Pom1 gradient buffering through intermolecular auto-phosphorylation.

Concentration gradients provide spatial information for tissue patterning and cell organization, and their robustness under natural fluctuations is an evolutionary advantage. In rod-shaped Schizosaccharomyces pombe cells, the DYRK-family kinase Pom1 gradients control cell division timing and placement. Upon dephosphorylation by a Tea4-phosphatase complex, Pom1 associates with the plasma membrane at cell poles, where it diffuses and detaches upon auto-phosphorylation. Here, we demonstrate that Pom1 auto-phosphorylates intermolecularly, both in vitro and in vivo, which confers robustness to the gradient. Quantitative imaging reveals this robustness through two system's properties: The Pom1 gradient amplitude is inversely correlated with its decay length and is buffered against fluctuations in Tea4 levels. A theoretical model of Pom1 gradient formation through intermolecular auto-phosphorylation predicts both properties qualitatively and quantitatively. This provides a telling example where gradient robustness through super-linear decay, a principle hypothesized a decade ago, is achieved through autocatalysis. Concentration-dependent autocatalysis may be a widely used simple feedback to buffer biological activities

Languages for safety-certification related propertis

The Safety Certification of Software-Intensive Systems with Reusable Components project, in short SafeCer (www.safecer.eu),is targeting increased efficiency and reduced time-to-market by composable safety certification of safety- relevant embedded systems. The industrial domains targeted are within automotive and construction equipment, avionics, and rail. Some of the companies involved are: Volvo Tech- nology, Thales, TTTech, and Intecs among others. SafeCer includes more than 30 partners in six different countries and has a budget of e25.7 millions. A primary objective is to provide support for system safety arguments based on arguments and properties of system components as well as to provide support for generation of corresponding evidence in a similar compositional way. By providing support for efficient reuse of certification and stronger links between certification and development, compo- nent reuse will be facilitated, and by providing support for reuse across domains the amount of components available for reuse will increase dramatically. The resulting efficiency and reduced time to market will, together with increased quality and reduced risk, increase competitiveness and pave the way for a cross-domain market for software components qualified for certification

Mechanisms of HsSAS-6 assembly promoting centriole formation in human cells

SAS-6 proteins are thought to impart the ninefold symmetry of centrioles, but the mechanisms by which their assembly occurs within cells remain elusive. In this paper, we provide evidence that the N-terminal, coiled-coil, and C-terminal domains of HsSAS-6 are each required for procentriole formation in human cells. Moreover, the coiled coil is necessary and sufficient to mediate HsSAS-6 centrosomal targeting. High-resolution imaging reveals that GFP-tagged HsSAS-6 variants localize in a torus around the base of the parental centriole before S phase, perhaps indicative of an initial loading platform. Moreover, fluorescence recovery after photobleaching analysis demonstrates that HsSAS-6 is immobilized progressively at centrosomes during cell cycle progression. Using fluorescence correlation spectroscopy and three-dimensional stochastic optical reconstruction microscopy, we uncover that HsSAS-6 is present in the cytoplasm primarily as a homodimer and that its oligomerization into a ninefold symmetrical ring occurs at centrioles. Together, our findings lead us to propose a mechanism whereby HsSAS-6 homodimers are targeted to centrosomes where the local environment and high concentration of HsSAS-6 promote oligomerization, thus initiating procentriole formation

Principles of mRNA transport in yeast

mRNA localization and localized translation is a common mechanism by which cellular asymmetry is achieved. In higher eukaryotes the mRNA transport machinery is required for such diverse processes as stem cell division and neuronal plasticity. Because mRNA localization in metazoans is highly complex, studies at the molecular level have proven to be cumbersome. However, active mRNA transport has also been reported in fungi including Saccharomyces cerevisiae, Ustilago maydis and Candida albicans, in which these events are less difficult to study. Amongst them, budding yeast S. cerevisiae has yielded mechanistic insights that exceed our understanding of other mRNA localization events to date. In contrast to most reviews, we refrain here from summarizing mRNA localization events from different organisms. Instead we give an in-depth account of ASH1 mRNA localization in budding yeast. This approach is particularly suited to providing a more holistic view of the interconnection between the individual steps of mRNA localization, from transcriptional events to cytoplasmic mRNA transport and localized translation. Because of our advanced mechanistic understanding of mRNA localization in yeast, the present review may also be informative for scientists working, for example, on mRNA localization in embryogenesis or in neurons

