Transglutaminase-dependent RhoA Activation and Depletion by Serotonin in Vascular Smooth Muscle Cells

The small G protein RhoA plays a major role in several vascular processes and cardiovascular disorders. Here we analyze the mechanisms of RhoA regulation by serotonin (5-HT) in arterial smooth muscle. 5-HT (0.1-10 microM) induced activation of RhoA followed by RhoA depletion at 24-72 h. Inhibition of 5-HT1 receptors reduced the early phase of RhoA activation but had no effect on 5-HT-induced delayed RhoA activation and depletion, which were suppressed by the 5-HT transporter inhibitor fluoxetine and the transglutaminase inhibitor monodansylcadaverin and in type 2 transglutaminase-deficient smooth muscle cells. Coimmunoprecipitations demonstrated that 5-HT associated with RhoA both in vitro and in vivo. This association was calcium-dependent and inhibited by fluoxetine and monodansylcadaverin. 5-HT promotes the association of RhoA with the E3 ubiquitin ligase Smurf1, and 5-HT-induced RhoA depletion was inhibited by the proteasome inhibitor MG132 and the RhoA inhibitor Tat-C3. Simvastatin, the Rho kinase inhibitor Y-27632, small interfering RNA-mediated RhoA gene silencing, and long-term 5-HT stimulation induced Akt activation. In contrast, inhibition of 5-HT-mediated RhoA degradation by MG132 prevented 5-HT-induced Akt activation. Long-term 5-HT stimulation also led to the inhibition of the RhoA/Rho kinase component of arterial contraction. Our data provide evidence that 5-HT, internalized through the 5-HT transporter, is transamidated to RhoA by transglutaminase. Transamidation of RhoA leads to RhoA activation and enhanced proteasomal degradation, which in turn is responsible for Akt activation and contraction inhibition. The observation of transamidation of 5-HT to RhoA in pulmonary artery of hypoxic rats suggests that this process could participate in pulmonary artery remodeling and hypertension

The cosmological analysis of X-ray cluster surveys: II- Application of the CR-HR method to the XMM archive

We have processed 2774 high-galactic observations from the XMM archive (as of May 2010) and extracted a serendipitous catalogue of some 850 clusters of galaxies based on purely X-ray criteria, following the methodology developed for the XMM-LSS survey. Restricting the sample to the highest signal-to-noise objects (347 clusters), we perform a cosmological analysis using the X-ray information only. The analysis consists in the modelling of the observed colour-magnitude (CR-HR) diagram constructed from cluster instrumental count-rates measured in the [0.5-2], [1-2] and [0.5-1] keV bands. A MCMC procedure simultaneously fits the cosmological parameters, the evolution of the cluster scaling laws and the selection effects. Our results are consistent with the sigma_8 and Omega_m values obtained by WMAP-5 and point toward a negative evolution of the cluster scaling relations with respect to the self-similar expectation. We are further able to constrain the cluster fractional radius xc0=r_c/r500c, to xc0=0.24 +/- 0.04. This study stresses again the critical role of selection effects in deriving cluster scaling relations, even in the local universe. Finally, we show that CR-HR method applied to the eRosita all-sky survey - provided that cluster photometric redshifts are available - will enable the determination of the equation of state of the dark energy at the level of the DETF stage IV predictions; simultaneously, the evolution of the cluster scaling-relations will be unambiguously determined. The XMM CLuster Archive Super Survey (XCLASS) serendipitous cluster catalogue is available online at: http://xmm-lss.in2p3.fr:8080/l4sdb/.Comment: 26 pages, 24 figures, 9 tables. Accepted for publication in MNRAS (minor changes with respect to submitted version). The corresponding galaxy cluster catalogue is available at http://xmm-lss.in2p3.fr:8080/l4sdb

The XXL Survey V: Detection of the Sunyaev-Zel'dovich effect of the Redshift 1.9 Galaxy Cluster XLSSU J021744.1-034536 with CARMA

We report the detection of the Sunyaev-Zel'dovich (SZ) effect of galaxy cluster XLSSU J021744.1-034536, using 30 GHz CARMA data. This cluster was discovered via its extended X-ray emission in the XMM-Newton Large Scale Structure survey, the precursor to the XXL survey. It has a photometrically determined redshift $z=1.91^{+0.19}_{-0.21}$, making it among the most distant clusters known, and nominally the most distant for which the SZ effect has been measured. The spherically integrated Comptonization is $Y_{500}=(3.0\pm0.4)\times 10^{-12}$, a measurement which is relatively insensitive to assumptions regarding the size and redshift of the cluster, as well as the background cosmology. Using a variety of locally calibrated cluster scaling relations extrapolated to z~2, we estimate a mass $M_{500} \sim (1$-$2)\times 10^{14}M_{sun}$ from the X-ray flux and SZ signal. The measured properties of this cluster are in good agreement with the extrapolation of an X-ray luminosity-SZ effect scaling relation calibrated from clusters discovered by the South Pole Telescope at higher masses and lower redshifts. The full XXL-CARMA sample will provide a more complete, multi-wavelength census of distant clusters in order to robustly extend the calibration of cluster scaling relations to these high redshifts.Comment: ApJ, in press. 9 pages, 4 figures, 4 table

