevivência de animais sépticos. Portanto, resolvemos investigar o papel do NO proveniente da isoforma neuronal da óxido nítrico sintase (NOS-1) sobre a reatividade a agentes vasoconstritores, e sua influência na progressão da sepse bem como o efeito de agonistas opióides sobre parâmetros comumente avaliados nesta doença. Nossos resultados demonstram que animais sépticos são sensíveis a analgesia com drogas opióides em modelo de dor por estímulo térmico e, além disso, os analgésicos opióides reduziram a hipotensão e hiporeatividade vascular induzidas pela sepse. Estes compostos quando administrados em doses baixas não interferiram na sobrevivência de animais sépticos, enquanto que doses maiores aumentam a mortalidade. A inibição da NOS-1 melhorou a reatividade vascular a agonistas e -adrenérgicos, tanto na fase inicial quanto na fase tardia da sepse. Tanto a NOS-1 quanto a guanilato ciclase solúvel tem sua expressão aumentada nas camadas de músculo liso vascular da aorta e do leito vascular mesentérico, e nos momentos mais tardios, ambas as enzimas interagem fisicamente no leito vascular mesentérico. Parte do mecanismo de reversão da hiporeatividade a agonistas -adrenérgicos, após inibição da NOS-1, se deve a redução na formação de GMPc. No entanto, a reversão da hiporeatividade vascular a agentes -adrenérgicos durante a sepse pelo 7-NI parece ser independente do aumento nos níveis de cAMP. As alterações promovidas pelo NO proveniente da NOS-1 no início da sepse estão relacionadas com a instalação da hipotensão, disfunção vascular, alterações na glicemia e nos níveis de leucócitos sanguíneos. A redução do conteúdo enzimático da NOS-1, reduz ou abole as alterações patológicas induzidas pela sepse. Nosso trabalho demonstra que o NO proveniente da NOS-1 participa ativamente na disfunção vascular promovida pela sepse.
Several studies have shown that overproduction of NO, associated with the increased expression of NOS-2, contributes to the hemodynamic changes observed in sepsis. However, inhibition of NOS-2 does not reverse hypotension, hyporesponsiveness to vasoconstrictor and does not influence the survival of septic animals. Therefore, we decided to investigate the role of NO derived from the neuronal isoform of nitric oxide synthase (NOS-1) on the reactivity to vasopressor agents and the progression of sepsis as well as the effect of opioid agonists on parameters commonly evaluated in this pathology. Our results demonstrate that septic animals are sensitive to analgesia with opioids in the pain model of thermal stimulation. In addition, opioids reduced the hypotension and vascular hyporesponsiveness induced by sepsis. When administered in low doses these drugs did not affect the survival of septic animals, whereas higher doses increased the mortality. The inhibition of NOS-1 improved the vascular reactivity to and -adrenergic agonists, both in early and late phase of sepsis. The expression of NOS-1 and soluble guanylate cyclase was increased in vascular smooth muscle layers of aorta and mesenteric vascular bed and both enzymes interact physically in the mesenteric vascular bed in late phase of sepsis. At least part of the mechanism of the recovery in the responsiveness to adrenergic agonists, after inhibition of NOS-1, is due to the reduced formation of cGMP. The changes promoted by NOS-1-derived NO in early sepsis are associated with the onset of hypotension, vascular dysfunction and changes in blood glucose levels and blood leukocytes. The reduction in the NOS-1 enzyme content reduces or abolishes the pathological changes induced by sepsis. Our work demonstrates that NOS-1-derived NO plays a role in promoting vascular dysfunction in sepsis.
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Coelho, Camila Henriques. "Análise da inibição da óxido nítrico sintase neuronal (nNOS) na liberação de vasopressina durante sepse experimental." Universidade de São Paulo, 2009. http://www.teses.usp.br/teses/disponiveis/60/60135/tde-30102009-022744/.
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A fisiopatologia da sepse se caracteriza por hipotensão acompanhada de aumento da secreção de vasopressina (AVP) na fase inicial e diminuição numa fase mais tardia. Essa hipotensão é em parte devido ao aumento da quantidade de óxido nítrico, que juntamente com outros mediadores tem sua produção aumentada durante a sepse. A óxido nítrico sintase (NOS) é responsável pela síntese deste mediador, e sua isoforma neuronal (nNOS) está presente no músculo esquelético, pulmões, testículos, próstata, pele e também nos neurônios vasopressinérgicos do hipotálamo. O presente trabalho avaliou a participação do óxido nítrico produzido pela isoforma neuronal de NOS sobre a secreção temporal de AVP durante a sepse experimental. Ratos Wistar receberam injeção i.p. de 7-nitroindazol (50mg/kg ou 80mg/kg), inibidor específico da NOS neuronal, ou DMSO 10% + óleo de gergelim na proporção 1:9 (veículo) e após 30 minutos foram submetidos ao estímulo séptico por ligadura e perfuração cecal (CLP) ou à operação fictícia (OF). Em um grupo de animais, a sobrevida foi avaliada durante 5 dias. Em outro grupo, os animais foram decapitados 0, 4, 6, 18 e 24 horas após a cirurgia e o sangue processado para determinação do hematócrito, sódio sérico, osmolalidade, proteínas, glicose, creatinina, nitrato sérico e AVP plasmática. A neurohipófise foi removida para a determinação do conteúdo de AVP, e o hipotálamo dissecado para a determinação da atividade da NOS total. A mortalidade observada após CLP não foi modificada com o pré-tratamento com 7-NI (50mg/kg), assim como os aumentos temporais de hematócrito, glicose e nitrato sérico observados. As proteínas plasmáticas e o sódio sérico apresentaram diminuição após CLP e o pré-tratamento com 7-NI antecipou a perda proteica e postergou a diminuição do sódio sérico. Os animais após CLP não apresentaram alterações de creatinina e osmolalidade, entretanto quando prétratados com 7-NI, apresentaram aumento em 6 e 18 horas e diminuição a partir de 4hs, respectivamente. A atividade da NOS total no hipotálamo aumentou nos tempos determinados de 4 e 24 horas após CLP e este aumento foi reduzido com o prétratamento com o 7-NI nas doses de 50 e 80mg/kg, respectivamente. O conteúdo neurohipofisário de AVP diminuiu em 4, 6 e 18 horas após CLP e o pré-tratamento com 7-NI reduziu os estoques apenas em 0 e 6 horas. As concentrações plasmáticas de vasopressina apresentaram-se aumentadas sómente 6 horas após CLP e o pré-tratamento não alterou essas concentrações. Esses resultados permitem concluir que o NO produzido pela NOS neuronal não teria uma tarefa substancial na secreção de vasopressina durante sepse experimental.The pathophysiology of sepsis is caracterized by hypotension accompanied by increase of vasopressin secretion (AVP) in early phase and decrease during late phase. This hypotension is due, in part, to the increase of nitric oxide (NO) production, that, like other mediators, shows high production during sepsis. Nitric oxide synthase (NOS) is responsible by synthesis of NO. The neuronal isoform of NOS is present in skeletic muscle, testicles, prostate, skin and vasopressinergics neurons of hypothalamus. The present work evaluated the participation of nitric oxide produced by neuronal NOS in temporal vasopressin secretion during experimental sepsis. Rats Wistar received intraperitoneal injection of 7-nitroindazole (50 or 80 mg/kg), an inhibitor of neuronal nitric oxide synthase activity, or DMSO 10% + sesame oil in the proportion 1:9 (vehicle) and after 30 minutes, they were submited to septic stimulus by cecal ligation and puncture (CLP) or to sham operation. In one of the groups, the survival rate was evaluated during 5 days. In other group, the animals were decapited 0, 4, 6, 18 and 24 hours after CLP and the blood was processed to determinate haematocrit, serum sodium, osmolality, proteins, glucose, creatinine, serum nitrate, and plasma AVP. Neurohypophysis was removed to determination of vasopressin content, and hypotalamus was dissected to determinate total NOS activity. Mortality observed after CLP was not affected by periferal injection of 7-nitroindazole (50 mg/kg) as well as haematocrit, glucose and nitrate increase. Serum sodium and plasma protein decreased after CLP and the treatment antecipated the loss protein, and delayed serum sodium decrease. CLP animals didn\'t show creatinine and osmolality alterations, but when treated with 7-nitroindazole, showed increase 6 and 18 hours, and decrease 4 hours, respectively. NOS activity in hypothalamus increased 4 and 24 hours after CLP, and was reduced with 7-NI pretreatment (50 and 80 mg/kg respectively). AVP neurohypophysis content diminished 4, 6 and 18 hours after CLP and 7-NI reduced the content just at 0 and 6 hours. Vasopressin plasma concentration increased just 6 hours after CLP and 7-NI pretreatment didn\'t alter this parameter. We concluded that NO produced by neuronal NOS doesn\'t have a substantial role in vasopressin secretion during experimental sepsis.
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Kirsten, Gabriela Pena Chaves. "O receptor canabinóide CB1 nos núcleos da base e a sua participação no processo degenerativo em modelos da Doença de Parkinson." Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/42/42137/tde-20092013-093533/.
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Os receptores canabinóides CB1 são abundantemente expressos nos núcleos da base (NB), sugerindo a participação do sistema canabinóide na Doença de Parkinson (DP). Os objetivos deste estudo foram investigar a localização do CB1 nos NB de ratos; avaliar o decurso temporal de sua expressão e de marcadores neuronais em modelo experimental da DP in vivo, e avaliar os efeitos do tratamento com compostos canabinóides em modelos experimentais da DP in vivo e in vitro. Nossos resultados mostraram que o CB1 é predominantemente expresso em neurônios GABAérgicos nos NB. A lesão dopaminérgica produziu mudanças temporais distintas da expressão do CB1 nas estruturas dos NB. O tratamento com o agonista canabinóide ACEA agravou à lesão dopaminérgica e o desempenho comportamental motor. Por outro lado, o tratamento com o antagonista AM 251, embora não tenha gerado diferenças neuroquímicas, gerou melhoras nos testes comportamentais. Por fim, em nosso modelo in vitro, o tratamento com inibidor de recaptação da anandamida AM 404 gerou uma discreta redução dos níveis de morte celular.Cannabinoid receptors CB1 are abundantly expressed in the basal ganglia (BG), suggesting the involvement of the cannabinoid system in Parkinson\'s disease (PD). The objectives of this study were to investigate the location of CB1 in BG of rats; evaluate the time course expression of CB1 and neuronal markers in an experimental model of PD in vivo, and evaluate the effects of treatment with cannabinoids compounds in experimental models of PD in vivo and in vitro. Our results showed that CB1 is predominantly expressed in GABAergic neurons in BG. The dopamine lesion produced distinct temporal changes in the expression of CB1 in BG structures. Treatment with the cannabinoid agonist ACEA aggravated the dopaminergic lesion and the motor behavioral performance. Moreover, the treatment with the antagonist AM 251, although have not generated neurochemical changes,it promoted improvements in behavioral tests. Finally, in our in vitro model, the treatment with Anandamide transport inhibitor AM 404 led to a slight reduction in the levels of cell death.
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Mari, Renata de Britto. "Efeitos da alimentação com diferentes níveis calóricos nos neurônios mioentéricos do cólon de ratos Wistar durante o processo de envelhecimento." Universidade de São Paulo, 2009. http://www.teses.usp.br/teses/disponiveis/10/10132/tde-10082010-160611/.
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Os últimos anos se caracterizaram pelo aumento significativo da população idosa mundial. Por esta razão, a preocupação com o idoso está se tornando uma constante em nossa sociedade, uma vez que o envelhecimento resulta em comprometimento das funções fisiológicas, acompanhado ou não de alterações estruturais. No trato gastrointestinal (TGI), o processo de envelhecimento pode provocar alterações morfofuncionais significativas. A regulação da motilidade do TGI é controlada principalmente pelos neurônios mioentéricos do sistema nervoso entérico. A diminuição na densidade destes neurônios no cólon pode levar à redução na frequência e na amplitude da contração colônica manifestada como constipação. As ações que visam diminuir os efeitos do envelhecimento no TGI incluem aquelas relacionadas à dieta alimentar, entre as quais se destaca a restrição calórica. A restrição calórica, além de apresentar efeito protetor nos neurônios mioentéricos durante o envelhecimento, também é responsável pela diminuição da morte neuronal por apoptose, processo este acentuado com o envelhecimento. Assim sendo, este trabalho teve por objetivo avaliar os efeitos de diferentes níveis de restrição calórica sobre a plasticidade dos neurônios mioentéricos NADPH e acetilcolinesterase positivos do cólon de ratos Wistar durante o processo de envelhecimento por meio das análises ultraestrutural (microscopia eletrônica de transmissão) e morfoquantitativa. Para tanto foram utilizados 40 ratos machos (Rattus norvegicus), da linhagem Wistar, distribuídos em quatro grupos (n= 10/grupo): CI- animais de seis meses; SR- animais de 18 meses alimentados com dieta normal; RCI- animais de 18 meses alimentados com dieta com 12% de restrição calórica; RCII- animais de 18 meses submetidos à restrição calórica de 30%. Aos seis meses de idade, os animais foram transferidos para o biotério setorial, onde permaneceram até aos 18 meses sob condições ambientais controladas de temperatura e de iluminação e água ad libitum. Foi possível observar que a RC em nível de 30% minimizou de forma eficaz os efeitos deletérios do envelhecimento nos neurônios mioentéricos, podendo ser adotada como alternativa contra os distúrbios gastrointestinais comuns em indivíduos idosos.The last years were characterized by a significant increase in the elderly population. For this reason, concern for the elderly is becoming a constant in our society, since the aging results in impairment of bodily function, or not accompanied by structural changes. In the gastrointestinal tract (GI), the aging process can cause significant morphological changes. The regulation of motility of the gut is controlled mainly by myenteric neurons of the enteric nervous system. The decrease in the density of neurons in the colon can lead to a reduction in the frequency and amplitude of contraction expressed as colonic constipation. The actions aimed at reducing the effects of aging on the GI system include those related to diet, among which stands out caloric restriction. Caloric restriction, and have a protective effect on the myenteric neurons during aging, is also responsible for the decrease of neuronal death by apoptosis, a process accentuated with aging. Thus, this study was to evaluate the effects of different levels of calorie restriction on the plasticity of myenteric neurons NADPH and acetylcholinesterase positive of the colon of rats during the aging process by means of ultrastructural (transmission electron microscopy) and morphoquantitative analysis. Therefore, we used 40 male Wistar rats (Rattus norvegicus), divided into four groups (n = 10): CI- animals six months; SR- animals 18 month fed a normal diet; RCI - animals 18 months fed a diet with 12% caloric restriction; RCII- animals 18 months fed a diet with 30% caloric restriction. At six months, the animals were transferred to the vivarium sector, where they remained up to 18 months under controlled conditions of temperature and light and water ad libitum. It was observed that the RC level of 30% effectively minimized the deleterious effects of aging on myenteric neurons, which may be adopted as an alternative against the common gastrointestinal disorders in the elderly.
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Hajj, Glaucia Noeli Maroso. "A proteína prion celular e seus ligantes-vitronectina, STI1 e laminina - nos mecanismos de plasticidade neuronal." Universidade de São Paulo, 2004. http://www.teses.usp.br/teses/disponiveis/46/46131/tde-21122015-165320/.
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Prions são agentes etiológicos das encefalopatias espongiformes transmissíveis, doenças que acometem tanto homens quanto animais. A proteína infecciosa, PrPsc, é uma isoforma de uma proteína celular normal denominada PrPc. As funções de PrPc ainda causam controvérsia na literatura, mas já foi demonstrada a participação de PrPc em uma variedade de fenômenos biológicos, como homeostase de íons cobre, proteção contra estresse oxidativo, sinalização celular e neuritogênese entre outros. A interação de PrPc com laminina, uma proteína de matriz extracelular, leva a formação e manutenção de neuritos em neurônios hipocampais. Seguindo este caminho, demonstramos no presente trabalho a interação de PrPc com outra proteína de matriz extracelular, vitronectina (Vn). Esta interação também leva ao crescimento neurítico, tanto em células do sistema nervoso central quanto do sistema nervoso periférico. No sistema nervoso periférico, a ausência de PrPc é compensada por integrinas, no fenômeno da neuritogênese. Relatamos também que a interação de PrPc com STI1, uma cochaperonina, leva tanto a neuritogênese quanto a neuroproteção por vias de sinalização distintas. A ligação de PrPc com Vn e STI1 se dá através de domínios contíguos, de modo que as interações são excludentes sendo aquela com Vn mais favorável, como observado em ensaios de ligação in vitro, quanto através do fenômeno de neuritogênese. Já a ligação de laminina se dá em um domínio distante daqueles de ligação à Vn e STI1. Assim, pode ser observada cooperatividade entre laminina e STI1 no fenômeno da neuritogênese. Por fim, demonstra-se que a interação PrPc-laminina in vivo é importante para os mecanismos de consolidação da memória.Prions are involved in numerous neurodegenerative diseases in humans and animals called transmissible spongiform encephalopathies. PrPsc, the infectious protein, is an isoform of a normal cellular protein named PrPc. PrPc functions are still under debate, among them Cu++ homeostase, protection against oxidative stress, cell survival signaling and neuritogenesis. PrPc interaction with laminin (Ln), an extracellular matrix protein, leads to neurite growth and maintenance. PrPc interaction with another extracellular matrix protein, vitronectin (Vn) is here demonstrated. This association leads to neurite growth in hippocampal and dorsal root ganglia cells. In dorsal root ganglia cells, PrPc ablation can be compensated by integrins, at least in the neuritogenesis phenomenon. PrPc is also a cellular ligand for STI1, a co-chaperone, mediating neuritogenesis or neuroprotection, depending on the activated cell signaling pathway. Vn and STI1 binding sites at the PrPc molecule are localized in contiguous domains what makes their binding to PrPc mutually exclusive. The first is more favorable, as observed in vitro and ex vivo. On the other hand, Ln binding site at PrPc is confined to a domain distinct from those where Vn or STI1 associate. Furthermore, laminin and STI1 have additive effects on neurite outgrowth. The importance of PrPc-Ln interaction is also observed in vivo, since the complex participates in memory consolidation mechanisms.
