IFI35, mir-99a and HCV Genotype to Predict Sustained Virological Response to Pegylated-Interferon Plus Ribavirin in Chronic Hepatitis C

International audienceAlthough, the treatment of chronic hepatitis C (CHC) greatly improved with the use of direct antiviral agents, pegylated-interferon (PEG-IFN) plus ribavirin remains an option for many patients, worldwide. The intra-hepatic level of expression of interferon stimulated genes (ISGs) and the rs12979860 CC genotype located within IFNL3 have been associated with sustained virological response (SVR), in patients with CHC. The aim of the study was to identify micro-RNAs associated with SVR and to build an accurate signature to predict SVR. Pre-treatment liver biopsies from 111 patients, treated with PEG-IFN plus ribavirin, were studied. Fifty-seven patients had SVR, 36 non-response (NR) and 18 relapse (RR). The expression of 851 human miRNAs and 30 selected mRNAs, including ISGs, was assessed by RT-qPCR. In the first group of patients (screen), 20 miRNAs out of the 851 studied were deregulated between NRs and SVRs. From the 4 miRNAs validated (mir-23a, mir-181a*, mir-217 and mir-99a), in the second group of patients (validation), 3 (mir-23a, mir-181a* and mir-99a) were down-regulated in NRs as compared to SVRs. The ISGs, studied, were accumulated in SVRs and IFNL3 rs12979860 CT/TT carriers compared respectively to NRs and CC carriers. Combining, clinical data together with the expression of selected genes and micro-RNAs, we identified a signature (IFI35, mir-99a and HCV genotype) to predict SVR (AUC:0.876) with a positive predictive value of 86.54% with high sensibility (80%) and specificity (80.4%). This signature may help to characterize patients with low chance to respond to PEG-IFN/ribavirin and to elucidate mechanisms of NR

Turbulent eddy-time-correlation in the solar convective zone

International audienceTheoretical modeling of the driving processes of solar-like oscillations is a powerful way of understanding the properties of the convective zones of solar-type stars. In this framework, the description of the temporal correlation between turbulent eddies is an essential ingredient to model mode amplitudes. However, there is a debate between a Gaussian or Lorentzian description of the eddy-time correlation function (Samadi et al. 2003b, A&A, 403, 303; Chaplin et al. 2005, MNRAS, 360, 859). Indeed, a Gaussian description reproduces the low-frequency shape of the mode amplitude for the Sun, but is unsatisfactory from a theoretical point of view (Houdek 2010, Ap&SS, 328, 237) and leads to other disagreements with observations (Samadi et al. 2007, A&A, 463, 297). These are solved by using a Lorentzian description, but there the low-frequency shape of the solar observations is not correctly reproduced. We reconcile the two descriptions by adopting the sweeping approximation, which consists in assuming that the eddy-time-correlation function is dominated by the advection of eddies, in the inertial range, by energy-bearing eddies. Using a Lorentzian function together with a cut-off frequency derived from the sweeping assumption allows us to reproduce the low-frequency shape of the observations. This result also constitutes a validation of the sweeping assumption for highly turbulent flows as in the solar case

Functional Heterogeneity of Mammalian IFITM Proteins against HIV-1

International audienceInterferon-induced transmembrane proteins (IFITMs) are a family of interferon-inducible proteins that inhibit a broad range of viruses by interfering with viral-to-cellular membrane fusion. The antiviral activity of IFITMs is highly regulated by several posttranslational modifications and by a number of protein domains that modulate steady-state protein levels, trafficking, and antiviral effectiveness. Taking advantage of the natural diversity existing among IFITMs of different animal species, we have compared 21 IFITMs for their ability to inhibit HIV-1 at two steps, during virus entry into cells (target cell protection) and during the production of novel virion particles (negative imprinting of virion particles’ infectivity). We found a high functional heterogeneity among IFITM homologs with respect to both antiviral modalities, with IFITM members that exhibit enhanced viral inhibition, while others have no ability to block HIV-1. These differences could not be ascribed to known regulatory domains and could only be partially explained through differential protein stability, implying the existence of additional mechanisms. Through the use of chimeras between active and inactive IFITMs, we demonstrate that the cross talk between distinct domains of IFITMs is an important contributor of their antiviral potency. Finally, we identified murine IFITMs as natural variants competent for target cell protection, but not for negative imprinting of virion particles’ infectivity, suggesting that the two properties may, at least in principle, be uncoupled. Overall, our results shed new light on the complex relationship between IFITMs and viral infection and point to the cross talk between IFITM domains as a novel layer of regulation of their activit

Mode lifetime and associated scaling relations

International audienceThanks to the CoRoT and Kepler spacecrafts, scaling relations (linking seismic indices and global stellar parameters) are becoming the cornerstone of ensemble asteroseismology. Among them, the relation between the cut-off frequency and the frequency of the maximum in the power spectrum of solar-like pulsators as well as the relation between mode lifetime and the effective temperature remain poorly understood. However, a solid theoretical background is essential to assess the accuracy of those relations and subsequently of the derived stellar parameters. We will thus present recent advances on the understanding of the underlying mechanisms governing those relations and show that the physics of mode lifetime (thus of mode damping) plays a major role

Modified Akuamma Alkaloids with Increased Potency at the Mu-opioid Receptor

Akuammine (1) and pseudo-akuammigine (2) are indole alkaloids found in the seeds of the akuamma tree (Picralima nitida). Both alkaloids are weak agonists of the mu opioid receptor (µOR); however, they produce minimal effects in animal models of antinociception. To probe the interactions of 1 and 2 at the opioid receptors, we have prepared a collection of 22 semi-synthetic derivatives. Evaluation of this collection at the µOR and kappa opioid receptor (κOR) revealed structural-activity relationship trends and derivatives with improved potency at the OR. Most notably, the introduction of a phenethyl moiety to the N1 of 2 produces a 70-fold increase in potency and a 7-fold increase in selectivity for the µOR. The in vitro potency of this compound resulted in increased efficacy in the tail-flick and hot-plate assays of antinociception. The improved potency of these derivatives highlights the promise of exploring natural product scaffolds to probe the opioid receptors

Mode Line Widths in Red-Giant Stars

International audienc

Mode Line Widths in Red-Giant Stars

International audienc

Mode Line Widths in Red-Giant Stars

International audienc