Modulation of CaV1.2 Channels by Mg2+ Acting at an EF-hand Motif in the COOH-terminal Domain

Magnesium levels in cardiac myocytes change in cardiovascular diseases. Intracellular free magnesium (Mgi) inhibits L-type Ca2+ currents through CaV1.2 channels in cardiac myocytes, but the mechanism of this effect is unknown. We hypothesized that Mgi acts through the COOH-terminal EF-hand of CaV1.2. EF-hand mutants were engineered to have either decreased (D1546A/N/S/K) or increased (K1543D and K1539D) Mg2+ affinity. In whole-cell patch clamp experiments, increased Mgi reduced both Ba2+ and Ca2+ currents conducted by wild type (WT) CaV1.2 channels expressed in tsA-201 cells with similar affinity. Exposure of WT CaV1.2 to lower Mgi (0.26 mM) increased the amplitudes of Ba2+ currents 2.6 ± 0.4–fold without effects on the voltage dependence of activation and inactivation. In contrast, increasing Mgi to 2.4 or 7.2 mM reduced current amplitude to 0.5 ± 0.1 and 0.26 ± 0.05 of the control level at 0.8 mM Mgi. The effects of Mgi on peak Ba2+ currents were approximately fit by a single binding site model with an apparent Kd of 0.65 mM. The apparent Kd for this effect of Mgi was shifted ∼3.3- to 16.5-fold to higher concentration in D1546A/N/S mutants, with only small effects on the voltage dependence of activation and inactivation. Moreover, mutant D1546K was insensitive to Mgi up to 7.2 mM. In contrast to these results, peak Ba2+ currents through the K1543D mutant were inhibited by lower concentrations of Mgi compared with WT, consistent with approximately fourfold reduction in apparent Kd for Mgi, and inhibition of mutant K1539D by Mgi was also increased comparably. In addition to these effects, voltage-dependent inactivation of K1543D and K1539D was incomplete at positive membrane potentials when Mgi was reduced to 0.26 or 0.1 mM, respectively. These results support a novel mechanism linking the COOH-terminal EF-hand with modulation of CaV1.2 channels by Mgi. Our findings expand the repertoire of modulatory interactions taking place at the COOH terminus of CaV1.2 channels, and reveal a potentially important role of Mgi binding to the COOH-terminal EF-hand in regulating Ca2+ influx in physiological and pathophysiological states

Triassic alkaline magmatism of the Hawasina Nappes: Post-breakup melting of the Oman lithospheric mantle modified by the Permian Neotethyan Plume

International audienceMiddle to Late Triassic lavas were sampled within three tectonostratigraphic groups of the Hawasina Nappes in the Oman Mountains. They are predominantly alkali basalts and trachybasalts, associated with minor sub-alkaline basalts, trachyandesites, trachytes and rhyolites. Their major, trace elements and Nd-Pb isotopic compositions are very similar to those of the Permian plume-related high-Ti basalts which also occur in the Hawasina Nappes. The Triassic lavas derive from low-degree melting of an enriched OIB-type mantle source, characterized by εNdi = 0.3-5.3 and (206Pb/204Pb)i = 16.96-19.31 (for t = 230 My). With time, melting depths decreased from the garnet + spinel to the spinel lherzolite facies and the degree of melting increased. The oldest are distinguished from the others by unradiogenic Nd and Pb signatures, with εNdi = − 4.5 to − 1.2 and (206Pb/204Pb)i = 16.35-17.08, which we attribute to their contamination by Arabo-Nubian lower crust. The lavas likely derived from the Oman lithospheric mantle, the original DMM-HIMU signature of which was overprinted during its pervasive metasomatism by the Permian plume-related melts. We suggest that these lavas were emplaced during post-breakup decompression-triggered melting in the Middle Triassic during global kinematic reorganization of the Tethyan realm

Cooperative regulation of Cav1.2 channels by intracellular Mg2+, the proximal C-terminal EF-hand, and the distal C-terminal domain

L-type Ca2+ currents conducted by Cav1.2 channels initiate excitation–contraction coupling in cardiac myocytes. Intracellular Mg2+ (Mgi) inhibits the ionic current of Cav1.2 channels. Because Mgi is altered in ischemia and heart failure, its regulation of Cav1.2 channels is important in understanding cardiac pathophysiology. Here, we studied the effects of Mgi on voltage-dependent inactivation (VDI) of Cav1.2 channels using Na+ as permeant ion to eliminate the effects of permeant divalent cations that engage the Ca2+-dependent inactivation process. We confirmed that increased Mgi reduces peak ionic currents and increases VDI of Cav1.2 channels in ventricular myocytes and in transfected cells when measured with Na+ as permeant ion. The increased rate and extent of VDI caused by increased Mgi were substantially reduced by mutations of a cation-binding residue in the proximal C-terminal EF-hand, consistent with the conclusion that both reduction of peak currents and enhancement of VDI result from the binding of Mgi to the EF-hand (KD ≈ 0.9 mM) near the resting level of Mgi in ventricular myocytes. VDI was more rapid for L-type Ca2+ currents in ventricular myocytes than for Cav1.2 channels in transfected cells. Coexpression of Cavβ2b subunits and formation of an autoinhibitory complex of truncated Cav1.2 channels with noncovalently bound distal C-terminal domain (DCT) both increased VDI in transfected cells, indicating that the subunit structure of the Cav1.2 channel greatly influences its VDI. The effects of noncovalently bound DCT on peak current amplitude and VDI required Mgi binding to the proximal C-terminal EF-hand and were prevented by mutations of a key divalent cation-binding amino acid residue. Our results demonstrate cooperative regulation of peak current amplitude and VDI of Cav1.2 channels by Mgi, the proximal C-terminal EF-hand, and the DCT, and suggest that conformational changes that regulate VDI are propagated from the DCT through the proximal C-terminal EF-hand to the channel-gating mechanism

