Chronic hyperlipidemia (lipotoxicity) and hyperglycemia (glucotoxicity) have recently been shown to induce Endoplasmic Reticulum (ER) stress, which may contribute to pancreatic beta-cell dysfunction in type 2 diabetes. This thesis examined the involvement of ER stress in beta-cell lipotoxicity and glucotoxicity. Although chronic treatment with saturated free fatty acids (FFA) in vitro induced ER stress, altering ER stress by increasing or knocking-down GRP78 chaperone expression had no effect on apoptosis induction. Conversely, overexpression of ER chaperones rescued the reduction in proinsulin protein levels caused by chronic exposure to high glucose, although it had no effect on the decreased insulin mRNA levels and proinsulin translation rate. Thus, ER stress is likely not the main mechanism involved in saturated FFA-induced beta-cell apoptosis in vitro, but it may contribute to glucotoxic effects on proinsulin levels. These findings have increased our understanding of the link between ER stress and beta-cell dysfunction in type 2 diabetes.

University of Macau / Faculty of Social Sciences and Humanities / Department of Chinese

Chronic hyperlipidemia (lipotoxicity) and hyperglycemia (glucotoxicity) have recently been shown to induce Endoplasmic Reticulum (ER) stress, which may contribute to pancreatic beta-cell dysfunction in type 2 diabetes. This thesis examined the involvement of ER stress in beta-cell lipotoxicity and glucotoxicity. Although chronic treatment with saturated free fatty acids (FFA) in vitro induced ER stress, altering ER stress by increasing or knocking-down GRP78 chaperone expression had no effect on apoptosis induction. Conversely, overexpression of ER chaperones rescued the reduction in proinsulin protein levels caused by chronic exposure to high glucose, although it had no effect on the decreased insulin mRNA levels and proinsulin translation rate. Thus, ER stress is likely not the main mechanism involved in saturated FFA-induced beta-cell apoptosis in vitro, but it may contribute to glucotoxic effects on proinsulin levels. These findings have increased our understanding of the link between ER stress and beta-cell dysfunction in type 2 diabetes.

En esta tesis se estudian los efectos farmacológicos de derivados lipídicos frente el glioma y el Alzheimer. Los beneficios de este tipo de fármacos, basados en la terapia lipídica de membrana, están asociados con la modulación de la composición y las propiedades fisicoquímicas de membrana. En concreto, el ácido 2-hidroxioleico (2OHOA) es un potente fármaco antitumoral que fue diseñado para regular la composición y la estructura de la membrana lipídica así como la función de importantes proteínas de membrana. Por otro lado, el ácido 2-hidroxiaraquidónico (2OHARA), el ácido 2-hidroxieicosapentaenóico (2OHEPA), y el ácido 2-hidroxidocosahexanóico (2OHDHA) son derivados lipídicos hidroxilados que fueron diseñados en nuestro grupo de investigación para el tratamiento del Alzheimer. Este trabajo se ha basado en el estudio del funcionamiento de estos derivados de ácidos grasos hidroxilados en la modulación de las vías de señalización de la UPR (respuesta a las proteínas mal plegadas) y de la autofagia en células de glioma y células neuronales. / In this thesis, the pharmacological effects of lipid derivatives against glioma and Alzheimer's Disease are studied. The benefits of this type of drugs, which are based on the lipid membrane therapy, are associated with the modulation of the composition and physicochemical properties of membranes. 2-Hydroxyoleic acid (2OHOA) is a potent antitumor drug designed to regulate membrane lipid composition and structure and the function of important membrane proteins. In addition, 2- hydroxyarachidonic acid (2OHARA; LP204A1), 2-hydroxyeicosapentaenoic acid (2OHEPA; LP205A1), and 2-hydroxydocosahexanoic acid (2OHDHA; LP226A1) are new hydroxy derivated lipids designed in our group for the treatment of Alzheimer’s Disease. The main goal of this work was to study how these synthetic hydroxy derivates modulate the unfolded protein response and the autophagy pathways in glioma cells and neuron-like cells for Alzheimer’s Disease.

