Glycine binding primes NMDA receptor internalization

NMDA (N-methyl-d-aspartate) receptors (NMDARs) are a principal subtype of excitatory ligand-gated ion channel with prominent roles in physiological and disease processes in the central nervous system. Recognition that glycine potentiates NMDAR-mediated currents as well as being a requisite co-agonist of the NMDAR subtype of 'glutamate' receptor profoundly changed our understanding of chemical synaptic communication in the central nervous system. The binding of both glycine and glutamate is necessary to cause opening of the NMDAR conductance pore. Although binding of either agonist alone is insufficient to cause current flow through the channel, we report here that stimulation of the glycine site initiates signalling through the NMDAR complex, priming the receptors for clathrin-dependent endocytosis. Glycine binding alone does not cause the receptor to be endocytosed; this requires both glycine and glutamate site activation of NMDARs. The priming effect of glycine is mimicked by the NMDAR glycine site agonist d-serine, and is blocked by competitive glycine site antagonists. Synaptic as well as extrasynaptic NMDARs are primed for internalization by glycine site stimulation. Our results demonstrate transmembrane signal transduction through activating the glycine site of NMDARs, and elucidate a model for modulating cell-cell communication in the central nervous system.     

Disruption of fragmented parent bodies as the origin of asteroid families

Asteroid families are groups of small bodies that share certain orbit and spectral properties. More than 20 families have now been identified, each believed to have resulted from the collisional break-up of a large parent body in a regime where gravity controls the outcome of the collision more than the material strength of the rock. The size and velocity distributions of the family members provide important constraints for testing our understanding of the break-up process, but erosion and dynamical diffusion of the orbits over time can erase the original signature of the collision. The recently identified young Karin family provides a unique opportunity to study a collisional outcome almost unaffected by orbit evolution. Here we report numerical simulations modelling classes of collisions that reproduce the main characteristics of the Karin family. The sensitivity of the outcome of the collision to the internal structure of the parent body allows us to show that the family must have originated from the break-up of a pre-fragmented parent body, and that all large family members formed by the gravitational reaccumulation of smaller bodies. We argue that most of the identified asteroid families are likely to have had a similar history.     

Precise dating of Dansgaard-Oeschger climate oscillations in western Europe from stalagmite data

The signature of Dansgaard-Oeschger events--millennial-scale abrupt climate oscillations during the last glacial period--is well established in ice cores and marine records. But the effects of such events in continental settings are not as clear, and their absolute chronology is uncertain beyond the limit of (14)C dating and annual layer counting for marine records and ice cores, respectively. Here we present carbon and oxygen isotope records from a stalagmite collected in southwest France which have been precisely dated using 234U/230Th ratios. We find rapid climate oscillations coincident with the established Dansgaard-Oeschger events between 83,000 and 32,000 years ago in both isotope records. The oxygen isotope signature is similar to a record from Soreq cave, Israel, and deep-sea records, indicating the large spatial scale of the climate oscillations. The signal in the carbon isotopes gives evidence of drastic and rapid vegetation changes in western Europe, an important site in human cultural evolution. We also find evidence for a long phase of extremely cold climate in southwest France between 61.2 +/- 0.6 and 67.4 +/- 0.9 kyr ago.     

An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus

Hepatitis C virus (HCV) infection is a serious cause of chronic liver disease worldwide with more than 170 million infected individuals at risk of developing significant morbidity and mortality. Current interferon-based therapies are suboptimal especially in patients infected with HCV genotype 1, and they are poorly tolerated, highlighting the unmet medical need for new therapeutics. The HCV-encoded NS3 protease is essential for viral replication and has long been considered an attractive target for therapeutic intervention in HCV-infected patients. Here we identify a class of specific and potent NS3 protease inhibitors and report the evaluation of BILN 2061, a small molecule inhibitor biologically available through oral ingestion and the first of its class in human trials. Administration of BILN 2061 to patients infected with HCV genotype 1 for 2 days resulted in an impressive reduction of HCV RNA plasma levels, and established proof-of-concept in humans for an HCV NS3 protease inhibitor. Our results further illustrate the potential of the viral-enzyme-targeted drug discovery approach for the development of new HCV therapeutics.     

Near-infrared flares from accreting gas around the supermassive black hole at the Galactic Centre

Recent measurements of stellar orbits provide compelling evidence that the compact radio source Sagittarius A* (refs 4, 5) at the Galactic Centre is a 3.6-million-solar-mass black hole. Sgr A* is remarkably faint in all wavebands other than the radio region, however, which challenges current theories of matter accretion and radiation surrounding black holes. The black hole's rotation rate is not known, and therefore neither is the structure of space-time around it. Here we report high-resolution infrared observations of Sgr A* that reveal 'quiescent' emission and several flares. The infrared emission originates from within a few milliarcseconds of the black hole, and traces very energetic electrons or moderately hot gas within the innermost accretion region. Two flares exhibit a 17-minute quasi-periodic variability. If the periodicity arises from relativistic modulation of orbiting gas, the emission must come from just outside the event horizon, and the black hole must be rotating at about half of the maximum possible rate.