Expression and regulation of the Msx1 natural antisense transcript during development

Bidirectional transcription, leading to the expression of an antisense (AS) RNA partially complementary to the protein coding sense (S) RNA, is an emerging subject in mammals and has been associated with various processes such as RNA interference, imprinting and transcription inhibition. Homeobox genes do not escape this bidirectional transcription, raising the possibility that such AS transcription occurs during embryonic development and may be involved in the complexity of regulation of homeobox gene expression. According to the importance of the Msx1 homeobox gene function in craniofacial development, especially in tooth development, the expression and regulation of its recently identified AS transcripts were investigated in vivo in mouse from E9.5 embryo to newborn, and compared with the S transcript and the encoded protein expression pattern and regulation. The spatial and temporal expression patterns of S, AS transcripts and protein are consistent with a role of AS RNA in the regulation of Msx1 expression in timely controlled developmental sites. Epithelial–mesenchymal interactions were shown to control the spatial organization of S and also AS RNA expression during early patterning of incisors and molars in the odontogenic mesenchyme. To conclude, this study clearly identifies the Msx1 AS RNA involvement during tooth development and evidences a new degree of complexity in craniofacial developmental biology: the implication of endogenous AS RNAs

Defining the roughness sublayer and its turbulent statistics

The roughness sublayer in a turbulent openchannel flow over a very rough wall is investigated experimentally both within the canopy and above using particle image velocimetry by gaining complete optical access with new methodologies without disturbing the flow. This enabled reliable estimates of the double-averaged mean and turbulence profiles to be obtained by minimizing and quantifying the usual errors introduced by limited temporal and spatial sampling. It is shown, for example, that poor spatial sampling can lead to erroneous vertical profiles in the roughness sublayer. Then, in order to better define and determine the roughness sublayer height, a methodology based on the measured spatial dispersion is proposed which takes into account temporal sampling errors. The results reveal values well below the usual more ad hoc estimates for all statistics. Finally, the doubleaveraged mean and turbulence statistics in the roughness sublayer are discussed

The creatine kinase pathway is a metabolic vulnerability in EVI1-positive acute myeloid leukemia

Expression of the MECOM (also known as EVI1) proto-oncogene is deregulated by chromosomal translocations in some cases of acute myeloid leukemia (AML) and is associated with poor clinical outcome. Here, through transcriptomic and metabolomic profiling of hematopoietic cells, we reveal that EVI1 overexpression alters cellular metabolism. A screen using pooled short hairpin RNAs (shRNAs) identified the ATP-buffering, mitochondrial creatine kinase CKMT1 as necessary for survival of EVI1-expressing cells in subjects with EVI1-positive AML. EVI1 promotes CKMT1 expression by repressing the myeloid differentiation regulator RUNX1. Suppression of arginine-creatine metabolism by CKMT1-directed shRNAs or by the small molecule cyclocreatine selectively decreased the viability, promoted the cell cycle arrest and apoptosis of human EVI1-positive cell lines, and prolonged survival in both orthotopic xenograft models and mouse models of primary AML. CKMT1 inhibition altered mitochondrial respiration and ATP production, an effect that was abrogated by phosphocreatine-mediated reactivation of the arginine-creatine pathway. Targeting CKMT1 is thus a promising therapeutic strategy for this EVI1-driven AML subtype that is highly resistant to current treatment regimens. Keywords: AML; RUNX1; CKMT1; cyclocreatine; arginine metabolismNational Cancer Institute (U.S.) (NIH 1R35 CA210030-01)Stand Up To CancerBridge ProjectNational Cancer Institute (U.S.) (David H. Koch Institute for Integrative Cancer Research at MIT. Grant P30-CA14051

Methode multigrilles parallèle pour les simulations 3D de mise en forme de matériaux

