The loss of water from Mars to space is thought to result from the transport of water to the upper atmosphere, where it is dissociated to hydrogen and escapes the planet. Recent observations have ...suggested large, rapid seasonal intrusions of water into the upper atmosphere, boosting the hydrogen abundance. We use the Atmospheric Chemistry Suite on the ExoMars Trace Gas Orbiter to characterize the water distribution by altitude. Water profiles during the 2018-2019 southern spring and summer stormy seasons show that high-altitude water is preferentially supplied close to perihelion, and supersaturation occurs even when clouds are present. This implies that the potential for water to escape from Mars is higher than previously thought.
Inflammatory responses mediated by NOD2 rely on RIP2 kinase and ubiquitin ligase XIAP for the activation of nuclear factor κB (NF-κB), mitogen-activated protein kinases (MAPKs), and cytokine ...production. Herein, we demonstrate that selective XIAP antagonism blocks NOD2-mediated inflammatory signaling and cytokine production by interfering with XIAP-RIP2 binding, which removes XIAP from its ubiquitination substrate RIP2. We also establish that the kinase activity of RIP2 is dispensable for NOD2 signaling. Rather, the conformation of the RIP2 kinase domain functions to regulate binding to the XIAP-BIR2 domain. Effective RIP2 kinase inhibitors block NOD2 signaling by disrupting RIP2-XIAP interaction. Finally, we identify NOD2 signaling and XIAP-dependent ubiquitination sites on RIP2 and show that mutating these lysine residues adversely affects NOD2 pathway signaling. Overall, these results reveal a critical role for the XIAP-RIP2 interaction in NOD2 inflammatory signaling and provide a molecular basis for the design of innovative therapeutic strategies based on XIAP antagonists and RIP2 kinase inhibitors.
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•NOD2 requires RIP2 kinase and E3 XIAP for the activation of inflammatory signaling•XIAP antagonists block NOD2 signaling by interfering with XIAP binding to RIP2•The kinase activity of RIP2 is dispensable for NOD2 signaling•RIP2 kinase inhibitors block NOD2 signaling by disrupting RIP2-XIAP interaction
Goncharov et al. demonstrate that the kinase activity of RIP2 is dispensable for NOD2 signaling. Instead, effective RIP2 kinase inhibitors block NOD2 signaling by disrupting RIP2-XIAP interaction in a similar fashion as XIAP antagonists. These findings provide a novel therapeutic strategy for targeting the NOD2 pathway.
•Vertical distributions of H2O have been measured during the MY28 global dust storm.•Strong increase of the H2O density at 60–80 km was observed at Ls = 268°–285° in both hemispheres.•In high ...northern latitudes the large water content was not correlated with the dust loading and was not repeated in MY32.•In the Southern hemisphere the increase of H2O was also observed in quiet MY32.
Recent observations of the Martian hydrogen corona in the UV H Ly-alpha emission by the Hubble Space Telescope (HST) (Clarke et al., 2014) and the SPICAM UV spectrometer on Mars Express (Chaffin et al., 2014) reported its rapid change by an order of magnitude over a short few months period in 2007 (MY28), which is inconsistent with the existing models. One proposed explanation of the observed increase of the coronal emission is that during the global dust storm water vapor from the lower atmosphere can be transported to higher altitudes, where its photodissociation rate by near-UV sunlight increases, providing an additional source of hydrogen for the upper atmosphere.