The XMM-LSS survey. Survey design and first results

We have designed a medium deep large area X-ray survey with XMM - the XMM Large Scale Structure survey, XMM-LSS - with the scope of extending the cosmological tests attempted using ROSAT cluster samples to two redshift bins between 0<z<1 while maintaining the precision of earlier studies. Two main goals have constrained the survey design: the evolutionary study of the cluster-cluster correlation function and of the cluster number density. The results are promising and, so far, in accordance with our predictions as to the survey sensitivity and cluster number density. The feasibility of the programme is demonstrated and further X-ray coverage is awaited in order to proceed with a truly significant statistical analysis. (Abridged)Comment: Published in Journal of Cosmology and Astroparticle Physic

The XXL survey: XLVI. Forward cosmological analysis of the C1 cluster sample

We present the forward cosmological analysis of an $XMM$ selected sample of galaxy clusters out to a redshift of unity. Following our previous 2018 study based on the dn/dz quantity alone, we perform an upgraded cosmological analysis of the same XXL C1 cluster catalogue (178 objects), with a detailed account of the systematic errors. We follow the ASpiX methodology: the distribution of the observed X-ray properties of the cluster population is analysed in a 3D observable space (count rate, hardness ratio, redshift) and modelled as a function of cosmology. Compared to more traditional methods, ASpiX allows the inclusion of clusters down to a few tens of photons. We obtain an improvement by a factor of 2 compared to the previous analysis by letting the normalisation of the M-T relation and the evolution of the L-T relation free. Adding constraints from the XXL cluster 2-point correlation function and the BAO from various surveys decreases the uncertainties by 23 and 53 % respectively, and 62% when adding both. Switching to the scaling relations from the Subaru analysis, and letting free more parameters, our final constraints are $\sigma_8$ = $0.99^{+0.14}_{-0.23}$, $\Omega_m$ = 0.296 $\pm$ 0.034 ($S_8 = 0.98^{+0.11}_{-0.21}$) for the XXL sample alone. Finally, we combine XXL ASpiX, the XXL cluster 2-point correlation function and the BAO, with 11 free parameters, allowing for the cosmological dependence of the scaling relations in the fit. We find $\sigma_8$ = $0.793^{+0.063}_{-0.12}$, $\Omega_m$ = 0.364 $\pm$ 0.015 ($S_8 = 0.872^{+0.068}_{-0.12}$), but still compatible with Planck CMB at 2.2$\sigma$. The results obtained by the ASpiX method are promising; further improvement is expected from the final XXL cosmological analysis involving a cluster sample twice as large. Such a study paves the way for the analysis of the eROSITA and future Athena surveys.Comment: 20 pages, 10 figures, accepted for publication in A&A, A&A version has the unabridged abstrac

Identification de nouveaux mécanismes de régulation de la protéine G monomérique RhoA dans les cellules musculaires lisses et leurs implications en physiopathologie vasculaire

La protéine G monomérique RhoA a un rôle important dans la cellule musculaire lisse, il s agit d un relais moléculaire entre les informations provenant de multiples stimuli et le contrôle de fonctions déterminant le tonus et la structure des vaisseaux. C est pourquoi une dérégulation de RhoA est souvent un élément important de la pathogénie des maladies vasculaires. Dans ce contexte, il apparaît essentiel de comprendre les processus et les acteurs de sa régulation dans la cellule musculaire lisse. L objectif de ce travail a été d identifier les mécanismes biochimiques de la régulation de l activité de RhoA et d analyser leurs implications dans le développement des maladies vasculaires. Nos résultats mettent en évidence que la sérotonine est transaminée sur RhoA, une réaction catalysée par les transglutaminases de type 2 qui conduit à la modification du domaine d hydrolyse du GTP de RhoA et à son activation. D autre part, cette sérotonylation de RhoA est stimulée par l hypoxie et pourrait ainsi contribuer à l activation excessive de RhoA observée lors d hypertension artérielle pulmonaire. Nous avons également montré que l angiotensine II, via les récepteurs de type 1, active RhoA par l intermédiaire du facteur d échange guanylique p115 et que l activité de p115 est augmentée dans les cellules musculaires lisses vasculaires lors d hypertension artérielle suggérant ainsi une implication de la voie p115/RhoA dans l établissement de cette maladie. Nos résultats ont permis de montrer que la phosphorylation de RhoA sur sa sérine 188 est un mécanisme finement régulé au niveau de la cellule musculaire lisse, d une part via la PKG, mais également par l intermédiaire de SLK. En effet l angiotensine II, via les récepteurs de type 2, provoque l activation de SLK qui phosphoryle et inhibe RhoA. Cette inhibition est responsable des effets vasodilatateurs des récepteurs de type 2 à l angiotensine. Nos résultats démontrent également que la stimulation de la phosphorylation de RhoA, in vivo, provoque une inhibition de la voie RhoA/ROCK bénéfique au cours de la mise place de l hypertension artérielle pulmonaire. Ces travaux ont donc permis d identifier des nouveaux mécanismes de la régulation de RhoA dans la cellule musculaire lisse qui pourraient contribuer au développement de maladies vasculaires.The small G-protein RhoA plays an important role in smooth muscle cells, it acts as a molecular relay between informations coming from multiple stimuli and controls functions establishing blood vessel tonus and structure. This is why deregulation of RhoA is often an important element in the pathogenesis of vascular diseases. In this context, it seems essential to understand the processes and the players regulating it in smooth muscle cells. The objective of this work was to identify the biochemical mechanisms of the regulation of RhoA activity and analyse their implications in the development of vascular diseases. Our results show that serotonin transaminated on RhoA, a reaction catalysed by type 2 transglutaminases, leeading to the modification of the GTP hydrolysis domain and activation of RhoA. This serotonylation is stimulated by hypoxia and this way could contribute to the over activation of RhoA observed in pulmonary hypertension. We have also shown that angiotensin II, via type 1 receptors, activates RhoA through the guanine exchange factor p115 and that the activity of p115 is increased in vascular smooth muscle cells in arterial hypertension suggesting an implication of the p115/RhoA pathway in the development of this disease. Our results showed that the phosphorylation of RhoA on serine 188 is a finely tuned mechanism in smooth muscle cells, partly through PKG, but also by SLK. Angiotensin II, via type 2 receptors, causes the activation of SLK which phosphorylates and inhibits RhoA. This inhibition is responsible for the vasodilatory effects of type 2 angiotensin receptors. Our results also demonstrate bthat the stimulation of RhoA phosphorylation in vivo induces a beneficial inhibition of the RhoA/ROCK pathway in the deveopment of pulmonary hypertension.NANTES-BU Sciences (441092104) / SudocSudocFranceF