L'épissage de l'ARN oskar est couplé à sa localisation cytoplasmique

La localisation intracellulaire d'un ARN messager constitue un moyen très efficace de restreindre une activité protéique en un site cellulaire précis. Dans l'ovocyte de Drosophila melanogaster, l'ARNm oskar localise au pôle postérieur et induit la formation du plasme germinal et des structures postérieures de l'embryon. Son transport est réalisé par l'intermédiaire de facteurs en trans, comme Mago nashi, qui forment avec l'ARNm oskar un complexe de localisation ribonucléoprotéique.Nous montrons que la protéine Drosophila Y14 s'associe avec Mago nashi et est essentielle à la localisation de l'ARNm oskar. Chez les vertébrés, les homologues respectifs de Drosophila Y14 et Mago nashi, Y14 et Magoh, appartiennent au complexe de jonction exon-exon (EJC). Ce complexe, recruté par le processus d'excision-épissage, s'assemble 20 à 24 nucléotides en amont des jonctions exon-exon des ARNm, indépendamment de leur séquence.Nous démontrons que l'excision-épissage de l'ARN oskar est couplé à sa localisation cytoplasmique. De plus, nous montrons que la position d'excision-épissage relative à l'ARN oskar est cruciale pour sa localisation cytoplasmique, indiquant que la position de l'EJC est critique pour la formation du complexe de localisation de l'ARNm oskar.Ces résultats mettent en évidence l'existence d'un mécanisme de couplage entre le processus nucléaire d'excision-épissage et la localisation cytoplasmique de l'ARNm oskar. Cette étude révèle une nouvelle fonction de l'excision-épissage : la régulation de la localisation cytoplasmique d'ARNm par l'organisation de complexes ribonucléoprotéiques.Cytoplasmic messenger RNA localization is a powerful strategy for restricting protein activity in a precise cellular location. In the Drosophila melanogaster oocyte, oskar mRNA localizes at the posterior pole to specify the germline and pattern the abdomen of the future embryo. Its transport to the oocyte posterior is mediated by trans factors, such as Mago nashi, that form together with oskar mRNA a ribonucleoproteic localization complex.We show that Drosophila Y14 interacts with Mago nashi and is essential for oskar mRNA localization. In vertebrates, the homologues of Drosophila Y14 and Mago nashi, Y14 and Magoh, are core components of the exon-exon junction complex. This complex is recruited in a splicing-dependent manner and associates with mRNAs 20 to 24 nucleotides upstream of exon-exon junctions, independent of the RNA sequence.We demonstrate that splicing of oskar RNA is coupled to its cytoplasmic localization. Interestingly, we show that the position of splicing on oskar mRNA is crucial for its cytoplasmic localization, thereby indicating that the position of the EJC is critical for the formation of the oskar mRNA localization complex.These results demonstrate a mechanistic coupling between the nuclear process of splicing and the cytoplasmic localization of oskar mRNA. It reveals an important new function for splicing: regulation of messenger ribonucleoprotein complex assembly and organization for mRNA cytoplasmic localization.ORSAY-PARIS 11-BU Sciences (914712101) / SudocSudocFranceF

Fréquence et facteurs prédictifs d'un accident vasculaire cérébral après un infarctus du myocarde (caractéristiques selon la survenue intra ou extrahospitalière)

Introduction : La survenue d un accident vasculaire cérébral après un infarctus du myocarde est une complication sévère et associée à un risque accru de décès, mais ses mécanismes physiopathologiques sont encore mal connus. L objectif de cette étude était d évaluer la fréquence, les caractéristiques et les facteurs prédictifs d accident vasculaire cérébral chez des patients admis pour infarctus du myocarde, selon leur survenue à la phase intra ou extrahospitalière. Méthodes : A partir de l obseRvatoire régional des Infarctus de Côte d Or (RICO), 8485 patients consécutifs admis aux soins intensifs de cardiologie pour infarctus du myocarde entre janvier 2001 et juillet 2010 ont été inclus. Parmi d autres évènements cardiaques majeurs, la survenue d un accident vasculaire cérébral (ischémique ou hémorragique) ou d un accident ischémique transitoire était collectée de façon prospective pendant une année de suivi.Résultats : 168 (1.98%) accidents vasculaires cérébraux ont été enregistrés sur la période d un an de suivi après la survenue de l infarctus du myocarde. 123 patients (1.4%) ont présenté cet accident vasculaire cérébral à la phase intra-hospitalière, dont pour 87% d entre eux dans les 5 premiers jours après leur admission. En analyse multivariée, les facteurs prédictifs indépendants d accident vasculaire cérébral intra-hospitalier étaient le sexe féminin (OR: 1.99, IC 95%: 1.19-2.51, p=0.004), un antécédent d accident vasculaire cérébral (OR: 2.21, IC 95%: 1.28-3.83, p=0.004), la fraction d éjection ventriculaire gauche (OR: 0.96, 95% IC: 0.95-0.98, p<0.001), la fibrillation atriale de novo (OR: 1.99, IC 95%: 1.25-3.16, p=0.004) et la CRP à l admission (OR: 1.006, IC 95%: 1.003-1.009, p<0.001). Après ajustement à de multiples facteurs pronostiques, la survenue d un accident vasculaire cérébral intra-hospitalier était toujours associée à une augmentation significative de la mortalité à 1 an (OR: 1.82, IC 95%: 1.05-3.15, p=0.031). Parmi les survivants (n=7808), 45 patients ont présentés un accident vasculaire cérébral extrahospitalier (0.64%) dans l année post-infarctus. En analyse multivariée, les facteurs prédictifs indépendants d accident vasculaire cérébral extrahospitalier étaient l âge (OR:1.04, IC 95%: 1.01-1.07, p=0.003), un antécédent d accident vasculaire cérébral (OR: 3.69, IC 95%: 1.83-7.43, p<0.001) et l hypertension artérielle (OR: 2.77, IC 95%: 1.26-6.08, p=0.011). De 2001 à 2010, le taux annuel d accident vasculaire cérébral post infarctus du myocarde est resté stable, sans variation temporelle significative. Conclusions : Cette étude décrit la fréquence et les facteurs prédictifs d accident vasculaire cérébral post-infarctus du myocarde, complication responsable d une mortalité à un an très élevée. Les caractéristiques différentes selon leur survenue intra ou extrahospitalière suggèrent des mécanismes physiopathologiques distincts. Cependant, au cours du suivi, la survenue d un accident vasculaire cérébral reste un évènement rare et principalement associée à un haut risque cardiovasculaire.DIJON-BU Médecine Pharmacie (212312103) / SudocSudocFranceF

