33 research outputs found
ESA's wind Lidar mission ADM-AEOLUS; on-going scientific activities related to calibration, retrieval and instrument operation
The Earth Explorer Atmospheric Dynamics Mission
(ADM-Aeolus) of ESA will be the first-ever satellite to
provide global observations of wind profiles from
space. Its single payload, namely the Atmospheric
Laser Doppler Instrument (ALADIN) is a directdetection
high spectral resolution Doppler Wind Lidar
(DWL), operating at 355 nm, with a fringe-imaging
receiver (analysing aerosol and cloud backscatter) and a
double-edge receiver (analysing molecular backscatter).
In order to meet the stringent mission requirements on
wind retrieval, ESA is conducting various science
support activities for the consolidation of the on-ground
data processing, calibration and sampling strategies.
Results from a recent laboratory experiment to study
Rayleigh-Brillouin scattering and improve the
characterisation of the molecular lidar backscatter
signal detected by the ALADIN double-edge Fabry-
Perot receiver will be presented in this paper. The
experiment produced the most accurate ever-measured
Rayleigh-Brillouin scattering profiles for a range of
temperature, pressure and gases, representative of
Earth’s atmosphere. The measurements were used to
validate the Tenti S6 model, which is implemented in
the ADM-Aeolus ground processor.
First results from the on-going Vertical Aeolus
Measurement Positioning (VAMP) study will be also
reported. This second study aims at the optimisation of
the ADM-Aeolus vertical sampling in order to
maximise the information content of the retrieved
winds, taking into account the atmospheric dynamical
and optical heterogeneity. The impact of the Aeolus
wind profiles on Numerical Weather Prediction (NWP)
and stratospheric circulation modelling for the different
vertical sampling strategies is also being estimated
Simvastatin activates single skeletal RyR1 channels but exerts more complex regulation of the cardiac RyR2 isoform
Background and Purpose: Statins are amongst the most widely prescribed drugs for those at risk of cardiovascular disease, lowering cholesterol levels by inhibiting 3‐hydroxy‐3‐methylglutaryl (HMG)‐CoA reductase. Although effective at preventing cardiovascular disease, statin use is associated with muscle weakness, myopathies and, occasionally, fatal rhabdomyolysis. As simvastatin, a commonly prescribed statin, promotes Ca²⁺ release from sarcoplasmic reticulum (SR) vesicles, we investigated if simvastatin directly activates skeletal (RyR1) and cardiac (RyR2) ryanodine receptors. Experimental Approach: RyR1 and RyR2 single‐channel behaviour was investigated after incorporation of sheep cardiac or mouse skeletal SR into planar phospholipid bilayers under voltage‐clamp conditions. LC‐MS was used to monitor the kinetics of interconversion of simvastatin between hydroxy‐acid and lactone forms during these experiments. Cardiac and skeletal myocytes were permeabilised to examine simvastatin modulation of SR Ca²⁺ release. Key Results: Hydroxy acid simvastatin (active at HMG‐CoA reductase) significantly and reversibly increased RyR1 open probability (Po) and shifted the distribution of Ca²⁺ spark frequency towards higher values in skeletal fibres. In contrast, simvastatin reduced RyR2 Po and shifted the distribution of spark frequency towards lower values in ventricular cardiomyocytes. The lactone pro‐drug form of simvastatin (inactive at HMG‐CoA reductase) also activated RyR1, suggesting that the HMG‐CoA inhibitor pharmacophore was not responsible for RyR1 activation. Conclusion and Implications: Simvastatin interacts with RyR1 to increase SR Ca²⁺ release and thus may contribute to its reported adverse effects on skeletal muscle. The ability of low concentrations of simvastatin to reduce RyR2 Po may also protect against Ca²⁺‐dependent arrhythmias and sudden cardiac death
Cx43 hemichannel microdomain signaling at the intercalated disc enhances cardiac excitability
