Investigation on key molecular targets responsible for antidiabetic properties of Symplocos cochinchinensis (Lour.) S. Moore

Diabetes mellitus is a heterogeneous metabolic disorder characterized by hyperglycemia with disturbances in carbohydrate, protein and lipid metabolism resulting from defects in insulin secretion, insulin action or both. Currently there are 387 million people with diabetes worldwide and is expected to affect 592 million people by 2035. Insulin resistance in peripheral tissues and pancreatic beta cell dysfunction are the major challenges in the pathophysiology of diabetes. Diabetic secondary complications (like liver cirrhosis, retinopathy, microvascular and macrovascular complications) arise from persistent hyperglycemia and dyslipidemia can be disabling or even life threatening. Current medications are effective for control and management of hyperglycemia but undesirable effects, inefficiency against secondary complications and high cost are still serious issues in the present prognosis of this disorder. Hence the search for more effective and safer therapeutic agents of natural origin has been found to be highly demanding and attract attention in the present drug discovery research. The data available from Ayurveda on various medicinal plants for treatment of diabetes can efficiently yield potential new lead as antidiabetic agents. For wider acceptability and popularity of herbal remedies available in Ayurveda scientific validation by the elucidation of mechanism of action is very much essential. Modern biological techniques are available now to elucidate the biochemical basis of the effectiveness of these medicinal plants. Keeping this idea the research programme under this thesis has been planned to evaluate the molecular mechanism responsible for the antidiabetic property of Symplocos cochinchinensis, the main ingredient of Nishakathakadi Kashayam, a wellknown Ayurvedic antidiabetic preparation. A general introduction of diabetes, its pathophysiology, secondary complications and current treatment options, innovative solutions based on phytomedicine etc has been described in Chapter 1. The effect of Symplocos cochinchinensis (SC), on various in vitro biochemical targets relevant to diabetes is depicted in Chapter 2 including the preparation of plant extract. Since diabetes is a multifactorial disease, ethanolic extract of the bark of SC (SCE) and its fractions (hexane, dichloromethane, ethyl acetate and 90 % ethanol) were evaluated by in vitro methods against multiple targets such as control of postprandial hyperglycemia, insulin resistance, oxidative stress, pancreatic beta cell proliferation, inhibition of protein glycation, protein tyrosine phosphatase-1B (PTP-1B) and dipeptidyl peptidase-IV (DPPxxi IV). Among the extracts, SCE exhibited comparatively better activity like alpha glucosidase inhibition, insulin dependent glucose uptake (3 fold increase) in L6 myotubes, pancreatic beta cell regeneration in RIN-m5F and reduced triglyceride accumulation in 3T3-L1 cells, protection from hyperglycemia induced generation of reactive oxygen species in HepG2 cells with moderate antiglycation and PTP-1B inhibition. Chemical characterization by HPLC revealed the superiority of SCE over other extracts due to presence of bioactives (beta-sitosterol, phloretin 2’glucoside, oleanolic acid) in addition to minerals like magnesium, calcium, potassium, sodium, zinc and manganese. So SCE has been subjected to oral