Nitric oxide regulates the heart by spatial confinement of nitric oxide synthase isoforms

Subcellular localization of nitric oxide (NO) synthases with effector molecules is an important regulatory mechanism for NO signalling. In the heart, NO inhibits L-type Ca2+ channels but stimulates sarcoplasmic reticulum (SR) Ca2+ release, leading to variable effects on myocardial contractility. Here we show that spatial confinement of specific NO synthase isoforms regulates this process. Endothelial NO synthase (NOS3) localizes to caveolae, where compartmentalization with beta-adrenergic receptors and L-type Ca2+ channels allows NO to inhibit beta-adrenergic-induced inotropy. Neuronal NO synthase (NOS1), however, is targeted to cardiac SR. NO stimulation of SR Ca2+ release via the ryanodine receptor (RyR) in vitro, suggests that NOS1 has an opposite, facilitative effect on contractility. We demonstrate that NOS1-deficient mice have suppressed inotropic response, whereas NOS3-deficient mice have enhanced contractility, owing to corresponding changes in SR Ca2+ release. Both NOS1-/- and NOS3-/- mice develop age-related hypertrophy, although only NOS3-/- mice are hypertensive. NOS1/3-/- double knockout mice have suppressed beta-adrenergic responses and an additive phenotype of marked ventricular remodelling. Thus, NOS1 and NOS3 mediate independent, and in some cases opposite, effects on cardiac structure and function.     

Extraterrestrial meteors: a martian meteor and its parent comet

Regular meteor showers occur when a planet approaches the orbit of a periodic comet--for example, the Leonid shower is evident around 17 November every year as Earth skims past the dusty trail of comet Tempel-Tuttle. Such showers are expected to occur on Mars as well, and on 7 March last year, the panoramic camera of Spirit, the Mars Exploration Rover, revealed a curious streak across the martian sky. Here we show that the timing and orientation of this streak, and the shape of its light curve, are consistent with the existence of a regular meteor shower associated with the comet Wiseman-Skiff, which could be characterized as martian Cepheids.     

An electrochemical and microstructural characterization of steel-mortar admixed with corrosion inhibitors

The present research brings new insights on the role of admixed corrosion inhibitors in the processes of cement hydration and rebar corrosion.The admixing of NaCl and the corrosion inhibitors in fresh mortar was found to alter the morphology and microstructure of the hardened mortar at the steel-mortar interfacial region.The admixing of the inhibitors increased the risk of carbonation of cement hydrates at the steel-mortar interfacial region,but partially displaced chloride ions. Chloride and the admixed in...     

Solar eclipses of Phobos and Deimos observed from the surface of Mars

The small martian satellites Phobos and Deimos orbit in synchronous rotation with inclinations of only 0.01 degrees and 0.92 degrees , respectively, relative to the planet's equatorial plane. Thus, an observer at near-equatorial latitudes on Mars could occasionally observe solar eclipses by these satellites (see ref. 1, for example). Because the apparent angular diameter of the satellites is much smaller than that of the Sun, however, such events are more appropriately referred to as transits. Transit data can be used for correcting and refining the orbital ephemerides of the moons. For example, Phobos is known to exhibit a secular acceleration that is caused by tidal dissipation within Mars. Long-term, accurate measurements are needed to refine the magnitude and origin of this dissipation within the martian interior as well as to refine the predicted orbital evolution of both satellites. Here we present observations of six transits of Phobos and Deimos across the solar disk from cameras on Mars aboard the Mars Exploration Rovers Spirit and Opportunity. These are the first direct imaging observations of satellites transiting the Sun from the surface of another planet.     

Rain, winds and haze during the Huygens probe's descent to Titan's surface

The irreversible conversion of methane into higher hydrocarbons in Titan's stratosphere implies a surface or subsurface methane reservoir. Recent measurements from the cameras aboard the Cassini orbiter fail to see a global reservoir, but the methane and smog in Titan's atmosphere impedes the search for hydrocarbons on the surface. Here we report spectra and high-resolution images obtained by the Huygens Probe Descent Imager/Spectral Radiometer instrument in Titan's atmosphere. Although these images do not show liquid hydrocarbon pools on the surface, they do reveal the traces of once flowing liquid. Surprisingly like Earth, the brighter highland regions show complex systems draining into flat, dark lowlands. Images taken after landing are of a dry riverbed. The infrared reflectance spectrum measured for the surface is unlike any other in the Solar System; there is a red slope in the optical range that is consistent with an organic material such as tholins, and absorption from water ice is seen. However, a blue slope in the near-infrared suggests another, unknown constituent. The number density of haze particles increases by a factor of just a few from an altitude of 150 km to the surface, with no clear space below the tropopause. The methane relative humidity near the surface is 50 per cent.     

Argos inhibits epidermal growth factor receptor signalling by ligand sequestration

The epidermal growth factor receptor (EGFR) has critical functions in development and in many human cancers. During development, the spatial extent of EGFR signalling is regulated by feedback loops comprising both well-understood activators and less well-characterized inhibitors. In Drosophila melanogaster the secreted protein Argos functions as the only known extracellular inhibitor of EGFR, with clearly identified roles in multiple stages of development. Argos is only expressed when the Drosophila EGFR (DER) is activated at high levels, and downregulates further DER signalling. Although there is ample genetic evidence that Argos inhibits DER activation, the biochemical mechanism has not been established. Here we show that Argos inhibits DER signalling without interacting directly with the receptor, but instead by sequestering the DER-activating ligand Spitz. Argos binds tightly to the EGF motif of Spitz and forms a 1:1 (Spitz:Argos) complex that does not bind DER in vitro or at the cell surface. Our results provide an insight into the mechanism of Argos function, and suggest new strategies for EGFR inhibitor design.     

Structural basis for EGFR ligand sequestration by Argos

Members of the epidermal growth factor receptor (EGFR) or ErbB/HER family and their activating ligands are essential regulators of diverse developmental processes. Inappropriate activation of these receptors is a key feature of many human cancers, and its reversal is an important clinical goal. A natural secreted antagonist of EGFR signalling, called Argos, was identified in Drosophila. We showed previously that Argos functions by directly binding (and sequestering) growth factor ligands that activate EGFR. Here we describe the 1.6-A resolution crystal structure of Argos bound to an EGFR ligand. Contrary to expectations, Argos contains no EGF-like domain. Instead, a trio of closely related domains (resembling a three-finger toxin fold) form a clamp-like structure around the bound EGF ligand. Although structurally unrelated to the receptor, Argos mimics EGFR by using a bipartite binding surface to entrap EGF. The individual Argos domains share unexpected structural similarities with the extracellular ligand-binding regions of transforming growth factor-beta family receptors. The three-domain clamp of Argos also resembles the urokinase-type plasminogen activator (uPA) receptor, which uses a similar mechanism to engulf the EGF-like module of uPA. Our results indicate that undiscovered mammalian counterparts of Argos may exist among other poorly characterized structural homologues. In addition, the structures presented here define requirements for the design of artificial EGF-sequestering proteins that would be valuable anti-cancer therapeutics.