Akt-mediated phosphorylation controls the activity of the Y-box protein MSY3 in skeletal muscle

Background: The Y-box protein MSY3/Csda represses myogenin transcription in skeletal muscle by binding a highly conserved cis-acting DNA element located just upstream of the myogenin minimal promoter (myogHCE). It is not known how this MSY3 activity is controlled in skeletal muscle. In this study, we provide multiple lines of evidence showing that the post-translational phosphorylation of MSY3 by Akt kinase modulates the MSY3 repression of myogenin. Methods: Skeletal muscle and myogenic C2C12 cells were used to study the effects of MSY3 phosphorylation in vivo and in vitro on its sub-cellular localization and activity, by blocking the IGF1/PI3K/Akt pathway, by Akt depletion and over-expression, and by mutating potential MSY3 phosphorylation sites. Results: We observed that, as skeletal muscle progressed from perinatal to postnatal and adult developmental stages, MSY3 protein became gradually dephosphorylated and accumulated in the nucleus. This correlated well with the reduction of phosphorylated active Akt. In C2C12 myogenic cells, blocking the IGF1/PI3K/Akt pathway using LY294002 inhibitor reduced MSY3 phosphorylation levels resulting in its accumulation in the nuclei. Knocking down Akt expression increased the amount of dephosphorylated MSY3 and reduced myogenin expression and muscle differentiation. MSY3 phosphorylation by Akt in vitro impaired its binding at the MyogHCE element, while blocking Akt increased MSY3 binding activity. While Akt over-expression rescued myogenin expression in MSY3 overexpressing myogenic cells, ablation of the Akt substrate, (Ser126 located in the MSY3 cold shock domain) promoted MSY3 accumulation in the nucleus and abolished this rescue. Furthermore, forced expression of Akt in adult skeletal muscle induced MSY3 phosphorylation and myogenin derepression. Conclusions: These results support the hypothesis that MSY3 phosphorylation by Akt interferes with MSY3 repression of myogenin circuit activity during muscle development. This study highlights a previously undescribed Akt-mediated signaling pathway involved in the repression of myogenin expression in myogenic cells and in mature muscle. Given the significance of myogenin regulation in adult muscle, the Akt/MSY3/myogenin regulatory circuit is a potential therapeutic target to counteract muscle degenerative disease

Skeletal Myogenic Progenitors Originating from Embryonic Dorsal Aorta Coexpress Endothelial and Myogenic Markers and Contribute to Postnatal Muscle Growth and Regeneration

Skeletal muscle in vertebrates is derived from somites, epithelial structures of the paraxial mesoderm, yet many unrelated reports describe the occasional appearance of myogenic cells from tissues of nonsomite origin, suggesting either transdifferentiation or the persistence of a multipotent progenitor. Here, we show that clonable skeletal myogenic cells are present in the embryonic dorsal aorta of mouse embryos. This finding is based on a detailed clonal analysis of different tissue anlagen at various developmental stages. In vitro, these myogenic cells show the same morphology as satellite cells derived from adult skeletal muscle, and express a number of myogenic and endothelial markers. Surprisingly, the latter are also expressed by adult satellite cells. Furthermore, it is possible to clone myogenic cells from limbs of mutant c-Met-/- embryos, which lack appendicular muscles, but have a normal vascular system. Upon transplantation, aorta-derived myogenic cells participate in postnatal muscle growth and regeneration, and fuse with resident satellite cells. The potential of the vascular system to generate skeletal muscle cells may explain observations of nonsomite skeletal myogenesis and raises the possibility that a subset of satellite cells may derive from the vascular system

Histoire des théologies chrétiennes dans l’Occident médiéval

Albert le Grand : De intellectu et intelligibili On a, après des années, repris le dossier du De Intellectu d’Albert le Grand. Sur la base d’un nouvel échantillon de manuscrits collationnés [Munich, BSB Clm 8001 (xiiie s.), f. 124vb-134vb ; Oxford, Merton Coll. 0.1.8 (Coxe n° 292) (xive s.), f. 350v-356v (fausse numérotation) ; Oxford, Merton Coll. 0.2.1 (Coxe n° 285) (xive s.), f. 232vb-236va ; Pommersfelden, Gräflich Schönbornsche B 103 (xiiie s.), f. 166vb‑175va ; Prag, Bkap L 77 (xiiie s...