A parallel multigrid method is developed to reduce large computational costs involved by the finite element simulation of 3D metal forming applications. These applications are characterized by a mixed velocity/pressure implicit formulation with a penalty formulation to enforce contact and lead to large deformations, handled by frequent remeshings of unstructured meshes of tetrahedral. The developed multigrid method follows a hybrid approach where the different levels of non-nested meshes are geometrically constructed by mesh coarsening, while the linear systems of the intermediate and coarse levels result from the algebraic approach. A close to linear asymptotical behavior is expected along with parallel efficiency in order to allow simulations with large number of degrees of freedom under reasonable computation times. These objectives lead to a parallel mesh coarsening algorithm and parallel transfer operators allowing fields transfer between the different levels of partitioned meshes. Physical specificities of metal forming applications lead to select a more complex multigrid smoother than those classically used in literature. A direct resolution method is used on the coarsest mesh, in sequential and in parallel computing. The developed multigrid method is used as a preconditioner for a Conjugate Residual algorithm within FORGE NxT software and shows an asymptotical behavior and a parallel efficiency close to optimal. The automatic mesh coarsening algorithm enables compatibility with frequent remeshings and allows the simulation of a forging process from beginning to end with the multigrid method. Computation times are significantly reduced, even on simulations with particular material flows on which the multigrid method is not optimal. This robustness allows, for instance, reducing from 4.5 to 2.5 days the computation of a forging process.Cette thèse porte sur le développement d’une méthode multigrilles parallèle visant à réduire les temps de calculs des simulations éléments finis dans le domaine de la mise en forme de pièces forgées en 3D. Ces applications utilisent une méthode implicite, caractérisées par une formulation mixte en vitesse/pression et une gestion du contact par pénalisation. Elles impliquent de grandes déformations qui rendent nécessaires des remaillages fréquents sur les maillages tétraédriques non structurés utilisés. La méthode multigrilles développée suit une approche hybride, se basant sur une construction géométrique des niveaux grossiers par déraffinement de maillage non emboîtés et sur une construction algébrique des systèmes linéaires intermédiaires et grossiers. Un comportement asymptotique quasi-linéaire et une bonne efficacité parallèle sont attendus afin de permettre la réalisation de simulations à grand nombre de degrés de liberté dans des temps plus raisonnables qu’aujourd’hui. Pour cela, l’algorithme de déraffinement de maillages est compatible avec le calcul parallèle, ainsi que les opérateurs permettant les transferts de champs entre les différents niveaux de maillages partitionnés. Les spécificités des problèmes à traiter ont mené à la sélection d'un lisseur plus complexe que ceux utilisés plus fréquemment dans la littérature. Sur la grille la plus grossière, une méthode de résolution directe est utilisée, en séquentiel comme en calcul parallèle. La méthode multigrilles est utilisée en tant que préconditionneur d’une méthode de résidu conjugué et a été intégrée au logiciel FORGE NxT et montre un comportement asymptotique et une efficacité parallèle proches de l’optimal. Le déraffinement automatique de maillages permet une compatibilité avec les remaillages fréquents et permet à la méthode multigrilles de simuler un procédé du début à la fin. Les temps de calculs sont significativement réduits, même sur des simulations avec des écoulements particuliers, sur lesquelles la méthode multigrilles ne peut être utilisée de manière optimale. Cette robustesse permet, par exemple, de réduire de 4,5 à 2,5 jours le temps de simulation d’un procédé

Hybrid parallel multigrid preconditioner based on automatic mesh coarsening for 3D metal forming simulations

International audienceA parallel multigrid (MG) method is developed to reduce the large computational costs involved by the finite element simulation of highly viscous fluid flows, especially those resulting from metal forming applications, which are characterized by using a mixed velocity/pressure implicit formulation, unstructured meshes of tetrahedra and frequent remeshings. The developed MG method follows a hybrid approach where the different levels of nonnested meshes are geometrically constructed by mesh coarsening, while the linear systems of the intermediate levels result from the Galerkin algebraic approach. A linear O(N) convergence rate is expected (with N the number of unknowns), while keeping software parallel efficiency. These objectives lead to selecting unusual MG smoothers (iterative solvers) for the upper grid levels and to developing parallel mesh coarsening algorithms along with parallel transfer operators between the different levels of partitioned meshes. Within the utilized PETSc library, the developed MG method is employed as a preconditioner for the usual Conjugate Residual algorithm because of the symetric undefinite matrix of the system to solve. It shows a convergence rate close to optimal, an excellent parallel efficiency, and the ability to handle the complex forming problems encountered in 3D hot forging, which involve large material deformations and frequent remeshings

Méthode de préconditionnement multigrille hybride et parallèle pour l'accélération des calculs en mise en forme des matériaux

International audienceLe préconditionnement d’un algorithme itératif de résolution à l’aide d’une méthode multigrille (MG) permet d’approcher le comportement asymptotique en O(N) recherché pour les très grands problèmes. La méthode MG retenue est hybride : algébrique pour la construction des systèmes linéaires des grilles grossières et géométrique pour celle de s opérateurs de passage. Adaptée à une formulation mixte en vitesse et pression, compatible avec le calcul parallèle et avec les nombreux remaillages inhérents à la mise en forme, elle accélère les calculs par un facteur compris entre 1,5 et 2

Oceanic Plankton group

Use of a targeted metagenomic approach to study in sit

FETI-DP method for 3D magnetostatic simulations

International audienc

Domain decomposition for 3D nonlinear magnetostatic problems: Newton-Krylov-Schur vs. Schur-Newton-Krylov methods

International audienceDomain decomposition is a strategy designed to be used on parallel machines. This strategy leads to hybrid methods between direct and iterative solvers and allows users to benefit from the advantages of both. Lately, the growing size of simulations in electromagnetics brought to light the interest of using domain decomposition. Nonlinearity is also one of the problems specificities where the need for an efficient solver is high. This paper provides a comparison between two techniques of domain decomposition for solving 3D nonlinear magnetostatic problems. A test case illustrates the results that can be expected