Les cellules beta pancréatiques sécrètent l’insuline lors d’une augmentation post-prandiale du glucose dans le sang. Ce processus essentiel est contrôlé par des facteurs physiologiques, nutritionnels et pathologiques. D’autres sources d’énergie, comme les acides aminés (leucine et glutamine) ou les acides gras potentialisent la sécrétion d’insuline. Une sécrétion d’insuline insuffisante au besoin du corps déclanche le diabète. Le rôle que joue l’augmentation du calcium intracellulaire et les canaux K+/ATP dans la sécrétion d’insuline est bien connu. Bien que le mécanisme exact de la potentialisation de la sécrétion d’insuline par les lipides est inconnu, le cycle Glycérolipides/Acides gras (GL/FFA) et son segment lipolytique ont été reconnu comme un composant essentiel de la potentialisation lipidique de la sécrétion d’insuline. Le diacylglycérol, provenant de la lipolyse, a été proposé comme un signal lipidique important d’amplification. Cependant, l’hydrolyse des triglycérides et des diacylglycérides a été démontrée essentielle pour la sécrétion d’insuline stimulée par le glucose, en suggérant un rôle du monoacylglycérol (MAG) dans ce processus. Dans cette étude, on démontre que la réduction de la sécrétion d’insuline stimulée par le glucose, lors d’une inhibition de la lipolyse, est restaurée par l’addition de MAG. Dans les cellules beta pancréatiques, le niveau de MAG augmente en présence des concentrations élevées du glucose, et également lorsqu’on inhibe l’enzyme MAG hydrolase abhydrolase-6 (ABHD6) avec l’inhibiteur spécifique WWL70. L’analyse lipidomique a démontré qu’après la stimulation des cellules beta pancréatiques avec le glucose et aussi avec le WWL70, l’espèce la plus accumulée de MAG était le 1-stearoylglycérol (1-SG). L’addition de 1-SG, de 1-palmitoylglycérol (1-PG) ou de WWL70 augmente la sécrétion d’insuline stimulée par le glucose, et cette augmentation est indépendante de la génération de acides gras à partir de MAG. Cela suggère que le MAG est un signal lipidique pour la potentialisation de la sécrétion d’insuline stimulée par le glucose. De plus, la surexpression du gène d’ABHD6 dans les cellules INS832/13 cause une réduction de la sécrétion d’insuline, due probablement à la diminution des niveaux intracellulaire de MAG. Avec le but de comprendre le mécanisme moléculaire impliqué dans la potentialisation de la sécrétion d’insuline par le MAG, on a bloqué l’action du récepteur vanilloid-1 (TRPV1) liant le MAG par l’agent pharmacologiste, AMG9810. Le traitement des cellules beta pancréatique par AMG9810 entraîne une diminution de la potentialisation de la sécrétion de l’insuline induite par le MAG. Il est a noter que le MAG pourrait activer TRPV1 par une liaison physique dans la membrane cellulaire interne; ce qui entraînerai l’entrée du calcium dans la cellule, et ensuite la stimulation de l’exocytose des granules à insuline. En soutien de cette hypothèse, on a trouvé une diminution du calcium intracellulaire lorsqu’on traite au AMG9810 des cellules beta pancréatique de rat (provenant des îlots dispersés) stimulées au glucose et au WWL70. L’ensemble des résultats suggère que le MAG est un médiateur de la potentialisation lipidique de la sécrétion d’insuline stimulée par le glucose. Vu que l’inhibition pharmacologique d’ABHD6 augmente la sécrétion d’insuline, on pourra conclure que cette enzyme représente une cible thérapeutique potentielle dans le développement des médicaments anti-diabétiques, visant une augmentation de la sécrétion d’insuline. / Insulin secretion by the pancreatic b-cell in response to post-prandial increase in blood glucose levels is an essential physiological process that is governed by cellular, nutritional and pathological factors. Other fuels including amino acids like leucine and glutamine and also fatty acids contribute to further augment insulin secretion. Failure to secrete adequate amount of insulin according to the changing demands of the body by b-cell is a key determinant of diabetes. The role played by the elevated Ca2+ influx and K+-ATP channels in insulin secretion is well known. Even though the precise mechanism of the lipid amplification of insulin secretion and the involved molecular signals are not clear, Glycerolipid/Free fatty acid (GL/FFA) cycle and its lipolytic segment have been recognized as essential components in the lipid amplification pathway of insulin secretion. Diacylglycerol produced by lipolysis was proposed as an important lipid amplification signal. However, hydrolysis of triglycerides and also of diacylglycerols is shown to be essential for glucose stimulated insulin secretion (GSIS), indicating a possible role for monoacylglycerol (MAG) in this process. In the present study we demonstrate that the obliterated GSIS due to lipolysis inhibition in b-cells can be restored by providing exogenous MAG. In the b-cells MAG levels increase significantly in the presence of high glucose concentration and specific inhibition of the major MAG hydrolase, abhydrolase-6 (ABHD6), in b-cells and islets with WWL70 leads to accumulation of MAG with concomitant increase in insulin secretion. Lipidomics analysis indicated that the major MAG species that is elevated by high glucose as well as WWL70 addition is 1-stearoylglycerol (1-SG). Exogenously added 1-SG and also 1-palmitoylglycerol (1-PG) strongly enhanced GSIS and this augmentation is not dependent on the generation of FFA by these MAGs. This indicates that MAG is a potential candidate for being the lipid signal for GSIS amplification. Further evidence for this was provided by the observation that overexpression of the MAG hydrolase ABHD6 in INS832/13 cells, resulted in decreased insulin secretion, probably owing to the lowered MAG level inside the b-cells. Pharmacological studies using AMG9810, a specific antagonist of transient receptor potential vanilloid-1 (TRPV1) receptor that binds MAG, revealed that a blockade of TRPV1 strongly attenuated the MAG-augmented insulin secretion. Since MAG is a potential activator of TRPV1, it is likely that MAG binds on the inner surface of the cell membrane to TRPV1, which in turn triggers rapid influx of Ca2+ thereby promoting insulin granule exocytosis. Thus, AMG9810 was found to lower Ca2+ influx into dispersed rat islet cells that was induced by high glucose and also WWL70. These results collectively suggest that MAG is the potential mediator of the lipid amplification of glucose-stimulated insulin secretion. Our results also indicate that pharmacological intervening at the ABHD6 hydrolysis step enhances insulin secretion; this enzyme protein can be a promising thrapeutic target for the development of anti-diabetic drugs that promote insulin secretion.

CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / O uso de componentes revestidos por ligas de nÃquel do sistema Ni-Cr-Mo em equipamentos da indÃstria do petrÃleo pode vir a ser mais freqÃente, pois os aumentos no Ãndice de acidez naftÃnica e no peso molecular do petrÃleo nacional requerem materiais mais resistentes à corrosÃo, temperatura e pressÃo. Desta forma, como parte de um estudo sistemÃtico, este trabalho pretende definir faixas operacionais para revestir de forma adequada aÃo estrutural com o eletrodo ERNiCrMo-3, atravÃs da soldagem MIG/MAG, e avaliar caracterÃsticas microestruturais e propriedades mecÃnicas de revestimentos na condiÃÃo como soldados e envelhecidos. Para atingir o objetivo, foram realizadas soldagens automÃticas com utilizaÃÃo de robà industrial, fonte eletrÃnica e argÃnio puro como gÃs de proteÃÃo. Para definiÃÃo das faixas operacionais, as soldagens foram em simples deposiÃÃo, com avaliaÃÃo de aspecto superficial, geometria e diluiÃÃo da solda. Nesta etapa, foi constatado que a solda apresenta alta convexidade em corrente eficaz abaixo de 200 A e a variaÃÃo da corrente, para o cÃlculo da energia, influencia de forma mais significativa na convexidade e na diluiÃÃo da solda, em comparaÃÃo com a variaÃÃo da velocidade de soldagem, para o cÃlculo das mesmas energias. AtravÃs dos testes preliminares, foi selecionada a corrente de 290 A em duas energias de soldagem (10 e 14 kJ/cm). O revestimento foi em Ãnica camada aplicada em aÃo ASTM A516 g60 de 12,7 mm de espessura, com sobreposiÃÃo acima de 40 % e temperatura de interpasse abaixo de 100 oC. A diluiÃÃo em ambas as energias ficou em torno de 15 %. O envelhecimento foi na temperatura de 600 oC por tempos de 100 e 300 horas. Para caracterizaÃÃo metalÃrgica foram utilizados: perfis de microdureza, microscopia Ãtica (MO) e eletrÃnica de varredura (MEV), energia dispersiva de raio X (EDX), difraÃÃo de raio X, energia de elÃtrons retro-espalhados (EBSD) e ensaio de arrancamento, segundo norma ASTM A 265-03. Os perfis de microdureza e estruturas observadas foram semelhantes para ambas as energias de soldagem utilizadas. ApÃs envelhecimento foi observado uma descarbonetaÃÃo da ZAC-GG onde as ferritas passaram a nÃo possuir segundas fases (carbonetos). A estrutura dendrÃtica do revestimento apresentou microfases do tipo MC e Laves na condiÃÃo como soldada. ApÃs o envelhecimento, houve formaÃÃo de carbonetos secundÃrios, dissoluÃÃo de carbonetos primÃrios e formaÃÃo de fase gamaââ. Os perfis de dureza indicaram que na condiÃÃo como soldada a dureza do revestimento foi de 240 HV e da ZAC-GG de 190 HV, com o envelhecimento a dureza na ZAC-GG caiu para 120 HV, e a do revestimento cresceu para 290 HV em 100 h e 310 HV em 300 h. Na interface foram observadas, somente apÃs o envelhecimento, regiÃes duras da ordem de 800 HV, devido a grande concentraÃÃo de carbonetos e envelhecimento da zona parcialmente diluÃda, com teor elevado de ferro, que atua na formaÃÃo de gamaââ. Apesar das elevadas diferenÃas de dureza entre o revestimento, metal base e interface nÃo foram identificadas trincas nas anÃlises metalogrÃficas. A carga mÃxima no ensaio de arrancamento foi superior a da norma (140 MPa) nas condiÃÃes analisadas. O perfil de penetraÃÃo dos cordÃes (tipo taÃa) favoreceu esse resultado, e o envelhecimento provocou um aumento gradativo de resistÃncia ao cisalhamento. / The use of nickel alloy cladding components could be more frequently in petroleum industry. The crescent naphthenic corrosion and high molecular weight of national petroleum contribute for needs of materials with more resistance to corrosion, to temperature and to pressure. At this way, how part of systematic study, this work pretends to define operational range for adequate ERNiCrMo-3 weld overlay in structural steel with application of GMAW process, and to evaluate microstructural characteristics and mechanical properties in as welded and aging conditions. To realize the objective, were used an industrial robot, an electronic power source and an argon shielding gas for automated welding. To define the operational range, simple deposit welds and evaluation of superficial aspect, geometry and dilution were conducted. This step indicated that the welds in efficient current below 200 A showed high convexity and the variation of current for the calc of heat input is more significant for convexity and dilution of the weld than the variation of welding speed for the calc of same heat input. It was selected 290 A as welding current in two heat inputs (10 and 14 kJ/cm). The overlay at ASTM A 516 g60 steel was in simple layer, had overlap up to 40 pct between passes and had about 15 pct of dilution at the two heat inputs. The aging temperature employed was 600 oC for times of 100 and 300 hours. To metallurgical characterization was used: microhardness measures, optical microscope, scanning electron microscope, composition variations (EDAX), x-ray diffraction, electron backscatter diffraction and shear tests according ASTM A 265-03 standard specification. The microhardness and structures observed were, approximately, the same for the two heat inputs. Post aging HAZ showed absence of carbides. The dendritic structure had MC and Laves micro-phases in as welded condition and the aging provoked formation of secondary carbides, dissolution of primary carbides and formation of gamaââ. As welded overlay microhardness was 240 HV and as welded HAZ was 190 HV. Aging HAZ was 120 HV and aging overlay was 290 HV for 100 h and 310 HV for 300 h. Only for aging conditions, were observed hard zones (800 HV) in interface of overlay, due to carbide concentration and aging of partially dilution zone, where the Fe favored the formation of gamaââ. Despite the hardness differences of overlay, base metal and interface, were identified no cracks in metallographic analyses. The maximum shear strength was above of the specification requirement (140 MPa) in all conditions employed, the penetration shape (like finger) favored this result, and the aging provoked a gradual grow up in shear resistance.