In this work we study the water vapor vertical distribution in the middle atmosphere of Mars during the 2007 global dust storm based on solar occultation measurements by the SPICAM IR spectrometer onboard the Mars-Express spacecraft. The vertical profiles of H2O density and mixing ratio have been obtained for solar longitudes Ls = 255°–300° in MY28. In the Northern hemisphere from Ls = 268° to Ls = 285° the H2O density at altitudes of 60–80 km increased by an order of magnitude. During the dust storm the profiles extended up to 80 km, with an H2O density exceeding 1010 molecules/cm3 (mixing ratio ≥200 ppm). Two maxima of the H2O density were detected. The largest H2O densities observed at latitudes higher than 60°N, over Ls = 269°–275°, do not directly correlate with the aerosol loading and likely relate to the downwelling branch of the meridional circulation that was intensified during the dust storm, and transported water from the Southern hemisphere to high northern latitudes. The second smaller maximum coincides with the high dust loading at middle northern latitudes. The comparison with geographically close observations in the quiet Mars year MY32, when the H2O content in the Northern hemisphere did not exceed 2 × 1010 molecules/cm3 and 50 ppm at 60 km, showed that the global dust storm was a unique event. The situation was different in the Southern hemisphere. During the dust storm the water density at 50–80 km increased by a factor of 4–5 with a mixing ratio >100 ppm, well correlated with the aerosol vertical extension. A somewhat weaker increase of the H2O density by a factor of 2–3 with a mixing ratio > 100 ppm was also observed during MY32 starting from Ls = 260°, suggesting a seasonal repeatability.
The observed amount of water at high altitudes in both hemispheres can produce a large increase in the H escape rate on a timescale of weeks, as was shown in the photochemical modeling by Chaffin et al. (2017). Future modeling would be necessary to separate the seasonal and the dust storm contributions to the hydrogen escape.
The inhibitor of apoptosis (IAP) proteins are a family of anti-apoptotic regulators found in viruses and metazoans. c-IAP1 and c-IAP2 are recruited to tumor necrosis factor receptor 1 ...(TNFR1)-associated complexes where they can regulate receptor-mediated signaling. Both c-IAP1 and c-IAP2 have been implicated in TNFα-stimulated NF-κB activation. However, individual c-IAP1 and c-IAP2 gene knock-outs in mice did not reveal changes in TNF signaling pathways, and the phenotype of a combined deficiency of c-IAPs has yet to be reported. Here we investigate the role of c-IAP1 and c-IAP2 in TNFα-stimulated activation of NF-κB. We demonstrate that TNFα-induced NF-κB activation is severely diminished in the absence of both c-IAP proteins. In addition, combined absence of c-IAP1 and c-IAP2 rendered cells sensitive to TNFα-induced cell death. Using cells with genetic ablation of c-IAP1 or cells where the c-IAP proteins were eliminated using IAP antagonists, we show that TNFα-induced RIP1 ubiquitination is abrogated in the absence of c-IAPs. Furthermore, we reconstitute the ubiquitination process with purified components in vitro and demonstrate that c-IAP1, in collaboration with the ubiquitin conjugating enzyme (E2) enzyme UbcH5a, mediates polymerization of Lys-63-linked chains on RIP1. Therefore, c-IAP1 and c-IAP2 are required for TNFα-stimulated RIP1 ubiquitination and NF-κB activation.
In 2020, hydrogen chloride (HCl) in the gas phase was discovered in the atmosphere of Mars with the Atmospheric Chemistry Suite (ACS) onboard the Trace Gas Orbiter (TGO) mission (Korablev et al., ...2021). Its volume mixing ratio (VMR) shows a seasonal increase of up to 5 ppbv during the perihelion season, followed by a sudden drop to undetectable levels, contradicting modelling estimates of the HCl lifetime of several months. In the Earth's stratosphere, heterogeneous uptake of HCl onto water ice is known to be a major sink for this species. This reaction is now also considered when modelling HCl abundances in the Martian atmosphere. In this work, we use simultaneous measurements of water ice and HCl obtained by the ACS instrument to find particular structures in the vertical profiles as detached gas layers at ice-free altitudes (“ice-holes”). From these particular examples we conclude that the heterogeneous uptake of HCl onto water ice operates on Mars and is a fast mechanism regulating the HCl abundance in the atmosphere of Mars.
