No detection of methane on Mars from early ExoMars Trace Gas Orbiter observations.

The detection of methane on Mars has been interpreted as indicating that geochemical or biotic activities could persist on Mars today1. A number of different measurements of methane show evidence of transient, locally elevated methane concentrations and seasonal variations in background methane concentrations2-5. These measurements, however, are difficult to reconcile with our current understanding of the chemistry and physics of the Martian atmosphere6,7, which-given methane's lifetime of several centuries-predicts an even, well mixed distribution of methane1,6,8. Here we report highly sensitive measurements of the atmosphere of Mars in an attempt to detect methane, using the ACS and NOMAD instruments onboard the ESA-Roscosmos ExoMars Trace Gas Orbiter from April to August 2018. We did not detect any methane over a range of latitudes in both hemispheres, obtaining an upper limit for methane of about 0.05 parts per billion by volume, which is 10 to 100 times lower than previously reported positive detections2,4. We suggest that reconciliation between the present findings and the background methane concentrations found in the Gale crater4 would require an unknown process that can rapidly remove or sequester methane from the lower atmosphere before it spreads globally.

Publisher Correction: No detection of methane on Mars from early ExoMars Trace Gas Orbiter observations.

The surname of author Cathy Quantin-Nataf was misspelled 'Quantin-Nata', authors Ehouarn Millour and Roland Young were missing from the ACS and NOMAD Science Teams list, and minor changes have been made to the author and affiliation lists; see accompanying Amendment. These errors have been corrected online.

Martian dust storm impact on atmospheric H2O and D/H observed by ExoMars Trace Gas Orbiter.

Global dust storms on Mars are rare1,2 but can affect the Martian atmosphere for several months. They can cause changes in atmospheric dynamics and inflation of the atmosphere3, primarily owing to solar heating of the dust3. In turn, changes in atmospheric dynamics can affect the distribution of atmospheric water vapour, with potential implications for the atmospheric photochemistry and climate on Mars4. Recent observations of the water vapour abundance in the Martian atmosphere during dust storm conditions revealed a high-altitude increase in atmospheric water vapour that was more pronounced at high northern latitudes5,6, as well as a decrease in the water column at low latitudes7,8. Here we present concurrent, high-resolution measurements of dust, water and semiheavy water (HDO) at the onset of a global dust storm, obtained by the NOMAD and ACS instruments onboard the ExoMars Trace Gas Orbiter. We report the vertical distribution of the HDO/H2O ratio (D/H) from the planetary boundary layer up to an altitude of 80 kilometres. Our findings suggest that before the onset of the dust storm, HDO abundances were reduced to levels below detectability at altitudes above 40 kilometres. This decrease in HDO coincided with the presence of water-ice clouds. During the storm, an increase in the abundance of H2O and HDO was observed at altitudes between 40 and 80 kilometres. We propose that these increased abundances may be the result of warmer temperatures during the dust storm causing stronger atmospheric circulation and preventing ice cloud formation, which may confine water vapour to lower altitudes through gravitational fall and subsequent sublimation of ice crystals3. The observed changes in H2O and HDO abundance occurred within a few days during the development of the dust storm, suggesting a fast impact of dust storms on the Martian atmosphere.

Publisher Correction: Martian dust storm impact on atmospheric H2O and D/H observed by ExoMars Trace Gas Orbiter.

The surname of author Cathy Quantin-Nataf was misspelled 'Quantin-Nata' , authors Ehouarn Millour and Roland Young were missing from the ACS Science Team list, and minor changes have been made to the author and affiliation lists; see accompanying Amendment. These errors have been corrected online.

Assignment of the methanol OH-stretch overtone spectrum using the pattern recognition method.

We present the measurement and analysis of the 2OH stretching band of methanol between 7165 cm-1 and 7230 cm-1 cooled down to 26 ± 12 K in a buffer gas cooling experiment. Measurements were performed with a cavity ring-down spectrometer having a detection limit αmin = 2 × 10-10 cm-1. A total of 350 rovibrational transitions were assigned and 62 rovibrational transitions were tentatively assigned. This assignment was performed using the pattern recognition method developed by Rakvoský et al. [Phys. Chem. Chem. Phys., 2021, 23, 20193-20200]. In this work, we extended their method by using information on the relative intensities of the transitions to add one criterion to the validation of the assignments, allowing us to firmly assign 188 additional rovibrational transitions and to tentatively assign 14 more compared to the ir work.

Improved algorithm for the transmittance estimation of spectra obtained with SOIR/Venus Express.

