Activation of MEK1 or MEK2 isoform is sufficient to fully transform intestinal epithelial cells and induce the formation of metastatic tumors

<p>Abstract</p> <p>Background</p> <p>The Ras-dependent ERK1/2 MAP kinase signaling pathway plays a central role in cell proliferation control and is frequently activated in human colorectal cancer. Small-molecule inhibitors of MEK1/MEK2 are therefore viewed as attractive drug candidates for the targeted therapy of this malignancy. However, the exact contribution of MEK1 and MEK2 to the pathogenesis of colorectal cancer remains to be established.</p> <p>Methods</p> <p>Wild type and constitutively active forms of MEK1 and MEK2 were ectopically expressed by retroviral gene transfer in the normal intestinal epithelial cell line IEC-6. We studied the impact of MEK1 and MEK2 activation on cellular morphology, cell proliferation, survival, migration, invasiveness, and tumorigenesis in mice. RNA interference was used to test the requirement for MEK1 and MEK2 function in maintaining the proliferation of human colorectal cancer cells.</p> <p>Results</p> <p>We found that expression of activated MEK1 or MEK2 is sufficient to morphologically transform intestinal epithelial cells, dysregulate cell proliferation and induce the formation of high-grade adenocarcinomas after orthotopic transplantation in mice. A large proportion of these intestinal tumors metastasize to the liver and lung. Mechanistically, activation of MEK1 or MEK2 up-regulates the expression of matrix metalloproteinases, promotes invasiveness and protects cells from undergoing anoikis. Importantly, we show that silencing of MEK2 expression completely suppresses the proliferation of human colon carcinoma cell lines, whereas inactivation of MEK1 has a much weaker effect.</p> <p>Conclusion</p> <p>MEK1 and MEK2 isoforms have similar transforming properties and are able to induce the formation of metastatic intestinal tumors in mice. Our results suggest that MEK2 plays a more important role than MEK1 in sustaining the proliferation of human colorectal cancer cells.</p

Validation de méthodes de contrainte aux frontières d'un modèle océanique (application à un modèle hauturier de l'Atlantique nord et à un modèle régional du Golfe de Gascogne)

Le choix des conditions limites aux frontières d'un modèle d'océan côtier demeure un réel problème, en particulier pour des simulations longues de plusieurs années. Dans ce travail, nous comparons différentes méthodes permettant aux flux de traverser les frontières d'un modèle d'océan régional sur une longue période d'intégration. Nous considèrerons d'abord les conditions aux frontières spécifiées et radiatives, puis les méthodes de raffinement de maillage dans un modèle de plus grande échelle et enfin des méthodes de couplage entre un modèle côtier et un modèle de circulation générale. Durant une période de trois ans (de 1996 à 1998), un modèle à basse résolution de l'Atlantique Nord au 1/3 de degré (NATL3 : North ATLantique) fournit l'information aux frontières d'un modèle régional à haute résolution du Golfe de Gascogne au 1/15 de degré (BABY15 : BAy of BiscaY). Les champs du modèle NATL3 alimentent le modèle côtier suivant différentes méthodes de contraintes aux frontières. Celles-ci peuvent être de type spécifiées ou radiatives, quand BABY15 est intégré seul. NATL3 peut être aussi raffiné du 1/3 au 1/15 de degré dans la région de BABY 15 à l'aide de l'outil AGRIF développé par l'équipe du Laboratoire de Modélisation et de Calcul (LMC, Grenoble), la grille fine pouvant rétroagir sur la grille grossière (sans rétroaction le raffinement fonctionne en mode dit" One- Way" , avec rétroaction il fonctionne en mode dit "Two-Way") [...].GRENOBLE1-BU Sciences (384212103) / SudocSudocFranceF

ENIGME: Interannual Evolution of the Dynamics in the Bay of Biscay and the English Channel