Il existe aujourd'hui de nombreux procédés de soudage répondant à la très grande variété d'assemblage à réaliser et aux caractéristiques des métaux utilisés. Le premier chapitre décrit les différentes sources d'énergie utilisées en soudage. Suite à cela, une explication plus détaillée du soudage à l'arc électrique est donnée. Enfin nous présentons la conception d'une plateforme d'essai de soudage.<br />Il est possible, bien sûr, d'utiliser une approche empirique pour optimiser un procédé. Néanmoins il y a des avantages à choisir une approche analytique puisqu'on peut en attendre des avancées significatives dans la compréhension des interactions dynamiques présentes dans l'arc. C'est pourquoi nous présentons dans le chapitre 2 les connaissances théoriques de la physique quant au comportement du métal liquide transféré en soudage MIG/MAG.<br />Ce travail comporte donc également un aspect expérimental nécessaire à l'élaboration des bases de données utilisées pour la construction des modèles. Les différents enregistrements ont été effectués au CTAS sur une plate forme équipée d'un système d'acquisition de données pour les mesures de tension, courant, vitesse fil et d'un système de vidéo rapide. Le chapitre 3 présente notre recherche d'une méthode de segmentation permettant d'obtenir le suivi de variables pertinentes. Nous y proposons un capteur logiciel basé sur la théorie des contours actifs et montrons de bons résultats obtenus sur des vidéos expérimentales.<br />Une étape d'ajustement de certains paramètres est indispensable. Elle est donnée dans le chapitre 4. Le simulateur créé permet d'interpréter certains phénomènes importants en soudage, de réaliser une étude de sensibilité « sans risque » et de donner les signatures théoriques de défauts.

Les MEMS magnétiques présentent encore des champs de recherches quasi inexplorées. La course à la recherche de faisabilité d'une nouvelle structure (actionneur, capteur) est un enjeu pour les concepteurs dans ce domaine.<br />Pour répondre à ce besoin, ce travail expose des méthodes et des outils permettant de faciliter et d'automatiser des taches répétitives qui sont à la charge de ces concepteurs. Le processus de génération automatique des équations représentant le modèle est maintenant délégué à l'outil que nous avons développé. La dérivation formelle des modèles est aussi étudiée et réalisée, notamment dans le cas des applications contenant des matériaux non linéaires (ferromagnétiques). A partir de ces travaux, il alors possible de dimensionner rapidement les MEMS magnétiques généralement soumis à de nombreuses contraintes non linéaires. La méthodologie peut être aussi étendu aux MEMS électrostatiques.

