G018 Evaluation of IKr blocking properties of different molecules with or without torsadogenic properties

Currently, industrials and regulatory authorities are worried by Torsades de Pointes (TdP), a type of ventricular tachycardia, which can lead to sudden death. The most recent guidelines from the International Committee of Harmonization, recommend to assess properly the risk of TdP, by different approaches, among others an in vitro method. This method consists on studying the blockade of a voltage-dependant potassium channel, called hERG. Indeed, hERG channel, responsible for the IKr current, seems to be blocked by the majority of the torsadogenic molecules and, is thus considered as an important marker of pro arrhythmic risk.CERB developed a bio-computerized database named TdPScreen® to predict the risk of TdP. Known molecules are classified according to their pro arrhythmic potential, from group A to C. The group A corresponds to drugs with numerous or several reports of TdP, the group B to compounds causing QT prolongation with TdP at very low frequency; and in group C to drugs with no report of TdP or QT prolongation. This database suggests that other factors than a single blockade of IKr could be involved in the genesis of druginduced TdP.We performed experiments in patch-clamp using HEK cells expressing stably the hERG channel. Different compounds from the different groups, above mentioned, were evaluated for their IKr blocking potency and compared to the TdPScreen® database.Results show some torsadogenic drugs might exhibit very low IKr blocking properties (e.g. D-sotalol), whereas other non-torsadogenic drugs are potent IKr inhibitors (e.g. verapamil, diltiazem…).These results, and others, indicate that drugs can block hERG current without any influence on TdP appearance.We conclude that assessing pro arrhythmic potential of compounds, only on the blocking effects of IKr, in vitro, can lead to the eviction of interesting molecules

Low divergence proton beams from a laser-plasma accelerator at kHz repetition rate

Proton beams with up to 100 pC bunch charge, 0.48 MeV cut-off energy and divergence as low as a $3^{\circ}$ were generated from solid targets at kHz repetition rate by a few-mJ femtosecond laser under controlled plasma conditions. The beam spatial profile was measured using a small aperture scanning time-of-flight detector. Detailed parametric studies were performed by varying the surface plasma scale length from 8 to 80 nm and the laser pulse duration from 4 fs to 1.5 ps. Numerical simulations are in good agreement with observations and, together with an in-depth theoretical analysis of the acceleration mechanism, indicate that high repetition rate femtosecond laser technology could be used to produce few-MeV protons beams for applications.Comment: 6 pages, 4 figures (main text). 7 pages, 6 figures (supplemental material

Relativistic high-harmonic generation and correlated electron acceleration from plasma mirrors at 1 kHz repetition rate

We report evidence for the first generation of XUV spectra from relativistic surface high-harmonic generation (SHHG) on plasma mirrors at a kilohertz repetition rate, emitted simultaneously and correlated to the emission of energetic electrons. We present measurements of SHHG spectra and electron angular distributions as a function of the experimentally controlled plasma density gradient scale length L for three increasingly short and intense driving pulses: 24 fs (9 optical cycles) and a0 = 1.1, 9 fs (3.5 optical cycles) and a0 = 1.8, and finally 4 fs (1.7 optical cycles) and a0 ≈ 2.0. For all driver pulses, we observe relativistic SHHG in the range L ∈ [λ/25, λ/10], with an optimum gradient scale length of L ≈ λ/15. Surface high-harmonic generation (SHHG) [1] from relativistic plasma mirrors is a promising method for greatly enhancing the available energy of attosecond XUV pulses. This is motivated by the absence of an inherent limitation for the driving intensity such that extremely large numbers of photons from ultra-high intensity lasers can can be converted into attosecond XUV pulses. In strongly relativistic conditions with a normalized vector potential a 0 = I[W cm −2 ] λ 2 0 [µm 2 ]/(1.37 × 10 18) 1, where I is the laser intensity and λ 0 the central wavelength, this is expected to occur with extremely high, percent-level conversion efficiencies [2-4]. Reported experimentally observed laser-to-XUV conversion efficiencies for plasma mirrors with a 0 ∼ 1 are ∼ 10 −4 [5-8], but are expected to increase with higher-intensity drivers. Reaching relativistic SHHG regime with a 0 > 1 requires an on-target intensity of > ∼ 10 18 W/cm 2 for an 800-nm laser while retaining a very steep surface plasma density profile, i.e. a profile n(x) = n c exp [x/ L], with a scale length L of a small fraction of the diving laser wavelength. Here n c is the nonrelativstic critical plasma density for the driving wavelength and x is the coordinate in the target normal direction. Technically this requires a highly focusable terawatt-class driver laser with a temporal contrast of > ∼ 10 10. These conditions are typically met by Joule-class amplifier chains with dedicated contrast filters [9, 10] and operating at ∼ 10 Hz repetition rate [4-9]. Many applications as well as parametric studies of this regime would benefit from a higher repetition rate. At LOA, we have developed a unique laser chain with power-scaled hollow-core-fiber postcompression system [11] operating at 1 kHz repetition rate. Using this kHz-laser, which achieves ultra-high intensties with few-mJ pulse energy and few-cycle pulse duration, we have demonstrated laser-plasma interaction in the relativistic regime through laser-wakefield acceleration of electrons both in under-dense gas jets [11, 12] and in the underdense part of a smooth plasma density gradient on a plasma mirror [13]. Here we report on the first experimental demonstration of relativistic SHHG at kHz-repetition rate, the arguably most demanding application in terms of laser performance as it depends critically on the spatio-temporal pulse quality and the temporal contrast. For relativistic driving intensities, a 0 > ∼ 1, the SHHG emission mechanism is described by a push-pull process [14], also dubbed "relativistic electron spring" [15, 16], repeating once per driving laser period. The incident laser field first pushes electrons into the plasma, piling up a dense electron bunch and creating a restoring internal plasma field. As the laser field changes sign, the combined plasma and laser fields accelerate the electron bunch to a relativistic velocity towards the vacuum. SHH

Relativistic-intensity near-single-cycle light source at 1kHz

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Control of Relativistic Plasma-Mirrors with Few-Cycle and Two-Colour Laser Waveforms

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Laser-Produced Magnetic-Rayleigh-Taylor Unstable Plasma Slabs in a 20 T Magnetic Field

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Laboratory disruption of scaled astrophysical outflows by a misaligned magnetic field

International audienceMass outflow is a common process in astrophysical objects. Here the authors investigate in which conditions an astrophysically-scaled laser-produced plasma flow can be collimated and evolves in the presence of a misaligned external magnetic field