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Carvalho, Altiere Araujo. "Estudo da plasticidade cruzada nos centros de fala e audição em pessoas ouvintes e surdas através de psicofísica e ressonância magnética funcional." Universidade de São Paulo, 2009. http://www.teses.usp.br/teses/disponiveis/47/47135/tde-26112009-151337/.
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O dito popular afirma que quando uma pessoa perde um dos sentidos há uma compensação por parte dos outros sentidos para suprir a perda. Através de três experimentos psicofísicos baseados no modelo de Posner (Inibição de Retorno) e técnicas de Ressonância Magnética Funcional, surdos congênitos foram comparados a pessoas ouvintes com o objetivo de verificar se os surdos possuem processos atencionais diferentes dos ouvintes, e se as mesmas áreas corticais como a área de Wernicke, Broca e Córtex auditivo - eram ativadas em ambos os grupos. A tarefa consistia em pressionar um botão todas as vezes que os sujeitos detectassem a presença de um quadrado maior (alvo) apresentado em uma tela, enquanto também eram apresentados quadrados menores (pista) ora do mesmo lado, ora do lado oposto ao alvo. Através do Experimento I se pôde verificar que ambos os grupos apresentaram os fenômenos clássicos do Paradigma de Posner: Facilitação ou Inibição de Retorno, o que denotou a possibilidade de mecanismos atencionais semelhantes para ambos os grupos. Foi observado, porém, que os ouvintes eram mais rápidos que os surdos para responder à tarefa quando o intervalo temporal entre pista e alvo era longo (800ms), comparado ao tempo que levavam para responder quando o intervalo entre pista e alvo era curto (100 ms). O Experimento I suscitou a hipótese de que os surdos possivelmente apresentassem uma diferença de processamento temporal. No Experimento I todas as condições eram apresentadas de forma randômica. O Experimento II foi elaborado com o objetivo de por em evidência a 22 diferença dos TRM para intervalos curtos e longos, portanto os intervalos entre pista e alvo passaram a ser apresentados de forma fixa. Ao comparar os resultados do Experimento I com os do Experimento II (Intervalos Temporais Fixos), se pode verificar que os ouvintes apresentaram Tempos de Reação Manual mais lentos, enquanto os surdos apresentaram as mesmas médias a despeito da vantagem temporal, o que levou a sugerir a hipótese de que os surdos apresentem um déficit no processamento temporal. O experimento III consistiu na utilização do Paradigma de Posner enquanto os sujeitos eram submetidos ao exame de Ressonância Magnética Funcional com o objetivo de investigar se as regiões corticais ativadas poderiam ser semelhantes nos dois grupos. As imagens por Ressonância Magnética Funcional (RMF) demonstraram ativações nas áreas de Wernickie, Broca, e córtex auditivo em ambos os grupos enquanto executavam a tarefa, que embora não possuísse nenhum contexto semântico explícito, possuía o tempo como o principal parâmetro físico no qual os sujeitos pudessem se basear para melhorar o desempenho na tarefa. O tempo é um dos parâmetros físicos primários da língua oral, diferente da língua de sinais que possui o parâmetro visual e espacial como primário. Os resultados sugerem que as ativações corticais nos centros de audição e fala podem indicar uma plasticidade cruzada no grupo de surdos. Ainda, a participação do córtex auditivo no processamento da elaboração de estratégias para responder a uma tarefa que não contenha um contexto semântico explicito possivelmente indica sua participação no processamento de linguagem.It is popularly said that when a person loses one sense, there is a compensation by the other remaining senses to suppress the loss. Throughout three Phsycophysic Experiments based on Inhibition of Return Posners Paradigm and Functional Magnetic Resonance (fMRI) Techniques, congenital deaf people were compared to normal hearing people in order to check if deaf people possess different attentional pattern compared to normal hearing people, and if the same cortical areas Wernicke and Brocas area and Hearing Cortex were activated in both groups. Experiment I consisted on pressing a button every time the presence of a big square (target) was detected by subjects while non-predictive small squares (cue) were also presented at the same or opposite side of the target. At Experiment I it was observed that both groups presented Posners Paradigm classical phenomena: Facilitation or Inhibition of Return, what suggested the possibility that attentional pattern may be similar to both groups. Therefore, it was observed that normal hearing people were faster than deaf people to respond to the task when time interval between cue and target was long (800 ms) when compared to the time they spent to respond when time interval between cue and target as short (100 ms). 24 Experiment I raised the hypotheses that possibly deaf people may present a temporal processing difference. At Experiment I every condition was randomly presented. Experiment II was elaborated to highlight MRT differences between short and long time intervals, so every time interval was presented on a fixed order. Comparison of Experiment I and II (Fixed Time Intervals) showed that normal hearing people presented shorter Manual Reaction Times (MRT), while deaf people kept the same averages despite the temporal advantage, what suggested that deaf people may present a deficit on temporal processing. Experiment III used Posners Paradigm while subjects were submitted to fMRI scanning in order to check if activated cortical regions could be similar in both groups. fMRI images demonstrate Wernicke and Brocas area and hearing cortex activations in both groups while executing the task, which, although did not have any explicit semantic content, had time as the main physical parameter on which subjects could be based to increase performance to respond to the task. Time is one of the oral language primary physical parameter, different of signed language which has visual and spatial parameters as primaries. Results suggest that cortical audition center activations may indicate a cross-modal plasticity at the deaf group. Yet, participation of hearing cortex on strategy elaboration to respond to a task which does not have any explicit semantic content possibly indicates the participation of hearing cortex on language processing.
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Candemir, Esin [Verfasser], and Andreas [Gutachter] Reif. "Involvement of neuronal nitric oxide synthase (NOS-I) PDZ interactions in neuropsychiatric disorders / Esin Candemir ; Gutachter: Andreas Reif." Würzburg : Universität Würzburg, 2018. http://d-nb.info/1162444371/34.
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Tajouri, Lotfi, and n/a. "Gene Expression Analysis and Genetic Studies in Multiple Sclerosis." Griffith University. School of Health Science, 2005. http://www4.gu.edu.au:8080/adt-root/public/adt-QGU20060111.123933.
Full textAbstract:
Multiple Sclerosis (MS) is a neurodegenerative disease of the central nervous system (CNS). As part of this disorder the myelin sheath undergoes degeneration, leading to alterations in the conductivity of axons, and impaired function. The onset of the disease occurs in young adults and clinical pathology is characterised by varying severity. These include i) Relapsing Remitting MS (RR-MS), ii) Secondary Progressive MS (SP-MS) and iii) Primary Progressive MS (PP-MS). MS is more prevalent in women and accounts for more than two thirds of all MS sufferers. MS is considered to be a multifactorial disorder with both genetic and environmental components. The prevalence of MS is dependent on geographical localisation, with lower sunlight exposure linked to higher prevalence. Also, studies show an increased risk in close relatives, or in identical twins, indicating a significant genetic component to the disorder. There are a number of genes that may plausibly be involved in MS pathophysiology. These include myelin-related genes, such as the myelin basic protein (MBP), immune-related genes, such FC receptor and osteopontin, and heat shock proteins such as xb crystallin. These candidate genes have been implicated in a variety of ways but usually through immunological and/or genetic studies. One of the most consistent findings in recent years has been the association of disease with alterations in the specific major histocompatibility complex (MHC) localised to chromosome 6p21.3, and includes MHC I, II, III. Genome wide screens have permitted the identification of loci in the genome, which are associated with MS susceptibility. The number of genes involved in MS is unknown and several case-control association studies have been undertaken to reveal the involvement of potential candidate genes. In general terms, current research is aimed at determining allelic variation of candidate genes. Such genes have been implicated in MS because they reside within susceptible regions of the chromosome associated with MS or they have a plausible potential pathophysiological role in MS. Candidate loci investigated in this study, for association with MS susceptibility, include members of the nitric oxide synthase family of metabolic proteins (inducible NOS, iNOS/NOS2A and neuronal NOS, nNOS), methylenetetrahydrofolate reductase (MTHFR), catechol-O-methyl transferase (COMT), and vitamin D receptor (VDR). The MS population used in all studies consisted of over 100 MS cases and gender, age and ethnicity matched controls. In our study of inducible and neuronal NOS genes, PCR based assays were developed to amplify a region of both promoters that contained known microsatellite variation. Supporting phyisological data suggests that the neuroinflammatory aspects of MS are associated with aberrant NO production, which may be due to aberrant regulation of NOS activity. Specific amplified products were identified by fluorescent capillary electrophoresis and allele frequencies were statistically compared using chi-squared analysis. In the nNOS and iNOS study, no association was identified with allele frequency variation and MS susceptibility (nNOS: ?2=5.63, P=0.962; iNOS: ?2=3.4; P=0.082). Similarly, no differences in allele frequencies were observed for gender or clinical course for both markers (Pvalue greater than 0.05). In short, results from this study indicate that the NOS promoter variations studied do not play a significant role in determining susceptibility to MS in the tested population. The COMT and MTHFR genes are localised at 22q12-13 and 1p36.3 respectively, regions of the genome that have been found to be positively associated with MS susceptibility. In our research, we set out to examine the G158A change in the 4th exon of the COMT gene. This functional mutation leads to an amino acid change (valine to methionine) that is directly associated with changes in the activity of COMT. The MTHFR enzyme plays a role in folate metabolism, and can be implicated in the turnover of homocysteine. Previous investigations have shown that high levels of homocysteine are encountered in MS patients, where it is also linked to demyelination in the CNS. In our study the aim was to examine the C677T variation (alanine to valine amino acid change) in the exon 4 coding region of the MTHFR gene and the G158A variation in the COMT gene. Restriction fragment length polymorphism (RFLP) analysis and gel electrophoresis was used to identify specific alleles for both COMT and MTHFR. However, as with the NOS study, no specific association was identified between MS susceptibility and variation for either of the tested COMT or MTHFR (Pvalue greater than 0.05) variants. In a final genomic investigation of the MS population, three variations in the VDR gene were analysed for association with MS susceptibility and pathology. Using RFLP analysis, three VDR variants were investigated with genotypes detected using the Taq I, Apa I and Fok I restriction enzymes. In contrast to previous genotypic analyses, this study did show a positive association, specifically between the functional variation in exon 9 of the VDR gene and MS (Taq I, 2= 7.22, P= 0.0072). Interestingly, the Apa I variant of VDR was also found to be associated with MS ( 2=4.2, P=0.04). The Taq I and Apa I variants were also found to be in very strong and significant linkage disequilibrium (D'=0.96, Pvalue less than 0.0001) and their associations were more prominent with the progressive forms of MS (SP-MS and PP-MS). In addition to genotypic analysis of a clinical population, additional research was undertaken to identify novel targets for MS susceptibility studies. Global gene expression analysis was undertaken using comparative subtractive fluorescent microarray technology to examine differences in gene activity (expression) in age and sex matched MS plaque tissue and anatomically matched normal white matter (NWM). MS plaques were obtained post mortem from MS sufferers with no drug history in the last two months before death and matched anatomically to healthy white matter from donors with no previous neurological disorders. Target arrays consisted of 5000 cDNAs and analysis was conducted using the Affymetrix 428 scanner. In this way, 139 genes were shown to be differentially regulated in MS plaque tissue compared to NWM. Of these, 69 genes showed a common pattern of expression in the chronic active and acute plaque tissues investigated (Pvalue less than 0.0001, a=0.73); while 70 transcripts were uniquely differentially expressed ( 1.5-fold) in either acute or chronic active lesions. To validate the gene expression profile results, quantitative real time reverse transcriptase (RT) PCR (Q-PCR) analysis was performed. 12 genes were selected because they were shown to be differentially expressed by array analysis in this study, or because of their involvement in MS pathology. These included transferrin (TF), superoxide dismutase 1 (SOD1), glutathione peroxidase 1 (GPX1), glutathione S-transferase pi (GSTP1), crystallin, alpha-B (CRYAB), phosphomannomutase 1 (PMM1), tubulin beta-5 (TBB5), inositol 1,4,5-trisphosphate 3-kinase B (ITPKB), calpain 1 (CAPNS1), osteopontin (SPP1 or OPN), as well as the signal transducer and activator of transcription 1 (STAT1) and protein inhibitor of activated STAT1 (PIAS1). Both absolute (copy number) and comparative differences in the relative levels of expression in MS lesions and NWM were determined for each gene. The results from this study revealed a significant correlation of real time PCR results with the microarray data, while a significant correlation was also found between comparative and absolute determinations of fold. As with the results of array analysis, a significant difference in gene expression patterning was identified between chronic active and acute plaque pathologies. For example, a up to 50-fold increase in SPP1 and ITPKB levels in acute plaques contrasted with the 5-fold or less increase in chronic active plaques (P less than 0.0.1, unpaired t-Test). Of particular note, gamma-amino butyric acid receptor ?2 (GABG2), integrin ?5 (ITGB5), complement component 4B (C4B), parathyroid hormone receptor 1 (PTHR1) were found up-regulated in MS and glial derived neurotropic factor ?2 (GDNFA2), insulin receptor (INSR), thyroid hormone receptor ZAKI4 (ZAKI4) were found down-regulated in MS. Data also revealed a decreased expression of the immune related genes STAT1 and PIAS1 in acute plaques. In conclusion, this research used both genomic analysis and technologies in gene expression to investigate both known and novel markers of MS pathology and susceptibility. The study developed tools that may be used for further investigation of clinical pathology in MS and have provided interesting initial expression data to further investigate the genes that play a role in MS development and progression.
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Tajouri, Lotfi. "Gene Expression Analysis and Genetic Studies in Multiple Sclerosis." Thesis, Griffith University, 2005. http://hdl.handle.net/10072/366467.
Full textAbstract:
Multiple Sclerosis (MS) is a neurodegenerative disease of the central nervous system (CNS). As part of this disorder the myelin sheath undergoes degeneration, leading to alterations in the conductivity of axons, and impaired function. The onset of the disease occurs in young adults and clinical pathology is characterised by varying severity. These include i) Relapsing Remitting MS (RR-MS), ii) Secondary Progressive MS (SP-MS) and iii) Primary Progressive MS (PP-MS). MS is more prevalent in women and accounts for more than two thirds of all MS sufferers. MS is considered to be a multifactorial disorder with both genetic and environmental components. The prevalence of MS is dependent on geographical localisation, with lower sunlight exposure linked to higher prevalence. Also, studies show an increased risk in close relatives, or in identical twins, indicating a significant genetic component to the disorder. There are a number of genes that may plausibly be involved in MS pathophysiology. These include myelin-related genes, such as the myelin basic protein (MBP), immune-related genes, such FC receptor and osteopontin, and heat shock proteins such as xb crystallin. These candidate genes have been implicated in a variety of ways but usually through immunological and/or genetic studies. One of the most consistent findings in recent years has been the association of disease with alterations in the specific major histocompatibility complex (MHC) localised to chromosome 6p21.3, and includes MHC I, II, III. Genome wide screens have permitted the identification of loci in the genome, which are associated with MS susceptibility. The number of genes involved in MS is unknown and several case-control association studies have been undertaken to reveal the involvement of potential candidate genes. In general terms, current research is aimed at determining allelic variation of candidate genes. Such genes have been implicated in MS because they reside within susceptible regions of the chromosome associated with MS or they have a plausible potential pathophysiological role in MS. Candidate loci investigated in this study, for association with MS susceptibility, include members of the nitric oxide synthase family of metabolic proteins (inducible NOS, iNOS/NOS2A and neuronal NOS, nNOS), methylenetetrahydrofolate reductase (MTHFR), catechol-O-methyl transferase (COMT), and vitamin D receptor (VDR). The MS population used in all studies consisted of over 100 MS cases and gender, age and ethnicity matched controls. In our study of inducible and neuronal NOS genes, PCR based assays were developed to amplify a region of both promoters that contained known microsatellite variation. Supporting phyisological data suggests that the neuroinflammatory aspects of MS are associated with aberrant NO production, which may be due to aberrant regulation of NOS activity. Specific amplified products were identified by fluorescent capillary electrophoresis and allele frequencies were statistically compared using chi-squared analysis. In the nNOS and iNOS study, no association was identified with allele frequency variation and MS susceptibility (nNOS: ?2=5.63, P=0.962; iNOS: ?2=3.4; P=0.082). Similarly, no differences in allele frequencies were observed for gender or clinical course for both markers (Pvalue greater than 0.05). In short, results from this study indicate that the NOS promoter variations studied do not play a significant role in determining susceptibility to MS in the tested population. The COMT and MTHFR genes are localised at 22q12-13 and 1p36.3 respectively, regions of the genome that have been found to be positively associated with MS susceptibility. In our research, we set out to examine the G158A change in the 4th exon of the COMT gene. This functional mutation leads to an amino acid change (valine to methionine) that is directly associated with changes in the activity of COMT. The MTHFR enzyme plays a role in folate metabolism, and can be implicated in the turnover of homocysteine. Previous investigations have shown that high levels of homocysteine are encountered in MS patients, where it is also linked to demyelination in the CNS. In our study the aim was to examine the C677T variation (alanine to valine amino acid change) in the exon 4 coding region of the MTHFR gene and the G158A variation in the COMT gene. Restriction fragment length polymorphism (RFLP) analysis and gel electrophoresis was used to identify specific alleles for both COMT and MTHFR. However, as with the NOS study, no specific association was identified between MS susceptibility and variation for either of the tested COMT or MTHFR (Pvalue greater than 0.05) variants. In a final genomic investigation of the MS population, three variations in the VDR gene were analysed for association with MS susceptibility and pathology. Using RFLP analysis, three VDR variants were investigated with genotypes detected using the Taq I, Apa I and Fok I restriction enzymes. In contrast to previous genotypic analyses, this study did show a positive association, specifically between the functional variation in exon 9 of the VDR gene and MS (Taq I, 2= 7.22, P= 0.0072). Interestingly, the Apa I variant of VDR was also found to be associated with MS ( 2=4.2, P=0.04). The Taq I and Apa I variants were also found to be in very strong and significant linkage disequilibrium (D'=0.96, Pvalue less than 0.0001) and their associations were more prominent with the progressive forms of MS (SP-MS and PP-MS). In addition to genotypic analysis of a clinical population, additional research was undertaken to identify novel targets for MS susceptibility studies. Global gene expression analysis was undertaken using comparative subtractive fluorescent microarray technology to examine differences in gene activity (expression) in age and sex matched MS plaque tissue and anatomically matched normal white matter (NWM). MS plaques were obtained post mortem from MS sufferers with no drug history in the last two months before death and matched anatomically to healthy white matter from donors with no previous neurological disorders. Target arrays consisted of 5000 cDNAs and analysis was conducted using the Affymetrix 428 scanner. In this way, 139 genes were shown to be differentially regulated in MS plaque tissue compared to NWM. Of these, 69 genes showed a common pattern of expression in the chronic active and acute plaque tissues investigated (Pvalue less than 0.0001, a=0.73); while 70 transcripts were uniquely differentially expressed ( 1.5-fold) in either acute or chronic active lesions. To validate the gene expression profile results, quantitative real time reverse transcriptase (RT) PCR (Q-PCR) analysis was performed. 12 genes were selected because they were shown to be differentially expressed by array analysis in this study, or because of their involvement in MS pathology. These included transferrin (TF), superoxide dismutase 1 (SOD1), glutathione peroxidase 1 (GPX1), glutathione S-transferase pi (GSTP1), crystallin, alpha-B (CRYAB), phosphomannomutase 1 (PMM1), tubulin beta-5 (TBB5), inositol 1,4,5-trisphosphate 3-kinase B (ITPKB), calpain 1 (CAPNS1), osteopontin (SPP1 or OPN), as well as the signal transducer and activator of transcription 1 (STAT1) and protein inhibitor of activated STAT1 (PIAS1). Both absolute (copy number) and comparative differences in the relative levels of expression in MS lesions and NWM were determined for each gene. The results from this study revealed a significant correlation of real time PCR results with the microarray data, while a significant correlation was also found between comparative and absolute determinations of fold. As with the results of array analysis, a significant difference in gene expression patterning was identified between chronic active and acute plaque pathologies. For example, a up to 50-fold increase in SPP1 and ITPKB levels in acute plaques contrasted with the 5-fold or less increase in chronic active plaques (P less than 0.0.1, unpaired t-Test). Of particular note, gamma-amino butyric acid receptor ?2 (GABG2), integrin ?5 (ITGB5), complement component 4B (C4B), parathyroid hormone receptor 1 (PTHR1) were found up-regulated in MS and glial derived neurotropic factor ?2 (GDNFA2), insulin receptor (INSR), thyroid hormone receptor ZAKI4 (ZAKI4) were found down-regulated in MS. Data also revealed a decreased expression of the immune related genes STAT1 and PIAS1 in acute plaques. In conclusion, this research used both genomic analysis and technologies in gene expression to investigate both known and novel markers of MS pathology and susceptibility. The study developed tools that may be used for further investigation of clinical pathology in MS and have provided interesting initial expression data to further investigate the genes that play a role in MS development and progression.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Health Sciences
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Filippini, Renata. "Eficácia do treinamento auditivo por meio do potencial evocado para sons complexos nos transtornos de audição e linguagem." Universidade de São Paulo, 2012. http://www.teses.usp.br/teses/disponiveis/5/5162/tde-19032012-114450/.