This project focuses on the design and modeling of a two degree-of-freedom dissipative passive haptic display. Haptic displays are man-machine interfaces that transmit forces to the human operator. A dissipative passive haptic display is one that may only remove energy from the system using actuators such as brakes and dampers, thus ensuring the safety of the human operator. These devices may be used to implement virtual constraints such as desired paths and obstacles. Traditional friction brakes have previously been used as dissipative and coupling elements in a two degree-of-freedom parallel manipulator, resulting in undesired effects such as vibration, stiction, and slow response times. Alternatively, the new robot is actuated by rheological brakes, which feature fast response times and smooth application of torque. This approach aims to improve upon the accuracy and feel of the previous design. A commercial magnetorheological (MR) fluid brake was selected and put through an extensive series of tests. The data was used to develop a model that characterizes MR fluid behavior in low speed braking applications. A parallel five bar linkage was designed and built that has separate configurations corresponding to 3-brake and 4-brake operation. The length of each arm was chosen by means of a geometrical optimization that weighs the size and area of the workspace and actuator effects. A simulation was then developed by incorporating the brake model into the equations of motion of the robot. Next, two forms of path following velocity control were devised and tested in simulation. Finally, the accuracy, workload, and smoothness of both controllers and both configurations were examined in preliminary tests with human operators.

The computerize information systems are widely used in the companies of Lithuania now. A lot of them are universal enough and fit to solve the various administrative problems in the companies. These systems excel in large complexity and high price. So develops the need to create more simple and cheap information systems. An aim of the project is to create system which are accomulating the information about received and given flows of the electricity energy instruments, are doing the namesake and guantity account of the accounting instruments, are formating analysis reports for the directed period. The client of the project is Rytų skirstomieji tinklai AB branch Alytus electricity network Elekctricity energy realization division. The need of the project to the client may be given an outline: · to boost the guality of work and account results; · to reduce expenditure of time to do account works; · to eliminate the information duplicate; · to ease analysis reports composing; · to escape mistakes; · to effective account work. The project is realized by MS Access data base with integrated Microsoft Visual Basic for Aplication. The posibilities of this base complete enough to accomplish those project. Also this packet helps to realize grafic users link (GUL). There are realized those functions to help users work in this project: buttons, the facilitation of the repetitive information installing, help. The project was created to satisfy the users all needs and to diminish the use... [to full text]

La mort cellulaire programmée (PCD pour Programmed Cell Death) est un processus essentiel aux cellules. Le PCD a d’abord été caractérisé dans le développement cellulaire et peut être divisé en plusieurs groupes selon les caractéristiques observées. L’apoptose, un sous-groupe du PCD, est caractérisé par plusieurs distinctions morphologiques et signalétiques attribué tout d’abord aux organismes complexes pour son rôle dans le développement et dans le maintien de l’intégrité tissulaire. Depuis la dernière décennie, de nombreuses études font état de l’existence d’un programme apoptotique dans des organismes unicellulaires comme les levures. Ce programme apoptotique a surtout été étudié chez les levures Saccharomyces cerevisiae et Schizosaccharomyces pombe et partage certaines caractéristiques avec l’apoptose des mammifères. Par contre, l’apoptose associé aux levures est distinct à certains égards entre autre par l’absence de certains homologues présents chez les mammifères. L’intérêt au niveau de l’étude du phénomène apoptotique chez les levures est sans cesse grandissant par la facilité avec laquelle les levures peuvent être utilisées comme système modèle. L’apoptose peut être induit dans les cellules de différentes façons en réponse à des stimuli internes ou externes. L’accumulation de protéines mal repliées au niveau du réticulum endoplasmique (RE) causant un stress est un inducteur bien caractérisé de la voie apoptotique. La signalisation de l’apoptose dans un cas de stress au RE fait appel aux transducteurs des signaux de la voie du UPR ( Unfolded Protein Response). Récemment, il a été montré que la calnexine, une chaperone transmembranaire du RE connue et caractérisée surtout pour ses fonctions d’aide au repliement des protéines et au contrôle de qualité, joue un rôle dans la transduction du signal apoptotique en réponse au stress du RE chez mammifères. Le rôle de la calnexine dans ce cas consiste principalement en l’échafaudage pour le clivage par la caspase 8 de la protéine apoptotique Bap31. Nous avons tout d’abord démontré que le stress du RE et que la déficience en inositol, un précurseur essentiel de nombreuses molécules signalétiques, sont deux inducteurs de l’apoptose chez la levure S. pombe. Ces deux voies semblent induire l’apoptose par deux voies distinctes puisque seule la voie de la déficience en inositol induit l’apoptose de façon dépendante à la métacaspase Pca1p. La calnexine, essentielle à la viabilité chez la levure S. pombe, est impliquée dans ces deux phénomènes apoptotiques. L’apoptose induit par le stress du RE nécessite une version de la calnexine ancrée à la membrane du RE pour être optimal. De façon opposée, l’apoptose induit par une déficience en inositol nécessite la présence de la queue cytosolique ancrée à la membrane de la calnexine pour être retardé. Ces deux actions différentes imputables à une même protéine laisse croire à une double fonction pro et anti-apoptotique de celle-ci. Suite à la découverte de l’existence d’un clivage endogène de la calnexine en situation normale de croissance, un modèle a été élaboré expliquant les rôles distincts de la calnexine dans ces deux voies apoptotiques. Ce modèle fait état d’un rôle associé au clivage de la calnexine dans l’apoptose. / Programmed Cell Death (PCD) is an essential process to the cells. PCD was first characterized in cell development and can be separated in sub-groups depending of cell death characteristics observed. Apoptosis is one of the PCD sub-groups that was first associated to complex organisms for its roles in cell development and in maintenance of tissues integrity. The apoptotic pathway is characterized by specific morphological and signalization characteristics. In the last ten years, numerous studies demonstrated the existence of apoptosis in unicellular organisms such as yeast. This apoptotic program was extensively studied in the two yeast Saccharomyces cerevisiae and Schizosaccharomyces pombe and share characteristics with the mammalian one. However, yeast apoptosis is distinctive at many points as yeast do not encodes all the mammalian homologues of the apoptotic pathway. Although yeast and mammalian apoptosis seems to differs, the interest about yeast apoptosis is growing given that yeast is an excellent and easily tractable model system. External and internal stimuli can induce apoptosis by different ways. Accumulation of unfolded or incompletely folded proteins in the endoplasmic reticulum (ER) causing ER stress is a well-known inducer of the apoptotic pathway. Signalization of ER-stress induced apoptosis involves the same transducers than the UPR (Unfolded Protein Response) pathway. It was recently shown that calnexin, a transmembrane chaperone of the ER, is implicated in ER-stress apoptosis in mammalian cells. In this particular case, it was demonstrated that calnexin acts as a scaffold in the cleavage of the apoptotic protein Bap31 by caspase 8. We demonstrated that ER stress and inositol deficiency, a precursor of many important signalization molecules, are two situations leading to apoptosis in the yeast S. pombe. These two pathways leading to apoptosis seems to differ as only inositol deficiency is dependant of the yeast metacaspase Pca1p. We also demonstrated that S. pombe calnexin, essential for cell viability of this yeast, takes part in these two apoptotic process. ER stress induced apoptosis needs a calnexin anchors to the ER membrane to be efficient. However, apoptosis induced by inositol starvation needs the calnexin C-terminal tail with the transmembrane domain to be delayed. These two opposite actions from the same protein lead to the hypothesis that calnexin encodes both pro and anti-apoptotic functions. By the discovery that calnexin is cleaved under normal culture conditions, a model was elaborated explaining the distinctive roles of calnexin in these two apoptotic pathways. This model proposed a role of calnexin cleavage to apoptosis.