Uno de los objetivos principales que se plantea en cualquier campo, tanto en investigación como en la clínica, consiste en lograr la estandarización de estudios para así poder obtener conclusiones generales, poder determinar parámetros y patrones de normalidad y, consecuentemente, determinar con precisión la patología valorando la desviación de estos índices.En los estudios renográficos, una función que posibilita esta estandarización es la función de retención renal que representa la fracción de trazador que es retenida en el riñón, a través del tiempo, como respuesta a una entrada instantánea en forma de bolo radiactivo si el trazador se hubiese introducido directamente en la arteria renal.Puesto que en un estudio real, la inyección se realiza en una vena periférica, la función de retención renal se ha de obtener mediante la deconvolución de la curva actividad/tiempo del área renal con la curva correspondiente a un área vascular representativa de la actividad sanguínea.El objetivo fundamental de este trabajo fue obtener un método de cálculo de la función de retención renal que incluyese una optimización en el grado de filtrado. Mediante simulación numérica de un estudio gammagráfico renal, se simularon estudios con 131I-Hippuran y 99mTc-MAG3.Mediante simulación numérica se ha demostrado la existencia de un valor mínimo en el error cuadrático medio entre las funciones de retención renal teóricas y las obtenidas mediante deconvolución. La presencia de este valor mínimo se manifiesta para los tres filtros considerados (filtro de tres puntos, filtros de Butterworth y filtro "data bounding") y para los dos trazadores, 131I-Hippuran y 99mTc-MAG3, estudiados en este trabajo.La ordenación de los tres filtros en base al valor mínimo del error cuadrático medio es: filtro de Butterworth, filtro de tres puntos y filtro "data bounding", éste con valores mucho más altos del error que los dos filtros lineales. Esta ordenación es la misma para los dos trazadores, siendo los valores del error correspondiente a 99mTc-MAG3 aproximadamente la mitad que los de 131I-Hippuran.El valor del factor de suavizado que hace mínimo el error, depende del tiempo de tránsito y de la relación señal/ruido. Se ha comprobado que para 99mTc-MAG3 el valor del suavizado que hace mínimo el error es menor que para 131I-Hippuran, lo que está de acuerdo con su mayor relación señal/ruido. Asimismo para cada trazador, se ha demostrado que la dependencia respecto al tiempo de tránsito es mayor que respecto a la relación señal/ruido. Este hecho, que se repite para los tres filtros, ha permitido obtener valores de los factores de suavizado óptimos para cada trazador como funciones del tiempo de tránsito exclusivamente. Se ha analizado el comportamiento de los tres filtros en la determinación de los parámetros de interés funcional derivados de la función de retención renal. Para ello, se modelizó la función de retención renal mediante una función de cuatro parámetros: h(t) = (A-D) / (1+t/C)**B) + D donde A corresponde a la altura de la función de retención renal par aun tiempo igual a cero, B se relaciona con la dispersión de tiempos de tránsito, C es el tiempo medio de tránsito intrarrenal y D es el valor de estabilización relacionado con una posible retención de trazador en el riñón. De este estudio se ha concluído: La estima del parámetro A es mejor para los métodos de filtrado lineales que para el no lineal, ya que proporciona información no sesgada y presenta valores del error relativo menores que para el filtro no lineal. De los filtros lineales, el algoritmo que incluye un filtro de Butterworth optimizado presenta los mejores resultados.Los resultados hallados para el parámetro B, indican que el filtro de Butterworth es el que determina mejor este parámetro, lo que se refleja en un valor medio próximo al teórico.La estima del parámetro C es mejor para los métodos de filtrado lineal que para el no lineal. En ambos, el error relativo es menor y no existe sesgo, siendo el filtro de Butterworth el que presenta los mejores resultados.Respecto al parámetro D, los valores hallados en todos los casos están muy próximos al valor teórico que es cero.En consecuencia, el método de deconvolución propuesto es el algoritmo matricial y un filtro de Butterworth optimizado en función del tiempo de tránsito.Se ha valorado la aplicabilidad del algoritmo de deconvolución en estudios reales con 131I-Hippuran. Además del filtro de Butterworth, se utilizó el filtro de tres puntos por ser el más empleado en Medicina Nuclear. De este estudio se ha concluído que los dos métodos de filtrado lineal determinan los parámetros derivados de la función de retención renal de forma equivalente. Se ha estudiado la relación existente entre las estimas del tiempo de tránsito renal y de la función renal relativa efectuadas sobre la función de retención renal, y sobre el renograma. Los resultados obtenidos al aplicar el algoritmo de deconvolución propuesto permiten concluir: El tiempo en el instante de máxima actividad en el renograma sobreestima el tiempo de tránsito renal, hecho que se comprobó que también sucedía en los estudios simulados. Se ha comprobado que esta sobrevaloración, que se acentúa para valores de tiempo en el máximo elevados, es debida fundamentalmente al valor de la constante de tiempo de la primera exponencial de la curva de aclaramiento plasmático y al grado de dispersión del tiempo de tránsito.La estima de la función renal relativa realizada sobre el renograma corregido de actividad extrarrenal da valores comparables a los obtenidos sobre la función de retención renal, no existiendo diferencias significativas.Se aplicó al algoritmo de deconvolución propuesto a estudios reales con 99mTc-MAG3. Al ser la relación señal/ruido unas tres veces mayor que la del Hippuran permitió obtener la función de retención con menor filtrado. De este estudio se ha concluído:La estima del tiempo de tránsito renal efectuada sobre el renograma como tiempo en el máximo sobrevalora el tiempo de tránsito intrarrenal en relación a la estima efectuada sobre la función de retención renal. Esta sobrevaloración es mayor para tiempos de tránsito largos.La estima de la función renal relativa realizada sobre el renograma presenta, en general, valores inferiores a los obtenidos a partir de la función de retención renal. Esto es debido a la presencia de la actividad de tipo vascular no eliminada totalmente al efectuar la corrección de la actividad extrarrenal. / The main aim of the study was to obtain a calculation method of the renal retention function which includes an optimization of the degree of filtering. Studies with (131)I-Hippuran and 99m Tc-Mag 3 were simulated by means of the numerical simulation of a renal gammagraphic study. The existence of an optimum filtering was demonstrated. This minimum value is present for the three filterings considered (smoothing, Butterworth and data bounding) and for the two tracers. Consequently the functions of the corresponding filterings were obtained. The renal retention functions were obtained and the derived parameters were calculated: relative renal function and the mean transit time. The algorithm of the deconvolution proposed consist of a matrix algorithm to perform the deconvolution and a Butterworth filtering optimized in function of renal transit time. The algorithm of deconvolution was subsequently applied to one group of renal studies with (131)I-Hippuran and to another with (99m)Tc-Mag(3) in order to assess its applicability in real cases. Likewise, we evaluated the degree of correlation between the values of the two parameters calculated on the renogram (which is normally performed in clinical practice) and those obtained from the renal retention function. For both tracers it was demonstrated the value of the transit time estimated on the renogram overestimated the value of the transit time especially in all the cases presenting renal obstruction. In the cases of (131)I-Hippuran the estimate of the relative renal function performed on the corrected renogram of the extrarrenal background gives values comparable to those obtained from the renal retention function. For the (99m)Tc-Mag(3) , the estimate carried out on the renogram yields, in general, values that are lower than those obtained from the renal retention function. This is due to the presence of the vascular background which was not wholly eliminated when correcting the renogram.