The Solar Occultation in the InfraRed (SOIR) instrument onboard the ESA Venus Express spacecraft, an infrared spectrometer sensitive from 2.2 to 4.3 µm, probed the atmosphere of Venus from June 2006 until December 2014. During this time, it performed more than 750 solar occultations of the Venus mesosphere and lower thermosphere. A new procedure has been developed for the estimation of the transmittance in order to decrease the number of rejected spectra, to check that the treated spectra are well calibrated, and to improve the quality of the calibrated spectra by reducing the noise and accurately normalizing it to the solar spectrum.

Optical and radiometric models of the NOMAD instrument part I: the UVIS channel.

The NOMAD instrument has been designed to best fulfil the science objectives of the ExoMars Trace Gas Orbiter mission that will be launched in 2016. The instrument is a combination of three channels that cover the UV, visible and IR spectral ranges and can perform solar occultation, nadir and limb observations. In this series of two papers, we present the optical models representing the three channels of the instrument and use them to determine signal to noise levels for different observation modes and Martian conditions. In this first part, we focus on the UVIS channel, which will sound the Martian atmosphere using nadir and solar occultation viewing modes, covering the 200-650nm spectral range. High SNR levels (>1000) can easily be reached for wavelengths higher than 300nm both in solar occultation and nadir modes when considering binning. Below 300nm SNR are lower primarily because of the lower signal and the impact of atmospheric absorption.

Possible Effects of Volcanic Eruptions on the Modern Atmosphere of Venus.

This work reviews possible signatures and potential detectability of present-day volcanically emitted material in the atmosphere of Venus. We first discuss the expected composition of volcanic gases at present time, addressing how this is related to mantle composition and atmospheric pressure. Sulfur dioxide, often used as a marker of volcanic activity in Earth's atmosphere, has been observed since late 1970s to exhibit variability at the Venus' cloud tops at time scales from hours to decades; however, this variability may be associated with solely atmospheric processes. Water vapor is identified as a particularly valuable tracer for volcanic plumes because it can be mapped from orbit at three different tropospheric altitude ranges, and because of its apparent low background variability. We note that volcanic gas plumes could be either enhanced or depleted in water vapor compared to the background atmosphere, depending on magmatic volatile composition. Non-gaseous components of volcanic plumes, such as ash grains and/or cloud aerosol particles, are another investigation target of orbital and in situ measurements. We discuss expectations of in situ and remote measurements of volcanic plumes in the atmosphere with particular focus on the upcoming DAVINCI, EnVision and VERITAS missions, as well as possible future missions.

Improved calibration of SOIR/Venus Express spectra.

The SOIR instrument on board the ESA Venus Express mission has been operational since the insertion of the satellite around Venus in April 2006. Since then, it has delivered high quality IR solar occultation spectra of the atmosphere of Venus. The different steps from raw spectra to archived data are described and explained in detail here. These consist of corrections for the dark current and for the non-linearity of the detector; removing bad pixels, as well as deriving noise. The spectral calibration procedure is described, along with all ancillary data necessary for the understanding and interpretation of the SOIR data. These include the full characterization of the AOTF filter, one of the major elements of the instrument. All these data can be found in the ESA PSA archive.

Vibration-rotation pattern in acetylene. II. Introduction of Coriolis coupling in the global model and analysis of emission spectra of hot acetylene around 3 microm.

A high temperature source has been developed and coupled to a high resolution Fourier transform spectrometer to record emission spectra of acetylene around 3 mum up to 1455 K under Doppler limited resolution (0.015 cm(-1)). The nu(3)-ground state (GS) and nu(2)+nu(4)+nu(5) (Sigma(u) (+) and Delta(u))-GS bands and 76 related hot bands, counting e and f parities separately, are assigned using semiautomatic methods based on a global model to reproduce all related vibration-rotation states. Significantly higher J-values than previously reported are observed for 40 known substates while 37 new e or f vibrational substates, up to about 6000 cm(-1), are identified and characterized by vibration-rotation parameters. The 3 811 new or improved data resulting from the analysis are merged into the database presented by Robert et al. [Mol. Phys. 106, 2581 (2008)], now including 15 562 lines accessing vibrational states up to 8600 cm(-1). A global model, updated as compared to the one in the previous paper, allows all lines in the database to be simultaneously fitted, successfully. The updates are discussed taking into account, in particular, the systematic inclusion of Coriolis interaction.

Novel 3-carboxamide-coumarins as potent and selective FXIIa inhibitors.

Recently, FXIIa was highlighted as an original attractive target for the development of new anticoagulant drugs with low rates of therapy-related hemorrhages. In this work, we describe the development of a new series of 3-carboxamide-coumarins that are the first potent and selective nonpeptidic inhibitors of FXIIa.

Mechanism-based thrombin inhibitors: design, synthesis, and molecular docking of a new selective 2-oxo-2H-1-benzopyran derivative.