Full textAbstract:
Introdução: Alterações de audição e linguagem como o Distúrbio Específico de Linguagem (DEL) e o Transtorno do Processamento Auditivo (TPA), tem sido associadas a alterações na codificação neural de sons acusticamente complexos. A percepção destes sons depende da integridade nos processos de codificação analisados pelo Sistema Nervoso Auditivo, principalmente em situações de escuta desafiadora, como em ambientes ruidosos. O Potencial Evocado Auditivo de Tronco Encefálico (PEATE) para estímulos complexos investiga a representação neural destes sons em níveis subcorticais, pois reflete com fidelidade as características do estímulo, e está alterado em crianças com problemas de audição, linguagem e aprendizado quando comparadas a crianças com desenvolvimento típico (DT). Um método para remediar algumas dificuldades dessas crianças, é o Treinamento Auditivo Formal (TAF), que já teve sua eficácia demonstrada tanto por meios comportamentais quanto eletrofisiológicos. Objetivo: Verificar a eficácia do TAF em crianças com transtornos de audição e linguagem por meio da avaliação comportamental e do PEATE para sons complexos, na presença e na ausência de ruído de fundo. Métodos: Participaram do estudo 30 crianças (7a - 12a11m), divididas nos grupos DT (N=7), TPA (N=9) submetido ao TAF, DELa submetido ao TAF (N=6), e DELb não submetido ao TAF (N=8). Todos apresentaram audição periférica e respostas do PEATE para cliques normais, e foram submetidos à avaliação comportamental do PA(C) e ao PEATE para sons complexos, no silêncio e na presença de ruído. Apenas os grupos TPA e DELa foram submetidos a TAF, porém todos realizaram reavaliação cerca de 12 semanas após a avaliação inicial. Resultados: Os grupos TPA, DELa e DELb apresentaram desempenho inferior ao do grupo DT para as habilidades de Figura-Fundo e Ordenação Temporal, e apenas os grupos submetidos ao TAF apresentaram melhoras na avaliação final. No PEATE para sons complexos no silêncio não se observaram diferenças entre grupos quanto à latência das ondas, porém o grupo TPA apresentou alterações nas medidas de amplitude e do complexo VA, as quais se mantiveram após o TAF. No PEATE para sons complexos na presença de ruído, o grupo DELa apresentou latências mais atrasadas para todas as ondas, sem outras alterações. Este grupo apresentou melhoras significantes nas latências, equilibrando as respostas apresentadas pelos outros grupos estudados. Conclusão: O TAF parece ter sido responsável pelas mudanças no desempenho comportamental dos grupos TPA e DELa, já que os grupos DT e DELb não apresentaram variações em suas respostas. Pudemos observar neste estudo que o PEATE para sons complexos apresentados no ruído pode ser um instrumento válido na monitoração dos efeitos do TAFDisorder (SLI) and Auditory Processing Disorder (APD) have been associated with disorders at neural decoding of acoustic complex sounds. These sounds perception depends on the integrity of decoding processes analyzed by the auditory nervous system, especially in challenging acoustic situations as in background noise. The Auditory Brainstem Response to complex sounds (c- ABR), investigate de neural representation of these sounds at subcortical levels because they reflect with fidelity the stimulus features, and it is altered in children with auditory, language and learning problems when compared to typical development children (TD). The formal Auditory training (AT) is a method to remediate some of these children difficulties, and its efficacy has been demonstrated using behavioral and electrophysiological assessments. Objective: Verify the efficacy of formal AT in children with hearing and language disorders through behavioral assessment and c-ABR, with and without background noise. Methods: Thirty children (aged 712 years and 11 months), were divided in four groups: TD(N=7), APD(N=9) underwent formal AT, SLIa (N=6) underwent formal AT - and SLIb(N=8) did not undergo formal AT. All had normal peripheral hearing and click-evoked ABR, and all underwent behavioral assessment of auditory processing and c-ABR with and without background noise. Only APD and SLIa groups underwent formal AT, although all children were reevaluated after 12 weeks from the initial assessment. Results: Groups APD, SLIa and SLIb showed worst behavioral performance than TD group, although only groups that underwent formal AT showed improvements at final assessment. To c-ABR in silence, no differences were observed among the groups concerning wave latencies, but APD group presented smaller amplitudes to transient portion of the response, and altered VA complex duration and slope, which did not change after AT. To c-ABR with background noise, SLIa group presented delayed latencies to all waves. This same group, after AT, presented significant improvements to wave latencies, balancing the responses among all studied groups. Conclusion: Formal AT seemed to be responsible for the behavioral performance changes seen in groups APD and SLIa. This study suggests that the c-ABR with background noise may be an effective tool to monitor the effects of formal AT
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Marosti, Aline Rosa. "Análise morfoquantitativa e ultraestrutural dos componentes do plexo mioentérico do intestino delgado de ratos submetidos à dieta padrão de Moçambique nos períodos pré e pós-natal." Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/5/5160/tde-08092016-095400/.
Full textAbstract:
Admite-se que mais de 40% das crianças são acometidas pela desnutrição crônica em Moçambique (África Oriental). A doença pode estar relacionada, entre outros fatores, à qualidade da dieta que é oferecida à população, já que é bastante precária, pois exibe sérias deficiências de ferro, gordura e, principalmente, proteína animal em sua composição. Essa insuficiência proteica poderia acarretar em prejuízo ao desenvolvimento do organismo, pois a proteína animal é considerada uma boa fonte de aminoácidos essenciais, em decorrência de sua maior digestibilidade e absorção no intestino delgado, quando comparadas às fontes de origem vegetal. Na presente pesquisa foi reproduzida em laboratório, a dieta básica da população de Moçambique (DM), com o objetivo de avaliar seus efeitos nos componentes do plexo mioentérico e na mucosa dos segmentos do intestino delgado de ratos Wistar. Para isso, os animais foram divididos nos grupos Controle, com dieta AIN-93G com adição de 20% de caseína (NN21 e NN42); Dieta de Moçambique (DM21 e DM42) e Dieta Moçambique suplementada, acrescida de 20% de caseína (NM21 e NM42); e grupo Renutrido (RM42), composto por animais do grupo DM21 que, a partir do 22º dia, receberam a dieta NM até atingirem 42 dias de vida. Os segmentos foram coletados e submetidos às técnicas histoquímicas da NADH-diaforase e da NADPH-diaforase para evidenciação de neurônios do plexo mioentérico; histológicas (HE, Picro-sírius, Weigert) para avaliação da parede intestinal, mucosa, gânglios e seu tecido conjuntivo associado; de microscopia eletrônica de varredura (MEV) para observação da estrutura da mucosa; e de microscopia eletrônica de transmissão (MET) para a ultraestrutura dos componentes ganglionares. Estatisticamente, o peso corporal e o comprimento dos animais submetidos à dieta de Moçambique estavam abaixo dos valores encontrados para os animais controle. Na análise qualitativa, observou-se a presença de fibras elásticas, elaunínicas e oxitalânicas, assim como predominância de fibras colágenas do tipo I nos grupos NN42 e DM42, e do tipo III nos grupos NM42 e RM42 ao redor dos gânglios. A mucosa apresentou uma menor área no grupo DM21 com recuperação em DM42, com diminuição da altura das vilosidades nos dois grupos. Foram observadas alterações na organização do retículo endoplasmático rugoso e disposição dos materiais fibrilares e granulares do nucléolo dos animais DM. Sob MEV as vilosidades do grupo DM42 apresentaram superfície mais lisa, com poucas delimitações entre elas. A densidade dos neurônios reativos à NADH diminuiu de 21 para 42 dias em todos os grupos; porém, o DM21 e DM42 apresentou uma maior densidade. Os neurônios reativos à NADPH apresentaram a diminuição da densidade de 21 para 42 dias nos grupos DM e NM, quando comparados ao controle. Assim, conclui-se que a dieta vegetal de Moçambique levou à alterações na morfologia da mucosa, parede intestinal e neurônios entéricos, como uma forma de adaptação à dieta impostaIt is assumed that more than 40% of children are affected by chronic malnutrition in Mozambique (East Africa). The disease may be related, among other factors, the quality of diet that is offered to the population, since it is quite precarious, because it displays serious deficiencies of iron, fat and especially animal protein in their composition. This protein failure could result in damage to the development of the organism, as animal protein is considered a good source of essential amino acids, due to its higher digestibility and absorption in the small intestine when compared to vegetable sources. In this research has been reproduced in the laboratory, the staple diet of the population of Mozambique (DM), in order to evaluate its effects on components of the myenteric plexus and the mucosa of the small intestine segments of Wistar rats. For this, the animals were divided into control groups with AIN-93G diet with the addition of 20% casein (NN21 and NN42); Diet Mozambique (DM21 and DM42) and diet supplemented Mozambique, plus 20% casein (NM21 and NM42); and Refeeding group (RM42), consisting of the animals DM21 group, from the 22th day, given NM diet until they reached 42 days of life. The segments were collected and submitted to histochemical techniques of NADH-diaphorase and NADPH-diaphorase for disclosure of neurons of the myenteric plexus; histologic (HE, Sirius red, Weigert) for evaluation of the intestinal wall, mucosa, lymph nodes and its associated connective tissue; scanning electron microscopy (SEM) for observation of mucosal structure; and Transmission electron microscopy (TEM) ultrastructure to ganglion components. Statistically, body weight and length of the animals submitted to Mozambique diet were below the values found for control animals. Qualitative analysis showed the presence of elastic fibers, and elauninic oxytalan, and predominance of type I collagen fibers in the NN42 and DM42 groups, and type III in the NM42 and RM42 groups around the ganglia. The mucosa showed a smaller area in DM21 group recovery DM42, with a decrease in villus height in both groups. There have been changes in the organization of the rough endoplasmic reticulum and arrangement of fibrillar and granular materials nucleolus of DM animals. Under SEM the villi of the DM42 group showed smoother surface, with few boundaries between them. The density of reactive NADH decreased from 21 to 42 days in all groups; however, the DM21 and DM42 had a higher density. Reactive neurons to NADPH had decreased from 21 to 42 days density in DM and NM groups when compared to the control. Thus, it is concluded that vegetable diet Mozambique led to changes in the morphology of the mucosa, the intestinal wall and enteric neurons, as a way to adapt to the imposed diet
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Silva, Liana Gouveia da [UNIFESP]. "Efeitos da inibição da óxido nítrico sintase neuronal sobre as respostas cardiovasculares causadas pela estimulação de receptores colinérgicos nos Núcleos do Tracto Solitário de ratos não anestesiados." Universidade Federal de São Paulo (UNIFESP), 2009. http://repositorio.unifesp.br/handle/11600/9400.
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Publico-121g.pdf: 1321792 bytes, checksum: 79c868582d382c14204c0f2a71cf7fd1 (MD5)O NTS é o sítio primário das terminações das aferências dos reflexos cardiovasculares no sistema nervoso central (SNC). A presença da acetilcolina (ACh) no NTS e sua participação na transmissão ou modulação central das funções neurovegetativas foi sugerida desde a década de 80 (Kobayashi et al., 1978; Simon et al., 1981; Criscione et al., 1983; Helke et al., 1983). Contudo, a maioria dos estudos da literatura foram realizados in vitro e não há evidências de estudos da transmissão colinérgica in vivo em animais não anestesiados. Estudos prévios de nosso laboratório mostraram que a microinjeção de ACh no NTS de ratos não anestesiados causa hipotensão e bradicardia dose-dependentes e estas respostas parecem ser mediadas ou moduladas em parte pela liberação de óxido nítrico derivado da isoforma neuronal da enzima óxido nítrico sintase (NOS). A queda de pressão arterial causada pela ACh não foi abolida após o bloqueio parassimpático com metilatropina, indicando que a ativação do sistema colinérgico no NTS causa redução significante do componente simpático. A fim de discriminar as respostas de pressão arterial média (PAM) e frequência cardíaca (FC) causadas pela estimulação dos receptores colinérgicos nicotínicos e muscarínicos no NTS, realizamos as curvas dose-resposta para os agonistas seletivos nicotina (NIC) e pilocarpina (PIL) microinjetados no NTS de ratos não anestesiados. Além disso, investigamos também os efeitos do bloqueio central da NOS neuronal (TRIM) sobre estas respostas. Ratos Wistar foram preparados de acordo com a técnina de implante crônico de cânulas guia em direção ao NTS e da metodologia para microinjeção de drogas em animais não anestesiados e registro de pressão arterial in vivo. A microinjeção unilateral do agonista colinérgico de receptor nicotínico (nicotina) no NTS de ratos não anestesiados causou significante hipotensão e bradicardia que se mostrou dosedependente. Com a microinjeção unilateral do agonista colinérgico de receptor muscarínico (pilocarpina) no NTS observamos significante hipotensão e bradicardia, onde as doses maiores que 1 nmol/100 nL causaram hipotensão seguida de aumento da pressão arterial e bradicardia. A microinjeção unilateral do inibidor da nNOS (TRIM 13,3 nmol/100 nL) no NTS reduziu significantemente a hipotensão e bradicardia causadas pela nicotina e pilocarpina no NTS. O bloqueio da nNOS também reduziu significantemente o aumento de pressão arterial média causado pela microinjeção de pilocarpina na dose de 5 nmol/100 nL. Os resultados são a primeira evidência funcional, em animais não anestesiados, da participação de ambos os subtipos de receptores colinérgicos (nicotínico e muscarínico) na resposta da ACh no NTS. As diferenças observadas com a estimulação seletiva dos receptores colinérgicos no NTS sugerem a participação de cada subtipo de receptor na modulação da transmissão de estímulos cardiovasculares distintos, e, a função do sistema colinérgico sofre influência, ainda por meios desconhecidos, do óxido nítrico de origem central.
