Cardiac Glycosides Induce Cell Death in Human Cells by Inhibiting General Protein Synthesis

BACKGROUND: Cardiac glycosides are Na(+)/K(+)-pump inhibitors widely used to treat heart failure. They are also highly cytotoxic, and studies have suggested specific anti-tumor activity leading to current clinical trials in cancer patients. However, a definitive demonstration of this putative anti-cancer activity and the underlying molecular mechanism has remained elusive. METHODOLOGY/PRINCIPAL FINDINGS: Using an unbiased transcriptomics approach, we found that cardiac glycosides inhibit general protein synthesis. Protein synthesis inhibition and cytotoxicity were not specific for cancer cells as they were observed in both primary and cancer cell lines. These effects were dependent on the Na(+)/K(+)-pump as they were rescued by expression of a cardiac glycoside-resistant Na(+)/K(+)-pump. Unlike human cells, rodent cells are largely resistant to cardiac glycosides in vitro and mice were found to tolerate extremely high levels. CONCLUSIONS/SIGNIFICANCE: The physiological difference between human and mouse explains the previously observed sensitivity of human cancer cells in mouse xenograft experiments. Thus, published mouse xenograft models used to support anti-tumor activity for these drugs require reevaluation. Our finding that cardiac glycosides inhibit protein synthesis provides a mechanism for the cytotoxicity of CGs and raises concerns about ongoing clinical trials to test CGs as anti-cancer agents in humans

Understanding the atmospheric properties and chemical composition of the ultra-hot Jupiter HAT-P-7b : I. Cloud and chemistry mapping

Context . Of the presently known ≈3900 exoplanets, sparse spectral observations are available for ≈100. Ultra-hot Jupiters have recently attracted interest from observers and theoreticians alike, as they provide observationally accessible test cases. Confronting detailed theoretical models with observations is of preeminent importance in preparation for upcoming space-based telescopes. Aims . We aim to study cloud formation on the ultra-hot Jupiter HAT-P-7b, the resulting composition of the local gas phase, and how their global changes affect wavelength-dependent observations utilised to derive fundamental properties of the planet. Methods . We apply a hierarchical modelling approach as a virtual laboratory to study cloud formation and gas-phase chemistry. We utilise 97 vertical 1D profiles of a 3D GCM for HAT-P-7b to evaluate our kinetic cloud formation model consistently with the local equilibrium gas-phase composition. We use maps and slice views to provide a global understanding of the cloud and gas chemistry. Results . The day/night temperature difference on HAT-P-7b (ΔT ≈ 2500 K) causes clouds to form on the nightside (dominated by H2/He) while the dayside (dominated by H/He) retains cloud-free equatorial regions. The cloud particles vary in composition and size throughout the vertical extension of the cloud, but also globally. TiO2[s]/Al2O3[s]/CaTiO3[s]-particles of cm-sized radii occur in the higher dayside-latitudes, resulting in a dayside dominated by gas-phase opacity. The opacity on the nightside, however, is dominated by 0.01…0.1μm particles made of a material mix dominated by silicates. The gas pressure at which the atmosphere becomes optically thick is ~10−4 bar in cloudy regions, and ~0.1 bar in cloud-free regions. Conclusions . HAT-P-7b features strong morning/evening terminator asymmetries, providing an example of patchy clouds and azimuthally-inhomogeneous chemistry. Variable terminator properties may be accessible by ingress/egress transmission photometry (e.g., CHEOPS and PLATO) or spectroscopy. The large temperature differences of ≈2500 K result in an increasing geometrical extension from the night- to the dayside. The H2O abundance at the terminator changes by <1 dex with altitude and ≲0.3 dex (a factor of 2) across the terminator for a given pressure, indicating that H2O abundances derived from transmission spectra can be representative of the well-mixed metallicity at P ≳ 10 bar. We suggest the atmospheric C/O as an important tool to trace the presence and location of clouds in exoplanet atmospheres. The atmospheric C/O can be sub- and supersolar due to cloud formation. Phase curve variability of HAT-P-7b is unlikely to be caused by dayside clouds.Publisher PDFPeer reviewe

Identification of carbon dioxide in an exoplanet atmosphere

Carbon dioxide (CO2) is a key chemical species that is found in a wide range of planetary atmospheres. In the context of exoplanets, CO2 is an indicator of the metal enrichment (that is, elements heavier than helium, also called 'metallicity')1-3, and thus the formation processes of the primary atmospheres of hot gas giants4-6. It is also one of the most promising species to detect in the secondary atmospheres of terrestrial exoplanets7-9. Previous photometric measurements of transiting planets with the Spitzer Space Telescope have given hints of the presence of CO2, but have not yielded definitive detections owing to the lack of unambiguous spectroscopic identification10-12. Here we present the detection of CO2 in the atmosphere of the gas giant exoplanet WASP-39b from transmission spectroscopy observations obtained with&nbsp;JWST as part of the Early Release Science programme13,14. The data used in this study span 3.0-5.5 micrometres in wavelength and show a prominent CO2 absorption feature at 4.3 micrometres (26-sigma significance). The overall spectrum is well matched by one-dimensional, ten-times solar metallicity models that assume radiative-convective-thermochemical equilibrium and have moderate cloud opacity. These models predict that the atmosphere should have water, carbon monoxide and hydrogen sulfide in addition to CO2, but little methane. Furthermore, we also tentatively detect a small absorption feature near 4.0 micrometres that is not reproduced by these models