In a context of global change, ocean regions as the Bay of the Biscay and the English Channel represent key domains to estimate the local impact on the coasts of these evolutions. Indeed, the coastal (considering in this project regions above the continental shelf) and regional (including the continental slope and the abyssal plain) environments are sensitive to these long- term evolutions driven by the open ocean, the atmosphere and the watersheds. These evolutions can have impacts on the whole ecosystem. To understand and, by extension, forecast evolutions of these ecosystems, we need to go further in the description and the analysis of the past interannual variability over decadal to pluri-decadal periods. The ENIGME project is organised following three main axes: (a) the interannual evolutions (haline and thermal budgets, currents), (b) the occurrence of intermittent events and the mesoscale dynamics, (c) the sea level in regional models. To illustrate the first results from the ENIGME project, we introduce the study of the interannual variability based on 53-years long simulations. These numerical experiments have been performed using the MARS3D model with a 4 km spatial resolution. In terms of hydrological content, daily results show a broad agreement between temperature/salinity decadal trends and climatology (regional climatology BOBYCLIM). Obtained evolutions have also been compared with the global DRAKKAR simulation (GRD100 configuration, 0.25° spatial resolution). Following this comparison, we can note that the dynamics at regional scale improves our estimation of decadal trends. Further interannual metrics (in temperature and salinity) have been computed to evaluate the improvements related to a high resolution solving of the shelf and regional dynamics. The bathymetry of the Bay of Biscay, including a wide continental shelf, induces different current regimes (i.e. wind driven, tidal, density driven and slope currents). In this framework, we analyse the interannual occurrence of the autumn current over the Armorican shelf as one of the main features of the shelf circulation. This poleward current has been observed using drifters in 2002 and its strong interannual variability has been highlighted. Based on our simulation and after validating this current, it has been described and analysed during the whole period. Beyond these two major hydrodynamical concerns, this numerical experiment is a first step in the analysis of the interannual variability in the Bay of Biscay. Following exploration will target, for example increasing the spatial resolution, to understand this variability and the associated processes

Comparison of different numerical methods used to handle the open boundary of a regional ocean circulation model of the Bay of Biscay

International audienceSeveral methods for specifying boundary conditions at the limits of a regional model are compared. The methods investigated are those using clamped and radiation boundary conditions, one-way and two-way nesting in a model for a more extensive area, and "full" coupling based on domain decomposition techniques. These methods are compared in the realistic framework of interactions between a 1/15° model of the Bay of Biscay and a 1/3° model of the North Atlantic, over a 3-year simulation (1996-1998). The clamped and radiation boundary conditions systematically lead to energy accumulation and problematic recirculations along the boundary, and can disturb the internal dynamics of the regional domain. The one-way or two-way-nesting and the full-coupling methods result in far more satisfactory behaviour. For long periods of integration, the two-way mode improves both the fine and coarse-grid solutions. The full coupling method provides the most regular solution at the boundary, and also opens interesting new perspectives since it should enable the coupling of models with different physics. However it requires much more computation time

Ordering phenomena of high-spin/low-spin states in stepwise spin-crossover materials described by the ANNNI model

We study the complex spin-state switching mechanism in a bistable molecular crystal undergoing a stepwise conversion from high-spin to low-spin states at thermal equilibrium as well as during the relaxation process from the photoinduced metastable state. We experimentally evidence that such steps are associated with complex types of long-range and short-range ordering phenomena, resulting from the occupational modulation of bistable molecular magnetic states. The conversion is then described by using two order parameters: the totally symmetric average high spin fraction and the symmetry breaking ordering parameter. The use of the anisotropic next-nearest-neighbor Ising (ANNNI) model allows us to describe the microscopic origin of the ordering, and Monte Carlo simulations reproduce the observed stepwise thermal phase transition as well as the stepwise relaxation from the photoinduced high-spin state to the low-spin state.Etude femtoseconde rayons X et optique de la dynamique ultrarapide de photocommutation de matériaux moléculaires magnétique

Ordering phenomena of high-spin/low-spin states in stepwise spin-crossover materials described by the ANNNI model