Mid1p/anillin and the septation initiation network orchestrate contractile ring assembly for cytokinesis

In both animal cells and fungi, cytokinesis proceeds via a contractile actomyosin ring (CAR). Many CAR components and regulators are evolutionarily conserved. In Schizosaccharomyces pombe, the spatial cue for cytokinesis is provided by Mid1p/Anillin, whereas temporal coordination is ensured by the septation initiation network (SIN). However, neither Mid1p nor the SIN is considered to be essential for CAR assembly per se. Here, using 4D imaging, we reveal an unanticipated, novel role for the SIN in CAR assembly. We demonstrate that CAR assembly involves three, genetically separable steps: establishment of a cortical network of CAR proteins, its lateral condensation, and finally, the formation of a homogeneous CAR. We show that SIN mutants fail to form a homogeneous CAR; we identify hypophosphorylation and recruitment of the conserved PCH-family protein Cdc15p to the CAR as critical steps requiring SIN function. Furthermore, we show that in the absence of Mid1p, CAR assembly proceeds via an actomyosin filament, rather than a cortical network of CAR proteins. This mode of assembly is totally dependent on SIN signaling, thereby demonstrating a direct role for the SIN in CAR formation. Taken together, these data establish that Mid1p and the SIN are the key regulators that orchestrate CAR assembly

Towards VE that are More Closely Related to the Real World

This chapter provides an overview of the current state of augmented reality (AR). It examines the questions of pose computation, which could be used to locate a user in an immersive room or to model the real world, interactions in AR, and the concept of presence in environments that combine real and virtual elements. The chapter describes important innovations in the field of 3D interaction over the last decade. While 3D interaction is less central to AR, its importance is rising nonetheless. From simple applications to visualize digital data that is superimposed on the natural view, RA systems today are offering users increasingly more refined interaction systems in order to enhance usage. The chapter overviews recent developments allowing users to easily and efficiently interact with 3D content displayed on tactile surfaces. In the current interfaces, a trend towards an integration of the interaction styles can be observed

Pre-operative growth differentiation factor 15 as a novel biomarker of acute kidney injury after cardiac bypass surgery

International audienc

Anthracyclines / Trastuzumab: new aspects of cardiotoxicity and molecular mechanisms

International audienceAnticancer drugs continue to cause significant reductions in left ventricular ejection fraction resulting in congestive heart failure. The best-known cardiotoxic agents are anthracyclines such as doxorubicin. For several decades, cardiotoxicity was almost exclusively associated with anthracyclines, for which cumulative dose-related cardiac damage was the use-limiting step. Human epidermal growth factor receptor 2 (HER2; ErbB2) has been identified as an important target for breast cancer. Trastuzumab (TRZ), a humanized anti-HER2 monoclonal antibody, is currently recommended as first-line treatment for patients with metastatic HER2+ tumours. The use of TRZ may be limited by the development of drug intolerance, such as cardiac dysfunction. Cardiotoxicity has been attributed to free-iron-based, radical-induced oxidative stress. Many approaches have been promoted to minimize these serious side effects, but they are still clinically problematic. A new approach to personalized medicine for cancer that involves molecular screening for clinically relevant genomic alterations and genotype-targeted treatments is emerging