Nightside clouds and disequilibrium chemistry on the hot Jupiter WASP-43b

Hot Jupiters are among the best-studied exoplanets, but it is still poorly understood how their chemical composition and cloud properties vary with longitude. Theoretical models predict that clouds may condense on the nightside and that molecular abundances can be driven out of equilibrium by zonal winds. Here we report a phase-resolved emission spectrum of the hot Jupiter WASP-43b measured from 5-12 μm with JWST's Mid-Infrared Instrument (MIRI). The spectra reveal a large day-night temperature contrast (with average brightness temperatures of 1524±35 and 863±23 Kelvin, respectively) and evidence for water absorption at all orbital phases. Comparisons with three-dimensional atmospheric models show that both the phase curve shape and emission spectra strongly suggest the presence of nightside clouds which become optically thick to thermal emission at pressures greater than ~100 mbar. The dayside is consistent with a cloudless atmosphere above the mid-infrared photosphere. Contrary to expectations from equilibrium chemistry but consistent with disequilibrium kinetics models, methane is not detected on the nightside (2σ upper limit of 1-6 parts per million, depending on model assumptions)

Nightside clouds and disequilibrium chemistry on the hot Jupiter WASP-43b

Hot Jupiters are among the best-studied exoplanets, but it is still poorly understood how their chemical composition and cloud properties vary with longitude. Theoretical models predict that clouds may condense on the nightside and that molecular abundances can be driven out of equilibrium by zonal winds. Here we report a phase-resolved emission spectrum of the hot Jupiter WASP-43b measured from 5 μm to 12 μm with the JWST’s Mid-Infrared Instrument. The spectra reveal a large day–night temperature contrast (with average brightness temperatures of 1,524 ± 35 K and 863 ± 23 K, respectively) and evidence for water absorption at all orbital phases. Comparisons with three-dimensional atmospheric models show that both the phase-curve shape and emission spectra strongly suggest the presence of nightside clouds that become optically thick to thermal emission at pressures greater than ~100 mbar. The dayside is consistent with a cloudless atmosphere above the mid-infrared photosphere. Contrary to expectations from equilibrium chemistry but consistent with disequilibrium kinetics models, methane is not detected on the nightside (2σ upper limit of 1–6 ppm, depending on model assumptions). Our results provide strong evidence that the atmosphere of WASP-43b is shaped by disequilibrium processes and provide new insights into the properties of the planet’s nightside clouds. However, the remaining discrepancies between our observations and our predictive atmospheric models emphasize the importance of further exploring the effects of clouds and disequilibrium chemistry in numerical models.Peer reviewe

Identification of carbon dioxide in an exoplanet atmosphere

Carbon dioxide (CO2) is a key chemical species that is found in a wide range of planetary atmospheres. In the context of exoplanets, CO2 is an indicator of the metal enrichment (that is, elements heavier than helium, also called ‘metallicity’), and thus the formation processes of the primary atmospheres of hot gas giants. It is also one of the most promising species to detect in the secondary atmospheres of terrestrial exoplanets. Previous photometric measurements of transiting planets with the Spitzer Space Telescope have given hints of the presence of CO2, but have not yielded definitive detections owing to the lack of unambiguous spectroscopic identification. Here we present the detection of CO2 in the atmosphere of the gas giant exoplanet WASP-39b from transmission spectroscopy observations obtained with JWST as part of the Early Release Science programme. The data used in this study span 3.0–5.5 micrometres in wavelength and show a prominent CO2 absorption feature at 4.3 micrometres (26-sigma significance). The overall spectrum is well matched by one-dimensional, ten-times solar metallicity models that assume radiative–convective–thermochemical equilibrium and have moderate cloud opacity. These models predict that the atmosphere should have water, carbon monoxide and hydrogen sulfide in addition to CO2, but little methane. Furthermore, we also tentatively detect a small absorption feature near 4.0 micrometres that is not reproduced by these models

Chemical and (Photo)-Catalytical Transformations in Photonic Crystal Fibers

The concept of employing photonic crystal fibers for chemical and (photo)-catalytical transformations is presented. These optofluidic microdevices represent a versatile platform where light and fluids can interact for spectroscopic or photoactivation purposes. The use of photonic crystal fibers in chemistry and sensing is reviewed and recent applications as catalytic microreactors are presented. Results on homogeneous catalysis and the immobilization of homogeneous and heterogeneous catalysts in the fiber channels are discussed. The examples demonstrate that combining catalysis and the excellent light guidance of photonic crystal fibers provides unique features for example, for photocatalytic activation and quantitative photospectroscopic reaction analysis

Growth and electronic structure of nitrogen doped graphene on Ni 111

We report on experimental and theoretical investigations of nitrogen-doped graphene. The incorporation of nitrogen was achieved during chemical-vapor deposition on Ni(111) using pyridine as a precursor. The obtained graphene layers were investigated using photoelectron spectroscopy. By studying C 1s and N 1s core levels, we show that the nitrogen content is influenced by the growth temperature and determine the atomic arrangement of the nitrogen atoms. Valence-band photoelectron spectra show that the incorporation of nitrogen leads to a broadening of the photoemission lines and a shift of the π band. Density functional calculations for two possible geometric arrangements, the substitution of carbon atoms by nitrogen and vacancies in the graphene sheet with pyridinic nitrogen at the edges, reveal that the two arrangements have opposite effects on the band structure. For the present experimental approach, vacancies with pyridinic nitrogen are dominant. In the latter case the vacancies generated by the nitrogen doping, not the nitrogen itself, have the main effect on the band structure. By intercalating gold between the doped graphene layer and the Ni(111) substrate electronic decoupling is achieved. After intercalation the doping remains