Les cellules beta pancréatiques sécrètent l’insuline lors d’une augmentation post-prandiale du glucose dans le sang. Ce processus essentiel est contrôlé par des facteurs physiologiques, nutritionnels et pathologiques. D’autres sources d’énergie, comme les acides aminés (leucine et glutamine) ou les acides gras potentialisent la sécrétion d’insuline. Une sécrétion d’insuline insuffisante au besoin du corps déclanche le diabète. Le rôle que joue l’augmentation du calcium intracellulaire et les canaux K+/ATP dans la sécrétion d’insuline est bien connu. Bien que le mécanisme exact de la potentialisation de la sécrétion d’insuline par les lipides est inconnu, le cycle Glycérolipides/Acides gras (GL/FFA) et son segment lipolytique ont été reconnu comme un composant essentiel de la potentialisation lipidique de la sécrétion d’insuline. Le diacylglycérol, provenant de la lipolyse, a été proposé comme un signal lipidique important d’amplification. Cependant, l’hydrolyse des triglycérides et des diacylglycérides a été démontrée essentielle pour la sécrétion d’insuline stimulée par le glucose, en suggérant un rôle du monoacylglycérol (MAG) dans ce processus. Dans cette étude, on démontre que la réduction de la sécrétion d’insuline stimulée par le glucose, lors d’une inhibition de la lipolyse, est restaurée par l’addition de MAG. Dans les cellules beta pancréatiques, le niveau de MAG augmente en présence des concentrations élevées du glucose, et également lorsqu’on inhibe l’enzyme MAG hydrolase abhydrolase-6 (ABHD6) avec l’inhibiteur spécifique WWL70. L’analyse lipidomique a démontré qu’après la stimulation des cellules beta pancréatiques avec le glucose et aussi avec le WWL70, l’espèce la plus accumulée de MAG était le 1-stearoylglycérol (1-SG). L’addition de 1-SG, de 1-palmitoylglycérol (1-PG) ou de WWL70 augmente la sécrétion d’insuline stimulée par le glucose, et cette augmentation est indépendante de la génération de acides gras à partir de MAG. Cela suggère que le MAG est un signal lipidique pour la potentialisation de la sécrétion d’insuline stimulée par le glucose. De plus, la surexpression du gène d’ABHD6 dans les cellules INS832/13 cause une réduction de la sécrétion d’insuline, due probablement à la diminution des niveaux intracellulaire de MAG. Avec le but de comprendre le mécanisme moléculaire impliqué dans la potentialisation de la sécrétion d’insuline par le MAG, on a bloqué l’action du récepteur vanilloid-1 (TRPV1) liant le MAG par l’agent pharmacologiste, AMG9810. Le traitement des cellules beta pancréatique par AMG9810 entraîne une diminution de la potentialisation de la sécrétion de l’insuline induite par le MAG. Il est a noter que le MAG pourrait activer TRPV1 par une liaison physique dans la membrane cellulaire interne; ce qui entraînerai l’entrée du calcium dans la cellule, et ensuite la stimulation de l’exocytose des granules à insuline. En soutien de cette hypothèse, on a trouvé une diminution du calcium intracellulaire lorsqu’on traite au AMG9810 des cellules beta pancréatique de rat (provenant des îlots dispersés) stimulées au glucose et au WWL70. L’ensemble des résultats suggère que le MAG est un médiateur de la potentialisation lipidique de la sécrétion d’insuline stimulée par le glucose. Vu que l’inhibition pharmacologique d’ABHD6 augmente la sécrétion d’insuline, on pourra conclure que cette enzyme représente une cible thérapeutique potentielle dans le développement des médicaments anti-diabétiques, visant une augmentation de la sécrétion d’insuline. / Insulin secretion by the pancreatic b-cell in response to post-prandial increase in blood glucose levels is an essential physiological process that is governed by cellular, nutritional and pathological factors. Other fuels including amino acids like leucine and glutamine and also fatty acids contribute to further augment insulin secretion. Failure to secrete adequate amount of insulin according to the changing demands of the body by b-cell is a key determinant of diabetes. The role played by the elevated Ca2+ influx and K+-ATP channels in insulin secretion is well known. Even though the precise mechanism of the lipid amplification of insulin secretion and the involved molecular signals are not clear, Glycerolipid/Free fatty acid (GL/FFA) cycle and its lipolytic segment have been recognized as essential components in the lipid amplification pathway of insulin secretion. Diacylglycerol produced by lipolysis was proposed as an important lipid amplification signal. However, hydrolysis of triglycerides and also of diacylglycerols is shown to be essential for glucose stimulated insulin secretion (GSIS), indicating a possible role for monoacylglycerol (MAG) in this process. In the present study we demonstrate that the obliterated GSIS due to lipolysis inhibition in b-cells can be restored by providing exogenous MAG. In the b-cells MAG levels increase significantly in the presence of high glucose concentration and specific inhibition of the major MAG hydrolase, abhydrolase-6 (ABHD6), in b-cells and islets with WWL70 leads to accumulation of MAG with concomitant increase in insulin secretion. Lipidomics analysis indicated that the major MAG species that is elevated by high glucose as well as WWL70 addition is 1-stearoylglycerol (1-SG). Exogenously added 1-SG and also 1-palmitoylglycerol (1-PG) strongly enhanced GSIS and this augmentation is not dependent on the generation of FFA by these MAGs. This indicates that MAG is a potential candidate for being the lipid signal for GSIS amplification. Further evidence for this was provided by the observation that overexpression of the MAG hydrolase ABHD6 in INS832/13 cells, resulted in decreased insulin secretion, probably owing to the lowered MAG level inside the b-cells. Pharmacological studies using AMG9810, a specific antagonist of transient receptor potential vanilloid-1 (TRPV1) receptor that binds MAG, revealed that a blockade of TRPV1 strongly attenuated the MAG-augmented insulin secretion. Since MAG is a potential activator of TRPV1, it is likely that MAG binds on the inner surface of the cell membrane to TRPV1, which in turn triggers rapid influx of Ca2+ thereby promoting insulin granule exocytosis. Thus, AMG9810 was found to lower Ca2+ influx into dispersed rat islet cells that was induced by high glucose and also WWL70. These results collectively suggest that MAG is the potential mediator of the lipid amplification of glucose-stimulated insulin secretion. Our results also indicate that pharmacological intervening at the ABHD6 hydrolysis step enhances insulin secretion; this enzyme protein can be a promising thrapeutic target for the development of anti-diabetic drugs that promote insulin secretion.