No description available.

No description available.

Orientador: Nobuo Oki / Banca: Alexandre Cesar Rodrigues da Silva / Banca: José Raimundo de Oliveira / Resumo: Neste trabalho descreve-se um Software de comando para o acionamento de um braço mecânico do robô SCORBOT ER - III. O software desenvolvido tem a capacidade de controlar e monitorar o robô remotamente em tempo real através da Rede Mundial de Computadores (WWW), utilizando bibliotecas de JAVA como: métodos nativos (JNI - JAVA Native Interface), Invocação de Métodos Remotos (RMI - Remote Method Invocation), Conectividade com Banco de Dados JAVA (JDBC - JAVA Database Connecvity) e JMF (JAVA Media Frameworks) com o Protocolo de Tempo Real - RTP (Real Time Protocol). Para controle do robô, o circuito de controle originalmente desenvolvido pelo fabricante, foi reprojetado utilizando-se o ambiente Max+Plus II da Altera e a conexão entre Robô e o PC é feita através de um dispositivo lógico programável tipo FPGA, que recebe os comandos provenientes da Porta Paralela do PC, o monitoramento através de câmeras digitais do tipo WEBCAM conectadas em uma Porta do tipo USB. / Abstract: This work describes the development of a Software for the control of a mechanical arm type SCORBOT ER - III. This software has the capacity to control and to monitor the robot remotely in real time through the World Wide Web (WWW), using libraries of JAVA as: native methods (JNI-JAVA Native Interface), Invocation of Remote Methods (RMI - Remote Method Invocation), Connecvity with database JAVA (JDBC - JAVA Database Connecvity) and JMF (JAVA Media Frameworks) with the Protocol of Real Time - RTP (Real Time Protocol). The robot control circuit was redesigned using the Altera Max+Plus II environment and the connection between the robot and personal computer was made by the Parallel Port and digital cameras of the type WEBCAM, connected USB port. / Mestre