Targeting a phospho-STAT3-miRNAs pathway improves vesicular hepatic steatosis in an in vitro and in vivo model

Non-alcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease. Although genetic predisposition and epigenetic factors contribute to the development of NAFLD, our understanding of the molecular mechanism involved in the pathogenesis of the disease is still emerging. Here we investigated a possible role of a microRNAs-STAT3 pathway in the induction of hepatic steatosis. Differentiated HepaRG cells treated with the fatty acid sodium oleate (fatty dHepaRG) recapitulated features of liver vesicular steatosis and activated a cell-autonomous inflammatory response, inducing STAT3-Tyrosine-phosphorylation. With a genome-wide approach (Chromatin Immunoprecipitation Sequencing), many phospho-STAT3 binding sites were identified in fatty dHepaRG cells and several STAT3 and/or NAFLD-regulated microRNAs showed increased expression levels, including miR-21. Innovative CARS (Coherent Anti-Stokes Raman Scattering) microscopy revealed that chemical inhibition of STAT3 activity decreased lipid accumulation and deregulated STAT3-responsive microRNAs, including miR-21, in lipid overloaded dHepaRG cells. We were able to show in vivo that reducing phospho-STAT3-miR-21 levels in C57/BL6 mice liver, by long-term treatment with metformin, protected mice from aging-dependent hepatic vesicular steatosis. Our results identified a microRNAs-phosphoSTAT3 pathway involved in the development of hepatic steatosis, which may represent a molecular marker for both diagnosis and therapeutic targeting

Technical support for Life Sciences communities on a production grid infrastructure

Production operation of large distributed computing infrastructures (DCI) still requires a lot of human intervention to reach acceptable quality of service. This may be achievable for scientific communities with solid IT support, but it remains a show-stopper for others. Some application execution environments are used to hide runtime technical issues from end users. But they mostly aim at fault-tolerance rather than incident resolution, and their operation still requires substantial manpower. A longer-term support activity is thus needed to ensure sustained quality of service for Virtual Organisations (VO). This paper describes how the biomed VO has addressed this challenge by setting up a technical support team. Its organisation, tooling, daily tasks, and procedures are described. Results are shown in terms of resource usage by end users, amount of reported incidents, and developed software tools. Based on our experience, we suggest ways to measure the impact of the technical support, perspectives to decrease its human cost and make it more community-specific.Comment: HealthGrid'12, Amsterdam : Netherlands (2012

Deep search for companions to probable young brown dwarfs

We have obtained high contrast images of four nearby, faint, and very low mass objects 2MASSJ04351455-1414468, SDSSJ044337.61+000205.1, 2MASSJ06085283-2753583 and 2MASSJ06524851-5741376 (here after 2MASS0435-14, SDSS0443+00, 2MASS0608-27 and 2MASS0652-57), identified in the field as probable isolated young brown dwarfs. Our goal was to search for binary companions down to the planetary mass regime. We used the NAOS-CONICA adaptive optics instrument (NACO) and its unique capability to sense the wavefront in the near-infrared to acquire sharp images of the four systems in Ks, with a field of view of 28"*28". Additional J and L' imaging and follow-up observations at a second epoch were obtained for 2MASS0652-57. With a typical contrast DKs= 4.0-7.0 mag, our observations are sensitive down to the planetary mass regime considering a minimum age of 10 to 120 Myr for these systems. No additional point sources are detected in the environment of 2MASS0435-14, SDSS0443+00 and 2MASS0608-27 between 0.1-12" (i.e about 2 to 250 AU at 20 pc). 2MASS0652-57 is resolved as a \sim230 mas binary. Follow-up observations reject a background contaminate, resolve the orbital motion of the pair, and confirm with high confidence that the system is physically bound. The J, Ks and L' photometry suggest a q\sim0.7-0.8 mass ratio binary with a probable semi-major axis of 5-6 AU. Among the four systems, 2MASS0652-57 is probably the less constrained in terms of age determination. Further analysis would be necessary to confirm its youth. It would then be interesting to determine its orbital and physical properties to derive the system's dynamical mass and to test evolutionary model predictions.Comment: Research note, 5 pages, 2 tables and 3 figures, accepted to A&