The MIG/MAG process is nowadays the most important welding process. This is due to its high production capacity, characteristic searched by industries to improve their manufacturing processes. Thus, due to this process relevance, development of tools that helps to understanding how it works comes out as necessary, especially in relation to proper welding setting up. One tool for this task is the transfer mode map, which predicts the type of metal transfer according to the welding setting up. However, these maps, normally, are more scientific oriented rather that for practical purposes. In this context, the objective of this work was to map the transfer modes in such a way that welders, supervisors and engineers could be helped in the choice of the best setting up needed. For this purpose, a methodology was developed to provide more information than transfer modes according to the parameter setting up. The proposed mapping had the intention of obtaining transfer regions with proper operating characteristics (stable transfer resulting of appropriate welding conditions) and also information about weld bead conditions, production, thermal cycle and arc radiation. For each transfer mode looked for working at typical welding conditions, which mean that the contact tip-to-work distance was different for the two main transfer modes (short-circuit and spray). A large number of experiments was performed to map the transfers, with the objective to determine a stable operating regions of short-circuit and spray transfer mode using the ER70S-6 welding wire with three different shielding gases. After mapping, single-welded butt joint were carried-out using specific points of the maps instead of bead-on-plate. The proposed methodology was efficient in exterminating regions of operational stability, according to the experiments. It was also possible to have better welding geometries, in general, for setting ups within the map region of operational stability, but the results also depend on the shielding gas and the transfer mode. For setting ups outside the map region of operational stability the bead finish gets worse, except for spray transfer mode when working below the region of operational stability. The deposition efficiency is lower for setting ups outside the region and with gases containing higher levels of CO2, except for short-circuit transfer. The arc radiation intensity is lower in regions below the operational stability and higher above this position, but it is highly dependent of the arc length. Changes in the contact tip-to-work distance and/or in the power source inductance have no influence on the region of operational stability, except for short-circuit transfer, in which the contact tip-to-work distance is able to reduce the set voltage for this region. / O processo de soldagem MIG/MAG é dos mais importantes processos de união de metais na atualidade. Isto se deve à sua alta capacidade de produção, característica constantemente cobiçada pelas indústrias em seus processos de fabricação. Assim, devido à relevância desse processo, torna-se necessária a construção de ferramentas que auxiliem no entendimento do funcionamento do mesmo, principalmente no que se refere à correta regulagem dos parâmetros de soldagem. Uma ferramenta utilizada para isto são os mapas de transferência metálica, que a partir dos parâmetros de regulagem, prevêem como resposta o tipo de transferência metálica. Porém, estes mapas, da forma que são normalmente confeccionados, são de caráter mais científico do que prático. Neste contexto, o objetivo deste trabalho foi a confecção de mapas de transferência práticos que venham auxiliar os usuários de soldagem (soldadores, supervisores e engenheiros) na escolha da melhor regulagem em função de suas necessidades. Para isto, foi desenvolvida uma metodologia que proporcionasse mais do que a informação sobre o tipo de transferência a partir da regulagem dos parâmetros. Nestes mapas propostos, objetivou-se obter uma região de transferência com característica operacional (transferência estável com condições de soldagem apropriadas) e também informações sobre o acabamento e perfil do cordão, rendimento de deposição, ciclo térmico e radiação emitida pelo arco. E para cada modo de transferência se procurou trabalhar apenas em condições típicas, o que fez com que a DBCP fosse diferenciada para dois modos principais de transferência (curto-circuito e goticular). Uma grande quantidade de experimentos foi realizada para mapear as transferências, com objetivo de delimitar uma região de estabilidade operacional de transferências por curto-circuito e outra goticular, utilizando o arame ER70S-6 e três gases de proteção para cada tipo de transferência. Após o levantamento, foram realizadas soldagens em pontos específicos dos mapas utilizando juntas ao invés de soldagem de cordão sobre chapa. Os resultados obtidos mostram que a metodologia proposta foi eficiente na determinação das regiões de estabilidade operacional. Mostraram também que o acabamento e a geometria do cordão, em geral, ficam melhores para regulagens dentro da região de estabilidade operacional, mas com resultados também dependentes do gás de proteção e tipo de transferência utilizada. Para regulagens fora da região de estabilidade operacional o acabamento piora, exceto para transferência goticular em regulagens abaixo da região. O rendimento de deposição é menor fora da região e com gases de proteção com maior teor de CO2, exceto para transferência por curto-circuito, onde, regulagens acima desta região não causam prejuízo. A intensidade de radiação emitida pelo arco é menor abaixo da região e maior acima desta, sendo dependente principalmente do comprimento de arco. A mudança da DBCP e da indutância da fonte não mostraram influência sobre a região de estabilidade operacional, exceto para transferência por curto-circuito, onde a DBCP promove a diminuição da regulagem das tensões desta região. / Mestre em Engenharia Mecânica