Influence of pumping operational schedule on solute concentrations at a well in randomly heterogeneous aquifers

We investigate the way diverse groundwater extraction strategies affect the history of solute concentration recovered at a pumping well while taking into account random spatial variability of the system hydraulic conductivity. Considering the joint effects of spatially heterogeneous hydraulic conductivity and temporally varying well pumping rates leads to a realistic evaluation of groundwater contamination risk at the pumping well location. We juxtapose the results obtained when the pumping well extracts a given amount of water operating (a) at a uniform pumping rate and (b) under a transient regime. The analysis is performed within a numerical Monte Carlo framework. Our results show that contaminant concentration breakthrough curves (BTCs) at the well are markedly affected by the transient pumping strategy according to which the well is operated. Our results document the occurrence in time of multiple peaks in the mean and variance of flux-averaged concentrations at the extraction well operating at a transient rate. Our findings suggest that lowest and largest values of mean and variance of flux-averaged concentration at the well tend to occur at the same time. We show that uncertainty associated with detected BTCs at the well increases for pumping regimes displaying a high degree of temporal variability. As such, the choice of the type of engineering control to the temporal sequence of pumping rates could represent a key factor to drive quantification of uncertainty of the contaminant concentration detected at the well. It is documented that pumping rate fluctuations induce a temporally oscillating risk pattern at the well, thus suggesting that the selection of a dynamic pumping regime has a clear influence on the temporal evolution of risk at the well

Histoire des théologies chrétiennes dans l’Occident médiéval

Albert le Grand : De intellectu et intelligibili On a, après des années, repris le dossier du De Intellectu d’Albert le Grand. Sur la base d’un nouvel échantillon de manuscrits collationnés [Munich, BSB Clm 8001 (xiiie s.), f. 124vb-134vb ; Oxford, Merton Coll. 0.1.8 (Coxe n° 292) (xive s.), f. 350v-356v (fausse numérotation) ; Oxford, Merton Coll. 0.2.1 (Coxe n° 285) (xive s.), f. 232vb-236va ; Pommersfelden, Gräflich Schönbornsche B 103 (xiiie s.), f. 166vb‑175va ; Prag, Bkap L 77 (xiiie s...

Histoire de la philosophie médiévale

Enseignement Cours – Destructionis destructio (II). Existence et vérité Donné sur quatorze leçons d’une heure, le cours a poursuivi la confrontation entre histoire de l’Être (Sein) et/ou de l’Estre (Seyn) selon Heidegger et histoire de la vérité selon Foucault en examinant d’un point de vue archéologique leurs restitutions respectives de la généalogie du rapport entre existence et vérité, à partir de la « victoire » alléguée de la « philosophie » platonico-aristotélicienne et de l’« apophanti..

Histoire des théologies chrétiennes dans l’Occident médiéval

Prolongeant les recherches de l’année 2008-2009 sur les « modèles de la psychê », la première partie du séminaire a été consacrée à la Querelle d’Utrecht (1641-1645) – une entrée privilégiée dans l’archéologie du sujet et de la subjectivité, notamment pour ce qui est du rôle de Descartes dans la naissance du sujet moderne, d’une part et, d’autre part, un document majeur sur la relation du cartésianisme à la scolastique médiévale et à la « Seconde scolastique ». Il y va, de fait, de deux questions fondamentales : 1. Qu’est-ce qu’un homme ? 2. Le corps est-il le sujet de l’esprit ? La deuxième partie des conférences a été consacrée à l’étude de problèmes de sémantique et de philosophie du langage transmis dans des sophismata logicalia du xiiie siècle

Solute concentration at a well in non-Gaussian aquifers under constant and time-varying pumping schedule

