Negative Regulation of the Kinase LIN-45 By the E3/E4 Ubiquitin Ligase UFD-2

The serine/threonine kinase BRAF is a key part of the Ras-Raf-MEK-ERK pathway, an inducer of cell growth, differentiation, and survival. In humans, activating mutations, most commonly BRAF(V600E), have been detected in several cancers, including melanoma and thyroid cancer. In the Caenorhabditis elegans ortholog LIN-45, the equivalent mutation LIN-45(V627E) results in elevated Raf-MEK-ERK signaling. We performed an unbiased genetic screen to identify negative regulators of LIN-45(V627E). Here, we report the identification of the E3/E4 ubiquitin ligase UFD-2, and show it is a negative regulator of LIN-45 protein activity and levels. Loss of UFD-2 leads to accumulation of wild-type LIN-45 protein as well as LIN-45(V627E). Based on analysis of truncations in the LIN-45 protein and mutations in the conserved 14-3-3 sites, we propose a model where UFD-2-dependent regulation requires binding by 14-3-3 proteins. This contrasts with the previously characterized degradation of LIN-45 by the E3 ubiquitin ligase SEL-10, which only requires a minimal phospho-degron sequence. We also identify the AAA ATPase CDC-48.1/2, a known interactor of UFD-2, as a negative regulator of LIN-45 protein stability. These findings represent a previously unrecognized mechanism of Ras-Raf-MEK-ERK regulation and will be the basis of future investigations of ubiquitin-mediated degradation of Raf

Conception complexe et ingénierie système.

S'il est une tendance admise en matière de dynamique technique de longue période, c'est bien celle de la complication croissante des « objets techniques » [SIM 58] voulus, conçus, produits et utilisés par l'Homme. Pour s'en convaincre, il suffit de procéder à une comparaison facile et de mettre en rapport une plaque de métal - objet banal du XIX° siècle - avec un téléphone portable – objet banal de notre époque - de même dimension et masse. Il ne fait alors aucun doute que celui-ci répond à plus nombreuses fonctions que celle-là. Il permet en effet de communiquer des messages par la voix, l'écrit ou l'image, de photographier, de filmer, de jouer, d'avoir l'heure, de gérer ses rendez-vous, etc., si bien, d'ailleurs, que sa compréhension par l'utilisateur relève de plus en plus du pensum [MOR 07]. Pour assurer toutes ses fonctions, il intègre de nombreux composants, matériels et logiciels, relevant, qui plus est, de domaines techniques et scientifiques éloignés : télécommunications, électronique, énergie, traitement du signal, logiciel enfoui et interface homme-machine, etc. Du fait de cette densité fonctionnelle particulièrement élevée, il ne peut donc pas se comprendre comme un simple composant, mais comme une véritable architecture multiphysique. Il exhibe aussi différents comportements : il répond aux commandes venant de l'utilisateur lorsque celui-ci appuie sur ses touches ou effleure son écran, il cherche les émetteurs les plus proches, il vérifie l'état de la batterie, il vibre ou sonne, etc. Enfin, il est à la fois produit en masse et varié, ce qui suppose un système de production et une chaîne logistique particulièrement compliqués

Design and Core Competency, The Missing Links.

International audienceDesigning in an industrial context is a very complex activity. It needs the integration of heterogeneous knowledge or skills, to transform a set of ill-defined requirements into an artefact that satisfies esthetical, functional, technical, economical criteria. Design process optimization with methods like system engineering and core competency building are key issues for managers of product development process, design skills networks, communities of design practices... In the literature, these issues have been dealt with separately. In this paper, we propose a framework of reference that helps us to explicit the content of the core design competency. This framework is a first step beyond an efficient compentency based management of design structures

Propagating product architecture decisions onto the project organization : a comparison between two methods.

International audienceConcepts like product architecture and modularity have been introduced in order to limit the effects of technological change on complex product design. Researchers have highlighted that product architectures and design organizations (projects, teams...) are strongly interrelated. However, little research has analyzed this relationship. System architects and design managers need a method that helps them to simulate the mapping of the product architecture onto the project organization by propagating choices and then assessing alternatives. In this paper, two propagation methods are presented and compared. The first one is based on a fuzzy process, which is proposed by the authors. The second one is based on a matrix approach. Both are applied to define new robotized gearbox architectures. A sensitivity analysis is conducted. It is concluded that in new product development situations or in re-engineering projects, system architects could use these methods in the early design stages to forecast the more appropriate design project organization

Towards an objective measure of presence: examining startle reflexes in a commercial virtual reality game

A large body of literature is concerned with models of presence-the sensory illusion of being part of a virtual scene-but there is still no general agreement on how to measure it objectively and reliably. For the presented study, we applied contemporary theory to measure presence in virtual reality. Thirty-seven participants explored an existing commercial game in order to complete a collection task. Two startle events were naturally embedded in the game progression to evoke physical reactions and head tracking data was collected in response to these events. Subjective presence was recorded using a post-study questionnaire and real-time assessments. Our novel implementation of behavioral measures lead to insights which could inform future presence research: We propose a measure in which startle reflexes are evoked through specific events in the virtual environment, and head tracking data is compared to the range and speed of baseline interactions

Dimensionnement des éléments passifs d'un convertisseur cascadé en vue de l'intégration d'organes de stockage au réseau

International audienceNous présentons dans ce papier une méthode de dimensionnement des éléments passifs d'un convertisseur multi-niveaux de topologie ponts complets cascadés. Ce convertisseur est assemblé en étoile et intègre des batteries de stockage chimique. La topologie présente une bonne tolérance aux défauts et permet une montée en tension plus facile. Les éléments passifs du convertisseur, tels que les inductances de ligne et les condensateurs de bus continu sont quantifiés de manière générique en fonction du nombre de modules.Les modèles de dimensionnement, couplés à une fonction objectif, permettent de mettre en place un algorithme de dimensionnement optimal du convertisseur multi-niveau, permettant de choisir le nombre de niveaux en optimisant un rapport coût/volume/performance moins restrictif comparé à une approche classique.</p