Syftet med studien är att, med hjälp av metoden contingent valuation (CV), undersöka betalningsviljan (willingness to pay, WTP) för en reducerad risk att drabbas av mag- och tarmsjukdomar på grund av förorenat dricksvatten i Skellefteå kommun. Studien undersöker också sambandet mellan WTP och tidigare erfarenheter av förorenat dricksvatten. Respondenterna fick besvara en sluten och en öppen WTP-fråga för ett föreslaget projekt. WTP varierar mellan 39 – 67 kronor per månad utöver den nuvarande avgiften för vatten och avlopp (VA-taxan). De variabler som förklarar individuella skillnader i WTP är budnivån, upplevd dricksvattenkvalitet, huruvida personen blev drabbad vid tidigare utbrottet, om konsumtionsbeteendet har förändrats, ålder, inkomst och hushåll med barn. Resultaten visar att de respondenter som drabbats vid ett tidigare utbrott är mindre benägna att acceptera en högre kostnad. Ett förändrat konsumtionsbeteende visar däremot att respondenter i genomsnitt har en högre WTP för en minskad risk av mag- och tarmsjukdomar. / The purpose of the study is to examine the willingness to pay (WTP) for a reduced risk of gastrointestinal diseases due to contaminated drinking water in the municipality of Skellefteå using the contingent valuation method (CV). The study also examines the relationship between WTP and previous experiences of contaminated drinking water. The respondents answered to a closed and an open WTP question for a proposed project.  WTP varies between SEK 39 – 67 per month in addition to the current fee on water and wastewater. The variables that explain individual differences in WTP are the bid level, experienced drinking water quality, impact of the previous outbreak, changed consumption behavior, age, income and households with children. The results show that respondents affected by the previous outbreak are less likely to accept a higher cost. Respondents who changed their consumption behavior want, on average, pay more for a reduced risk of gastrointestinal diseases.

Conselho Nacional de Desenvolvimento Científico e Tecnológico / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Fundação de Amparo a Pesquisa do Estado de Minas Gerais / Atualmente a busca por melhorias de processos e técnicas de soldagem mecanizados/automatizados tem sido intensa devido à escassez de mão de obra qualificada. Nesta linha, a combinação de processos e mesmo de modos operacionais (polaridade e/ou modo de transferência metálica) dentro de um só processo, em adição à possibilidade de combinar níveis de corrente de soldagem, vem ganhando espaço. Por meio dos modos operacionais e/ou dos níveis de corrente, é possível variar a energia do arco (tanto térmica quanto cinética) entregue à peça de trabalho. Combinando este recurso com o movimento do arco, pode-se distribuir a energia do mesmo de forma otimizada para controlar a formação do cordão de solda. Uma forma relativamente simples de controlar o movimento do arco é por meio de oscilação magnética – deflexão do arco elétrico através de um eletroímã. Assim, este trabalho explora a sincronização da oscilação magnética com processos de soldagem a arco de modo a controlar a distribuição da energia do arco sobre a peça. Para tal, foi desenvolvido um sistema de oscilação sincronizada, incluindo hardware e software, para permitir controlar a oscilação magnética e a fonte de soldagem (multiprocesso) de forma sincronizada. Em seguida, foi feita uma caracterização da deflexão (em função da tensão do eletroímã, da corrente e do comprimento do arco de soldagem) baseada em filmagens de alta velocidade. Como forma de explorar a técnica de oscilação magnética sincronizada com diferentes processos de soldagem, foram realizadas duas abordagens, ambas com oscilação do arco transversal à direção de soldagem, e depois comparadas a condições de referência (soldagem sem oscilação e com oscilação não sincronizada). O processo TIG foi sincronizado à oscilação magnética variando o nível de corrente de soldagem de acordo com a posição do arco, tendo como base de análise o efeito sobre o controle da largura dos cordões de solda formados. Já o processo MIG/MAG foi sincronizado à oscilação magnética variando os modos operacionais de soldagem de acordo com a posição do arco, avaliando o efeito sobre o controle da geometria das áreas fundidas dos cordões resultantes. O sistema de oscilação magnética sincronizada demonstrou ser capaz de controlar a formação do cordão tanto na soldagem TIG quanto na MIG/MAG. No caso do TIG sincronizado, foi possível aumentar a largura do cordão do lado com maiores corrente e tempo de parada lateral e vice-versa. Já no caso do MIG/MAG sincronizado, foi possível controlar a geometria da zona fundida formada, podendo-se diminuir a diluição dos cordões resultantes, com pouca variação no reforço superior e ao mesmo tempo com aumento de largura dos cordões e com tendência de maior concentração da penetração nas laterais dos mesmos. Acredita-se que a técnica de oscilação magnética sincronizada com processos de soldagem possa ser explorada visando diversas aplicações, nas quais é importante otimizar a distribuição de energia do arco sobre a peça de trabalho. / Currently the search for improvements in processes and mechanized/automated welding techniques has been intense due to the skilled labor shortage. In this line, the combination of processes and even operational modes (polarity and/or metal transfer mode) within a process, in addition to the possibility of combining welding current levels, has gained attention. Through operational modes and/or current levels, the arc energy (both thermal and kinetic) delivered to the workpiece can be changed. By combining this feature with the arc motion, the arc energy can be optimally distributed to control the formation of the weld bead. A relatively simple way to control the arc motion is by magnetic oscillation - deflection of the electric arc by an electromagnet. Thus, this work exploits the synchronization between the arc oscillation and the welding process to control the arc energy distribution on the workpiece. To this end, a synchronized oscillation system, including hardware and software, was devised to enable to control the magnetic oscillation and a multiprocess welding power source synchronously. Then, a characterization of the magnetic arc deflection was carried out (according to the electromagnet voltage, welding current and arc length) based on high-speed filming. In order to exploit the synchronized