New 2-oxo-2H-1-benzopyran derivatives were prepared to optimize 2a,b, initially developed as mechanism-based alpha-chymotrypsin (alpha-CT) inhibitors, into potent and selective thrombin (THR) inhibitors. From this study, 22, characterized by a 2-(N-ethyl-2'-oxoacetamide)-5'-chlorophenyl ester side chain, was shown to be a good THR inhibitor (ki/KI = 3455 M(-1) x s(-1)), displaying an excellent selectivity profile against other serine proteases such as factor Xa, trypsin, and alpha-CT. Docking analysis of this compound into the different protein structures revealed the molecular basis responsible for its potency and selectivity.

3,6-disubstituted coumarins as mechanism-based inhibitors of thrombin and factor Xa.

In this work, coumarins were screened on thrombin (THR) and factor Xa (FXa), two of the most promising targets for the development of anticoagulant drugs. This allowed us to highlight compound 30, characterized by a 2,5-dichlorophenyl ester in the 3-position and a chloromethyl moiety in the 6-position, as a very potent THR inhibitor (ki/KI= 37,000 M(-1) s(-1)). Moreover, this compound exhibits good selectivity over FXa (168-fold) and trypsin (54-fold). The mechanism of inactivation was investigated in this series and significantly differs from that previously observed with alpha-chymotrypsin. Indeed, the addition of hydrazine on the THR-inhibitor complex promotes a partial induced THR reactivation. This reactivation, confirmed by LC/MS, showed the resurgence of the native THR and a new dihydrazide complex. Docking experiments were then efficiently used to explain the trends observed in the enzymatic assays as well as to corroborate the postulated inhibition mechanism. Finally, the cell permeability of our derivatives was estimated using a computational approach.

Impact of dabigatran on a large panel of routine or specific coagulation assays. Laboratory recommendations for monitoring of dabigatran etexilate.

Due to low bioavailability and high inter-individual variability, monitoring of dabigatran may be required in specific situations to prevent the risk of bleedings or thrombosis. The aim of the study was to determine which coagulation assay(s) could be used to assess the impact of dabigatran on secondary haemostasis. Dabigatran was spiked at concentrations ranging from 4.7 ng/ml to 943.0 ng/ml in pooled citrated human platelet-poor plasma. The following clotting assays were performed: prothrombin time (PT); activated partial thromboplastin time (aPTT); thrombin time (TT); ecarin clotting time (ECT); ecarin chromogenic assay (ECA); prothrombinase-induced clotting time (PiCT); activated clotting time (ACT); Hemoclot Thrombin Inhibitor (HTI) and thrombin generation assay (TGA). A concentration-dependent prolongation of PT, dPT, and aPTT was observed with aPTT being the more sensitive test. The results varied mostly due to the clotting reagent. HTI, ECT and TGA were the most sensitive tests but are not available 24 hours a day. In addition, HTI showed a linear correlation with a good reproducibility. Dabigatran induced a concentration-dependent delay and inhibition of tissue factor-induced TGA. Cut-offs related with higher risk of bleedings or thrombosis were defined for each reagent of aPTT and HTI. In conclusion, aPTT could be used for the monitoring of dabigatran and as screening test for the risk of overdose. However, because of its higher sensitivity, good reproducibility, excellent linear correlation at all doses, its simplicity of use, and possibilities of automation, HTI should be considered as the gold-standard.

Validation of the calibrated thrombin generation test (cTGT) as the reference assay to evaluate the procoagulant activity of nanomaterials.

We validated a preclinical toxicological screening assay and provided guidelines to evaluate the potential impact of nanoparticles (NPs) on blood coagulation. Five NPs with various physicochemical properties were studied using several existing methods of clotting times and thrombin generation assays in human normal pool plasma. In both recalcification clotting time (RCT) and calibrated thrombin generation test (cTGT), the NPs exhibited procoagulant activity (SiO2 ≥ SiC ≥ TiC > CuO > CB) but cTGT was more sensitive and relevant than RCT. Thus, the cTGT appears as a reference assay to investigate the nanoparticle (NP) procoagulant activity in human plasma. It should be used as the reference toxicity test for evaluating the effects of nanomaterials on coagulation cascade. In addition, we also showed that the use of the Pluronic F-108 dispersant and/or the sonication for the NP suspension preparation may mask their procoagulant activity and thus should be avoided.

Effects of leaf extracts from Croton zambesicus Müell. Arg. on hemostasis.