The Nucleus of the Solitary Tract is the first sites of cardiovascular reflex afferent terminations in the central nervous system (CNS). Acetylcholine (ACh) is present within neurons and terminals in the NTS and its participation in modulation of neurovegetative function was suggested since the 80´s. However, most part of the studies in literature was performed in vitro and there were no evidences in nonanesthetized rats. Previous studies of our laboratory showed that ACh microinjection into the NTS of non-anesthetized rats elicits dose-dependent hypotension and bradicardia; and NO from nNOS may have a role in modulating these responses. Peripheral blockade of cholinergic muscarinic receptors (i.v. injection of methylatropine) did not alter hypotension induced by microinjection of ACh into the NTS of non-anesthetized rats, indicating that the activation of cholinergic system in the NTS elicits reduction of the sympathetic component. In order to discriminate cardiovascular responses elicited by cholinergic receptors stimulation in the NTS, we performed the dose-response curves for selective agonists nicotine (NIC) and pilocarpine (PIL) microinjected into the NTS of non-anesthetized rats. In addition, we investigated whether inhibition of the nNOS in the NTS affects the responses caused by cholinergic agonists. Male Wistar rats were prepared according to the methodology of guide cannulas implantation in the direction of the NTS for microinjection in freely-moving rats; and recording of blood pressure in nonanesthetized rats. Unilateral nicotine microinjection in the NTS of non-anesthetized rats caused dose-dependent hypotension and bradicardia. Microinjection of the muscarinic agonist (pilocarpine) in the NTS of non-anesthetized rats elicited significant hypotension and bradicardia, and with doses higher than 1nmol/ 100 nL it was observed hypotension followed by an increased in arterial pressure, and bradicardia. Blockade of neuronal nitric oxide syntase (nNOS) (TRIM 13.3 nmol/ 100 nL), in the NTS, significantly reduced responses elicited by nicotine and pilocarpine. Microinjection of TRIM also inhibited the increase in arterial pressure elicited by PIL 5 nmol/ 100 nL. These results are the first functional evidence in non-anesthetized rats of cholinergic receptors participation in ACh transmission s in the NTS. Differences observed with selective stimulation of cholinergic receptors in the NTS suggest the participation of each receptor subtype in modulation of distinct pathways of stimulus of cardiovascular integration to the NTS. Finally, the physiological effects of cholinergic transmission in the NTS are still unclear and NO modulation of this system remains to be elucidated.
TEDE
BV UNIFESP: Teses e dissertações
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Capitelli, Caroline Santos. "Efeito da manipulação do microambiente neuronal indiretamente através da pinealectomia ou transplante de células derivadas de medula óssea nos modelos animais da Doença de Parkinson induzido por neurotoxinas." reponame:Repositório Institucional da UFPR, 2014. http://hdl.handle.net/1884/36928.
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Orientadora : Profa. Dra. Maria Aparecida Barbato Frazão VitalCo-orientadora : Profª Drª Valdo José Dias da Silva
Tese (doutorado) - Universidade Federal do Paraná, Setor de Ciências Biológicas, Programa de Pós-Graduação em Farmacologia. Defesa: Curitiba,17/09/2014
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Área de concentração: Farmacologia
Resumo: A Doença de Parkinson é uma doença neurodegenerativa caracterizada pela perda de neurônios dopaminérgicos na SNpc. O presente trabalho visou investigar em duas linhas distintas o papel do microambiente celular na neurodegeneração. Na primeira linha de investigação, os animais foram avaliados quanto ao efeito da pinealectomia sobre a neurodegeneração e estresse oxidativo induzido pela administração de MPTP e 6-OHDA. A administração dessas neurotoxinas resultou em comprometimento motor em ambos os grupos Sham e Px 24 h após a lesão no teste do campo aberto. Contudo, 7 e 14 dias após a cirurgia, os animais lesados pertencentes ao grupo Sham apresentavam recuperação motora, ao contrário dos grupos Px e lesados. No teste de natação forçada os animais lesados apresentavam menor tempo de natação em relação aos grupos controles, e ainda, os grupos Sham- 6-OHDA e Px-6-OHDA apresentaram maior tempo de imobilidade comparado aos controles. Corroborando com essas alterações, significativa degeneração dopaminérgica foi evidenciada nos animais lesados, e ainda, aumento na quantidade de células contendo ROS nesses grupos em relação aos grupos controles. Já no segundo estudo, o modelo do MPTP foi empregado para avaliar o efeito do transplante de BMMC ou BM-MSC em diferentes tempos, imediatamente e 24 h após a infusão da neurotoxina. A infusão de MPTP resultou em quebra da BHE e prejuízo motor 24 h após a infusão de MPTP, e o tratamento com BMMC imediatamente após a lesão aumentou significativamente a perda de células TH-ir nesses animais, ao contrário do tratamento com BM-MSCs. Por outro lado, o tratamento com BMMC 24 h após a infusão de MPTP resultou em similar perda de neurônios TH-ir comparado ao grupo MPTP-salina. No teste de natação forçada, o grupo MPTP-BMMC apresentou aumento no tempo de imobilidade comparado aos grupos Sham e MPTP, e ainda, aumento no número de células CD45+ e micróglia ativada nas secções estudadas. O presente estudo sugere que o transplante de BM-MSC em animais lesados com MPTP module positivamente o microambiente neuronal favorecendo a sobrevivência neuronal, enquanto que o transplante com BMMCs e a redução dos níveis fisiológicos de melatonina mostraram-se desfavorável ao microambiente neuronal. Palavras-chave: MPTP, 6-OHDA, BMMC, BM-MSC, pinealectomia e DP.
Abstract: Parkinson's disease (PD) is a neurodegenerative disease characterized by loss of dopaminergic neurons in the SNpc. This study aimed to investigate the role of cellular microenvironment on the neurodegenration in two distinct investigation lines. In the first line, the animals were evaluated for the effect of pinealectomy (Px) on neurodegeneration and oxidative stress induced by MPTP or 6-OHDA. The administration of these neurotoxins results in motor impairment in both sham and Px groups 24 h after injury in the open field test. However, 7 and 14th days after injury, the injured animals belonging to Sham group showed recovery of motor abnormalities, unlike injured animals of the Px-groups. In the forced swim test, the injured animals exhibited shorter swimming compared to control groups, and futher, Sham-6-OHDA and Px-6-OHDA groups showed a significant increase in immobility time compared to control groups. Supporting these alterations, significant dopaminergic loss in animals injured was observed in comparison to control groups, and futher, increased quantity of cellular ROS in these groups. In the second study, the MPTP model was used to evaluate the effect of BMMC and BM-MSCs at different times, immediately and 24 hours, after neurotoxins infusion. The MPTP infusion resulted in breakdown of bloodbrain barrier and motor impairment 24h after MPTP infusion, and the BMMC treatment immediately after lesion induced a significant increase loss of TH-ir neurons in these animals when compared to MPTP-saline group, in opposite to the BM-MSCs treatment. In the other hand, MPTP-lesioned rats treated with BMMCs 24 h after to neurotoxin infusion showed similar loss of dopaminergic neurons to MPTP-saline. In the forced swimming test, MPTP-BMMC treated group presented an increase in the immobility time compared to sham and MPTP-saline group, and futher increase in the number of CD45-labeled cells and activated microglial cells in the sections studied. This study suggests that the BM-MSCs transplantation in MPTP-lesioned rats positively modulate the microenvironment favoring neuronal neuronal survival, whereas transplantation BMMCs and the reduction of physiological levels of melatonin have proved unfavorable neuronal microenvironment. Keywords: MPTP, 6-OHDA, BMMC, BM-MSC, pinealectomy e PD.
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Barreiro, Portela Esther. "Study of reactive oxygen species (ROS) and nitric oxide (NO) as molecular mediators of the sepsis-induced diaphragmatic contractile dysfunction : protective effect of heme oxygenases." Doctoral thesis, Universitat Pompeu Fabra, 2002. http://hdl.handle.net/10803/7066.
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Protein nitration is considered as a marker of reactive nitrogen species formation. Heme oxygenases (HOs) are important for the defence against oxidative stress. We evaluated the involvement of the neuronal (nNOS), the endothelial (eNOS), and the inducible (iNOS) in nitrotyrosine formation and localitzation, and both the expression and funcional significance (HO inhibition and contractility studies) of HOs in sepsis-induced muscle contractile dysfunction. Sepsis was elicited by injecting rats and transgenic mice deficient in either nNOS, eNOS, or iNOS isoforms with E.Coli lipolysaccharide (LPS). Nitrotyrosine formation and HO expressions were assessed by immunoblotting. Oxidative stress was assessed measuring protein oxidation, lipid peroxidation, and muscle glutathione. We conclude that protein tyrosine nitration occurs in normal muscles, and sepsis-mediated increase in nitrotyrosine formation is limited to the mitochondria and membrane muscle fractions. The iNOS isoform is mostly involved in nitrotyrosine formation. HOs protect normal and septic muscles from the deleterious effects of oxidants.En un model de sepsi de disfunció diafragmàtica, s´ha avaluat el paper de les sintetases de l'òxid nítric (NOS) en la formació i localitzacio de 3-nitrotirosina, i l´expressió i significat biològic de les hemo oxigenases (HOs) (inhibidor de les HOs i estudis de contractilitat) davant l' estrès oxidatiu. La sepsi s'induí mitjançant injecció de 20 mg/kg del lipolisacàrid (LPS) d´Escherichia Coli a rates, i a ratolins deficients en les NOS induïble (iNOS), neuronal (nNOS) i endotelial (eNOS). Les proteïnes nitrificades i les HOs es van detectar amb anticossos específics. L' estrès oxidatiu s' avaluà mitjançant l' oxidació proteica, la peroxidació lipídica i el glutation muscular. Concloem que hi han proteïnes nitrificades en el múscul normal i aquestes s'incrementen durant la sepsi en les fraccions mitocondrial i membranar. L'isoforma iNOS és majorment responsable de la formació de nitrotirosina. Les HOs protegirien el múscul normal i sèptic dels efectes deleteris dels oxidants.
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Bahri, Nesrine. "Une commande neuronale adaptative basée sur des émulateurs neuronal et multimodèle pour les systèmes non linéaires MIMO et SIMO." Thesis, Le Havre, 2015. http://www.theses.fr/2015LEHA0024/document.
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La porosité d'une plaque composite carbone / époxy de type RTM est connue par tomographie X. Une méthode de détermination de cette porosité par mesure de l'atténuation des ondes longitudinales à travers l'épaisseur de cette plaque est proposée. Ces mesures sont effectuées sur des surfaces de dimensions variables (quelques cm2 à quelques mm2) et permettent l’obtention de cartographies. Une correspondance porosité (tomo X) – atténuation (onde US) est déduite et analysée en fonction de la structure du matériau composite. Dans chaque cas, on estime la qualité des relations obtenues et on en déduit les limites de validité de la correspondance porosité-atténuation. Des premiers résultats de tomographie acoustiques sont obtenusThe porosity of a composite plate in carbon / epoxy of type RTM is known by used of tomography X. A method of determination of this porosity by measure of the mitigation of the longitudinal waves through the thickness of this kind of plate is proposed. These measures are made on surfaces of different sizes (from some cm2 to some mm2) and allow the obtaining of cartographies. A correspondence porosity (tomo X) - Mitigation (US wave) is deducted and analyzed according to the structure of the composite material. In every case, we estimate the quality of the obtained relations and we deduct the limits of validity of the correspondence between porosity and mitigation. First results of acoustic tomography are obtained
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Imbeault, Emilie. "Le rôle du récepteur NOD-like, Nlrx1 dans la neuroprotection et la mort cellulaire." Mémoire, Université de Sherbrooke, 2015. http://hdl.handle.net/11143/6937.
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Résumé : La mort cellulaire neuronale est un phénomène qui se produit pendant le développement du cerveau, mais aussi dans les conditions pathologiques. Selon l’environnement où la cellule se retrouve; l’apoptose ou la nécrose peuvent contribuer à cette mort neuronale. La nécrose produit un environnement qui promeut l’inflammation ainsi que la cytotoxicité. L’apoptose est un processus hautement organisé qui permet l’homéostasie tissulaire. Un récepteur NOD récemment découvert, Nlrx1, jouerait un rôle dans la régulation de l’inflammation et de la mort cellulaire pendant les infections. Par conséquent, notre hypothèse suppose que Nlrx1 joue un rôle neuroprotecteur en contrôlant la mort neuronale. Afin de déterminer le mécanisme protecteur de Nlrx1 in vitro, un Knock-Down, un Knock-In et un témoin Scrambled de Nlrx1 dans les cellules N2a ont été générés. Des essais LDH de mort cellulaire avec la staurosporine ou le stress oxydatif comme la roténone, le MPP+ ou le H[indice inférieur 2]O[indice inférieur 2] ont été exécutés. Suite au traitement de 24 heures à la staurosporine, les cellules N2a Knock-In subissent plus de mort cellulaire que les cellules N2a Knock-Down et les cellules Scrambled. Quand ces cellules sont traitées à la roténone ou au H[indice inférieur 2]O[indice inférieur 2], les cellules Knock-In subissent moins de mort cellulaire que les cellules Scrambled. Les cellules N2a Knock-Down ont plus de mort cellulaire que les cellules Scrambled quand elles sont traitées à la roténone ou au MPP+. Les analyses par immunobuvardage de type Western des protéines HSP90 et HMGB1 ainsi que par cytométrie en flux ont montré que les cellules Knock-In ont moins de cellules nécrotiques lorsque traitées à la roténone comparé aux cellules contrôles Scrambled. Le ratio des cellules nécrotiques/cellules apoptotiques était aussi plus élevé dans les cellules Knock-Down comparé aux cellules Scrambled. Par microscopie électronique, il a été possible d’observer que les cellules N2a Knock-In contiennent plus de mitochondries que les cellules Knock-Down et Scrambled en conditions témoins. Ces résultats ont aussi été confirmés par marquage au mitotracker en cytométrie de flux L’immunobuvardage de type Western a montré que dans les cellules Knock-In, il y avait une augmentation de la protéine phosphorylée-DRP1 active, une protéine impliquée dans la fission mitochondriale. Ces résultats pourraient expliquer le nombre augmenté de mitochondries observé dans les cellules Knock-In. Des expériences d’immunoprécipitation ont montré une association entre Nlrx1 et DRP1, ainsi qu’avec la forme active phosphorylée de DRP1. En ajoutant le Mdivi, un inhibiteur de la fission mitochondriale, aux traitements de roténone ou H[indice inférieur 2]O[indice inférieur 2], la mort cellulaire était augmentée dans les cellules Knock-In comparé aux cellules Scrambled. Également, la nécrose était augmentée dans les cellules Knock-In à des niveaux semblables à ceux retrouvés chez les cellules Scrambled et Knock-Down. Ces résultats suggèrent que Nlrx1 serait impliquée dans la régulation de l’équilibre entre la nécrose et l’apoptose, en favorisant la survie cellulaire. Nlrx1 pourrait alors servir de molécule neuroprotectrice dans les maladies médiées par le stress oxydatif.Abstract : Neuronal cell death is a phenomenon that occurs during brain development as well as in pathological diseases. Depending on the environment in which the cells are; a poptosis or necrosis can contribute to neuronal cell death. Necrosis produces an environment that promotes inflammation and cytotoxicity and apoptosis is a highly organized process that maintains tissue homeostasis. A recently discovered NOD receptor, Nlrx1, is thought to play a role in regulation of inflammation and cell death during infection. Therefore, we hypothesize that Nlrx1 plays a neuroprotective role by controlling cell death in neurons. To determine the protective mechanism of Nlrx1 in vitro, a Knock-Down, a Knock-In and a Scrambled control of Nlrx1 in N2a cells was generated. LDH assays for cell death detection with staurosporine or oxidative stress, such as rotenone, MPP+ or H[subscript 2]O[subscript 2], have been done. After 24h treatment of staurosporine, N2a Knock-In cells showed higher cell death than N2a Knock-Down and Scrambled. When cells were treated with rotenone or H[subscript 2]O[subscript 2], N2a Knock-In cells had less cell death than Scrambled cells. N2a Knock-Down cells resulted in more cell death than Scrambled cells when treated with rotenone or MPP+.Western Blotting of HSP90 and HMGB1 as well as flow cytometry of cell death demonstrated N2a Knock-In cells to have less necrotic cells when treated with rotenone compared to Scrambled. The ratio of necrotic cells on apoptotic cells was also higher in N2a Knock-Down cells compared to Scrambled cells. Electron microscopy of control cells showed that Knock-In cells contains more mitochondria than Knock-Down and Scrambled cells. These results were confirmed by mitotracker staining by flow cytometry. Western blotting showed that there was an increased in Knock-In cells of active phosphorylated-DRP1 protein, a protein implicated in mitochondrial fission. Thus, it could explain the increased number of mitochondria seen in Knock-In cells. Immunoprecipitation showed that Nlrx1 protein interacts with DRP1 as well as active phosphorylated-DRP1. Adding Mdivi, a mitochondrial fission inhibitor, to rotenone or H[subscript 2]O[subscript 2] treatments, cell death was increased in Knock-In cells compared to Scrambled. Also, necrosis was also augmented in Knock-In cells to levels comparable to Scramble and Knoc k-Down cells. These results suggest an implication for Nlrx1 in regulating the balance of necrosis to apoptosis, permitting cells to survive. Nlrx1 could serve as a neuroprotective molecule in diseases mediated by oxidative stress.
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Gendron, Judith. "Les longs ARN non codants, une nouvelle classe de régulateurs génomique tissu-spécifique : signature moléculaire spécifique des neurones dopaminergiques et sérotoninergiques." Thesis, Paris 6, 2017. http://www.theses.fr/2017PA066518.