sucrose tolerance test (OGTT) to evaluate its antihyperglycemic property in mild diabetic and diabetic animal models. SCE showed significant antihyperglycemic activity in in vivo diabetic models. Chapter 3 highlights the beneficial effects of hydroethanol extract of Symplocos cochinchinensis (SCE) against hyperglycemia associated secondary complications in streptozotocin (60 mg/kg body weight) induced diabetic rat model. Proper sanction had been obtained for all the animal experiments from CSIR-CDRI institutional animal ethics committee. The experimental groups consist of normal control (NC), N + SCE 500 mg/kg bwd, diabetic control (DC), D + metformin 100 mg/kg bwd, D + SCE 250 and D + SCE 500. SCEs and metformin were administered daily for 21 days and sacrificed on day 22. Oral glucose tolerance test, plasma insulin, % HbA1c, urea, creatinine, aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin, total protein etc. were analysed. Aldose reductase (AR) activity in the eye lens was also checked. On day 21, DC rats showed significantly abnormal glucose response, HOMA-IR, % HbA1c, decreased activity of antioxidant enzymes and GSH, elevated AR activity, hepatic and renal oxidative stress markers compared to NC. DC rats also exhibited increased level of plasma urea and creatinine. Treatment with SCE protected from the deleterious alterations of biochemical parameters in a dose dependent manner including histopathological alterations in pancreas. SCE 500 exhibited significant glucose lowering effect and decreased HOMA-IR, % HbA1c, lens AR activity, and hepatic, renal oxidative stress and function markers compared to DC group. Considerable amount of liver and muscle glycogen was replenished by SCE treatment in diabetic animals. Although metformin showed better effect, the activity of SCE was very much comparable with this drug. xxii The possible molecular mechanism behind the protective property of S. cochinchinensis against the insulin resistance in peripheral tissue as well as dyslipidemia in in vivo high fructose saturated fat diet model is described in Chapter 4. Initially animal were fed a high fructose saturated fat (HFS) diet for a period of 8 weeks to develop insulin resistance and dyslipidemia. The normal diet control (ND), ND + SCE 500 mg/kg bwd, high fructose saturated fat diet control (HFS), HFS + metformin 100 mg/kg bwd, HFS + SCE 250 and HFS + SCE 500 were the experimental groups. SCEs and metformin were administered daily for the next 3 weeks and sacrificed at the end of 11th week. At the end of week 11, HFS rats showed significantly abnormal glucose and insulin tolerance, HOMA-IR, % HbA1c, adiponectin, lipid profile, liver glycolytic and gluconeogenic enzyme activities, liver and muscle triglyceride accumulation compared to ND. HFS rats also exhibited increased level of plasma inflammatory cytokines, upregulated mRNA level of gluconeogenic and lipogenic genes in liver. HFS exhibited the increased expression of GLUT-2 in liver and decreased expression of GLUT-4 in muscle and adipose. SCE treatment also preserved the architecture of pancreas, liver, and kidney tissues. Treatment with SCE reversed the alterations of biochemical parameters, improved insulin sensitivity by modifying gene expression in liver, muscle and adipose tissues. Overall results suggest that SC mediates the antidiabetic activity mainly via alpha glucosidase inhibition, improved insulin sensitivity, with antiglycation and antioxidant activities.

