Anti-Inflammatory Effect of Fluvastatin on IL-8 Production Induced by Pseudomonas aeruginosa and Aspergillus fumigatus Antigens in Cystic Fibrosis

International audienceBACKGROUND: Early in life, patients with cystic fibrosis (CF) are infected with microorganisms including bacteria and fungi, particularly Pseudomonas aeruginosa and Aspergillus fumigatus. Since recent research has identified the anti-inflammatory properties of statins (besides their lipid-lowering effects), we investigated the effect of fluvastatin on the production of the potent neutrophil chemoattractant chemokine, IL-8, in whole blood from CF patients, stimulated by Pseudomonas aeruginosa (LPS) and Aspergillus fumigatus (AFA) antigens. RESULTS: Whole blood from adult patients with CF and from healthy volunteers was collected at the Rennes University Hospital (France). Blood was pretreated for 1 h with fluvastatin (0-300 µM) and incubated for 24 h with LPS (10 µg/mL) and/or AFA (diluted 1/200). IL-8 protein levels, quantified by ELISA, were increased in a concentration-dependent manner when cells were stimulated by LPS or AFA. Fluvastatin strongly decreased the levels of IL-8, in a concentration-dependent manner, in whole blood from CF patients. However, its inhibitory effect was decreased or absent in whole blood from healthy subjects. Furthermore, the inhibition induced by fluvastatin in CF whole blood was reversed in the presence of intermediates within the cholesterol biosynthesis pathway, mevalonate, farnesyl pyprophosphate or geranylgeranyl pyrophosphate that activate small GTPases by isoprenylation. CONCLUSIONS: For the first time, the inhibitory effects of fluvastatin on CF systemic inflammation may reveal the important therapeutic potential of statins in pathological conditions associated with the over-production of pro-inflammatory cytokines and chemokines as observed during the manifestation of CF. The anti-inflammatory effect could be related to the modulation of the prenylation of signalling proteins

Operating a full tungsten actively cooled tokamak: overview of WEST first phase of operation

WEST is an MA class superconducting, actively cooled, full tungsten (W) tokamak, designed to operate in long pulses up to 1000 s. In support of ITER operation and DEMO conceptual activities, key missions of WEST are: (i) qualification of high heat flux plasma-facing components in integrating both technological and physics aspects in relevant heat and particle exhaust conditions, particularly for the tungsten monoblocks foreseen in ITER divertor; (ii) integrated steady-state operation at high confinement, with a focus on power exhaust issues. During the phase 1 of operation (2017–2020), a set of actively cooled ITER-grade plasma facing unit prototypes was integrated into the inertially cooled W coated startup lower divertor. Up to 8.8 MW of RF power has been coupled to the plasma and divertor heat flux of up to 6 MW m−2 were reached. Long pulse operation was started, using the upper actively cooled divertor, with a discharge of about 1 min achieved. This paper gives an overview of the results achieved in phase 1. Perspectives for phase 2, operating with the full capability of the device with the complete ITER-grade actively cooled lower divertor, are also described

2D imaging X-ray spectrometer on WEST : results and technical challenges

International audienceA new imaging X-Ray spectrometer has been installed, aligned and used on the WEST tokamak. A typical experimental spectrum is presented for each of the 3 interchangeable crystals, measuring respectively the Ar XVII, Ar XVIII and Fe XXV spectra. The instrument function exhibits a distortion for the Ar XVII spectrum, presumably due to the crystal splitting in 2 stripes and non-parallelism of the crystal layers. The Ar XVII and Ar XVIII spectra also display blends of unidentified spectral lines, presumably W line

Fluctuation spectra and velocity profile from Doppler backscattering on Tore Supra

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The ubiquitin-selective chaperone Cdc48/p97 associates with Ubx3 to modulate monoubiquitylation of histone H2B

Cdc48/p97 is an evolutionary conserved ubiquitin-dependent chaperone involved in a broad array of cellular functions due to its ability to associate with multiple cofactors. Aside from its role in removing RNA polymerase II from chromatin after DNA damage, little is known about how this AAA-ATPase is involved in the transcriptional process. Here, we show that yeast Cdc48 is recruited to chromatin in a transcription-coupled manner and modulates gene expression. Cdc48, together with its cofactor Ubx3 controls monoubiquitylation of histone H2B, a conserved modification regulating nucleosome dynamics and chromatin organization. Mechanistically, Cdc48 facilitates the recruitment of Lge1, a cofactor of the H2B ubiquitin ligase Bre1. The function of Cdc48 in controlling H2B ubiquitylation appears conserved in human cells because disease-related mutations or chemical inhibition of p97 function affected the amount of ubiquitylated H2B in muscle cells. Together, these results suggest a prominent role of Cdc48/p97 in the coordination of chromatin remodeling with gene transcription to define cellular differentiation processes

Inter-machine comparison of intrinsic toroidal rotation in tokamaks

Parametric scalings of the intrinsic (spontaneous, with no external momentum input) toroidal rotation observed on a large number of tokamaks have been combined with an eye towards revealing the underlying mechanism(s) and extrapolation to future devices. The intrinsic rotation velocity has been found to increase with plasma stored energy or pressure in JET, Alcator C-Mod, Tore Supra, DIII-D, JT-60U and TCV, and to decrease with increasing plasma current in some of these cases. Use of dimensionless parameters has led to a roughly unified scaling with M-A alpha beta(N), although a variety of Mach numbers works fairly well; scalings of the intrinsic rotation velocity with normalized gyro-radius or collisionality show no correlation. Whether this suggests the predominant role of MHD phenomena such as ballooning transport over turbulent processes in driving the rotation remains an open question. For an ITER discharge with beta(N) = 2.6, an intrinsic rotation Alfven Mach number of M-A similar or equal to 0.02 may be expected from the above deduced scaling, possibly high enough to stabilize resistive wall modes without external momentum input