We study the complex spin-state switching mechanism in a bistable molecular crystal undergoing a stepwise conversion from high-spin to low-spin states at thermal equilibrium as well as during the relaxation process from the photoinduced metastable state. We experimentally evidence that such steps are associated with complex types of long-range and short-range ordering phenomena, resulting from the occupational modulation of bistable molecular magnetic states. The conversion is then described by using two order parameters: the totally symmetric average high spin fraction and the symmetry breaking ordering parameter. The use of the anisotropic next-nearest-neighbor Ising (ANNNI) model allows us to describe the microscopic origin of the ordering, and Monte Carlo simulations reproduce the observed stepwise thermal phase transition as well as the stepwise relaxation from the photoinduced high-spin state to the low-spin state.Etude femtoseconde rayons X et optique de la dynamique ultrarapide de photocommutation de matériaux moléculaires magnétique

Assessment of the body development kinetic of broiler breeders by non-invasive imaging tools

International audienceIn order to determine the body compo-sition of parental broilers during growth from hatch-ing to adulthood (32 wk of age), we evaluated thekinetics of fattening, growth rate, reproduction param-eters, and body composition of the animals by usingnon-invasive tools such as medical imaging (ultrasoundand CT scan) and blood sample analysis. The use ofCT scanner allowed us to monitor the development ofthe body composition (fatness, bone, muscle, ovary, andtestis growth) of these same animals. These analyseswere accompanied by biochemical blood analyses suchas steroids, metabolites, and some adipokines concen-tration. Difference in the body composition betweenmales and females appeared at 16 wk of age. From20 wk of age, shortly before the onset of lay, the fe-males had 1.6-fold more adipose tissues than males(P<0.001) and 8-fold more elevated plasma triglyc-erides levels. In addition, females, from 16 wk of age,presented a weakened bone quality in comparison tomales (P<0.001). The ratio of the tibia volume/tibialength was 33.2% lower in female compared to malechicken at 32 wk of age (P<0.001). However, the pec-toral muscle had the same volume in both sexes. Theproduction of steroids by gonad started at 16 wk ofage for both sexes, and the testis and ovary develop-ment could be measured by imaging tools at 24 wk.The follicle development was correlated to the ovarianfat tissue (r = 0.80) and fatness. In conclusion, the useof CT scanner and ultrasound system has allowed inves-tigate the body composition of live animals and actualparental breeds with to the aim of using them for ge-netic selectio

Aperiodic spin state ordering of bistable molecules and its photoinduced erasing

International audienceWe describe a novel type of ordering phenomenon associated with the incommensurate occupational modulation of bistable molecular magnetic state in a spin-crossover material. This unusual type of aperiodicity resulting from the ordering of multistable electronic states opens new possibilities for addressing such materials by light. Here we show that light can switch the crystal from four- to threedimensional periodic structure. Mixing aperiodicity, multistability, and photoinduced phenomena' opens new perspectives for directing complex order and function in material science

NEMO on the shelf: assessment of the Iberia-Biscay-Ireland configuration.

International audienceThis work describes the design and validation of a high-resolution (1/36°) ocean forecasting model over the "Iberian-Biscay-Irish" (IBI) area. The system has been set-up using the NEMO model (Nucleus for European Modelling of the Ocean). New developments have been incorporated in NEMO to make it suitable to open- as well as coastal-ocean modelling. In this paper, we pursue three main objectives: (1) to give an overview of the model configuration used for the simulations; (2) to give a broad-brush account of one particular aspect of this work, namely consistency verification; this type of validation is conducted upstream of the implementation of the system before it is used for production and routinely validated; it is meant to guide model development in identifying gross deficiencies in the modelling of several key physical processes; and (3) to show that such a regional modelling system has potential as a complement to patchy observations (an integrated approach) to give information on non-observed physical quantities and to provide links between observations by identifying broader-scale patterns and processes. We concentrate on the year 2008. We first provide domain-wide consistency verification results in terms of barotropic tides, transports, sea surface temperature and stratification. We then focus on two dynamical subregions: the Celtic shelves and the Bay of Biscay slope and deep regions. The model-data consistency is checked for variables and processes such as tidal currents, tidal fronts, internal tides and residual elevation. We also examine the representation in the model of a seasonal pattern of the Bay of Biscay circulation: the warm extension of the Iberian Poleward Current along the northern Spanish coast (Navidad event) in the winter of 2007-2008