Cx43 can form functional channels at the nuclear envelope and modulate gene expression in cardiac cells

Conexina 43; Expresión génica; Translocación nuclearConnexina 43; Expressió gènica; Translocació nuclearConnexin 43; Gene expression; Nuclear translocationClassically associated with gap junction-mediated intercellular communication, connexin43 (Cx43) is increasingly recognized to possess non-canonical biological functions, including gene expression regulation. However, the mechanisms governing the localization and role played by Cx43 in the nucleus, namely in transcription modulation, remain unknown. Using comprehensive and complementary approaches encompassing biochemical assays, super-resolution and immunogold transmission electron microscopy, we demonstrate that Cx43 localizes to the nuclear envelope of different cell types and in cardiac tissue. We show that translocation of Cx43 to the nucleus relies on Importin-β, and that Cx43 significantly impacts the cellular transcriptome, likely by interacting with transcriptional regulators. In vitro patch-clamp recordings from HEK293 and adult primary cardiomyocytes demonstrate that Cx43 forms active channels at the nuclear envelope, providing evidence that Cx43 can participate in nucleocytoplasmic shuttling of small molecules. The accumulation of nuclear Cx43 during myogenic differentiation of cardiomyoblasts is suggested to modulate expression of genes implicated in this process. Altogether, our study provides new evidence for further defining the biological roles of nuclear Cx43, namely in cardiac pathophysiology.This work was supported by the European Regional Development Fund (ERDF) through the Operational Program for Competitiveness Factors (COMPETE) under the projects HealthyAging2020 CENTRO-01-0145-FEDER-000012-N2323, CENTRO-01-0145-FEDER-032179, CENTRO-01-0145-FEDER-032414, EXPL/MED-OUT/0590/2021, UIDB/04539/2020 and PPBI-Portuguese Platform of BioImaging (POCI-01-0145-FEDER-022122). This work was also supported by the European Union's Horizon 2020 research and innovation programme under grant agreement MIA-Portugal no. 857524 and the Comissão de Coordenação da Região Centro (CCDRC) through the Centro2020 Program. T.A. acknowledges funding from Instituto de Salud Carlos III, grant PI16/00772 co-financed by the ERDF, and Fundación Científica Asociación Española Contra el Cáncer (IDEAS20039AASE). This work used the platforms of the Grenoble Instruct-ERIC center (ISBG; UAR 3518 CNRS-CEA-UGA-EMBL) within the Grenoble Partnership for Structural Biology (PSB), supported by FRISBI (ANR-10-INBS-0005-02) and GRAL, financed within the University Grenoble Alpes graduate school (Ecoles Universitaires de Recherche) CBH-EUR-GS (ANR-17-EURE-0003), and the Microscopy and Bioimaging Lab (iLAB) at the Faculty of Medicine of the University of Coimbra (Coimbra, Portugal). The IBS Electron Microscope facility is supported by the Auvergne Rhône-Alpes Region, the Fonds Feder, the Fondation pour la Recherche Médicale and GIS-IBiSA. Super-resolution microscopy experiments benefited from access to CBI/IGBMC (Illkirch, France) and were supported by FRISBI (ANR-10-INBS-0005). Financial support was provided by Instruct-ERIC (PID 14677)

Microphysical and thermodynamic phase analyses of Arctic low-level clouds measured above the sea ice and the open ocean in spring and summer

Abstract. Airborne in situ cloud measurements were carried out over the northern Fram Strait between Greenland and Svalbard in spring 2019 and summer 2020. In total, 811 min of low-level cloud observations were performed during 20 research flights above the sea ice and the open Arctic ocean with the Polar 5 research aircraft of the Alfred Wegener Institute. Here, we combine the comprehensive in situ cloud data to investigate the distributions of particle number concentration N, effective diameter Deff, and cloud water content CWC (liquid and ice) of Arctic clouds below 500 m altitude, measured at latitudes between 76 and 83∘ N. We developed a method to quantitatively derive the occurrence probability of their thermodynamic phase from the combination of microphysical cloud probe and Polar Nephelometer data. Finally, we assess changes in cloud microphysics and cloud phase related to ambient meteorological conditions in spring and summer and address effects of the sea ice and open-ocean surface conditions. We find median N from 0.2 to 51.7 cm−3 and about 2 orders of magnitude higher N for mainly liquid clouds in summer compared to ice and mixed-phase clouds measured in spring. A southerly flow from the sea ice in cold air outbreaks dominates cloud formation processes at temperatures mostly below −10 ∘C in spring, while northerly warm air intrusions favor the formation of liquid clouds at warmer temperatures in summer. Our results show slightly higher N in clouds over the sea ice compared to the open ocean, indicating enhanced cloud formation processes over the sea ice. The median CWC is higher in summer (0.16 g m−3) than in spring (0.06 g m−3), as this is dominated by the available atmospheric water content and the temperatures at cloud formation level. We find large differences in the particle sizes in spring and summer and an impact of the surface conditions, which modifies the heat and moisture fluxes in the boundary layer. By combining microphysical cloud data with thermodynamic phase information from the Polar Nephelometer, we find mixed-phase clouds to be the dominant thermodynamic cloud phase in spring, with a frequency of occurrence of 61 % over the sea ice and 66 % over the ocean. Pure ice clouds exist almost exclusively over the open ocean in spring, and in summer the cloud particles are most likely in the liquid water state. The comprehensive low-level cloud data set will help us to better understand the role of clouds and their thermodynamic phase in the Arctic radiation budget and to assess the performance of global climate models in a region of the world with the strongest anthropogenic climate change. </jats:p