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Seul 1,2% du génome code des protéines :98,8% est non-codant,cependant 93% du génome est transcrit, principalement en longs ARN non-codants (lncRNA). Or ces lncRNA constituent une nouvelle classe de régulateurs génomique agissant à tous les niveaux d’expression des gènes et ils sont fortement spécifiques du tissu,modulés au cours du temps et en conditions physiopathologiques.Ainsi,nous proposons que chaque cellule spécifiée exprime son répertoire de lncRNA spécifique avec une carte des zones de chromatines ouvertes renseignant son identité cellulaire.Dans cette perspective,nous avons isolé par FACS 2types cellulaires impliqués dans des pathologies: i) des neurones dopaminergiques humains(nDA) différenciés à partir d’hiPS et ii) des neurones DA et sérotoninergiques (n5-HT)murins.Sur ces 2types neuraux isolés,nous avons identifié 1363 lncRNA exprimés dans les nDA (dont 989nouveaux) constituant le répertoire des neurones DA et 1257 lncRNA dans les n5-HT (719nouveaux) constituant le répertoire des n5-HT.Or leur comparaison a montré que seuls 194 lncRNA sont communs aux 2types cellulaires:la majorité des lncRNA est exprimée soit dans les nDA soit dans les n5-HT,attestant leur spécificité cellulaire.De plus,39%des zones de chromatines ouvertes/potentiellement régulatrices des nDA ne sont pas non plus retrouvées dans les n5-HT.Ainsi, nous avons généré un catalogue d’éléments non codants constituant des signatures moléculaires spécifiques des nDA et n5-HT,ouvrant de nouvelles pistes physiopathologiques:Dans cette optique,les signatures non codantes DA ont été comparées avec les SNP associés à la maladie de Parkinson et des études de fonction sur des lncRNA candidats ont été réaliséesOnly 1.2% of the genome codes for proteins; 98.8% is thus non-coding, despite 93% of the human genome being actively transcribed, mostly in long non-coding RNA (lncRNA).These lncRNA constitute a new class of genomic regulator capable of acting at all levels of gene expression and their expression is highly tissue-specific,modulated during the time and under normal/pathological conditions.Thus, we propose that each specified cell expresses a specific repertoire of lncRNA correlated to open/active chromatin regions specifying its cellular identity.In this context, we isolated by FACS 2neural types involved in many pathologies: i) human dopaminergic neurons (nDA) differentiated from hiPS and ii) DA and serotoninergic (n5-HT) neurons. From these 2neural types, we identified 1,363 lncRNA in nDA (among which 989 new, whether 73%) constituting the repertoire of nDA, and 1,257 lncRNA (among which 719 new) constituting the repertoire of n5-HT. Moreover,their comparison has shown that only 194 lncRNA are common to both neural types:thus the majority of lncRNA is expressed either in nDA or in n5-HT, indicating a high degree of cell-specificity.In addition, 39% of open chromatin regions, potentially regulatory, were also not detected in the n5-HT.Thus, we have generated DA and 5-HT specific catalogues of non-coding elements of the genome, which constitute DA and 5-HT specific molecular signatures, that could participate in deepening our knowledge regarding nDA or n5-HT development and dysfunctions. With this in mind,these DA specific elements have been compared with the SNP described as Parkinson Disease risk variants and candidate lncRNA were selected to perform studies of function
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Silva, Elizangela dos Anjos. "Avaliação morfológica e quantitativa dos neurônios do plexo mioentérico nas diferentes porções do ceco de ratos com seis e doze meses de idade, sedentários, e ratos submetidos à atividade física regular, com doze meses." Universidade de São Paulo, 2006. http://www.teses.usp.br/teses/disponiveis/10/10132/tde-25052007-152448/.
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Estudou-se o arranjo do plexo mioentérico, o número de neurônios e a área do perfil do corpo celular (µm2) dos neurônios mioentéricos, nas diferentes porções das regiões apical e basal, do ceco de ratos Wistar. Trinta ratos foram, igualmente, distribuídos em grupos de seis (G-6) e doze meses de idade (G-12S), sedentários, e um grupo com doze meses (G-12T), que foi submetido a um programa de atividade física de intensidade moderada. Foram montados preparados de membrana que receberam as técnicas histoquímica de NADH-diaforase (NADH-d) e NADPH-diaforase (NADPH-d). O arranjo do plexo mioentérico e o número de neurônios foram avaliados comparativamente entre os três grupos e entre as diferentes porções das regiões do ceco. Os neurônios das regiões apical e basal foram distribuídos em classes com intervalos de 100µm2, sendo comparadas às médias da mensuração dos pares, considerando as variáveis de idade e tratamento. Não foram observadas alterações na arquitetura do plexo mioentérico nas diferentes porções do ceco dos animais nos três grupos estudados. O número de neurônios NADH-d positivos foi maior do que o de NADPH-d em todas as porções, de ambas as regiões, de todos os grupos. O grupo G-12T apresentou maior número de neurônios NADH-d reativos do que os animais sedentários, com a mesma idade, em todas as porções do ceco, excetuando-se a porção próxima à ampola cecal. Os neurônios NADPH-d positivos não diferiram em número entre os grupos G-6 e G-12T (p-valor < 5%). A área do perfil dos neurônios NADH-d e NADPH-d reativos foi maior na região apical do que na basal em todos os grupos estudados, com exceção dos neurônios NADPH-d dos animais G-12T. Os neurônios NADH-d reativos são mais afetados pela idade do animal e pelo exercício físico do que os neurônios NADPH-d. Pela primeira vez, o número de neurônios do plexo mioentérico é reportado em porções pré-estabelecidas do ceco de ratos. Nossos resultados reiteram a importância da indicação precisa da porção estudada neste segmento intestinal.The arrangement of the myenteric plexus, the number of neurons, and the area of the profile of neuronal body (µm2) were studied in the different portions of the apical and basal regions of the cecum of rats. Thirty rats had been, equally, distributed in groups of six (G-6) and twelve months of age (G-12S), were sedentary, and a group with twelve months (G-12T), which was submitted to a program of physical activity of moderate intensity. They had been mounted whole mount preparation and were stained with the NADH-diaforase (NADH-d) and NADPH-diaforase (NADPH-d) histochemical techniques. The arrangement of the plexus and the number of neurons had been evaluated comparatively between the three groups, and the different portions of the regions of cecum. The neurons of the regions apical and basal had been distributed in class with intervals of 100µm2, and the averages of the measurements of the pairs were compared, considering the different ages and treatments. It was not observed alterations in the architecture of the myoenteric plexus in the portions of cecum, neither in the different studied groups. There was more NADH-d positive neurons than NADPH-d ones, in all the portions, of both the regions, of all the groups. The G-12T animals presented greater number of reactive NADH-d neurons than the sedentary ones, in all the portions of cecum, excepting the portion near to the cecal ampoule. The number of the positive NADPH-d neurons did not differ between G-6 and G-12T (p-value < 5%). The cellular profile area of the NADH-d and NADPH-d reactive neurons was bigger in the apical region than in the basal, in all groups, excepted of the NADPH-d neurons of animals G-12T. The NADH-d reactive neurons were more affected by the age of the animal and the physical exercise than the NADPH-d neurons. For the first time, the number of neurons of the myenteric plexus is reported in preset portions of ceco of rats. Our results reiterate the necessity of indication of the portion studied in this intestinal segment.
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Brot, Sébastien. "Etude structurale et fonctionnelle de la « Collapsin Response Mediator Protein » CRMP5." Thesis, Lyon 1, 2010. http://www.theses.fr/2010LYO10264.
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Le travail de cette thèse s’est articulé autour de l’étude de CRMP5 au cours du développement du système nerveux central. Nous avons mis en évidence une interaction directe entre CRMP5 et la tubuline, conduisant à une inhibition de la pousse neuritique dans différentes lignées cellulaires, ainsi qu’à une inhibition d’élongation uniquement au niveau des dendrites et non de l’axone, dans des cultures primaires de neurones de l’hippocampe. De plus, nous avons montré que CRMP5 pouvait annuler l’action de CRMP2, connue pour promouvoir la pousse neuritique, de façon dominante mais dépendante de la présence sur CRMP5 du site de fixation à la tubuline. Contrairement à CRMP2, l’expression de CRMP5 étant transitoire pendant la différentiation neuronale, elle permettrait de restreindre de façon spatio-temporelle l’effet de CRMP2 sur la pousse neuritique, régulant ainsi la polarité neuronale. D’autre part, nous avons également rapporté la présence de CRMP5 au niveau mitochondrial où elle pourrait jouer un rôle dans le processus d’autophagie des mitochondries. Enfin, nous nous sommes intéressés à l’étude de la CRMP5 exprimée en conditions pathologiques, et nous avons observé une nouvelle localisation nucléaire de la protéine dans certaines cellules cancéreuses. Etant localisée dans plusieurs compartiments subcellulaires et impliquée dans différents mécanismes moléculaires, l’ensemble de ce travail décrit donc la protéine CRMP5 comme une protéine « multi-fonctionnelle »The purpose of this work is to focus on the study of CRMP5 during development of the central nervous system. We have demonstrated a direct interaction between CRMP5 and tubulin, leading to inhibition of neurite outgrowth in different cell lines, and inhibition of growth only at dendritic but not axonal level, in hippocampal neurons. Furthermore, we showed that CRMP5 could counteract the previously described CRMP2 effect on neurite outgrowth. The CRMP5 acted as a dominant signal to counteract CRMP2 outgrowth promotion and this function is also dependent on the tubulin-binding capacity of CRMP5.Unlike CRMP2, the CRMP5 expression being transient during neuronal differentiation, it would imply in the spatiotemporal regulation of the CRMP2 effect on neurite outgrowth, thereby regulating neuronal polarity. In another part, we also reported the presence of CRMP5 at mitochondrial level in vivo where it could play a role in mitochondrial autophagic process.Finally, we were interested in the study of CRMP5 expressed in pathological conditions, and we discovered a new nuclear localization of the protein in some cancer cells. Being localizedin several subcellular compartments and involved in different molecular mechanisms, this work describes CRMP5 as a "multi-functional" protein
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Veltz, Romain. "Nonlinear analysis methods in neural field models." Thesis, Paris Est, 2011. http://www.theses.fr/2011PEST1056/document.
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Cette thèse traite de modèles mésoscopiques de cortex appelés champs neuronaux. Les équations des champs neuronaux décrivent l'activité corticale de populations de neurones, ayant des propriétés anatomiques/fonctionnelles communes. Elles ont été introduites dans les années 1950 et portent le nom d'équations de Wilson et Cowan. Mathématiquement, elles consistent en des équations intégro-différentielles avec retards, les retards modélisant les délais de propagation des signaux ainsi que le passage des signaux à travers les synapses et l'arbre dendritique. Dans la première partie, nous rappelons la biologie nécessaire à la compréhension de cette thèse et dérivons les équations principales. Puis, nous étudions ces équations du point de vue des systèmes dynamiques en caractérisant leurs points d'équilibres et la dynamique dans la seconde partie. Dans la troisième partie, nous étudions de façon générale ces équations à retards en donnant des formules pour les diagrammes de bifurcation, en prouvant un théorème de la variété centrale et en calculant les principales formes normales. Nous appliquons tout d'abord ces résultats à des champs neuronaux simples mono-dimensionnels qui permettent une étude détaillée de la dynamique. Enfin, dans la dernière partie, nous appliquons ces différents résultats à trois modèles de cortex visuel. Les deux premiers modèles sont issus de la littérature et décrivent respectivement une hypercolonne, /i.e./ l'élément de base de la première aire visuelle (V1) et un réseau de telles hypercolonnes. Le dernier modèle est un nouveau modèle de V1 qui généralise les deux modèles précédents tout en permettant une étude poussée des effets spécifiques des retardsThis thesis deals with mesoscopic models of cortex called neural fields. The neural field equations describe the activity of neuronal populations, with common anatomical / functional properties. They were introduced in the 1950s and are called the equations of Wilson and Cowan. Mathematically, they consist of integro-differential equations with delays, the delays modeling the signal propagation and the passage of signals across synapses and the dendritic tree. In the first part, we recall the biology necessary to understand this thesis and derive the main equations. Then, we study these equations with the theory of dynamical systems by characterizing their equilibrium points and dynamics in the second part. In the third part, we study these delayed equations in general by giving formulas for the bifurcation diagrams, by proving a center manifold theorem, and by calculating the principal normal forms. We apply these results to one-dimensional neural fields which allows a detailed study of the dynamics. Finally, in the last part, we study three models of visual cortex. The first two models are from the literature and describe respectively a hypercolumn, i.e. the basic element of the first visual area (V1) and a network of such hypercolumns. The latest model is a new model of V1 which generalizes the two previous models while allowing a detailed study of specific effects of delays
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El, Achkar Roger. "Contribution à l'étude et à la validation expérimentale de commandes neuronales d'un palier magnétique actif." Compiègne, 2008. http://www.theses.fr/2008COMP1747.
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Le palier magnétique actif présente une solution technologique à plusieurs problèmes puisqu'il assure le guidage en rotation du rotor par rapport au stator sans aucun contact mécanique entre les pièces tournantes et les pièces fixes. Ils constituent une solution technologique pour fonctionner à très grande vitesse de rotation. Toutefois, une vitesse plus élevée mène à l'augmentation des vibrations et du balourd. Ce travail porte sur la conception et réalisation d'une commande neuronale afin d'améliorer le comportement en stabilité et consommation d'énergie du palier magnétique actif. Nous avons développé deux méthodes de commandes neuronales. La première est utilisée afin d'optimiser toutes les réponses temporelles des positions des axes de point de vue dépassement et temps de réponse. Cette méthode sera aussi utiliser pour réduire l'effet du balourd. La deuxième méthode consiste à varier les gains du PID afin de commander le système. Cette méthode va éliminer les oscillations obtenues avec la méthode précédente et conduire à une économie importante au niveau d'énergie. La demière partie est consacrée aux simulations ainsi qu'aux essais obtenus sur un banc expérimental mis en oeuvre au laboratoire Heudiasyc de L'UTC. Les tests d'évaluations des méthodes proposées montrent des résultats satisfaisantsThe active magnetic bearing (AMB) presents a solution for technical proble since it ensures the total levitation of a body in space eliminating any mechanical contact between the rotor and the stator. The goal of o work is to show that the control of the AMB by Multilayer perceptions (MLP) involves an improvement of the responses compared to the non linear control of the AMB by classical controllers. Two methods with MLP were developed to control the AMB. The first consists in adding the MLP in order to stabilize the system around the desired answers. This method is also used to reduce the value of the unbalance. In the second method, the MLP controls the parameters of the PID in order to minimize the oscillations of the answers obtained with the previous method. This tuning, by neural network, of the parameters of the PID controller reduces the consumption of the energy used by the AMB. The last section is devoted to the simulation of these two methods and the implementation of the MLP in real time application on an active magnetic bearing at the Heudiasyc laboratory of the UTC
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Jönsson, Maria. "The neuronal and non-neuronal substance P, VIP and cholinergic systems in the colon in ulcerative colitis." Doctoral thesis, Umeå universitet, Anatomi, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-19946.
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Ulcerative colitis (UC) is a chronic relapsing inflammatory bowel disease. Neuropeptides, especially vasoactive intestinal peptide (VIP) and substance P (SP), have long been considered to play key roles in UC. Among other effects, these neuropeptides have trophic and growth-modulating as well as wound-healing effects. Furthermore, whilst VIP has anti-inflammatory properties, SP has pro-inflammatory effects. It is generally assumed that the main source of SP and VIP in the intestine is the tissue innervation. It is not known whether or not they are produced in the epithelial layer. The details concerning the expressions of their receptors in UC are also, to a great extent, unclear. Apart from the occurrence of peptidergic systems in the intestine, there are also neuronal as well as non-neuronal cholinergic systems. The pattern concerning the latter is unknown with respect to UC. The studies in this thesis aimed to investigate the expression of SP and VIP and their major receptors (NK-1R and VPAC1) in UC colon, compared to non-UC colon. The main emphasis was devoted to the epithelium. A second aim was to examine for levels of these neuropeptides in blood plasma in UC. Another aim was to examine for the non-neuronal cholinergic system in UC, thus, to investigate whether there is acetylcholine production outside nerves in the UC colon. Methods used in the thesis were immunohistochemistry, in situ hybridization, enzyme immunosorbent assay, and in vitro receptor autoradiography. For the first time, mRNA for VIP and SP has here been found in the colonic epithelium. That was especially noted in UC mucosa showing a rather normal morphology, and in non-UC mucosa. Marked derangement of the mucosa was found to lead to a distinct decrease in VIP binding, and also a decrease in the expression level of VIP receptor VPAC1 in the epithelium. In general, there was an upregulation of the SP receptor NK-1R in the epithelium when the mucosa was deranged. The plasma levels of SP and VIP were higher for UC patients compared to healthy controls. There were marked correlations between the levels of the peptides in plasma, their levels in the mucosa and the degree of mucosal derangement/inflammation. A pronounced nonneuronal cholinergic system was found in both UC and non-UC colon. Certain changes occurred in this system in response to inflammation/derangement in UC. The present study shows unexpectedly that expressions for VIP and SP are not only related to the nerve structures and the inflammatory cells. The downregulation of VPAC1 expression, and the tendencies of upregulation of NK-1R expression levels when there is marked tissue derangement, may be a drawback for the intestinal function. The study also shows that there is a marked release of neuropeptides to the bloodstream in parallel with a marked derangement of the mucosa in UC. The cholinergic effects in the UC colon appear not only to be associated with nerverelated effects, but also effects of acetylcholine produced in local non-neuronal cells. The thesis shows that local productions for not only acetylcholine, but also SP and VIP, occur to a larger extent than previously considered.
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BARJAUD, PASCAL. "Etude d'un protocole d'utilisation dans la determination de la nse et du rapport nse/nne pour le suivi des cancers anaplasiques a petites cellules du poumon." Clermont-Ferrand 1, 1992. http://www.theses.fr/1992CLF13051.
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Corson, Nathalie. "Dynamique d'un modèle neuronal, synchronisation et complexité." Phd thesis, Université du Havre, 2009. http://tel.archives-ouvertes.fr/tel-00453912.
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Le fonctionnement d'un neurone, cellule fondamentale du système nerveux, intéresse de nombreuses disciplines scientifiques. Il existe ainsi des modèles mathématiques qui décrivent leur comportement par des systèmes d'EDO. Plusieurs de ces modèles peuvent ensuite être couplés afin de pouvoir étudier le comportement de réseaux, systèmes complexes au sein desquels émergent des propriétés. Ce travail présente, dans un premier temps, les principaux mécanismes régissant ce fonctionnement afin d'en comprendre la modélisation. Plusieurs modèles sont alors présentés, jusqu'à celui de Hindmarsh-Rose (1984), qui présente une dynamique lente-rapide. C'est sur l'étude numérique mais également théorique de la dynamique asymptotique et transitoire de ce dernier modèle, que se concentre la seconde partie de cette thèse. Dans une troisième partie, des réseaux d'interactions sont construits en couplant les systèmes dynamiques précédemment étudiés. L'étude du phénomène de synchronisation complète au sein de ces réseaux montre l'existence de propriétés émergentes pouvant être caractérisées par des lois de puissance. Enfin, un algorithme de détection de la synchronisation de bursts est proposé.
