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.     

A common origin for cosmic explosions inferred from calorimetry of GRB030329

Past studies have suggested that long-duration gamma-ray bursts have a 'standard' energy of E(gamma) approximately 10(51) erg in the ultra-relativistic ejecta, after correcting for asymmetries in the explosion ('jets'). But a group of sub-energetic bursts, including the peculiar GRB980425 associated with the supernova SN1998bw (E(gamma) approximately 10(48) erg), has recently been identified. Here we report radio observations of GRB030329 that allow us to undertake calorimetry of the explosion. Our data require a two-component explosion: a narrow (5 degrees opening angle) ultra-relativistic component responsible for the gamma-rays and early afterglow, and a wide, mildly relativistic component that produces the radio and optical afterglow more than 1.5 days after the explosion. The total energy release, which is dominated by the wide component, is similar to that of other gamma-ray bursts, but the contribution of the gamma-rays is energetically minor. Given the firm link of GRB030329 with SN2003dh, our result indicates a common origin for cosmic explosions in which, for reasons not yet understood, the energy in the highest-velocity ejecta is extremely variable.     

Dodecahedral space topology as an explanation for weak wide-angle temperature correlations in the cosmic microwave background

The current 'standard model' of cosmology posits an infinite flat universe forever expanding under the pressure of dark energy. First-year data from the Wilkinson Microwave Anisotropy Probe (WMAP) confirm this model to spectacular precision on all but the largest scales. Temperature correlations across the microwave sky match expectations on angular scales narrower than 60 degrees but, contrary to predictions, vanish on scales wider than 60 degrees. Several explanations have been proposed. One natural approach questions the underlying geometry of space--namely, its curvature and topology. In an infinite flat space, waves from the Big Bang would fill the universe on all length scales. The observed lack of temperature correlations on scales beyond 60 degrees means that the broadest waves are missing, perhaps because space itself is not big enough to support them. Here we present a simple geometrical model of a finite space--the Poincaré dodecahedral space--which accounts for WMAP's observations with no fine-tuning required. The predicted density is Omega(0) approximately 1.013 > 1, and the model also predicts temperature correlations in matching circles on the sky.     

Programmable computing with a single magnetoresistive element

The development of transistor-based integrated circuits for modern computing is a story of great success. However, the proved concept for enhancing computational power by continuous miniaturization is approaching its fundamental limits. Alternative approaches consider logic elements that are reconfigurable at run-time to overcome the rigid architecture of the present hardware systems. Implementation of parallel algorithms on such 'chameleon' processors has the potential to yield a dramatic increase of computational speed, competitive with that of supercomputers. Owing to their functional flexibility, 'chameleon' processors can be readily optimized with respect to any computer application. In conventional microprocessors, information must be transferred to a memory to prevent it from getting lost, because electrically processed information is volatile. Therefore the computational performance can be improved if the logic gate is additionally capable of storing the output. Here we describe a simple hardware concept for a programmable logic element that is based on a single magnetic random access memory (MRAM) cell. It combines the inherent advantage of a non-volatile output with flexible functionality which can be selected at run-time to operate as an AND, OR, NAND or NOR gate.     

Nuclear cataract caused by a lack of DNA degradation in the mouse eye lens

The eye lens is composed of fibre cells, which develop from the epithelial cells on the anterior surface of the lens. Differentiation into a lens fibre cell is accompanied by changes in cell shape, the expression of crystallins and the degradation of cellular organelles. The loss of organelles is believed to ensure the transparency of the lens, but the molecular mechanism behind this process is not known. Here we show that DLAD ('DNase II-like acid DNase', also called DNase IIbeta) is expressed in human and murine lens cells, and that mice deficient in the DLAD gene are incapable of degrading DNA during lens cell differentiation--the undigested DNA accumulates in the fibre cells. The DLAD-/- mice develop cataracts of the nucleus lentis, and their response to light on electroretinograms is severely reduced. These results indicate that DLAD is responsible for the degradation of nuclear DNA during lens cell differentiation, and that if DNA is left undigested in the lens, it causes cataracts of the nucleus lentis, blocking the light path.