magnetic oscillation technique with different welding processes, two approaches were executed, both with arc oscillation transverse to the welding direction, and then compared to reference conditions (welding without oscillation and with unsynchronized oscillation). The TIG process was synchronized to the magnetic oscillation varying the level of welding current according to the arc position, being the effect on the control of the weld beads width the basis for analysis. The MIG/MAG process was synchronized to the magnetic oscillation with different welding operational modes according to the arc position, being the effect on the control of the molten zone geometry the basis for evaluation. The synchronized oscillation system was able to control the formation of the weld beads for the TIG as well as for the MIG/MAG welding. In the case of the synchronized TIG, it was possible to increase the weld bead width on the side with higher current and lateral stop time and vice versa. In the case of the synchronized MIG/MAG, it was possible to control the molten zone geometry, besides reduce the dilution of the resulting beads, with little variation in the top reinforcement and at the same time with increasing in the bead widths and with tendency for more side penetration. It is believed that the magnetic oscillation technique synchronized with the welding processes can be exploited in several applications, where it is important to optimize the arc energy distribution on the workpiece. / Dissertação (Mestrado)

Fundação de Amparo a Pesquisa do Estado de Minas Gerais / In recent years, the demand of the productive sector for more efficient processes has encouraged the research and development of products and processes to increase the production at a competitive cost. In this sense, the \"Plasma-MIG\" with Concentric Arcs process, being an evolution of the conventional MIG/MAG process, has emerged as a promising option. This process has been available to the market since the 70s. However, it is still necessary to consolidate a scientific and technological basis of that process. Only then the market will decide if it is applicable, either to replace or become an option instead of the other processes. Thus, the challenge is to collaborate with both the scientific and the production what actually is the overall goal of this work, that is to provide fundamental knowledge about functioning principles and operating parameters of the \"Plasma-MIG\" with Concentric Arcs. The influence of the gas flow, especially of the intermediate one on the weld bead surface appearance, the effect of external arc on the globular-spray transition current and on the axial spray-rotational transition current, as well as on the droplet kinematic parameters and the relation between the outer arc current/torch working angle/torch-piece distance and the weld geometry have been studied experimentally. The results showed that the intermediate arc gas flow rate was the very one which determined weld appearance. The globular-spray transition current rose and the axial spray-rotational transition current became lower in the presence of the outer arc. The presence of the outer arc also raised the momentum of the drops hitting the weld pool. The presence of current in the outer arc at low values reduces penetration and correlated parameters (either directly or inversely proportional), but causes their growing again when being increased. The bead geometry follows the similar behavior of the conventional MIG/MAG as regards to the torch working angle and the torch-piece distance, though being more intensified when using the outer arc. In conclusion, it is possible to say that the knowledge on the operational characteristics of the \"Plasma-MUG\" with Concentric Arcs welding process obtained in this work may serve as a basis for the perception of this process application potential. / Nos últimos anos, a demanda do setor produtivo por processos mais eficientes tem incentivado a pesquisa e o desenvolvimento de produtos e processos que permitam o aumento da produção a um custo compatível. Neste sentido, o processo de soldagem \"Plasma-MIG\" com Arcos Concêntricos, uma evolução do processo MIG/MAG convencional, tem surgido como uma opção promissora. Esse processo está à disposição do mercado desde a década de 70, no entanto, ainda é necessário consolidar uma base cientifica e tecnológica a respeito desse processo. Somente assim o mercado poderá decidir se o mesmo é aplicável, seja para substituir ou se tornar mais uma opção frente a outros processos. Desta forma, é no desafio de colaborar tanto com o meio cientifico como o produtivo que se enquadra o objetivo global deste trabalho, o qual é o de fornecer conhecimentos fundamentais sobre aspectos de funcionamento e parâmetros operacionais do processo \"Plasma-MIG\" com Arcos Concêntricos. Foram estudados experimentalmente a influência das vazões dos gases, principalmente o intermediário, sobre o aspecto superficial do cordão de solda, o efeito do arco externo sobre as correntes de transição globulargoticular e goticular axial-rotacional e sobre os parâmetros cinemáticos das gotas e a relação entre corrente do arco externo/ângulo de inclinação da tocha/distância da tocha a peça e a geometria do cordão. Os resultados apontam que a vazão governante sobre o acabamento do cordão é a do gás intermediário. A corrente de transição globular-goticular elevou-se e a goticular axial-rotacional ficou menor na presença do arco externo. A presença do arco externo também fez elevar o momentum das gotas atingindo a poça. A presença da corrente no arco externo em valores baixos reduz a penetração e parâmetros correlacionados (de forma direta ou inversamente proporcional), mas faz novamente crescêla ao ser aumentada. A geometria do cordão segue o comportamento similar ao do processo MIG/MAG convencional quanto ao ângulo de inclinação e distância da tocha à peça, mais intensificado quando se usa arco externo. Ao final, pode-se dizer que os conhecimentos gerados no presente trabalho sobre as características operacionais do processo \"Plasma- MIG\" com Arcos Concêntricos formam uma base para conceber a potencialidade aplicativa do processo. / Doutor em Engenharia Mecânica