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Loyer, Xavier. "Expression, rôle et régulation de l'isoforme neuronale NOS dans le myocarde sain et pathologique." Paris 7, 2007. http://www.theses.fr/2007PA077072.
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L'hypertrophie ventriculaire gauche (HVG) est un élément majeur dans la survenue de l'insuffisance cardiaque (IC). Au cours de PIC, l'expression et l'activité de l'isoforme neuronale (NOS1) des NO synthases (NOS) sont augmentées. Cependant le rôle précis de NOS1 dans le processus hypertrophique est inconnu. Ce travail a consisté à :1- déterminer le patron d'expression de NOS1 lors de l'HVG en fonction du genre et/ou du statut œstrogénique et 2- définir son rôle à l'aide d'un modèle sur-exprimant NOS1 au niveau du cardiomyocyte. En réponse à une sténose de l'aorte thoracique (TAC) chez le rat, l'induction de NOS1 est une réponse précoce chez le mâle. Des différences cinétiques, liées au genre, sont mises en évidence. L'induction et l'activité de NOS1 dans le cœur hypertrophié dépendent de signaux mécaniques et sont indépendantes des oestrogènes. Le modèle murin sur-exprimant NOS1 dans le cardiomyocyte a permis de démontrer après une TAC, le rôle bénéfique d'une sur-expression de NOS1. Ces animaux développent une HVG supérieure aux animaux sauvages et conservent une fonction cardiaque normale. Le rôle protrophique de NOS1 est démontré avec la technique d'interférence par l'ARN sur des cardiomyocytes en culture. La recherche des signaux mis en jeu, in vivo et in vitro, révèle l'implication de la voie dépendante de la calcineurine. Le rôle de NOS1 sur la prévention de l'IC est du au maintien de l'homéostasie calcique via des effets de NOS1 sur les protéines du réticulum sarcoplasmique impliquées dans le cycle calcique. En conclusion, ce travail révèle le rôle pro-trophique et bénéfique de NO SI dans le cœur en réponse à une surcharge sévère de pressionHypertrophy is crucial in the development of heart failure (HF). In failing hearts, NOS1 expression and activity are increased in cardiomyocytes,. However, the role of NOS1 in the setting of myocardial hypertrophy is unclear. Thus, the goals of the study were to 1- determine the pattern of NOS1 expression and 2- define its role in LVH. Using pressure overload-induced LVH in rats, we demonstrated that NOS1 expression and activity increased early in males and latter on in females, these regulations being only dependent on biomechanical stress. In vitro, the direct prohypertrophic role of NOS1 was confirmed on cultured cardiomyocyte, using RNA interference approach. In vivo, using a transgenic mouse with cardiac-specific overexpression of NOS1, we demonstrated that NOS1 protects against maladaptive remodeling and contractile dysfunction in response to pressure overload- Analyses of both in vivo and in vitro intracellular pathways showed that NO SI directly regulated the cardiac hypertrophic response through modulation of the calcineurin signalling pathway. Mechanistically, we showed that NOS 1 overexpression is beneficial in preventing the transition toward HF through the preservation of cardiomyocyte calcium cycling and contractility. In conclusion, our results suggest that targeting endogenous NOS1 could provide a useful strategy against adverse remodeling and functional deterioration during chronic pressure overload
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Chavy, Cyril. "Codeur neuronal prédictif : application au codage de phonèmes." Paris 6, 2004. http://www.theses.fr/2004PA066526.
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Ferreira, Brigham Marco Paulo. "Nonstationary Stochastic Dynamics of Neuronal Membranes." Thesis, Paris 6, 2015. http://www.theses.fr/2015PA066111/document.
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Les neurones interagissent à travers leur potentiel de membrane qui a en général une évolution temporelle complexe due aux nombreuses entrées synaptiques irrégulières reçues. Cette évolution est mieux décrite en termes probabilistes, en raison de ces entrées irrégulières ou «bruit synaptique». L'évolution temporelle du potentiel de membrane est stochastique mais aussi déterministe: stochastique, car conduite par des entrées synaptiques qui arrivent de façon aléatoire dans le temps, et déterministe, car un neurone biologique a une évolution temporelle très similaire quand soumis à une même séquence d'entrées synaptiques. Nous étudions les propriétés statistiques d'un modèle simplifié de neurone soumis à des entrées à taux variable d'où en résulte l'évolution non-stationnaire du potentiel de membrane. Nous considérons un modèle passif de membrane neuronale, sans mécanisme de décharge neuronale, soumis à des entrées à courant ou à conductance sous la forme d'un processus de «shot noise». Les fluctuations du potentiel de membrane sont aussi modélisées par un processus stochastique similaire, de «shot noise» filtré. Nous avons analysé les propriétés statistiques de ces processus dans le cadre des transformations de processus ponctuels de Poisson. Des propriétés de ces transformations sont dérivées les statistiques non-stationnaires du processus. Nous obtenons ainsi des expressions analytiques exactes pour les moments et cumulants du processus filtré dans le cas général des taux d'entrée variables. Ce travail ouvre de nombreuses perspectives pour l'analyse de neurones dans les conditions in vivo, en présence d'entrées synaptiques intenses et bruitéesNeurons interact through their membrane potential that generally has a complex time evolution due to numerous irregular synaptic inputs received. This complex time evolution is best described in probabilistic terms due to this irregular or "noisy" activity. The time evolution of the membrane potential is therefore both stochastic and deterministic: it is stochastic since it is driven by random input arrival times, but also deterministic, since subjecting a biological neuron to the same sequence of input arrival times often results in very similar membrane potential traces. In this thesis, we investigated key statistical properties of a simplified neuron model under nonstationary input from other neurons that results in nonstationary evolution of membrane potential statistics. We considered a passive neuron model without spiking mechanism that is driven by input currents or conductances in the form of shot noise processes. Under such input, membrane potential fluctuations can be modeled as filtered shot noise currents or conductances. We analyzed the statistical properties of these filtered processes in the framework of Poisson Point Processes transformations. The key idea is to express filtered shot noise as a transformation of random input arrival times and to apply the properties of these transformations to derive its nonstationary statistics. Using this formalism we derive exact analytical expressions, and useful approximations, for the mean and joint cumulants of the filtered process in the general case of variable input rate. This work opens many perspectives for analyzing neurons under in vivo conditions, in the presence of intense and noisy synaptic inputs
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Selmi, Foued. "Réponse excitable et propriétés neuromimétiques de micropiliers lasers à absorbant saturable." Thesis, Paris 11, 2015. http://www.theses.fr/2015PA112158/document.
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L'excitabilité est une propriété bien connue des neurones biologiques. Il s'agit d'une réponse de type tout-ou-rien à une perturbation au delà d'un seuil caractéristique appelé seuil excitable. D'autres propriétés importantes existent dans les neurones comme les périodes réfractaires et la sommation temporelle ou spatiale de stimuli d'entrée.L'excitabilité a été étudiée dans certains composants actifs à semiconducteur et notamment les composants à semiconducteurs III-V. Leurs propriétés neuro-mimétiques pourraient permettre de traiter l'information de façon tout-optique avec une grande bande passante et une faible consommation.Grâce aux nouvelles techniques de micro-nano fabrication, il est devenu possible de fabriquer des micropiliers lasers à absorbant saturable. Ces micropiliers pourraient permettre la réalisation de réseaux de micropiliers couplés excitables analogues à des réseaux de neurones photoniques.Dans cette thèse j'ai étudié les propriétés neuro-mimétiques de micropiliers lasers à absorbant saturable intégré. Les principaux résultats de cette thèse sont les suivants : 1) la technique de fabrication des micropiliers a été améliorée conduisant à une augmentation de leur durée de vie et une diminution du seuil laser. 2) des propriétés de base des neurones biologiques, comme l'excitabilité, l'existence des périodes réfractaires, la sommation temporelle, ont été mises en évidence expérimentalement et analysées à l'aide du modèle de Yamada. 3) des effets de propagation d'excitations ont été démontrés dans des structures unidimensionnelles : des lasers ligne et des chaînes de micropiliers couplés.La démonstration des propriétés neuromimétiques de micropiliers lasers à absorbant saturable et la mise en évidence de la propagation d'excitations ouvrent la voie à la réalisation de réseaux de micropiliers couplés pour les traitements neuromimétiques des signaux qui pourront être exploités pour de la logique codée à l'aide de pics excitables ainsi que pour du stockage d'information dans des circuits mémoires tout-optiquesExcitability is a well known property of biological neurons. In excitable systems, the response to a perturbation above the excitable threshold is of all-or-none type. Other properties exist in neurons such as the refractory periods and temporal or spatial summation of input stimuli.Excitability has been demonstrated in many III-V semiconductor material devices. Thanks to their nonlinear properties it could be possible to realize neuromimetic and all-optical signal processing with high speed and low energy consumption. Thanks to progress in fabrication techniques it is possible to fabricate high quality micropillar laser with saturable absorber. Thus, using micropillars it could be possible to realize neural photonic networks analog to neural networks.In this thesis work, I studied neuron-like properties of a micropillar laser with a saturable absorber. My main results are : 1) fabrication of micropillars has been improved leading to an increase of their robustness and a reduction of the laser threshold. 2) well known properties of biological neurons, such as excitability, existence of refractory periods, temporal summation, have been demonstrated experimentally and have been numerically analyzed with the Yamada model. 3) propagation effects of excitations have been demonstrated in one-dimensional structures : wire lasers and chains of coupled micropillars.The demonstration of neuromimetic properties in micropillar lasers with saturable absorber and the evidence of propagation of excitations pave the way to neuromorphic networks based on coupled micropillars for neuromimetic signal processing like information encoding with excitable pulses and realization of optical memories
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Ebrahimian, Talin. "Expression et fonction de la NOS neuronale dans les cellules musculaires lisses de la paroi vasculaire." Paris 7, 2003. http://www.theses.fr/2003PA077155.
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Lairi, Mostafa. "Identification et commande neuronales de systèmes non-linéaires : application à un système de sustentation magnétique." Nancy 1, 1998. http://www.theses.fr/1998NAN10156.
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Cette thèse est consacrée à l'identification et à la commande de systèmes dynamiques non linéaires SISO par réseaux de neurones. Dans un premier temps, une présentation des réseaux de neurones est effectuée en rappelant l'origine des nombreux travaux actuels et les différents modèles neuronaux existants. Dans le deuxième chapitre l'identification par réseaux de neurones est présentée étape par étape depuis la collecte des données jusqu'à l'obtention de la structure et des paramètres optimaux. Le chapitre suivant présente les différentes stratégies de commande neuronale. Une stratégie de contrôle neuronal par anticipation est appliquée à un système de sustentation magnétique, non linéaire et instable en boucle ouverte. Elle est comparée à une régulation PID standard : élimination des dépassements, poursuite parfaite de la référence, élargissement de la plage de stabilité. La stratégie proposée est mise en œuvre en temps réel en utilisant l'environnement logiciel Matlab Simulink et RTW, qui permet une conception rapide et modulaire et un changement en temps réel des paramètres et des consignes.
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Jurzik, Lars. "Veränderung der neuronalen Vasoregulation im mesenterialen Gefässbett bei portaler Hypertension mit besonderem Fokus auf die neuronale Stickstoffmonoxyd-Synthase (nNOS)-vermittelte Vasorelaxation und die Neuropeptid-Y-(NPY)-induzierte Vasokonstriktion /." [S.l.] : [s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=973326840.
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Júnior, André Oliveira Mota. "Caracterização molecular do gene ncsA de Aspergillus fumigatus." Universidade de São Paulo, 2008. http://www.teses.usp.br/teses/disponiveis/17/17136/tde-05012009-123104/.
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O foco do trabalho está direcionado para a construção da linhagem knock-out do gene ncsA de A. fumigatus, bem como a caracterização do fenótipo da linhagem DncsA e a investigação de interações deste gene com vias de sinalização importantes para o desenvolvimento do fungo. A linhagem mutante ncsA foi construída através da transformação do WT (Dku80) com o gene marcador pyrG de A. fumigatus. Foi confirmada a deleção por Southern blot e as alterações fenotípicas da linhagem foram analisadas. O gene ncsA em A. fumigatus não é essencial e a linhagem DncsA apresentou-se sensível EGTA e SDS, alé, de tolerante a altas concentrações de íons cálcio. Na linhagem NcsA:mRFP foi localizado a proteína NcsA no citoplasma das células e sua localização não é alterada pela em resposta ao aumento da concentração de cálcio. A linhagem DncsA foi sensível a drogas que afetam a biossíntese e a manutenção da membrana plasmática, tais como voriconazole, anfotericina e itraconazole. O crescimento polarizado em presença de lovastatina nessa linhagem foi consideravelmente mais afetado que no tipo selvagem. O Spitzenkörper não foi visualizado no mutante DncsA, e existe uma significante diminuição de estruturas vacuolares e endossomos. Os resultados obtidos em ensaios de TRPCR em tempo real sugerem que NcsA modula a expressão dos genes pmcA e pmcB, que codificam proteínas ATPases transportadoras de íons cálcio. Os ensaios de virulência no modelo animal revelaram que a mutação do gene ncsA não causa perda de virulência no A. fumigatus.Here, we characterize the A. fumigatus Neuronal Calcium Sensor, ncsA homologue. We showed that ncsA is not an essential gene and ncsA growth was decreased in the presence of EGTA and SDS. Furthermore, the ncsA mutant is more resistant to calcium chloride. NcsA:mRFP localizes to the cytoplasm that its cellular localization is not affected by the cellular response to calcium chloride. The ncsA mutant strain is more sensitive to voriconazole, itraconazole, and the ergosterol intercalating agent, amphotericin. Polar growth in the DncsA mutant strain was also considerably more affected by lovastatin than in the wild type mutant strain. The Spitzenkörper cannot be visualized in the DncsA mutant, and there is a significant decrease of the endosome/vacuole structures. NcsA supports pmcA and pmcB expression therefore reduced expression of these ion pumps, and also of other genes involved in the response to calcium in A. fumigatus. The ncsA inactivation mutation is not causing loss of virulence in a low dose murine infection when compared to the corresponding wild type strain.
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Magno, Luiz Alexandre Viana. "Fármacos estabilizadores do humor regulam a expressão do sensor neuronal de cálcio 1 (NCS-1)." Universidade Federal de Minas Gerais, 2012. http://hdl.handle.net/1843/BUOS-96LGMM.
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Mood stabilizers (MSDs) represent a class of drugs commonly prescribed for bipolar disorder (BD) treatment though the molecular mechanisms underlying their actions remain to be identified. The aim of this study was to evaluate the effect of the MSDs lithium (Li), valproate
(VPA), lamotrigine (LTG) and carbamazepine (CBZ) on the levels of neuronal calcium sensor 1 (Ncs-1), a multifunctional protein has been involved in many neuronal functions such as survival and dopamine signaling. Furthermore, the biological impact of the Ncs-1 genetic disruption was investigated in mice and Caenorhabditis elegans as well. Treatment with a therapeutically relevant dose of Li and VPA for 4 weeks caused an increase in the level of Ncs-1 in mouse frontal cortex. Interestingly, this effect was abolished in Arr2 (beta-arrestin 2) and D2R (dopamine receptor type 2) knockout (KO) mice. Two inhibitors of Gsk3
or Mek1/2 (TDZD and U0126, respectively), recently identified targets of Li and VPA, but not histone deacetylase specific inhibitors, also increased the levels of Ncs-1 protein and gene expression both in vitro and in vivo. On the other hand, Gsk3overexpression strongly reduced Ncs-1 mRNA levels. Cycloheximide, an inhibitor of protein biosynthesis in eukaryotic organisms, was found to impair the TDZD or U0126-induced Ncs-1 expression. Then, we developed a luciferase reporter system to investigate how the Gsk3 and Erk1/2 inhibition regulate the Ncs-1 gene expression. However, no significant luciferase activity was found in transfected cells with the constructs of the Ncs-1 promoter. Furthermore, we also found significant changes in cerebral oxidative stress and energy metabolism, memory impairment and lack of the d-amphetamine-induced hyperlocomotion in Ncs-1 KO mice. We
have found decreased levels of Ncs-1 in the frontal cortex of a d-amphetamine-based behavioral model of acute mania, however, one week VPA treatment restored both the behavior and the Ncs-1 levels. To our knowledge, this is the first report that has investigated the pharmacologic action of MSDs on Ncs-1 expression. Our data suggest that these drugs might exert their actions on Ncs-1 via Gsk3 and Erk inhibition. The finding that two widely prescribed mood stabilizers have a common action, the increased Ncs-1 protein expression in vitro and in vitro, raises the question of what the link is between the mechanisms of action of the mood stabilizers and Ncs-1 induction. It is also unclear whether Ncs-1 induction is involved in the mood-stabilizing effects of these drugs. Further studies will be needed to address these issues and the involvement of Ncs-1 in the pathogenesis of BD. In conclusion, the data obtained from this study identified Ncs-1, a protein that may play a role in psychiatric disorders, as a protein that is commonly induced by the two mood stabilizers, Li e VPA.Os fármacos estabilizadores do humor (FEHs) são uma classe de medicamentos empregados na terapia do transtorno afetivo bipolar (TAB) cujo mecanismo de ação responsável pelas suas ações terapêuticas ainda não é bem esclarecido. Neste estudo, nós investigamos pela primeira vez o efeito dos FEHs lítio (Li), valproato (VPA), lamotrigina (LTG) e carbamazepina (CBZ) sobre a regulação da expressão do sensor neuronal de cálcio tipo 1 (Ncs-1), uma proteína multifuncional desregulada em transtornos psiquiátricos e associada com a sobrevivência e a sinalização dopaminérgica. Além disso, o impacto biológico e farmacológico da deleção genética in vivo do Ncs-1 também foi investigado em camundongos e Caenorhabditis elegans. Através de diferentes modelos experimentais e regimes de tratamento farmacológico in vitro e in vivo, os resultados do estudo mostraram que a expressão do Ncs-1 é induzida por Li e VPA em células PC12 e córtex frontal de camundongos após tratamento crônico. Interessantemente, este efeito foi abolido em animais nocautes de Arr2 (beta arrestina 2) e D2R (receptor de dopamina tipo 2). A inibição das vias de sinalização de Gsk3 e Erk, as quais são alvos em comum de Li e VPA, mas não a inibição de histonas deacetilases, induziu a expressão o gene NCS-1 in vitro e in vivo, enquanto que a superexpressão de Gsk3reduziu drasticamente os níveis de RNAm deste gene. O efeito mediado pela inibição de Gsk3 ou Erk sobre o gene NCS-1 mostrou-se fundamental para a elevação dos níveis intracelulares de Ncs-1 pois a inibição da tradução impediu tal aumento observado. Com a finalidade de compreender como a expressão do gene NCS-1 é regulada, sequências candidatas a promotor foram clonadas em um sistema de gene repórter, porém, nenhuma atividade significante dessas sequências foi detectada em células transfectadas. Além disso, os diferentes modelos experimentais empregados pelo estudo mostraram que animais nocautes de Ncs-1 são caracterizados por alterações no estresse oxidativo e metabolismo energético cerebral, memória e perda de resposta hiperlocomotora induzida por anfetamina. Um modelo experimental de mania aguda induzida por anfetamina que foi caracterizado por níveis reduzidos de Ncs-1 especificamente no córtex frontal, foi tratado com VPA e obteve normalização dos níveis de Ncs-1. Até o momento, poucos alvos moleculares em comum relacionados com a ação farmacológica dos FEHs foram identificados. Desta forma, as evidências apresentadas por este estudo apontam a proteína multifuncional Ncs-1 como o mais novo alvo celular em comum regulado por Li, VPA, Gsk3 e Erk. Estes resultados inéditos, além de prover novos conhecimentos neurobiológicos, abrem uma janela de oportunidades para novas explorações que investiguem o papel celular do Ncs-1 através da inibição de Gsk3 e Erk na mediação dos efeitos terapêuticos e/ou adversos do tratamento com fármacos estabilizadores do humor.
