Cytoprotective Effect of Idebenone through Modulation of the Intrinsic Mitochondrial Pathway of Apoptosis in Human Retinal Pigment Epithelial Cells Exposed to Oxidative Stress Induced by Hydrogen Peroxide

Idebenone is a ubiquinone short-chain synthetic analog with antioxidant properties, which is believed to restore mitochondrial ATP synthesis. As such, idebenone is investigated in numerous clinical trials for diseases of mitochondrial aetiology and it is authorized as a drug for the treatment of Leber’s hereditary optic neuropathy. Mitochondria of retinal pigment epithelium (RPE) are particularly vulnerable to oxidative damage associated with cellular senescence. Therefore, the aim of this study was to explore idebenone’s cytoprotective effect and its underlying mechanism. We used a human-RPE cell line (ARPE-19) exposed to idebenone pre-treatment for 24 h followed by conditions inducing H2O2 oxidative damage for a further 24 h. We found that idebenone: (a) ameliorated H2O2-lowered cell viability in the RPE culture; (b) activated Nrf2 signaling pathway by promoting Nrf2 nuclear translocation; (c) increased Bcl-2 protein levels, leaving unmodified those of Bax, thereby reducing the Bax/Bcl-2 ratio; (d) maintained the mitochondrial membrane potential (ΔΨm) at physiological levels, preserving the functionality of mitochondrial respiratory complexes and counteracting the excessive production of ROS; and (e) reduced mitochondrial cytochrome C-mediated caspase-3 activity. Taken together, our findings show that idebenone protects RPE from oxidative damage by modulating the intrinsic mitochondrial pathway of apoptosis, suggesting its possible role in retinal epitheliopathies associated with mitochondrial dysfunction

Necdin mediates skeletal muscle regeneration by promoting myoblast survival and differentiation

Regeneration of muscle fibers that are lost during pathological muscle degeneration or after injuries is sustained by the production of new myofibers. An important cell type involved in muscle regeneration is the satellite cell. Necdin is a protein expressed in satellite cell–derived myogenic precursors during perinatal growth. However, its function in myogenesis is not known. We compare transgenic mice that overexpress necdin in skeletal muscle with both wild-type and necdin null mice. After muscle injury the necdin null mice show a considerable defect in muscle healing, whereas mice that overexpress necdin show a substantial increase in myofiber regeneration. We also find that in muscle, necdin increases myogenin expression, accelerates differentiation, and counteracts myoblast apoptosis. Collectively, these data clarify the function and mechanism of necdin in skeletal muscle and show the importance of necdin in muscle regeneration

Classical multiparty computation using quantum resources

International audienceIn this work, we demonstrate a way to perform classical multiparty computing among parties with limited computational resources. Our method harnesses quantum resources to increase the computational power of the individual parties. We show how a set of clients restricted to linear classical processing are able to jointly compute a nonlinear multivariable function that lies beyond their individual capabilities. The clients are only allowed to perform classical xor gates and single-qubit gates on quantum states. We also examine the type of security that can be achieved in this limited setting. Finally, we provide a proof-of-concept implementation using photonic qubits that allows four clients to compute a specific example of a multiparty function, the pairwise AND

Wave effects on coastal upwelling and water level

Traditional atmosphere, ocean and wave models are run independently of each other. This means that the energy and momentum fluxes do not fully account for the impact of the oceanic wave field at the air-sea interface. In this study, the Stokes drift impact on mass and tracer advection, the Stokes-Coriolis forcing, and the sea-state-dependent momentum and energy fluxes are introduced into an ocean circulation model and tested for a domain covering the Baltic Sea and the North Sea. Sensitivity experiments are designed to investigate the influence on the simulation of storms and Baltic Sea upwelling. Inclusion of wave effects improves the model performance compared with the stand-alone circulation model in terms of sea level height, temperature and circulation. The direct sea-state-dependent momentum and turbulent kinetic energy fluxes prove to be of higher importance than the Stokes drift related effects investigated in this study (i.e., Stokes-Coriolis forcing and Stokes drift advection on tracers and on mass). The latter affects the mass and tracer advection but largely balances the influence of the Stokes-Coriolis forcing. The upwelling frequency changes by >10% along the Swedish coast when wave effects are included. In general, the strong (weak) upwelling probability is reduced (increased) when adding the wave effects. From the results, we conclude that inclusion of wave effects can be important for regional, high-resolution ocean models even on short time scales, suggesting that they should be introduced in operational ocean circulation models. However, care should be taken when introducing the Stokes-Coriolis forcing as it should be balanced by the Stokes drift in mass and tracer advection

Effects of initial-state dynamics on collective flow within a coupled transport and viscous hydrodynamic approach