A narrow, edge-on disk resolved around HD 106906 with SPHERE

HD~106906AB is so far the only young binary system around which a planet has been imaged and a debris disk evidenced thanks to a strong IR excess. As such, it represents a unique opportunity to study the dynamics of young planetary systems. We aim at further investigating the close (tens of au scales) environment of the HD~106906AB system. We used the extreme AO fed, high contrast imager SPHERE recently installed on the VLT to observe HD~106906. Both the IRDIS imager and the Integral Field Spectrometer were used. We discovered a very inclined, ring-like disk at a distance of 65~au from the star. The disk shows a strong brightness asymmetry with respect to its semi-major axis. It shows a smooth outer edge, compatible with ejection of small grains by the stellar radiation pressure. We show furthermore that the planet's projected position is significantly above the disk's PA. Given the determined disk inclination, it is not excluded though that the planet could still orbit within the disk plane if at a large separation (2000--3000 au). We identified several additional point sources in the SPHERE/IRDIS field-of-view, that appear to be background objects. We compare this system with other debris disks sharing similarities, and we briefly discuss the present results in the framework of dynamical evolution.Comment: 7 pages, 6 figures, accepted by Astronomy & Astrophysic

Continuum of vasodilator stress from rest to contrast medium to adenosine hyperemia for fractional flow reserve assessment

Objectives: This study compared the diagnostic performance with adenosine-derived fractional flow reserve (FFR) ≤0.8 of contrast-based FFR (cFFR), resting distal pressure (Pd)/aortic pressure (Pa), and the instantaneous wave-free ratio (iFR). Background: FFR objectively identifies lesions that benefit from medical therapy versus revascularization. However, FFR requires maximal vasodilation, usually achieved with adenosine. Radiographic contrast injection causes submaximal coronary hyperemia. Therefore, intracoronary contrast could provide an easy and inexpensive tool for predicting FFR. Methods: We recruited patients undergoing routine FFR assessment and made paired, repeated measurements of all physiology metrics (Pd/Pa, iFR, cFFR, and FFR). Contrast medium and dose were per local practice, as was the dose of intracoronary adenosine. Operators were encouraged to perform both intracoronary and intravenous adenosine assessments and a final drift check to assess wire calibration. A central core lab analyzed blinded pressure tracings in a standardized fashion. Results: A total of 763 subjects were enrolled from 12 international centers. Contrast volume was 8 ± 2 ml per measurement, and 8 different contrast media were used. Repeated measurements of each metric showed a bias <0.005, but a lower SD (less variability) for cFFR than resting indexes. Although Pd/Pa and iFR demonstrated equivalent performance against FFR ≤0.8 (78.5% vs. 79.9% accuracy; p = 0.78; area under the receiver-operating characteristic curve: 0.875 vs. 0.881; p = 0.35), cFFR improved both metrics (85.8% accuracy and 0.930 area; p < 0.001 for each) with an optimal binary threshold of 0.83. A hybrid decision-making strategy using cFFR required adenosine less often than when based on either Pd/Pa or iFR. Conclusions: cFFR provides diagnostic performance superior to that of Pd/Pa or iFR for predicting FFR. For clinical scenarios or health care systems in which adenosine is contraindicated or prohibitively expensive, cFFR offers a universal technique to simplify invasive coronary physiological assessments. Yet FFR remains the reference standard for diagnostic certainty as even cFFR reached only ∼85% agreement

PRESLA: An original device to measure the mechanical interaction between tongue and teeth or palate during speech production

An original experimental procedure is presented to measure the mechanical interaction between tongue and teeth and palate during speech production. It consists in using edentulous people as subjects and to insert pressure sensors in the structure of a replication of their dental prosthesis. This is assumed to induce no speech production perturbation for subjects who are used to speak with their prosthesis. Data collected from 4 subjects of French demonstrate the usability of the system

Anomalous versus slowed-down Brownian diffusion in the ligand-binding equilibrium

Measurements of protein motion in living cells and membranes consistently report transient anomalous diffusion (subdiffusion) which converges back to a Brownian motion with reduced diffusion coefficient at long times, after the anomalous diffusion regime. Therefore, slowed-down Brownian motion could be considered the macroscopic limit of transient anomalous diffusion. On the other hand, membranes are also heterogeneous media in which Brownian motion may be locally slowed-down due to variations in lipid composition. Here, we investigate whether both situations lead to a similar behavior for the reversible ligand-binding reaction in 2d. We compare the (long-time) equilibrium properties obtained with transient anomalous diffusion due to obstacle hindrance or power-law distributed residence times (continuous-time random walks) to those obtained with space-dependent slowed-down Brownian motion. Using theoretical arguments and Monte-Carlo simulations, we show that those three scenarios have distinctive effects on the apparent affinity of the reaction. While continuous-time random walks decrease the apparent affinity of the reaction, locally slowed-down Brownian motion and local hinderance by obstacles both improve it. However, only in the case of slowed-down Brownian motion, the affinity is maximal when the slowdown is restricted to a subregion of the available space. Hence, even at long times (equilibrium), these processes are different and exhibit irreconcilable behaviors when the area fraction of reduced mobility changes.Comment: Biophysical Journal (2013