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Niksic, Laurent. "La vasopressine module l'expression de l'isoforme neuronale de la "Nitric oxyde synthetase" (NOS) dans la medulla du rat /." Genève : [s.n.], 2005. http://www.unige.ch/cyberdocuments/theses2005/NiksicL/these.pdf.
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Séjourné, Julien. "Dynamique des phases de mémoire et réseaux neuronaux chez Drosophila melanogaster." Phd thesis, Paris 6, 2009. http://pastel.archives-ouvertes.fr/pastel-00567093.
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Comment les différentes phases de mémoire interagissent-elles ? Quels sont les mécanismes moléculaires et cellulaires impliqués dans la formation de la mémoire consolidée ? Drosophila melanogaster s'avère être un excellent modèle pour l'étude des mécanismes neurologiques de l'apprentissage et de la mémoire car, malgré la relative simplicité de son cerveau, elle est capable d'apprentissages variés et performants. Ainsi, un protocole de conditionnement pavlovien associant une odeur à des chocs électriques permet la formation d'une mémoire olfactive aversive. Un cycle unique de conditionnement induit la formation d'une mémoire labile ne durant que quelques heures, alors que cinq cycles de conditionnement espacés avec un intervalle de repos induisent la formation de la mémoire à long terme (MLT). La MLT est une mémoire consolidée et dépendante d'une synthèse protéique de novo. Une autre forme de mémoire consolidée, la mémoire résistante à l'anesthésie (MRA), est formée après un cycle ou plusieurs cycles de conditionnement massés. Même si les mécanismes moléculaires impliqués dans la formation des mémoires labiles et de la MLT commencent à être relativement bien caractérisés, ceux de la MRA restent largement inconnus à ce jour, peu de mutants pour ce type de mémoire ayant été identifiés. Par ailleurs, les relations entre les deux formes de mémoire consolidée restaient à définir, certains modèles proposant que ces deux formes de mémoire coexistent après un conditionnement espacé, alors que notre équipe a suggéré que la MRA et la MLT étaient exclusives. Pendant ma thèse, j'ai recherché de nouveaux mutants de MRA afin d'essayer de répondre à ces questions. Le criblage après conditionnement de lignées homozygotes portant un élément transposable P(Gal4) a permis d'identifier un nouveau mutant de MRA, memory-gating-defective (megad). Le gène megad code un transporteur aux acides monocarboxyliques, tel que le lactate. Chez la souche sauvage la protéine Megad est exprimée dans le centre de la mémoire olfactive, les corps pédonculés (CPs), où elle pourrait jouer un rôle dans l'approvisionnement énergétique de certains neurones lors de la formation de la MRA. L'inhibition de l'expression de megad uniquement dans les CPs de l'adulte induit un défaut de MRA, indiquant que ce gène joue un rôle physiologique dans la formation de cette mémoire. Au contraire après un conditionnement espacé le mutant megad présente une performance mnésique normale, confirmant l'hypothèse proposée au laboratoire selon laquelle la MRA n'est plus détectée après un conditionnement espacé. Pourquoi la MRA est-elle effacée ou bloquée après un conditionnement espacé ? Nous montrons que la formation de la MLT est facilitée chez le mutant megad puisqu'elle se forme après trois seulement trois cycles de conditionnement espacés, alors qu'il en faut au moins 5 chez la souche sauvage. Ce résultat important suggère que la présence de la MRA contrôle chez la souche sauvage la formation de la MLT, empêchant cette mémoire coûteuse en énergie de se former après un conditionnement unique. Les rôles des CPs ainsi que de certains réseaux neuronaux extrinsèques aux CPs dans la mémorisation olfactive ont été bien caractérisés ces dernières années. Néanmoins, il n'est pas connu comment la trace mnésique sort des CPs lors du rappel mnésique. Dans le but de répondre à cette question j'ai criblé des neurones extrinsèques aux CPs à l'aide d'une toxine thermosensible permettant une inactivation spécifique et conditionnelle de ces neurones. J'ai ainsi montré que les neurones MB-V2, qui sont efférents aux lobes verticaux des CPs, sont impliqués dans le rappel de toutes les formes de mémoire olfactive aversive. De plus la neurotransmission des neurones MB-V2 n'est requise ni pendant l'apprentissage ni pendant la consolidation mnésique. Les neurones MB-V2 projettent sur la corne latérale, une structure impliquée dans l'évitement aux odeurs aversives chez les mouches naïves. Ainsi, pendant le rappel de la mémoire olfactive aversive, la trace mnésique présente dans les CPs activerait les neurones MB-V2 qui renforceraient, via la corne latérale, la voie naturelle d'évitement de l'odeur.
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Cheung, Nathan Yiutung. "Serotonin receptor and neuronal nitric oxide synthase expression in the rat brain : implications for MDMA toxicity." Thesis, King's College London (University of London), 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.368095.
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Jouffroy, Guillaume. "Contrôle oscillatoire par réseau de neurones récurrents." Paris 8, 2008. http://www.theses.fr/2008PA082918.
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Dans le domaine du contrôle, la plupart des applications nécessitent une commande continue non-périodique. Ce travail se focalise au contraire sur les contrôleurs à base de réseaux de neurones récurrents (RNR) générant une commande oscillatoire entretenue. L'objectif de ce travail est d'étudier les méthodes d'optimisation stochastiques continues permettant de déterminer les paramètres d'un réseau pour qu'il produise un comportement oscillatoire périodique. Nous dressons tout d'abord un bilan des connaissances sur les oscillateurs biologiques. Nous décrirons ensuite des outils mathématiques qui permettent de garantir la stabilité des oscillateurs. Le potentiel des RNR, particulièrement appliqués aux systèmes dynamiques, n'étant encore que très peu exploité, nous proposerons pour chaque méthode, une formalisation générale matricielle détaillée et préciserons la complexité des algorithmes. Nous validerons chacune de ces méthodes à l'aide d'un simple oscillateur, en démontrant analytiquement la stabilité du système résultant, et en montrant dans quelle mesure il est robuste face aux perturbations de ses paramètres. Nous comparerons les différentes méthodes sur ces critères ainsi que sur la vitesse de convergence. Nous terminerons cette thèse par une illustration, dans laquelle nous réaliserons toutes les étapes de la construction d'un contrôleurs oscillatoire neuronal, pour commander l'axe de direction d'un véhicule original. Ceci nous permettra de discuter de la viabilité des réseaux de neurones récurrents dans le domaine de contrôle oscillatoire, et de soulever des questions intéressantesIn the control field, most of the applications need a non-oscillatory continuous control. This work focuses instead on controllers with recurrent neural networks (RNN) which generate a periodic oscillatory control. The purpose of the present work is to study stochastic optimisation methods which can be used to discover the parameters of a network so that it generates a cyclic input. First we take a look at the knowledge about biological oscillators. Tthen we describe the mathematical tools to be able to guarantee the stability oscillators. The potential of RNN, especially applied to dynamical systems being still poorly used, we propose for each method, a general detailed matrix formalization and we precise the computational complexity of the methods. We validate each method using a simple example of oscillator, and we demonstrate analytically the stability of the resulting oscillator, but also how it is robust to parameters perturbations. We then compare these different methods with these criteria and the speed of convergence. We finish this thesis with an illustration, where we take all the steps of the construction of an oscillatory neural controller, to control the axis of direction of a particular vehicle. This will let us discuss how realistic is the use of recurrent neural networks in the field of control, and propose interesting questions
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Leber, Werner. "Characterisation of a bifunctional plasmodium falciparum phosphatidylinositol 4-phosphate 5-kinase/neuronal calcium sensor (PfPip5K/NCS)." Thesis, London School of Hygiene and Tropical Medicine (University of London), 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.502463.
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Guimaraes, Melissa Monteiro. "Envolvimento da proteína neuronal sensora de cálcio-1 (NCS-1) na sinalização muscarínica em células PC12." Universidade Federal de Minas Gerais, 2007. http://hdl.handle.net/1843/BUOS-9R6HWA.
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Neuronal calcium sensor-1 (NCS-1) belongs to the superfamily of EF-hand Ca2+ binding protein. Overexpression of NCS-1 was implicated on potentiation of synaptic transmission and plasticity in many experimental models. In this study we investigated the possible involvement of NCS-1 in the facilitation of glutamate release evoked by two distinct stimuli in the neuronal-like pheochromocytoma (PC12) cell: membrane depolarization induced by 60mM KCl and GPCR activation induced by 300ìM carbachol (CCH). Both KCl depolarization and G-protein coupled receptor activation by CCH evoked glutamate release from PC12 wild type cells (PC12-wt) and PC12 cells stable overexpressing NCS-1 (PC12-NCS-1) compared with control conditions. Both KCl depolarization and CCH stimulation were more efficient to evoke glutamate release from PC12-NCS-1 cells when compared with release evoked from PC12-wt cells. The increased glutamate release induced by CCH from PC12-NCS-1 cells was independent of extracellular calcium entry, however this effect was dependent on extracellular calcium influx when depolarized with KCl. At permeabilizing conditions both PC12-NCS-1 and PC12-wt stimulated with CCH were able to increase glutamate release compared with non-stimulated cells indicating that part of glutamate release could be originated from vesicles source. Thus, our results suggest together that the NCS-1 facilitation of glutamate release could respond to different stimuli and is related to the increase in intracellular calcium originated from the extracellular compartment when associated to depolarization stimuli and from intracellular stores when associated to GPCR activation.A proteína Neuronal Sensora de Cálcio-1 (NCS-1) pertence à superfamília de proteínas apresentando domínios EF-hand com afinidade ao Ca2+. É expressa em neurônios e células neuroendócrinas onde modula a transmissão sináptica e plasticidade celular. Trabalhos descritos mostraram aumento da expressão da proteína NCS-1 no córtex pre-frontal de pacientes esquizofrênicos a partir de análises pós-morte sugerindo o envolvimento de NCS-1 nos mecanismos moleculares de regulação da transmissão dopaminérgica associados aos transtornos mentais. Entretanto, pouco se sabe a respeito da participação de NCS-1 na regulação da via de sinalização muscarínica. Neste trabalho foram verificados efeitos da superexpressão da NCS-1 em células PC12 (PC12- NCS-1) nos processos de liberação de glutamato, níveis de Ca2+ e dinâmica de fosfoinositídeos provocados pela ativação da via muscarínica. Foi observado que o estímulo com carbacol (CCH) (300mM) induziu liberação de glutamato tanto nas células PC12 selvagens (PC12-wt) quanto nas células PC12-NCS-1. Entretanto a liberação de glutamato foi maior nas células PC12-NCS-1 em comparação às células PC12-wt respectivamente (14.4 ± 1.8 e 8.3 ± 0.9 nmol/mg de proteína). Níveis aumentados de glutamato liberado pelas células PC12-NCS-1 estimuladas com CCH foram observados tanto na presença quanto na ausência do influxo de Ca2+. Além disso, níveis aumentados de InsP3 (663,0 ± 63,0 e 310.0 ± 39.0 % de fluorescência em U.A. ± EPM) e na [Ca2+]i (766.35 ± 35.0 e 687.8 ± 37.0 em nM ± EPM) foram observados nas células PC12-NCS-1 em comparação às células PC12-wt estimuladas com CCH (300mM) respectivamente. Padrões distintos na dinâmica intracelular de Ca2+ foram observados após o estímulo das células com CCH. Nas células PC12-NCS-1 foi observado um aumento na [Ca2+]i seguido de um decaimento rápido. Nas células PC12-wt foi observado um decaimento lento na [Ca2+]i característico de um platô. Tanto o aumento na formação de InsP3 quanto na liberação de glutamato foram bloqueados pela atropina (10mM) nas células PC12-NCS-1 estimuladas com CCH. Esses resultados indicam que o aumento da expressão de NCS-1 nas células PC12 induz facilitação da dinâmica de formação de segundos mensageiros e da liberação de glutamato dependente da ativação muscarínica. Essas evidências sugerem que a proteína NCS-1 poderia estar envolvida na amplificação de processos adaptativos da sinalização muscarínica associados a patofisiologia dos transtornos neurais.
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Lu, Chieh-Ju. "Neuronal nitric oxide synthase-CAPON regulation of cardiac sympathetic activity in the development of hypertension." Thesis, University of Oxford, 2015. http://ora.ox.ac.uk/objects/uuid:1204dec9-9f09-458d-b361-c8d14589fcd1.
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The studies presented in this thesis were undertaken to investigate the cellular and molecular mechanisms responsible for sympathetic hyperactivity that is observed in the Spontaneous Hypertensive Rat (SHR) and whether these abnormalities arise even before the onset of hypertension. Moreover, selected molecular candidates related to oxidative state in cardiac autonomic signalling have been explored for their potential therapeutic effects. Chapter One is an overview of (i) the relevance of autonomic dysfunction in cardiovascular disease in both human and animal models, (ii) the physiological basis of cardiac sympathetic neurotransmission, (iii) the neuromodulators of peripheral cardiac sympathetic-vagal balance discussed along with how they may be involved in cardiac adrenergic control of neurotransmission and NO-cGMP signalling. This develops the formulation of the specific aims of the thesis. Chapter Two outlines a detailed rationale for the experimental approach taken to (i) characterise protein expression in the pre-hypertensive animal model with immunohistochemistry and Western blotting, (ii) manipulate selected gene expression to amplify NO-cGMP signalling in vivo and in vitro via viral gene transfer, (iii) investigate calcium handling in cardiac sympathetic stellate neurons with calcium imaging , (iv) measure cardiac noradrenergic neurotransmission from double atria using radioactive-labelled [3H]-noradrenaline. Chapter Three demonstrated abnormal NO-cGMP signalling in pre-hypertensive SHRs. Endogenous nNOS protein residing in both cardiac parasympathetic and sympathetic neurons was significantly lower in the pre-hypertensive SHR compared to aged-matched WKYs. This was associated with lower cGMP levels. An enhanced depolarization evoked [Ca2+]i transient was observed in cardiac stellate neurons from pre-hypertensive SHR when compared with the WKY, an effect that was reversed by nNOS or sGC inhibition. Chapter Four investigated the role of nNOS and brain natriuretic peptide (BNP) in cGMP signalling pathways. Gene transfer of nNOS via adenoviral vector in SHR cardiac sympathetic neurons increased cGMP concentration and normalised neuronal calcium handling during depolarization. BNP significantly reduces [3H]- noradrenaline release. Overexpression of PDE2 which facilitates the breakdown of cGMP caused an increase in [3H]- noradrenaline release in response to field stimulation and also prevented the inhibitory action of BNP. Chapter Five examined the role of the nNOS adaptor protein, CAPON in NO-cGMP signalling. Endogenous CAPON protein is present in cardiac sympathetic neurons in the WKY, and is significantly reduced in pre-hypertensive SHR cardiac neurons. Artificial up-regulation of cardiac sympathetic CAPON via targeted gene transfer directly attenuated neuronal Ca2+ transients, resulting in decreased noradrenaline release in the SHR. Chapter Six is a concluding discussion summarising the main findings from this thesis, placing them in a physiological context and discussing avenues for further research.
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Daachi, Boubaker. "Observateurs et commande neuronale adaptative pour systèmes robotisés." Versailles-St Quentin en Yvelines, 2000. http://www.theses.fr/2000VERS0020.