A framework to model the diversity of reproduction strategies in ruminant livestock farms: application to dairy herds.

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Optimization of an Air Filled Compact Re-Entrant Coaxial Resonator for a C-Band Bandpass Filter

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Ion-beam synthesis of amorphous SiC films: Structural analysis and recrystallization

The analysis of SiC films obtained by carbon ion implantation into amorphous Si (preamorphized by Ge ion implantation) has been performed by infrared and Raman scattering spectroscopies, transmission electron microscopy, Rutherford backscattering, and x‐ray photoelectron spectroscopy (XPS). The data obtained show the formation of an amorphous Si1−xCx layer on top of the amorphous Si one by successive Ge and C implantations. The fitting of the XPS spectra indicates the presence of about 70% of Si–C bonds in addition to the Si–Si and C–C ones in the implanted region, with a composition in the range 0.35<x<0.6. This points out the existence of a partial chemical order in the layer, in between the cases of perfect mixing and complete chemical order. Recrystallization of the layers has been achieved by ion‐beam induced epitaxial crystallization (IBIEC), which gives rise to a nanocrystalline SiC layer. However, recrystallization is not complete, observing still the presence of Si–Si and C–C bonds in an amorphous phase. Moreover, the distribution of the different bonds in the IBIEC processed samples is similar to that from the as‐implanted ones. This suggests that during IBIEC homopolar bonds are not broken, and only regions with dominant Si–C heteropolar bonds recrystallize

Hypertension, a Neglected Disease in Rural and Urban Areas in Moramanga, Madagascar

International audienceBackgroundHypertension is one of the main risk factors of cardiovascular diseases. In Madagascar,studies on hypertension in urban and rural communities are scarce.ObjectivesThe aim of this study was to determine the prevalence of hypertension and identify associated risk factors in adults living in a health and demographic system in Moramanga, Madagascar. MethodsThe study included people aged 15 years old and above living in a health and demographic system in Moramanga. A household census was performed in 2012 to enumerate the population in 3 communities in Moramanga. In addition to the questionnaire used in the initial census, a standardized questionnaire and blood pressure were taken twice after 5 and 10 minutes of rest. In urban areas, heights and weights were also measured to calculate the body mass index. ResultsThere were 3621 and 4010 participants respectively in rural and urban areas. Prevalence of hypertension in rural population was 27.0%(IC95%[25.6–28.5]) and 29.7% (IC95% [28.3– 31.1]) in urban population. Among hypertensive subjects, 1.7% (17/979) and 5.3% (64/ 1191) were on antihypertensive treatment for at least 1 month before the survey in rural and urban population, respectively. In rural areas, increasing age (65 years and older vs 18–25 years OR = 11.81, IC95% [7.79–18.07]), giving more than 3 positive responses to the usual risks factors of hypertension (OR = 1.67, IC95% [1.14–2.42]) and singles in comparison with married people (OR = 1.61, IC95% [1.20–2.17]) were associated to hypertension in a logistic regression model. In urban areas, increasing age (65 years and older vs 18–25 years OR = 37.54, IC95% [24.81–57.92]), more than 3 positive responses to the usual risks of hypertension (OR = 3.47, IC95% [2.58–4.67]) and obesity (OR = 2.45, IC95% [1.56– 3.87]) were found as risk factors. ConclusionHypertension is highly prevalent in rural areas although it is significantly less treated. As a result, a major epidemic of cardiovascular diseases is at risk in Madagascar’s progressively aging societ