Our study is keyed to the analysis of the interplay between engineering factors (i.e., transient pumping rates versus less realistic but commonly analyzed uniform extraction rates) and the heterogeneous structure of the aquifer (as expressed by the probability distribution characterizing transmissivity) on contaminant transport. We explore the joint influence of diverse (a) groundwater pumping schedules (constant and variable in time) and (b) representations of the stochastic heterogeneous transmissivity (T) field on temporal histories of solute concentrations observed at an extraction well. The stochastic nature of T is rendered by modeling its natural logarithm, Y = ln T, through a typical Gaussian representation and the recently introduced Generalized sub-Gaussian (GSG) model. The latter has the unique property to embed scale-dependent non-Gaussian features of the main statistics of Y and its (spatial) increments, which have been documented in a variety of studies. We rely on numerical Monte Carlo simulations and compute the temporal evolution at the well of low order moments of the solute concentration (C), as well as statistics of the peak concentration (Cp), identified as the environmental performance metric of interest in this study. We show that the pumping schedule strongly affects the pattern of the temporal evolution of the first two statistical moments of C, regardless the nature (Gaussian or non-Gaussian) of the underlying Y field, whereas the latter quantitatively influences their magnitude. Our results show that uncertainty associated with C and Cpestimates is larger when operating under a transient extraction scheme than under the action of a uniform withdrawal schedule. The probability density function (PDF) of Cpdisplays a long positive tail in the presence of time-varying pumping schedule. All these aspects are magnified in the presence of non-Gaussian Y fields. Additionally, the PDF of Cpdisplays a bimodal shape for all types of pumping schemes analyzed, independent of the type of heterogeneity considered

Acute inflammatory response to transgastric natural orifice transluminal endoscopic surgery peritoneoscopy: An experimental study in swine

OBJECTIVE: To investigate the impact of transgastric peritoneal access on plasma biomarkers of acute inflammatory response in comparison to laparoscopy. METHODS: This was a prospective and comparative study in a porcine model. Transgastric peritoneal access performed by natural orifice transluminal endoscopic surgery was compared with laparoscopy. Laparotomy and sham groups were used as positive and negative controls, respectively. Thirty-four pigs were assigned to receive transgastric natural orifice transluminal endoscopic surgery (n = 12), laparoscopy (n = 8), laparotomy (n = 8) or a sham procedure involving only anesthesia (n = 6). In the natural orifice transluminal endoscopic surgery group, peritoneoscopy was performed with a gastroscope via transgastric access. Blood samples were collected at baseline and 1, 3, 6, 9 and 24 h after the surgical procedure for measurement of interleukins 1β, 6 and 10 and tumor necrosis factor-α. A complete blood count was performed, and C-reactive protein levels were measured at baseline and at 24 h. RESULTS: All surgical and endoscopic procedures were performed without major complications. Peritoneal cavity inventory showed no signs of peritonitis in any animal. Interleukin 1β, interleukin 10 and tumor necrosis factor-α levels were below the threshold of detection. The mean level of interleukin 6 was statistically significantly higher in the laparotomy group than in the other groups (p;0.05). C-reactive protein analysis indicated significant increases in all groups, with no differences among the groups. Complete blood count analysis showed no differences among the groups. CONCLUSIONS: Based on the observed interleukin 6 patterns, the systemic inflammatory response resulting from transgastric peritoneal access by natural orifice transluminal endoscopic surgery is similar in intensity to the response that occurs after laparoscopy

INFLUENCE OF PULSATILE CATHETER PUMP SYNCHRONIZATION ON HAEMODYNAMIC VARIABLES: NUMERICAL SIMULATION

Severe cardiovascular diseases can be treated using left ventricular assist devices (LVAD). One of the possible LVADs is the Pulsatile Catheter (PUCA) pump that consists of a hydraulically or pneumatically driven membrane pump connected to a valved catheter. In this work a numerical model of the cardiocirculatory system and of the PUCA have been developed in order to study their interaction. In the numerical simulator a pathological condition of the left ventricle has been reproduced and successively the effects of the PUCA on the haemodynamic variables applied were studied. Different functioning modes were tested by changing the ratio between the pump frequency and the heart beat rate (HR) as 1:1, 1:2 or 1:3 and by introducing a delay time between the cardiac and the PUCA cycle. The performance of the pump was evaluated in terms of cardiac output, PUCA and coronary flows and it was studied for different HR values. Results show a good resemblance between the model and literature data and indicate that different synchronization and timing can influence the functioning of the pump. In particular, the frequency ratio and the time delay of the pump cycle can contribute to optimize the performance of the PUCA