A Language for Interactive Cooperative Agents

Cooperative behaviour of agents within highly dynamic and nondeterministic domains is an active field of research. In particular establishing highly responsive teamwork, where agents are able to react on dynamic changes in the environment while facing unreliable communication and sensory noise, is an open problem. Moreover, modelling such responsive, cooperative behaviour is difficult. In this work, we specify a novel model for cooperative behaviour geared towards highly dynamic domains. In our approach, agents estimate each other’s decision and correct these estimations once they receive contradictory information. We aim at a comprehensive approach for agent teamwork featuring intuitive modelling capabilities for multi-agent activities, abstractions over activities and agents, and a clear operational semantic for the new model. This work encompasses a complete specification of the new language, ALICA.

Hegemony, Private Actors, and International Institutions: Transnational Corporations as the agents of transformation of the trade regime from GATT to the WTO

Diese Dissertation hat das Ziel, zum einen die Transformation des Handelssystems von der GATT zur Welthandelsorganisation (WTO) im Kontext einer veränderten Weltordnung und zum anderen die Rollen von transnationalen Unternehmen im Rahmen dieser Transformation zu untersuchen und zu verstehen. Die Arbeit wird theoretisch vom Neogramscianismus angeleitet, da die etablierten Ansätzen in den Internationalen Beziehungen und der International Politischen Ökonomie nur unzureichend die intersubjektive Natur von Regimen und nicht-staatlichen Akteuren darstellen. Für Anhänger des Neogramscianismus sind internationale Regime intersubjektive Einheiten, deren Zusammenspiel von Ideen und Machtkonfigurationen historische Strukturen prägen. Die Hegemonie ist ein Konzept, das soziale Einflüsse als Agenten historischen Wandels in international Regimen und der Weltordnung zusammenbindet. Mit dem Konzept der Hegemonie wird eine Machtsituation beschrieben, in der politische Macht in legitime Autorität übersetzt wird, indem die Zustimmung subalterner Akteure eingeholt wird. Hegemonie beinhaltet die konsensuellen Aspekte von Machtausübung in einer jeweiligen Weltordnung. Diese Dissertation argumentiert vor allem, dass die Transformation des Handelssystems als hegemonisch bezeichnet werden kann, da sie parallel mit der Transformation der Weltordnung von einer von den USA dominierten Nachkriegszeit zu einer neoliberalen Hegemonie stattfand. Mit der Transformation zur Welthandlungsorganisation wird der legale Rahmen des Handelssystems neu strukturiert und ihre normative Grundlagen neu definiert, wodurch der ethische Rahmen des Neoliberalismus reflektiert wird. Diese Änderungen werden in der neuartigen Anerkennung der legitimen Autorität des Marktes gegenüber Nationalstaaten und der Anerkennung von der Notwendigkeit von bindenden Disziplinen, die Regierungen übergeordnet sind, reflektiert. Diese Dissertation analysiert zwei Fälle, um die Rolle von transnationalen Unternehmen innerhalb diese Transformationsprozesses zu erklären. Dabei wird der Fokus vor allem auf die Aktivitäten und Fähigkeiten der Unternehmen gerichtet, die Ausrichtung des Handelsregimes zu bestimmen. Die erste Studie untersucht die Eingliederung von Dienstleistungen in das GATT Regime vor und während der Uruguay-Runde (1986 – 1994) und argumentiert, dass diese Eingliederung zu einer Neudefinierung von Liberalisierung und Normen der Nichtdiskriminierung führte. Die zweite Studie analysiert den gescheiterten Versuch, ausländische Direktinvestitionen noch bevor und während der 2001 begonnenen Doha Runde in die Welthandelsorganisation zu integrieren. Letztendlich wird in dieser Dissertation argumentiert, dass transnationale Unternehmen, die in den Vereinigten Staaten ansässig sind, hegemonische Agenten der Regimetransformation waren und eine wichtige Rolle dabei gespielt haben, Dienstleistungen in das GATT einzubinden. Und zwar gelang ihnen dies durch eine in den späten 1970er Jahren begonnenen Kampagne. Auf der einen Seite war die Kampagne darin erfolgreich, etablierte Denkstrukturen zu Handelsthemen systematisch im Sinne des Neoliberalismus zu verändern – und zwar sowohl hinsichtlich der normativen Inhalte als auch der intersubjektiven Bedeutungen des Regimes. Auf der anderen Seite deutet der Fall des Investitionsabkommens die Grenzen der hegemonischen Ideen, Institutionen, und Strömungen seit den frühen 90er Jahren an. Transnationale Unternehmen, die in Europa ansässig waren, sind mit ihren Bemühungen gescheitert, das Regime weiter zu transformieren und das Thema Investitionen in die legalen und normativen Rahmenbedingungen der WTO zu integrieren. Die Prioritäten und Strategien der transnationalen Unternehmen, die Agenda der WTO zu beeinflussen, waren beschränkt und wurden im Kontext einer angefochtenen neoliberalen Hegemonie geformt, die wiederum von dem Widerstand und anti-hegemonischen Kampagnen der Zivilgesellschaft beeinflusst wurden. Die Analyse in dieser Dissertation wurde durch eine qualitative Diskursanalyse von Sekundär- und Primärquellen durchgeführt: Regierungsvorschläge, Verhandlungstexte, Konferenzzusammenfassungen und Statements von Unternehmen.