Cx43, a major cardiac connexin, forms precursor hemichannels that accrue at the intercalated disc to assemble as gap junctions. While gap junctions are crucial for electrical conduction in the heart, little is known about the potential roles of hemichannels. Recent evidence suggests that inhibiting Cx43 hemichannel opening with Gap19 has antiarrhythmic effects. Here, we used multiple electrophysiology, imaging, and super-resolution techniques to understand and define the conditions underlying Cx43 hemichannel activation in ventricular cardiomyocytes, their contribution to diastolic Ca2+ release from the sarcoplasmic reticulum, and their impact on electrical stability. We showed that Cx43 hemichannels were activated during diastolic Ca2+ release in single ventricular cardiomyocytes and cardiomyocyte cell pairs from mice and pigs. This activation involved Cx43 hemichannel Ca2+ entry and coupling to Ca2+ release microdomains at the intercalated disc, resulting in enhanced Ca2+ dynamics. Hemichannel opening furthermore contributed to delayed afterdepolarizations and triggered action potentials. In single cardiomyocytes, cardiomyocyte cell pairs, and arterially perfused tissue wedges from failing human hearts, increased hemichannel activity contributed to electrical instability compared with nonfailing rejected donor hearts. We conclude that microdomain coupling between Cx43 hemichannels and Ca2+ release is a potentially novel, targetable mechanism of cardiac arrhythmogenesis in heart failure. Copyright: © 2021, American Society for Clinical Investigation.We sincerely thank Ellen Cocquyt, Diego De Baere, Vicky Pauwelyn, Annemie Biesemans, Roxane Menten, and Mingliang Zhang for superb technical support. We would also like to thank the heart failure unit, the transplant surgical team, and the transplant coordinating team of UZ Leuven for help in providing the human explant hearts. This work was supported by the Fund for Scientific Research Flanders (project grants to LL, KRS, and GB; a postdoctoral fellowship to ED; and PhD fellowships to MDS and MA); Ghent University (a postdoctoral fellowship to KW and PhD fellowships to AL and TN); the Interuniversity Attraction Poles P7/10 to KRS and LL; NIH (project grants to ER and MD); the Fondation Leducq (transatlantic network award to MD); and a grant from the Ministry of Science and Higher Education of the Russian Federation, agreement 075-15-2020-800, to AVP
Who is the keeper of the gate? - single-channel properties after reciprocal exchange of the pore in the cation channels TRPM2 and TRPM8
Who is the keeper of the gate? - single-channel properties after reciprocal exchange of the pore in the cation channels TRPM2 and TRPM8
S4-S5 Linker is involved in voltage-dependent gating of human transient receptor potential ankyrin 1 channel
The transient receptor potential ankyrin 1 channel (TRPA1) is a versatile sensory channel that is gated by depolarizing voltages, deep cooling, membrane deformation, and structurally diverse compounds which include proalgesic agents such as allyl isothiocyanate. How these disparate stimuli converge on the channel protein to open the ion-conducting pore has not yet been fully resolved. The overall architecture of TRP channels shows clear similarities to that seen in the well characterized voltage-gated potassium channels. Here, activation of the voltage sensors in the fourth transmembrane segment (S4) is transduced into pore opening via coupling of the S4-S5 linker to the C-terminal S6 segment. In TRPA1, the gain-of-function mutation N855S located in the S4-S5 region has been associated with familial episodic pain syndrome. In an attempt to elucidate the role of the S4-S5 linker and its putative interaction(s) with S6 or the first C-terminal helix in the voltage-dependent gating of TRPA1, we used site-directed mutagenesis, whole-cell electrophysiology, single-channel recording, and molecular dynamics simulations. The charge-reversal mutations K868E and K969E resulted in a decrease in the rectification index compared to wild-type TRPA1 channels, and a virtually voltage-independent conductance-voltage (G-V) relationship. This effect was also observed in the adjacent charge-neutralizing mutant H970A, but was less pronounced in charge- reversal H970D. These results indicate that positively charged residues in the S4-S5 linker and the helix adjacent to the C-terminal S6 segment play a vital role in the voltage-dependent gating of TRPA1
Perception du risque cardio-vasculaire par le patient en prévention primaire d'une part et par son médecin traitant d'autre part (étude prospective et conséquences en pratique quotidienne)