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Dans cette thèse nous proposons une méthodologie de commande neuronale adaptative pour les systèmes robotisés. Lorsque la structure du modèle est connue (c'est le cas des robots manipulateurs) et que l'état du système est mesurable, nous avons développé une commande neuronale avec une estimation en ligne des fonctions du modèle. Dans le cas où seulement une partie de l'état du système est mesurable, nous avons proposé dans un premier temps, un observateur adaptatif basé sur une technique mixte utilisant la méthode des modes glissants et les réseaux de neurones. Dans un deuxième temps, nous avons développé une commande neuronale adaptative intégrant un observateur par modes glissants. En suivant la même démarche que précédemment, une méthode neuronale de compensation des frottements dans un actionneur électrique est proposée et appliquée. Nous proposons aussi une commande neuronale adaptative des robots manipulateurs redondants dans l'espace opérationnel sans avoir recours à l'inversion de matrices. Dans les différents schémas de commande proposés, un terme de robustesse est rajouté afin de réduire l'effet de l'erreur d'approximation inhérente à l'utilisation des réseaux de neurones. Lorsque le modèle du système est inconnu, une nouvelle démarche expérimentale de commande adaptative a été proposée. Cette démarche consiste à faire un apprentissage a priori dont le but est de déterminer le degré relatif du système, ensuite d'utiliser le résultat obtenu pour la commande adaptative. Cette commande a été appliquée pour l'asservissement en force d'un vérin hydraulique
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Ammar, Adel. "Restitution de la salinité de surface de l'océan à partir des mesures SMOS : une approche neuronale?" Toulouse 3, 2008. http://thesesups.ups-tlse.fr/475/.
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L'inversion des mesures du satellite SMOS par des réseaux de neurones pose plusieurs difficultés, liées principalement à la variabilité des angles d'incidence observés et à l'importance du bruit de mesure. Cette thèse propose des solutions à ces obstacles dans un cas réaliste, et montre qu'une approche neuronale peut être applicable à tous les pixels de l'océan pour restituer la salinité avec une bonne précision. Concernant le choix de la base d'apprentissage, nous montrons qu'une base équi-répartie en paramètres géophysiques permet de réduire notablement les biais systématiques sur la salinité restituée qui sont dus à l'importance du bruit de mesure. Par ailleurs, une technique de prolongation de l'apprentissage permet de faire disparaître la plupart de ces défauts dans une large gamme de latitude. Les travaux accomplis pendant cette thèse ont permis de définir la méthodologie à appliquer, en phase de vol, et de fixer l'architecture des réseaux d'inversionUsing neural networks to retrieve the sea surface salinity from the observed Soil Moisture and Ocean Salinity (SMOS) brightness temperatures (TBs) is an empirical approach that offers the possibility of being independent from any theoretical emissivity model. We prove that this approach is applicable to all pixels over ocean, by designing a set of neural networks with different inputs. Besides, we demonstrate that a judicious distribution of the geophysical parameters in the learning database allows to markedly reduce the systematic regional biases of the retrieved SSS, which are due to the high noise on the TBs. An equalization of the distribution of the geophysical parameters, followed by a new technique for boosting the learning process, makes the regional biases almost disappear for latitudes between 40°S and 40°N, while the global standard deviation remains between 0. 6 psu (at the center of the swath) and 1 psu (at the edges)
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McNamara, Tanner. "ENOS and nNOS contribution to reflex cutaneous vasodilation during dynamic exercise in humans." Thesis, Kansas State University, 2012. http://hdl.handle.net/2097/13788.
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Master of ScienceDepartment of Kinesiology
B.J. Wong
Recent data suggests nNOS mediates the NO-component of reflex cutaneous vasodilation with passive heat stress. Our hypothesis was nNOS, but not eNOS, inhibition would attenuate reflex cutaneous vasodilation during dynamic exercise. Protocol 1: subjects performed a VO[subscript]2 peak test on a supine cycle ergometer. Protocol 2: with experimental arm at heart level subjects cycled in supine posture at 60% VO[subscript]2 peak to raise core temperature (Tc) 0.8-1.0°C (35-45 min). In protocol 2 subjects were equipped with 4 microdialysis fibers on the forearm and each randomly assigned as: 1) lactated Ringer’s (control); 2) 5mM NPLA (nNOS inhibition); 3) 10mM L-NIO (eNOS inhibition); and 4) 20mM L-NAME (non- selective NOS inhibition). At the end of protocol 2 all sites were locally heated to 43°C and infused with SNP to elicit maximal dilation. Mean arterial pressure (MAP), skin blood flow via laser- Doppler flowmetry (LDF), and Tc via ingestible telemetric pill were measured; cutaneous vascular conductance (CVC) was calculated as LDF/MAP and normalized to maximum. In protocol 2 there was no significant difference between control (62±5 %CVCmax) and NPLA (61±6 %CVCmax). L-NIO (38±4 %CVCmax) and L-NAME (41±7 %CVCmax) significantly attenuated CVC compared to control and NPLA (p<0.001 all conditions). There was no difference between L-NIO and L- NAME. We conclude eNOS, not nNOS, contributes to reflex cutaneous vasodilation during dynamic exercise.
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Cherruel, Gildas. "Etude de commandes neuronales en environnement synchrone SIGNAL." Brest, 1996. http://www.theses.fr/1996BRES2011.
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Le but de cette thèse a deux objectifs : l'écriture de commandes neuronales et l'utilisation des réseaux de neurones en environnement synchrone signal. La conjonction de ce langage et des réseaux nous a permis d'écrire des commandes dont nous avons pu contrôler la qualité et l'évolution. Après une introduction aux réseaux de neurones et à la rétro-propagation, nous avons décrit les schémas de commandes neuronales qui existent à l'heure actuelle. Nous avons vu que la commande adaptative indirecte permet de n'avoir qu'un nombre minimum de contraintes et d'hypothèses sur le système à commander. Nous avons ensuite montré l'apport de l'approche synchrone pour l'écriture de commandes neuronales. En effet, celle-ci permet de s'affranchir d'un certain nombre de contraintes rencontrées dans la programmation traditionnelle. Nous avons alors développé un systeme complet qui permet non seulement d'écrire des systèmes neuronaux pour la commande, la reconnaissance, mais aussi de les tester et de vérifier leur comportement de manière formelle. Il est alors possible d'intégrer de tels réseaux dans des systèmes temps-réels embarqués en toute sécurité. Nous avons validé notre approche en écrivant de commandes neuronales pour divers systèmes non-linéaires
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Dumont, Grégory. "Analyse de modèles de population de neurones : cas des neurones à réponse postsynaptique par saut de potentiel." Thesis, Bordeaux 1, 2012. http://www.theses.fr/2012BOR14601/document.
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Ce travail de thèse concerne la modélisation mathématique et l’étude du comportement d’une population de neurones. Dans tout ce travail on s’arrêtera principalement sur une population de neurones auto-excitateurs où chaque cellule du réseau est supposée suivre la loi de l’intègre et tire. Néanmoins nous aborderons au détour d’un chapitre la modélisation d’une population de neurones inhibiteurs, et dans une dernière partie, nous discuterons la modélisation d’une population de neurones obéissant au modèle Ermentrout-Kopell aussi appelé le théta-neurone. L’angle de vue adopté dans cette thèse est donné par l’approche densité de population. Cette approche, dont nous rappellerons en détail les hypothèses et la construction, a été introduite il ya maintenant plus d’une dizaine d’années afin de faciliter la simulation d’une grande population de neurones. Dit plus précisément, une telle approche donne une équation aux dérivées partielles sur la densité de population de neurones dans l’espace d’état formé des potentiels admissibles du neurone. Nous ferons de plus l’hypothèse que la réponse d’un neurone à l’arrivée d’une impulsion est une dépolarisation instantanée, autrement dit un saut de potentiel. Comme nous le verrons,cette équation aux dérivées partielles est non linéaire (à cause du couplage de la population) et non locale (à cause du saut de potentiel). Si cette idée est compliquée et abstraite, elle anéanmoins prouvé tout au long de ces dix dernières années son importance dans la simulation numérique des grands réseaux.Il s’agit avant tout dans ce travail de thèse de donner un cadre mathématique adéquat aux équations aux dérivées partielles qui surgissent d’une telle approche. Ainsi nous discuterons,selon les différents choix de modélisation, du caractère bien posé du modèle par densité de populationet de sa possible explosion en temps fini. Nous discuterons comment la prise en compte d’hypothèses réalistes supplémentaires dans la modélisation, comme le retard entre l’émission d’un potentiel d’action et sa réception ou encore la période réfractaire peut stopper l’explosionen temps fini et garantir l’existence d’une solution globale. Un autre aspect abordé dans ce travail concerne les explications et la prédiction de la synchronisation des neurones. Deux définitions de la synchronisation seront explicitées selon encoreune fois les choix de modélisation. Nous verrons qu’en interprétant l’explosion en temps fini dela solution comme l’arrivée d’une masse de Dirac dans le taux de décharge de la populationon peut relier l’explosion à la synchronisation. Toutefois, avec des hypothèses de modélisation plus réalistes, comme les retards et la période réfractaire, ce phénomène est exclu. Nous verrons néanmoins qu’avec ces paramètres physiques supplémentaires des solutions périodiques apparaissent offrant différents rythmes de décharge de la population. Encore une fois, l’apparition de ces oscillations sera perçue comme la synchronisation de la populationThis thesis concerns the mathematical modelling and the study of the behavior of a population of neurons. In this work we will mainly consider a population of excitatory neurons whe reall the cells of the network follow the integrate-and-fire model. Nonetheless, we will tackle in a chapter the modelling of an inhibitory population of neurons, and we will discuss in the lastchapter the modelling of a population of neurons that follows the Ermentrout-Koppell model.The point of view of this thesis is given by the population density approach that has beenintroduced more than a decade ago in order to facilitate the simulation of a large assembly ofneurons. More precisely, this approach gives a partial differential equation that describes thedensity of neurons in the state space that is the set of all admissible potential of a neuron. We will assume that when receiving an action potential, the potential of the neuron makes a small jump. As we will see this partial differential equation is non linear (due to the coupling betweenneurons) and non-local (due to the potential jump). If this idea is complicated and abstract, itallows to simulate easily a large neural network.First of all, the thesis gives a mathematical framework for the equations that arise from thisthe population density approach. Then we will discuss the existence and the possible blow upin finite time of the solution. We will discuss how the consideration of more realistic modellingassumptions, as the refractory period and the delay between the emission and the reception ofan action potential can stop the blow up of the solution and give a well posed model.We will also try to caracterise the occurence of synchronization of the neural network. Twodifferent ways of seeing the synchronization will be describe. One relates the blow up in finitetime of the solution to the occurence of a Dirac mass in the firing rate of the population.Nonetheless, taking into account the delays, this kind of blow up will not be observed anymore.Nonetheless, as we will see, with this additional features the model will generate some periodicalsolutions that can also be related to the synchronization of the population
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Wira, Patrice. "Approches neuromimétiques pour l'identification et la commande." Habilitation à diriger des recherches, Université de Haute Alsace - Mulhouse, 2009. http://tel.archives-ouvertes.fr/tel-00605218.
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Les travaux présentés dans cette Habilitation à Diriger des Recherches visent le développement de nouvelles stratégies neuromimétiques destinées à l'identification et à la commande de systèmes physiques complexes, non linéaires et non stationnaires. Les réseaux de neurones artificiels, également appelés modèles connexionnistes, sont abordés d'un point de vue du traitement du signal et du contrôle. Insérés dans des schémas d'identification et de commande, leurs capacités d'apprentissage rendent ces tâches plus robustes et plus autonomes. Nos études cherchent à développer de nouvelles approches neuromimétiques en prenant en compte de manière explicite des connaissances a priori afin de les rendre plus fidèles au système considéré et d'en améliorer l'identification ou la commande. De nombreux développements sont présentés, ils touchent le neurone formel, l'architecture des réseaux de neurones et la stratégie neuromimétique. Un neurone formel est optimisé. Différentes approches neuronales modulaires basées sur plusieurs réseaux de neurones sont proposées. Des schémas neuronaux issus d'une formalisation théorique d'un système sont étudiés. Cette formalisation repose sur l'expression des signaux internes du système et utilise des signaux synthétisés représentatifs de son évolution. Des associations entre des réseaux neuromimétiques et des techniques telles que la logique floue, des modèles statistiques, ou des modèles paramétriques sont développées. Les techniques neuronales proposées ont été validées expérimentalement. Nous avons montré que les modèles connexionnistes permettent incontestablement de développer des commandes avancées et efficaces à travers une démarche réfléchie.
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Zerkaoui, Salem. "Commande neuronale adaptative des systèmes non linéaires." Le Havre, 2007. http://www.theses.fr/2007LEHA0010.
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Dans cette thèse nous proposons un Système de Commande Neuronale Indirecte (SCNI) auto-adaptatif, stable, et robuste pour commander une large variété de systèmes linéaires ou non linéaires, monovariables ou multivariables dont le modèle mathématique est mal connu ou pouvant varier dans le temps. Le SCNI, comporte le modèle instantané et le correcteur ainsi qu’un algorithme autonome d'adaptation des paramètres. Les paramètres du SCNI sont initialisés à zéro assurant ainsi des performances indépendantes de la phase d'initialisation. L’analyse et la synthèse de la stabilité du système en boucle fermée, la stabilité robuste et la robustesse vis-à-vis du bruit de mesure ont été étudiées à l’aide de l’approche de Lyapunov. La commande développée a été testée sur le simulateur du réacteur chimique du Tennessee Eastman et sur un bras manipulateur de robotique médicale. La structure de commande proposée, simple et flexible, s'avère utilisable en pratique pour de nombreuses applicationsThe main contribution of this work is to propose a robust stable self-adaptive InDirect neural Network Control "IDNC" to control a broad variety of unknown linear, nonlinear, SISO and MIMO systems. The control scheme is made of an adaptive instantaneous neural model, a neural controller and an on-line parameter updating law. The IDNC parameters start at zero initial conditions which ensure that the performances do not depend on the initialization phase. Closed loop performances as well as sufficient conditions for asymptotic stability and robustness are derived from the Lyapunov approach. The simulations and experimental tests are carried out in order to validate the performances of the proposed approach. In particular, our contribution is used for the control of the Tennessee Eastman Challenge Process and a medical robot. Also, the proposed structure can easily be implemented in several practical applications
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Glazar, Petar. "Expression and possible functions of circular RNAs." Doctoral thesis, Humboldt-Universität zu Berlin, 2020. http://dx.doi.org/10.18452/21396.
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Circular RNAs (circRNAs) sind eine große Klasse endogener RNAs, die in Organismen vorkommen, die RNA-Transkripte durch Spleißen prozessieren. Sie sind Produkte des „backsplicing“ – einer Art des alternativen Spleißens, bei der das 3‘-Ende eines Exons mit einer vorgelagerten 5‘-„splice site“ verbunden wird. Trotz ihrer Abundanz und spezifischen Expressionsmustern sind in vivo-Funktionen von circRNAs größtenteils unbekannt.
Wir haben den existierenden Kenntnisstand systematisiert und diesen in Form von circBase frei zugänglich gemacht. circBase ist eine Online-Datenbank, in der circRNA-Datensätze abgerufen und im genomischen Kontext durchsucht und visualisiert werden können. Für die Arbeit mit Hochdurchsatz-circRNA-Daten haben wir des Weiteren die Software ciRcus entwickelt. Um mehr bezüglich circRNA-Expression und möglicher Funktionen zu lernen, haben wir die Expressionsmuster im Säugetiergehirn umfassend erforscht. Mithilfe von eigenen und öffentlich zugänglichen RNA-Sequenzierungsdaten haben wir Tausende von neuralen circRNAs in Mensch und Maus entdeckt. circRNAs waren während der neuronalen Differenzierung und Reifung insgesamt hochreguliert, stark angereichert in Synapsen, und oft differentiell exprimiert im Vergleich zu ihren mRNA-Isoformen. Außerdem haben wir gezeigt, dass viele circRNAs zwischen Mensch und Maus konserviert sind. Schließlich haben wir in vivo-Funktionen von Cdr1as erforscht - einer konservierten und im Gehirn hoch exprimierten circRNA, die stark von microRNA (miRNA)-Effektor-Komplexen gebunden ist und zahlreiche miR-7-Bindestellen sowie eine Bindestelle für miR-671 aufweist. „Knockout“-Tiere, bei denen der Cdr1as-Lokus deletiert wurde, zeigten ein gestörtes sensomotorisches „gating“ und dysfunktionale synaptische Übertragung. Die Expression von miR-7 und miR-671 war in verschiedenen Hirnregionen der Tiere dereguliert. Die Expression von „immediate early“-Genen, von denen einige miR-7-Zielgene sind, war erhöht.circular RNAs (circRNAs) are a large class of endogenous RNAs present in organisms that process RNA transcripts by splicing. They are products of backsplicing - alternative splicing reactions where the 3’ end of an exon is spliced to an upstream 5’ splice site. Despite their abundance and tissue- and developmental-stage-specific expression patterns, their in vivo functions are largely unknown. We systematized the existing knowledge on circRNAs and made it freely available by developing circBase - an online database where circRNA datasets can be accessed, downloaded and browsed within the genomic context. Another technical challenge was addressed by developing ciRcus - a software package for working with high-throughput circRNA data, which allowed us to routinely handle, explore, annotate, quantify and integrate circRNA data with the external sources of biological data. To learn more about circRNA expression and potential functions, we have explored the expression patterns of circRNAs in the mammalian brain. Using own and public RNA-seq data, we discovered thousands of neural circRNAs in human and mouse. circRNAs were upregulated during neuronal differentiation and maturation, enriched in synapses, and often differentially expressed compared to their host mRNAs. Many circRNAs were conserved between human and mouse. Finally, we explored in vivo functions of Cdr1as - a conserved circRNA known to be highly expressed in the brain, heavily bound by microRNA (miRNA) effector complexes, and harbouring many binding sites for miR-7, as well as a single binding site for miR-671. Upon deleting the Cdr1as locus, knockout animals displayed impaired sensorimotor gating and dysfunctional synaptic transmission. Expression of miR-7 and miR-671 was deregulated in different brain regions of Cdr1as knockout animals. Expression of immediate early genes, some of which are miR-7 targets, was increased, providing a possible molecular link to the behavioral phenotype.