Leading order determination of the gluon polarisation from DIS events with high-p_T hadron pairs

We present a determination of the gluon polarisation Delta g/g in the nucleon, based on the longitudinal double-spin asymmetry of DIS events with a pair of large transverse-momentum hadrons in the final state. The data were obtained by the COMPASS experiment at CERN using a 160 GeV/c polarised muon beam scattering off a polarised ^6LiD target. The gluon polarisation is evaluated by a Neural Network approach for three intervals of the gluon momentum fraction x_g covering the range 0.04 < x_g < 0.27. The values obtained at leading order in QCD do not show any significant dependence on x_g. Their average is Delta g/g = 0.125 +/- 0.060 (stat.) +/- 0.063 (syst.) at x_g=0.09 and a scale of mu^2 = 3 (GeV/c)^2.Comment: 13 pages, 6 figures and 3 table

Hierarchical modelling of species sensitivity distribution: development and application to the case of diatoms exposed to several herbicides

The Species Sensitivity Distribution (SSD) is a key tool to assess the ecotoxicological threat of contaminant to biodiversity. It predicts safe concentrations for a contaminant in a community. Widely used, this approach suffers from several drawbacks: i)summarizing the sensitivity of each species by a single value entails a loss of valuable information about the other parameters characterizing the concentration-effect curves; ii)it does not propagate the uncertainty on the critical effect concentration into the SSD; iii)the hazardous concentration estimated with SSD only indicates the threat to biodiversity, without any insight about a global response of the community related to the measured endpoint. We revisited the current SSD approach to account for all the sources of variability and uncertainty into the prediction and to assess a global response for the community. For this purpose, we built a global hierarchical model including the concentration-response model together with the distribution law for the SSD. Working within a Bayesian framework, we were able to compute an SSD taking into account all the uncertainty from the original raw data. From model simulations, it is also possible to extract a quantitative indicator of a global response of the community to the contaminant. We applied this methodology to study the toxicity of 6 herbicides to benthic diatoms from Lake Geneva, measured from biomass reduction

Stroke with unknown time of symptom onset: baseline clinical and magnetic resonance imaging data of the first thousand patients in WAKE-UP (efficacy and safety of mri-based thrombolysis in wake-up stroke: a randomized, doubleblind, placebo-controlled trial)

Background and Purpose—We describe clinical and magnetic resonance imaging (MRI) characteristics of stroke patients with unknown time of symptom onset potentially eligible for thrombolysis from a large prospective cohort. Methods—We analyzed baseline data from WAKE-UP (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke: A Randomized, Doubleblind, Placebo-Controlled Trial), an investigator-initiated, randomized, placebo-controlled trial of MRI-based thrombolysis in stroke patients with unknown time of symptom onset. MRI judgment included assessment of the mismatch between visibility of the acute ischemic lesion on diffusion-weighted imaging and fluid-attenuated inversion recovery. Results—Of 1005 patients included, diffusion-weighted imaging and fluid-attenuated inversion recovery mismatch was present in 479 patients (48.0%). Patients with daytime-unwitnessed stroke (n=138, 13.7%) had a shorter delay between symptom recognition and hospital arrival (1.5 versus 1.8 hours; P=0.002), a higher National Institutes of Stroke Scale score on admission (8 versus 6; P&lt;0.001), and more often aphasia (72.5% versus 34.0%; P&lt;0.001) when compared with stroke patients waking up from nighttime sleep. Frequency of diffusion-weighted imaging and fluid-attenuated inversion recovery mismatch was comparable between both groups (43.7% versus 48.7%; P=0.30). Conclusions—Almost half of the patients with unknown time of symptom onset stroke otherwise eligible for thrombolysis had MRI findings making them likely to be within a time window for safe and effective thrombolysis. Patients with daytime onset unwitnessed stroke differ from wake-up stroke patients with regards to clinical characteristics but are comparable in terms of MRI characteristics of lesion age. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01525290. URL: https://www.clinicaltrialsregister.eu. Unique identifier: 2011-005906-32