Contexte : étude prospective de la perception du risque cardio-vasculaire par les patients et leur médecin généraliste, en prévention primaire, afin de déterminer l'impact de cette perception sur les comportements et la prise en charge thérapeutique. Méthode : Passation de questionnaires appareillés à 138 patients pris en charge par 18 médecins. Homme plus de 44 ans, femmes plus de 54 ans en prévention primaire. Modèle de Framingham modifiée. Résultats : La perception du RCV relatif, et par conséquent la perception du RCVA, par le patient est déterminée par celui-ci de façon aléatoire. La perception du RCVA par le médecin traitant est adéquate pour les valeurs hautes et pour les valeurs basses du RCVA. Elle apparaît moins performante pour les valeurs intermédiaires. La mauvaise perception du RCVr par le patient influe à la manière d'un rétrocontrôle négatif sur le nombre de traitements prescrits (p=0,0041). Une perception défaillante du RCVA par le médecin traitant n'entraîne pas une moins bonne prise en charge thérapeutique de son patient. Les recommandations de bonnes pratiques dans la prise en charge du patient dyslipidémique ne sont pas respectées. Il existe un feed back négatif du patient sur son médecin. Savoirs profanes, croyances et valeurs propres à chaque patient sont à l'origine de systèmes structurés de représentations subjectives et durables qui génèrent de façon objective et mesurable le phénomène du feed back. Nous préconisons l'utilisation de la méthode de sommation des facteurs de risque plutôt que la méthode d'évaluation du risque global. Proposition de la création du MeSH : Risk Perception. Conclusion : Les patients en prévention primaire ont une perception aléatoire du risque de développer une MCV. Cette mauvaise perception induit des défauts de prise en charge médicamenteuse par feed back négatif et entraîne des résistances aux changements de comportements. La méthode de sommation des facteurs de risque est adaptée à la prise en charge de ces patients.TOULOUSE3-BU Santé-Centrale (315552105) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF
Enhanced activity of multiple TRIC‐B channels: an endoplasmic reticulum/sarcoplasmic reticulum mechanism to boost counterion currents
KEY POINTS:There are two subtypes of trimeric intracellular cation (TRIC) channels but their distinct single-channel properties and physiological regulation have not been characterized. We examined the differences in function between native skeletal muscle sarcoplasmic reticulum (SR) K+ -channels from wild-type (WT) mice (where TRIC-A is the principal subtype) and from Tric-a knockout (KO) mice that only express TRIC-B. We find that lone SR K+ -channels from Tric-a KO mice have a lower open probability and gate more frequently in subconducting states than channels from WT mice but, unlike channels from WT mice, multiple channels gate with high open probability with a more than six-fold increase in activity when four channels are present in the bilayer. No evidence was found for a direct gating interaction between ryanodine receptor and SR K+ -channels in Tric-a KO SR, suggesting that TRIC-B-TRIC-B interactions are highly specific and may be important for meeting counterion requirements during excitation-contraction coupling in tissues where TRIC-A is sparse or absent. ABSTRACT:The trimeric intracellular cation channels, TRIC-A and TRIC-B, represent two subtypes of sarcoplasmic reticulum (SR) K+ -channel but their individual functional roles are unknown. We therefore compared the biophysical properties of SR K+ -channels derived from the skeletal muscle of wild-type (WT) or Tric-a knockout (KO) mice. Because TRIC-A is the major TRIC-subtype in skeletal muscle, WT SR will predominantly contain TRIC-A channels, whereas Tric-a KO SR will only contain TRIC-B channels. When lone SR K+ -channels were incorporated into bilayers, the open probability (Po) of channels from Tric-a KO mice was markedly lower than that of channels from WT mice; gating was characterized by shorter opening bursts and more frequent brief subconductance openings. However, unlike channels from WT mice, the Po of SR K+ -channels from Tric-a KO mice increased as increasing channel numbers were present in the bilayer, driving the channels into long sojourns in the fully open state. When co-incorporated into bilayers, ryanodine receptor channels did not directly affect the gating of SR K+ -channels, nor did the presence or absence of SR K+ -channels influence ryanodine receptor activity. We suggest that because of high expression levels in striated muscle, TRIC-A produces most of the counterion flux required during excitation-contraction coupling. TRIC-B, in contrast, is sparsely expressed in most cells and, although lone TRIC-B channels exhibit low Po, the high Po levels reached by multiple TRIC-B channels may provide a compensatory mechanism to rapidly restore K+ gradients and charge differences across the SR of tissues containing few TRIC-A channels