ETHNOPHARMACOLOGICAL RELEVANCE: The leaf decoction of Croton zambesicus Müell. Arg. (Euphorbiaceae; syn. Croton amabilis Müell. Arg., Croton gratissimus Burch) is traditionally used in Benin to treat hypertension. AIM OF THE STUDY: As hypertension and thromboembolism are often associated in several cardiovascular diseases, we studied the potential effects of leaf extracts from Croton zambesicus on hemostasis. MATERIALS AND METHODS: We prepared the dichloromethane and aqueous extracts from the air-dried leaves of Croton zambesicus and separated the aqueous extract in its aqueous and dichloromethane fractions. The potential effects of these four extracts/fractions were investigated on red blood cells integrity using spectrophotometric lysis assays, on primary hemostasis using platelet aggregation studies and on secondary hemostasis using calibrated automated thrombin generation assays and coagulation factors inhibition tests. RESULTS: In the in vitro testing, we found that none of the tested extracts/fractions exhibit hemolytic or antiplatelet activity. However, they display a moderate but significant anticoagulant activity which would be mediated through the direct inhibition of thrombin, FXa and TF/FVIIa. The active anticoagulant compound(s) seem to be mainly in the aqueous extract and especially in its aqueous fraction. CONCLUSIONS: This experimental work reported for the first time the anticoagulant effect of leaf extracts from Croton zambesicus. These findings are of particular interest as the leaves from Croton zambesicus are commonly used in infusion by local population and may provide a new natural source for the development of original anticoagulant agents. Furthermore, this activity, associated with the vasorelaxant properties of some of its diterpenes may prove to be interesting for the prevention of cardiovascular diseases in traditional medicine.

Is thrombin generation the new rapid, reliable and relevant pharmacological tool for the development of anticoagulant drugs?

The ex vivo testing emerges as an essential and critical step for the selection of the most promising prospective anticoagulant agents. The aim of the present study was to validate the thrombin generation assay as an ex vivo pharmacological screening test for measuring the anticoagulant behaviour and potency of molecules. The effects of six thrombin and/or factor Xa (FXa) inhibitors (argatroban, lepirudin, PPACK, enoxaparin, ZK-807834, fondaparinux) were investigated on the time course of thrombin catalytic activity triggered by the tissue factor pathway in platelet-poor plasma (PPP) of male healthy volunteers using the Calibrated Automated Thrombogram((R)) (CAT) method. In the presence of the anticoagulant drugs, the thrombin activity profiles were dose-dependently modified according to their specific enzyme inhibitory activity. ZK-807834 was the most potent drug for reducing the C(max) and the V(max) but also for prolonging the T(max). Lepirudin most efficiently delayed the lag time whereas enoxaparin was the most powerfully drug for diminishing the endogenous thrombin potential (ETP). In conclusion, the thrombin activity profile performed with the CAT method is a very rapid, suitable and reliable pharmacological tool for screening thrombin and/or FXa inhibitors whatever their inhibition mode. It consists of a powerful alternative for the classical PT clotting assay, especially regarding to the time course and the total amount of active thrombin generated. Last but not least, it provides insight into the mechanism of action of the compounds.

Ir-CPI, a coagulation contact phase inhibitor from the tick Ixodes ricinus, inhibits thrombus formation without impairing hemostasis.

Blood coagulation starts immediately after damage to the vascular endothelium. This system is essential for minimizing blood loss from an injured blood vessel but also contributes to vascular thrombosis. Although it has long been thought that the intrinsic coagulation pathway is not important for clotting in vivo, recent data obtained with genetically altered mice indicate that contact phase proteins seem to be essential for thrombus formation. We show that recombinant Ixodes ricinus contact phase inhibitor (Ir-CPI), a Kunitz-type protein expressed by the salivary glands of the tick Ixodes ricinus, specifically interacts with activated human contact phase factors (FXIIa, FXIa, and kallikrein) and prolongs the activated partial thromboplastin time (aPTT) in vitro. The effects of Ir-CPI were also examined in vivo using both venous and arterial thrombosis models. Intravenous administration of Ir-CPI in rats and mice caused a dose-dependent reduction in venous thrombus formation and revealed a defect in the formation of arterial occlusive thrombi. Moreover, mice injected with Ir-CPI are protected against collagen- and epinephrine-induced thromboembolism. Remarkably, the effective antithrombotic dose of Ir-CPI did not promote bleeding or impair blood coagulation parameters. To conclude, our results show that a contact phase inhibitor is an effective and safe antithrombotic agent in vivo.

Investigation of mechanism-based thrombin inhibitors: Implications of a highly conserved water molecule for the binding of coumarins within the S pocket.

The synthesis of novel coumarins bearing on the lateral side chain in the 3-position an amine or a guanidine group is described. In vitro evaluation highlighted 14d which possesses a meta aniline side chain as a very potent THR inhibitor. Surprisingly, the introduction of a guanidine moiety always led to a decrease in THR inhibiting properties. We, thus, used docking experiments to rationalize the SAR in the series. This study showed the crucial role of a conserved water molecule in the specificity pocket of THR during docking simulation in order to explain the inactivity of guanidine derivatives.