•Simultaneous vertical profiles of water ice and HCl analysed over 2.5 Martian years.•HCl gas layers at ice-free altitudes reveal local anticorrelation of HCl vs water ice.•Heterogeneous uptake of HCl onto water ice rapidly regulates HCl abundance.
New measurements of sulfur dioxide (SO2) and monoxide (SO) in the atmosphere of Venus by SPICAV/SOIR instrument onboard Venus Express orbiter provide ample statistics to study the behavior of these ...gases above Venus' clouds. The instrument (a set of three spectrometers) is capable to sound atmospheric structure above the clouds in several observation modes (nadir, solar and stellar occultations) either in the UV or in the near IR spectral ranges. We present the results from solar occultations in the absorption ranges of SO2(190-230nm, and at 4 mu m) and SO (190-230nm). The dioxide was detected by the SOIR spectrometer at the altitudes of 65-80km in the IR and by the SPICAV spectrometer at 85-105km in the UV. The monoxide's absorption was measured only by SPICAV at 85-105km. We analyzed 39 sessions of solar occultation, where boresights of both spectrometers are oriented identically, to provide complete vertical profiling of SO2of the Venus' mesosphere (65-105km). Here we report the first firm detection and measurements of two SO2layers. In the lower layer SO2mixing ratio is within 0.02-0.5ppmv. The upper layer, also conceivable from microwave measurements by Sandor et al. (Sandor, B.J., Todd Clancy, R., Moriarty-Schieven, G., Mills, F.P. 2010. Icarus 208, 49-60) is characterized by SO2increasing with the altitude from 0.05 to 2ppmv, and the SO2/SO ratio varying from 1 to 5. The presence of the high-altitude SO|>x species could be explained by H2SO4 photodissociation under somewhat warmer temperature conditions in Venus mesosphere. At 90-100km the content of the sulfur dioxide correlates with temperature increasing from 0.1ppmv at 165-170K to 0.5-1ppmv at 190-192K. It supports the hypothesis of SO2 production by the evaporation of H2SO4 from droplets and its subsequent photolysis at around 100km.
Inflammasomes activate caspase-1 for processing and secretion of the cytokines interleukin-1β (IL-1β) and IL-18. Cryopyrin/NALP3/NLRP3 is an essential component of inflammasomes triggered by ...microbial ligands, danger-associated molecular patterns (DAMPs), and crystals. Inappropriate Cryopyrin activity has been incriminated in the pathogenesis of gouty arthritis, Alzheimer's, and silicosis. Therefore, inhibitors of the Nalp3 inflammasome offer considerable therapeutic promise. In this study, we show that the type 2 diabetes drug glyburide prevented activation of the Cryopyrin inflammasome. Glyburide's cyclohexylurea group, which binds to adenosine triphosphatase (ATP)-sensitive K⁺ (KATP) channels for insulin secretion, is dispensable for inflammasome inhibition. Macrophages lacking KATP subunits or ATP-binding cassette transporters also activate the Cryopyrin inflammasome normally. Glyburide analogues inhibit ATP- but not hypothermia-induced IL-1β secretion from human monocytes expressing familial cold-associated autoinflammatory syndrome-associated Cryopyrin mutations, thus suggesting that inhibition occurs upstream of Cryopyrin. Concurrent with the role of Cryopyrin in endotoxemia, glyburide significantly delays lipopolysaccharide-induced lethality in mice. Therefore, glyburide is the first identified compound to prevent Cryopyrin activation and microbial ligand-, DAMP-, and crystal-induced IL-1β secretion.