Infohabitants: laboratori per la simulació d’ infohabitants com agents recomanadors (SIRA)

L’ objectiu del projecte és la implementació d’un simulador de sistema de recomanació que permeti estudiar algoritmes de dissociació entre agent-recomanador i usuari, combinant-los amb diverses tècniques de recomanació i fent servir infohabitants com Agents Recomanadors i veure com treballen en un sistema recomanador

Automatic self-configuration of the logical network using distributed software agents

We present a system for dynamic network resource configuration in environments with bandwidth reservation. The proposed system is completely distributed and automates the mechanisms for adapting the logical network to the offered load. The system is able to manage dynamically a logical network such as a virtual path network in ATM or a label switched path network in MPLS or GMPLS. The system design and implementation is based on a multi-agent system (MAS) which make the decisions of when and how to change a logical path. Despite the lack of a centralised global network view, results show that MAS manages the network resources effectively, reducing the connection blocking probability and, therefore, achieving better utilisation of network resources. We also include details of its architecture and implementation

Dynamic bandwidth management as part of an integrated network management system based on distributed agents

We present a system for dynamic network resource configuration in environments with bandwidth reservation and path restoration mechanisms. Our focus is on the dynamic bandwidth management results, although the main goal of the system is the integration of the different mechanisms that manage the reserved paths (bandwidth, restoration, and spare capacity planning). The objective is to avoid conflicts between these mechanisms. The system is able to dynamically manage a logical network such as a virtual path network in ATM or a label switch path network in MPLS. This system has been designed to be modular in the sense that in can be activated or deactivated, and it can be applied only in a sub-network. The system design and implementation is based on a multi-agent system (MAS). We also included details of its architecture and implementation

Interacting software-agents to support a kind of expert supervision systems

Expert supervision systems are software applications specially designed to automate process monitoring. The goal is to reduce the dependency on human operators to assure the correct operation of a process including faulty situations. Construction of this kind of application involves an important task of design and development in order to represent and to manipulate process data and behaviour at different degrees of abstraction for interfacing with data acquisition systems connected to the process. This is an open problem that becomes more complex with the number of variables, parameters and relations to account for the complexity of the process. Multiple specialised modules tuned to solve simpler tasks that operate under a co-ordination provide a solution. A modular architecture based on concepts of software agents, taking advantage of the integration of diverse knowledge-based techniques, is proposed for this purpose. The components (software agents, communication mechanisms and perception/action mechanisms) are based on ICa (Intelligent Control architecture), software middleware supporting the build-up of applications with software agent features

Embodied Autonomy in Digital Ecosystems: From Bio-Inspired Agents to Cognitive Systems

This paper proposes to promote autonomy in digital ecosystems so that it provides agents with information to improve the behavior of the digital ecosystem in terms of stability. This work proposes that, in digital ecosystems, autonomous agents can provide fundamental services and information. The final goal is to run the ecosystem, generate novel conditions and let agents exploit them. A set of evaluation measures must be defined as well. We want to provide an outline of some global indicators, such as heterogeneity and diversity, and establish relationships between agent behavior and these global indicators to fully understand interactions between agents, and to understand the dependence and autonomy relations that emerge between the interacting agents. Individual variations, interaction dependencies, and environmental factors are determinants of autonomy that would be considered. The paper concludes with a discussion of situations when autonomy is a milestone

Evaluation of conversational agents : Mariá and ET. 'Evaluación de agentes de conversación : Mariá y ET'.

Resumen tomado del autor. Artículo seleccionado del VIII Congreso Iberoamericano de informática Educativa RIBIE 2006, (San José, Costa Rica 2006), extendido y revisado para su publicación en IE Comunicaciones

Efecto de la hipoxia-reoxigenación y las radiaciones ionizantes en la captación de glucosa en líneas tumorales de seno y colon cocultivadas con células endoteliales.