Investigating an indirect aviation effect on mid-latitude cirrus clouds – linking lidar-derived optical properties to in situ measurements

Aviation has a large impact on the Earth's atmosphere and climate by various processes. Line-shaped contrails and contrail cirrus clouds lead to changes in the natural cirrus cloud cover and have a major contribution to the effective radiative forcing from aviation. In addition, aviation-induced aerosols might also change the microphysical properties and optical properties of naturally formed cirrus clouds. Latter aerosol–cloud interactions show large differences in the resulting effective radiative forcing, and our understanding on how aviation-induced aerosols affect cirrus cloud properties is still poor. Up to now, observations of this aviation-induced aerosol effect have been rare. In this study, we use combined airborne lidar and in situ ice cloud measurements to investigate differences in the microphysical and optical properties of naturally formed cirrus clouds, which formed in regions that are highly affected by aviation-induced aerosol emissions and, of those, which formed in regions rather unaffected by aviation. Urbanek et al. (2018) showed that those cirrus clouds, which are more affected by aviation-induced soot emission, are characterized by larger values of the particle linear depolarization ratio (PLDR). In this follow-on study we relate collocated lidar measurements performed aboard HALO during the ML-CIRRUS mission of the particle linear depolarization ratio with in situ cloud probe measurements of the number concentration and effective diameter of the ice particles. In situ measurements for both cloud types (high-PLDR-mode – aviation-affected – and low-PLDR-mode – pristine – cirrus) can be reliably compared in a temperature range between 210 and 215 K. Within this temperature range we find that high-PLDR-mode cirrus clouds tend to show larger effective ice particle diameters with a median value of 61.4 compared to 50.7 µm for low-PLDR-mode pristine cirrus clouds. Larger effective ice particles in aviation-influenced (high-PLDR-mode) cirrus are connected to lower ice particle number concentration with a median value of 0.05 compared to 0.11 cm−3 (low-PLDR-mode), which evolved in more pristine regions with only little impact from aviation. We suspect that a suppression of homogeneous ice formation by the heterogeneously freezing soot aerosol particles included in the areas affected by air traffic is the cause of the reduced ice crystal concentrations.</p

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

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

The North Atlantic Waveguide and Downstream Impact Experiment

The North Atlantic Waveguide and Downstream Impact Experiment (NAWDEX) explored the impact of diabatic processes on disturbances of the jet stream and their influence on downstream high-impact weather through the deployment of four research aircraft, each with a sophisticated set of remote sensing and in situ instruments, and coordinated with a suite of ground-based measurements. A total of 49 research flights were performed, including, for the first time, coordinated flights of the four aircraft: the German High Altitude and Long Range Research Aircraft (HALO), the Deutsches Zentrum für Luft- und Raumfahrt (DLR) Dassault Falcon 20, the French Service des Avions Français Instrumentés pour la Recherche en Environnement (SAFIRE) Falcon 20, and the British Facility for Airborne Atmospheric Measurements (FAAM) BAe 146. The observation period from 17 September to 22 October 2016 with frequently occurring extratropical and tropical cyclones was ideal for investigating midlatitude weather over the North Atlantic. NAWDEX featured three sequences of upstream triggers of waveguide disturbances, as well as their dynamic interaction with the jet stream, subsequent development, and eventual downstream weather impact on Europe. Examples are presented to highlight the wealth of phenomena that were sampled, the comprehensive coverage, and the multifaceted nature of the measurements. This unique dataset forms the basis for future case studies and detailed evaluations of weather and climate predictions to improve our understanding of diabatic influences on Rossby waves and the downstream impacts of weather systems affecting Europe

Aircraft-based observations of isoprene-epoxydiol-derived secondary organic aerosol (IEPOX-SOA) in the tropical upper troposphere over the Amazon region

During the ACRIDICON-CHUVA field project (September-October 2014;based in Manaus, Brazil) aircraft-based in situ measurements of aerosol chemical composition were conducted in the tropical troposphere over the Amazon using the High Altitude and Long Range Research Aircraft (HALO), covering altitudes from the boundary layer (BL) height up to 14.4 km. The submicron non-refractory aerosol was characterized by flash-vaporization/electron impact-ionization aerosol particle mass spectrometry. The results show that significant secondary organic aerosol (SOA) formation by isoprene oxidation products occurs in the upper troposphere (UT), leading to increased organic aerosol mass concentrations above 10 km altitude. The median organic mass concentrations in the UT above 10 km range between 1.0 and 2.5 mu g m(-3) (referring to standard temperature and pressure;STP) with interquartile ranges of 0.6 to 3.2 mu g m(-3) (STP), representing 78 % of the total submicron non-refractory aerosol particle mass. The presence of isoprene-epoxydiol-derived secondary organic aerosol (IEPOX-SOA) was confirmed by marker peaks in the mass spectra. We estimate the contribution of IEPOX-SOA to the total organic aerosol in the UT to be about 20 %. After isoprene emission from vegetation, oxidation processes occur at low altitudes and/or during transport to higher altitudes, which may lead to the formation of IEPOX (one oxidation product of isoprene). Reactive uptake or condensation of IEPOX on preexisting particles leads to IEPDX-SOA formation and subsequently increasing organic mass in the UT. This organic mass increase was accompanied by an increase in the nitrate mass concentrations, most likely due to NOx production by lightning. Analysis of the ion ratio of NO+ to NO2+ indicated that nitrate in the UT exists mainly in the form of organic nitrate. IEPOX-SOA and organic nitrates are coincident with each other, indicating that IEPDX-SOA forms in the UT either on acidic nitrate particles forming organic nitrates derived from IEPDX or on already neutralized organic nitrate aerosol particles