Peptides present an alternative modality to immunoglobulin domains or small molecules for developing therapeutics to either agonize or antagonize cellular pathways associated with diseases. However, ...peptides often suffer from poor chemical and physical stability, limiting their therapeutic potential. Disulfide-constrained peptides (DCP) are naturally occurring and possess numerous desirable properties, such as high stability, that qualify them as drug-like scaffolds for peptide therapeutics. DCPs contain loop regions protruding from the core of the molecule that are amenable to peptide engineering via direct evolution by use of phage display technology. In this study, we have established a robust platform for the discovery of peptide therapeutics using various DCPs as scaffolds. We created diverse libraries comprising seven different DCP scaffolds, resulting in an overall diversity of 2 x 1011. The effectiveness of this platform for functional hit discovery has been extensively evaluated, demonstrating a hit rate comparable to that of synthetic antibody libraries. By utilizing chemically synthesized and in vitro folded peptides derived from selections of phage displayed DCP libraries, we have successfully generated functional inhibitors targeting the HtrA1 protease. Through affinity maturation strategies, we have transformed initially weak binders against Notch2 with micromolar Kd values to high-affinity ligands in the nanomolar range. This process highlights a viable hit-to-lead progression. Overall, our platform holds significant potential to greatly enhance the discovery of peptide therapeutics.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Context
. Gravity waves redistribute energy and momentum between the lower and upper atmosphere, thus providing vertical coupling between layers, and they affect the state, dynamics, and variability ...of the upper atmosphere. The statistics of gravity wave activity on Mars is poorly explored but is required in order to characterize the atmospheric circulation and to constrain numerical models.
Aims
. We present the gravity wave statistics accumulated over two Martian years: from the second half of Martian year 34 to the middle of Martian year 36 (May 2018 to February 2022). The statistics includes seasonal and latitude distributions of the wave potential energy and drag, serving to represent the wave activity and impact on the atmospheric dynamics.
Methods
. The observations were performed by the middle- and near-infrared spectrometers of the Atmospheric Chemistry Suite on board the ExoMars Trace Gas Orbiter. The temperature profiles we obtained independently from both channels during simultaneous measurements show a good agreement, thus providing verification and enhancing confidence in the data. The gravity wave parameters included amplitudes of temperature fluctuations, potential energy per unit mass, and wave drag. These parameters were retrieved at altitudes up to 160 and 100 km from the middle- and near-infrared channels, respectively.
Results
. A comparison of the data obtained during the global dust storm of Martian year 34 with the corresponding period of Martian year 35 without a storm revealed a reduction of wave activity in mid-latitudes, which is in agreement with previous observations, and enhancement in the polar regions of the southern hemisphere, which was not predicted by simulations with a high-resolution circulation model.
Ubiquitin ligases are critical components of the ubiquitination process that determine substrate specificity and, in collaboration with E2 ubiquitin‐conjugating enzymes, regulate the nature of ...polyubiquitin chains assembled on their substrates. Cellular inhibitor of apoptosis (c‐IAP1 and c‐IAP2) proteins are recruited to TNFR1‐associated signalling complexes where they regulate receptor‐stimulated NF‐κB activation through their RING domain ubiquitin ligase activity. Using a directed yeast two‐hybrid screen, we found several novel and previously identified E2 partners of IAP RING domains. Among these, the UbcH5 family of E2 enzymes are critical regulators of the stability of c‐IAP1 protein following destabilizing stimuli such as TWEAK or CD40 signalling or IAP antagonists. We demonstrate that c‐IAP1 and UbcH5 family promote K11‐linked polyubiquitination of receptor‐interacting protein 1 (RIP1) in vitro and in vivo. We further show that TNFα‐stimulated NF‐κB activation involves endogenous K11‐linked ubiquitination of RIP1 within the TNFR1 signalling complex that is c‐IAP1 and UbcH5 dependent. Lastly, NF‐κB essential modifier efficiently binds K11‐linked ubiquitin chains, suggesting that this ubiquitin linkage may have a signalling role in the activation of proliferative cellular pathways.
Canonical Lys48‐ and Lys63‐linked as well as non‐canonical linear polyubiquitin chains are involved in receptor‐mediated NF‐κB activation. This study identifies c‐IAP1‐generated Lys11‐linked chains, so far implicated only in cell‐cycle control and proteasome targeting, as an additional signal in this pathway.
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