We evaluate the effects of preequilibrium dynamics on observables in ultrarelativistic heavy-ion collisions. We simulate the initial nonequilibrium phase within A MultiPhase Transport (AMPT) model, while the subsequent near-equilibrium evolution is modeled using (2+1)-dimensional relativistic viscous hydrodynamics. We match the two stages of evolution carefully by calculating the full energy-momentum tensor from AMPT and using it as input for the hydrodynamic evolution. We find that when the preequilibrium evolution is taken into account, final-state observables are insensitive to the switching time from AMPT to hydrodynamics. Unlike some earlier treatments of preequilibrium dynamics, we do not find the initial shear viscous tensor to be large. With a shear viscosity to entropy density ratio of $0.12$, our model describes quantitatively a large set of experimental data on Pb+Pb collisions at the Large Hadron Collider(LHC) over a wide range of centrality: differential anisotropic flow $v_n(p_T) ~(n=2-6)$, event-plane correlations, correlation between $v_2$ and $v_3$, and cumulant ratio $v_2\{4\}/v_2\{2\}$.Comment: 10 pages, v2: minor revisio

Climacostol reduces tumour progression in a mouse model of melanoma via the p53-dependent intrinsic apoptotic programme

Climacostol, a compound produced by the ciliated protozoan Climacostomum virens, displayed cytotoxic properties in vitro. This study demonstrates that it has anti-tumour potential. Climacostol caused a reduction of viability/proliferation of B16-F10 mouse melanoma cells, a rapidly occurring DNA damage, and induced the intrinsic apoptotic pathway characterised by the dissipation of the mitochondrial membrane potential, the translocation of Bax to the mitochondria, the release of Cytochrome c from the mitochondria, and the activation of Caspase 9-dependent cleavage of Caspase 3. The apoptotic mechanism of climacostol was found to rely on the up-regulation of p53 and its targets Noxa and Puma. In vivo analysis of B16-F10 allografts revealed a persistent inhibition of tumour growth rate when melanomas were treated with intra-tumoural injections of climacostol. In addition, it significantly improved the survival of transplanted mice, decreased tumour weight, induced a remarkable reduction of viable cells inside the tumour, activated apoptosis and up-regulated the p53 signalling network. Importantly, climacostol toxicity was more selective against tumour than non-tumour cells. The anti-tumour properties of climacostol and the molecular events associated with its action indicate that it is a powerful agent that may be considered for the design of pro-apoptotic drugs for melanoma therapy

The Copernicus Marine Service ocean forecasting system for the Mediterranean Sea

The Mediterranean Monitoring and Forecasting Center (MED-MFC) is part of the Copernicus Marine Environment and Monitoring Service (CMEMS) and provides regular and systematic information on the time-evolving Mediterranean Sea physical (including waves) and biogeochemical state. The systems consist of 3 components: 1) Med-Physics, a numerical ocean prediction systems, based on NEMO model, that operationally produces analyses, reanalysis and short term forecasts of the main physical parameters; 2) Med-Biogeochemistry, a biogeochemical analysis, reanalysis and forecasting system based on the Biogeochemical Flux Model (BFM) which provides information on chlorophyll, phosphate, nitrate, primary productivity, oxygen, phytoplankton biomass, pH and pCO2; 3) Med-Waves based on WAM model and providing analysis, forecast and reanalysis products for waves. The systems have been recently upgraded at a resolution of 1/24 degree in the horizontal and 141 vertical levels. The Med-Physics analysis and forecasting system is composed by the hydrodynamic model NEMO 2-way coupled with the third-generation wave model WaveWatchIII and forced by ECMWF atmospheric fields. The model solutions are corrected by the 3DVAR data assimilation system (3D variational scheme adapted to the oceanic assimilation problem) with a daily assimilation cycle of sea level anomaly and vertical profiles of temperature and salinity. The model has a non-linear explicit free surface and it is forced by surface pressure, interactive heat, momentum and water fluxes at the air-sea interface. The biogeochemical analysis and forecasts are produced by means of the MedBFM v2.1 modeling system (i.e. the physical-biogeochemical OGSTM-BFM model coupled with the 3DVARBIO assimilation scheme) forced by the outputs of the Med-Physics product. Seven days of analysis/hindcast and ten days of forecast are bi-weekly produced on Wednesday and on Saturday, with the assimilation of surface chlorophyll concentration from satellite observations. In-situ data are mainly used to estimate model uncertainty at different spatial scales. The Med-Waves modelling system is based on the WAM Cycle 4.5.4 wave model code. It consists of a wave model grid covering the Mediterranean Sea at a 1/24° horizontal resolution, nested to a North Atlantic grid at a 1/6° resolution. The system is forced by ECMWF winds at 1/8°. Refraction due to surface currents is accounted by the system which assimilates altimeter along-track significant wave height observations. On a daily basis, it provides 1-day analysis and 5-day forecast hourly wave parameters. Currently, wave buoy observations of significant wave height and mean wave period along with satellite observations are used to calibrate and validate the Med-waves modelling system.PublishedHalifax, Nova Scotia, Canada4A. Oceanografia e clim