Radio sur fibre pour un réseau local domestique millimétrique

National audienceLe projet FUI ORIGIN (Optical-Radio Infrastructure for Gigabit/s Indoor Networks) adresse le marché du Réseau Local Domestique pour lequel il propose une nouvelle infrastructure à très haut débit associant un câblage à fibre optique avec une diffusion radio 60GHz. Les premiers tests de cette infrastructure ont donné des résultats probants : un lien Radio sur Fibre en fréquence intermédiaire étendant la portée d'une transmission radio millimétrique est ici proposé et caractérisé complètement en termes d'EVM. Ce concept est validé par l'utilisation de produits commerciaux Wireless HD. Les études se poursuivent pour intégrer les systèmes optique-microondes en utilisant des composants bas coûts et innovants, comme les phototransistors SiGe/Si et des VCSEL analogiques

Campagne océanographique FLUPAC à bord du N.O. l'ATALANTE 23 septembre au 29 octobre 1994. Recueil des données. Tome 1 : météo, courantologie, hydrologie, données de surface

La campagne FLUPAC du N.O. L'Atalante, qui s'est déroulée du 23 septembre au 29 octobre 1994, s'est placée dans le cadre du programme international JGOFS (JOINT GLOBAL OCEAN FLUX STUDY). Elle a comporté deux radiales et deux stations équatoriales de 6-7 jours. La première radiale, le long de 165°E, a parcouru la zone comprise entre 20°S et 6°N. La seconde s'est déroulée le long de l'équateur entre 167°E et 150°W. Les deux stations de longue durée ont eu lieu à O°-167°E et 0°-150°W. Elles ont été l'occasion d'études détaillées des flux impliqués dans le cycle du carbone de la couche superficielle (0-500 m). Le premier tome du recueil de données présente des résultats, sous forme de graphiques et de tableaux, des paramètres enregistrés en continu et de ceux de la sonde CTD. Les paramètres chimiques, la chlorophylle "a" et les observations en cytomètrie de flux obtenus sur l'eau de la "rosette" couplée à la sonde CTD, sont également présentés. (Résumé d'auteur

Hypovitaminosis D is associated with depression and anxiety in schizophrenia: results from the national FACE-SZ cohort. Running title: hypovitaminosis D, depression and anxiety in schizophrenia

International audienceBackground. Guidelines have been edited for the treatment of schizophrenia (SZ) and bipola

Immune checkpoint inhibitor therapy and outcomes from SARS-CoV-2 infection in patients with cancer: a joint analysis of OnCovid and ESMO-CoCARE registries

BackgroundAs management and prevention strategies against COVID-19 evolve, it is still uncertain whether prior exposure to immune checkpoint inhibitors (ICIs) affects COVID-19 severity in patients with cancer.MethodsIn a joint analysis of ICI recipients from OnCovid (NCT04393974) and European Society for Medical Oncology (ESMO) CoCARE registries, we assessed severity and mortality from SARS-CoV-2 in vaccinated and unvaccinated patients with cancer and explored whether prior immune-related adverse events (irAEs) influenced outcome from COVID-19.FindingsThe study population consisted of 240 patients diagnosed with COVID-19 between January 2020 and February 2022 exposed to ICI within 3 months prior to COVID-19 diagnosis, with a 30-day case fatality rate (CFR30) of 23.6% (95% CI 17.8 to 30.7%). Overall, 42 (17.5%) were fully vaccinated prior to COVID-19 and experienced decreased CFR30 (4.8% vs 28.1%, p=0.0009), hospitalization rate (27.5% vs 63.2%, p<0.0001), requirement of oxygen therapy (15.8% vs 41.5%, p=0.0030), COVID-19 complication rate (11.9% vs 34.6%, p=0.0040), with a reduced need for COVID-19-specific therapy (26.3% vs 57.9%, p=0.0004) compared with unvaccinated patients. Inverse probability of treatment weighting (IPTW)-fitted multivariable analysis, following a clustered-robust correction for the data source (OnCovid vs ESMO CoCARE), confirmed that vaccinated patients experienced a decreased risk of death at 30 days (adjusted OR, aOR 0.08, 95% CI 0.01 to 0.69).Overall, 38 patients (15.8%) experienced at least one irAE of any grade at any time prior to COVID-19, at a median time of 3.2 months (range 0.13-48.7) from COVID-19 diagnosis. IrAEs occurred independently of baseline characteristics except for primary tumor (p=0.0373) and were associated with a significantly decreased CFR30 (10.8% vs 26.0%, p=0.0462) additionally confirmed by the IPTW-fitted multivariable analysis (aOR 0.47, 95% CI 0.33 to 0.67). Patients who experienced irAEs also presented a higher median absolute lymphocyte count at COVID-19 (1.4 vs 0.8 10(9) cells/L, p=0.0098).ConclusionAnti-SARS-CoV-2 vaccination reduces morbidity and mortality from COVID-19 in ICI recipients. History of irAEs might identify patients with pre-existing protection from COVID-19, warranting further investigation of adaptive immune determinants of protection from SARS-CoV-2