La captación de glucosa y su conversión en lactato juega un papel fundamental en el metabolismo tumoral, independientemente de la concentración de oxígeno presente en el tejido (efecto Warburg). Sin embrago, dicha captación varía de un tipo tumoral a otro, y dentro del mismo tumor, situación que podría depender de las características microambientales tumorales (fluctuaciones de oxígeno, presencia de otros tipos celulares) y de factores estresores asociados a los tratamientos. Se estudió el efecto de la hipoxia-reoxigenación (HR) y las radiaciones ionizantes (RI) sobre la captación de glucosa, en cultivos de líneas tumorales MCF-7 y HT-29, cultivadas de forma aislada o en cocultivo con la línea celular EAhy296. Se encontró que la captación de glucosa en HR es diferente para lo descrito en condiciones de hipoxia permanente y que es modificada en el cocultivo. Se identificaron poblaciones celulares dentro de la misma línea celular, de alta y baja captación de glucosa, lo que implicaría una simbiosis metabólica de la célula como respuesta adaptativa a las condiciones tumorales. Se evaluó la expresión de NRF2 y la translocación nuclear de NRF2 y HIF1a, como vías de respuesta a estrés celular e hipoxia. La translocación nuclear de las proteínas evaluadas explicaría el comportamiento metabólico de las células tumorales de seno, pero no de colon, por lo cual deben existir otras vías metabólicas implicadas. Las diferencias en el comportamiento de las células tumorales en HR en relación con hipoxia permitirá realizar planeaciones dosimétricas más dinámicas, que reevalúen las condiciones de oxigenación tumoral constantemente.

Agents de medi ambient. 'Agentes de medio ambiente'.

Se repasa las actividades que realizan durante una jornada de trabajo los agentes de medio ambiente. Las funciones de estos trabajadores son la vigilancia de la flora y la fauna, de los ecosistemas marinos, de las actividades humanas en el medio ambiente -control de recursos hídricos, control de residuos, etc-. Hasta el año 2003 sólo existían los guardas forestales pero hacía falta un cuerpo de personal más complejo que respondiera a las necesidades de la sociedad actual y los problemas del medio ambiente..

Exploratory Study on Occupational Health Exposure to Chemical Agents, in a Public Hospital in Valencia, Venezuela. Preliminar Assessment

Descriptive study that identified chemical agents (AQ) use and training on risk management and waste disposal techniques in a public Hospital in Valencia. A questionnaire was answered by 48 workers. Information obtained was: personal data, occupational history, AQ used; knowledge of risk management and waste disposal. There were 16 occupations from 12 “High Risk” areas. “Adult emergency” was the one with more workers (11 individuals), followed by “sterilization” and “clinical laboratory” (7 each) and oncology (5). The remained areas had less than 8.3% workers. The most used anesthetic agents were: Halothane, Enfluorane and Isofluorane 4.17% each and main antineoplastics used were: Doxorubicin 16.67% and Paclitaxel, 5-Fluoracil and Etoposide, 8.33% each. The most mentioned substances were: alcohol (70.8%) and Chlorine (64.6%). None of the answers regarding knowledge of AQ’ risk management and waste disposal was satisfactory. Statistical associations between training and several variables such as age, time in their job and being or not a professional, resulted non-significant. The correlation between training and the knowledge of AQ’s management was significant (p < 0.001). Participants showed that their knowledge about chemical occupational risk factors they are exposed to is still insufficient. Therefore, this theme should be included in graduate course curricula. These results provide important data and will serve as a pilot research for the follow up Phase II study that will include clinical aspects and environmental and biological monitoring.

L'escola com a espai de relació amb la resta d'agents educadors. 'La escuela como espacio de relación con el resto de agentes educadores'.

Resumen del autor en catalán

Evidence versus ideology in education policy : the recent history of initial teacher education in England and Wales and the implications for educational researchers as agents of change.

Resumen del autor. Este art??culo pertenece al monogr??fico 'John Elliott: su pensamiento y su influencia'

Relació i comunicació entre els agents educatius i l'escola en el territori. 'Relación y comunicación entre los agentes educativos y la escuela en el territorio'.

Se define y justifica el concepto y la metodología del trabajo en red. Los autores reflexionan sobre el modelo educativo del S.XXI y se debaten algunos cambios que consideran necesarios para que desde la escuela poder responder a las necesidades de las familias y de la sociedad actual. Se muestran algunos proyectos que se han llevado a cabo en algunas escuelas de Cataluña a través de las redes de trabajo.