Leaky ryanodine receptors contribute to diaphragmatic weakness during mechanical ventilation

Ventilator-induced diaphragmatic dysfunction (VIDD) refers to the diaphragm muscle weakness that occurs following prolonged controlled mechanical ventilation (MV). The presence of VIDD impedes recovery from respiratory failure. However, the pathophysiological mechanisms accounting for VIDD are still not fully understood. Here, we show in human subjects and a mouse model of VIDD that MV is associated with rapid remodeling of the sarcoplasmic reticulum (SR) Ca2+ release channel/ryanodine receptor (RyR1) in the diaphragm. The RyR1 macromolecular complex was oxidized, S-nitrosylated, Ser-2844 phosphorylated, and depleted of the stabilizing subunit calstabin1, following MV. These posttranslational modifications of RyR1 were mediated by both oxidative stress mediated by MV and stimulation of adrenergic signaling resulting from the anesthesia. We demonstrate in the murine model that such abnormal resting SR Ca2+ leak resulted in reduced contractile function and muscle fiber atrophy for longer duration of MV. Treatment with β-adrenergic antagonists or with S107, a small molecule drug that stabilizes the RyR1–calstabin1 interaction, prevented VIDD. Diaphragmatic dysfunction is common in MV patients and is a major cause of failure to wean patients from ventilator support. This study provides the first evidence to our knowledge of RyR1 alterations as a proximal mechanism underlying VIDD (i.e., loss of function, muscle atrophy) and identifies RyR1 as a potential target for therapeutic intervention

Concept and Design of Martian Far-IR ORE Spectrometer (MIRORES)

Sulfide ores are a major source of noble (Au, Ag, and Pt) and base (Cu, Pb, Zn, Sn, Co, Ni, etc.) metals and will, therefore, be vital for the self-sustainment of future Mars colonies. Martian meteorites are rich in sulfides, which is reflected in recent findings for surface Martian rocks analyzed by the Spirit and Curiosity rovers. However, the only high-resolution (18 m/pixel) infrared (IR) spectrometer orbiting Mars, the Compact Reconnaissance Imaging Spectrometer for Mars (CRISM), onboard the Mars Reconnaissance Orbiter (MRO), is not well-suited for detecting sulfides on the Martian surface. Spectral interference with silicates impedes sulfide detection in the 0.4–3.9 μm CRISM range. In contrast, at least three common hydrothermal sulfides on Earth and Mars (pyrite, chalcopyrite, marcasite) have prominent absorption peaks in a narrow far-IR (FIR) wavelength range of 23–28 μm. Identifying the global distribution and chemical composition of sulfide ore deposits would help in choosing useful targets for future Mars exploration missions. Therefore, we have designed a new instrument suitable for measuring sulfides in the FIR range called the Martian far-IR Ore Spectrometer (MIRORES). MIRORES will measure radiation in six narrow bands (~0.3 µm in width), including three bands centered on the sulfide absorption bands (23.2, 24.3 and 27.6 µm), two reference bands (21.5 and 26.1) and one band for clinopyroxene interference (29.0 µm). Focusing on sulfides only will make it possible to adapt the instrument size (32 × 32 × 42 cm) and mass (<10 kg) to common microsatellite requirements. The biggest challenges related to this design are: (1) the small field of view conditioned by the high resolution required for such a study (<20 m/pixel), which, in limited space, can only be achieved by the use of the Cassegrain optical system; and (2) a relatively stable measurement temperature to maintain radiometric accuracy and enable precise calibration

KORTES Mission for Solar Activity Monitoring Onboard International Space Station

peer reviewedWe present a description of the recent advances in the development of the KORTES assembly—the first solar oriented mission designed for the Russian segment of the International Space Station. KORTES consists of several imaging and spectroscopic instruments collectively covering a wide spectral range extending from extreme ultraviolet (EUV) wavelengths to X-rays. The EUV telescopes inside KORTES will trace the origin and dynamics of various solar phenomena, e.g., flares, CMEs, eruptions etc. EUV spectra provided by grazing-incidence spectroheliographs will enable precise DEM-diagnostics during these events. The monochromatic X-ray imager will observe the formation of hot plasma in active regions and outside them. The SolpeX module inside KORTES will offer an opportunity to measure fluxes, Doppler shifts and polarization of soft X-ray emission both in lines and continuum. SolpeX observations will contribute to studies of particle beams and chromospheric evaporation. The instrumentation of KORTES will employ a variety of novel multilayer and crystal optics. The deployment of KORTES is planned for 2024

Rapid Onset of Specific Diaphragm Weakness in a Healthy Murine Model of Ventilator-induced Diaphragmatic Dysfunction

International audienceBackground: Controlled mechanical ventilation is associated with ventilator-induced diaphragmatic dysfunction, which impedes weaning from mechanical ventilation. To design future clinical trials in humans, a better understanding of the molecular mechanisms using knockout models, which exist only in the mouse, is needed. The aims of this study were to ascertain the feasibility of developing a murine model of ventilator-induced diaphragmatic dysfunction and to determine whether atrophy, sarcolemmal injury, and the main proteolysis systems are activated under these conditions. Methods: Healthy adult male C57/BL6 mice were assigned to three groups: (1) mechanical ventilation with end-expiratory positive pressure of 2-4 cm H2O for 6 h (n = 6), (2) spontaneous breathing with continuous positive airway pressure of 2-4 cm H2O for 6 h (n = 6), and (3) controls with no specific intervention (n = 6). Airway pressure and hemodynamic parameters were monitored. Upon euthanasia, arterial blood gases and isometric contractile properties of the diaphragm and extensor digitorum longus were evaluated. Histology and immunoblotting for the main proteolysis pathways were performed. Results: Hemodynamic parameters and arterial blood gases were comparable between groups and within normal physiologic ranges. Diaphragmatic but not extensor digitorum longus force production declined in the mechanical ventilation group (maximal force decreased by approximately 40%) compared with the control and continuous positive airway pressure groups. No histologic difference was found between groups. In opposition with the calpains, caspase 3 was activated in the mechanical ventilation group. Conclusion: Controlled mechanical ventilation for 6 h in the mouse is associated with significant diaphragmatic but not limb muscle weakness without atrophy or sarcolemmal injury and activates proteolysis