Development of Th1-type immune responses requires the type I cytokine receptor TCCR

On antigen challenge, T-helper cells differentiate into two functionally distinct subsets, Th1 and Th2, characterized by the different effector cytokines that they secrete. Th1 cells produce interleukin (IL)-2, interferon-gamma (IFN-gamma) and lymphotoxin-beta, which mediate pro-inflammatory functions critical for the development of cell-mediated immune responses, whereas Th2 cells secrete cytokines such as IL-4, IL-5 and IL-10 that enhance humoral immunity. This process of T-helper cell differentiation is tightly regulated by cytokines. Here we report a new member of the type I cytokine receptor family, designated T-cell cytokine receptor (TCCR). When challenged in vivo with protein antigen, TCCR-deficient mice had impaired Th1 response as measured by IFN-gamma production. TCCR-deficient mice also had increased susceptibility to infection with an intracellular pathogen, Listeria monocytogenes. In addition, levels of antigen-specific immunoglobulin-gamma2a, which are dependent on Th1 cells, were markedly reduced in these mice. Our results demonstrate the existence of a new cytokine receptor involved in regulating the adaptive immune response and critical to the generation of a Th1 response.     

Regulation of segment polarity genes in the Drosophila blastoderm by fushi tarazu and even skipped

During the late cellular blastoderm stage of Drosophila embryo-genesis the segmentation genes engrailed, en, and wingless, wg, become expressed in two series of 14 stripes which will subsequently coincide with the anterior and posterior limits of each parasegment. Previous studies have shown that the establishment of the pattern of en stripes depends upon the activity of the homoeobox-containing pair-rule genes fushi tarazu, ftz and even skipped, eve. Here we show that these two genes also control the spatial expression of wg. Whereas ftz and eve behave as activators of en we find that both genes are required to repress wg expression, so that wg becomes expressed only in the narrow stripes of cells which come to separate the ftz and eve bands at the end of the blastoderm stage. In contrast, we propose that the precise positioning of the en stripes depends upon signals generated in a combinatorial manner by the overlaps between the ftz or eve domains and those of other pair rule genes, specifically odd paired, opa and paired, prd.     

High-resolution structure prediction and the crystallographic phase problem

The energy-based refinement of low-resolution protein structure models to atomic-level accuracy is a major challenge for computational structural biology. Here we describe a new approach to refining protein structure models that focuses sampling in regions most likely to contain errors while allowing the whole structure to relax in a physically realistic all-atom force field. In applications to models produced using nuclear magnetic resonance data and to comparative models based on distant structural homologues, the method can significantly improve the accuracy of the structures in terms of both the backbone conformations and the placement of core side chains. Furthermore, the resulting models satisfy a particularly stringent test: they provide significantly better solutions to the X-ray crystallographic phase problem in molecular replacement trials. Finally, we show that all-atom refinement can produce de novo protein structure predictions that reach the high accuracy required for molecular replacement without any experimental phase information and in the absence of templates suitable for molecular replacement from the Protein Data Bank. These results suggest that the combination of high-resolution structure prediction with state-of-the-art phasing tools may be unexpectedly powerful in phasing crystallographic data for which molecular replacement is hindered by the absence of sufficiently accurate previous models.     

A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis

Mycobacterium tuberculosis, which causes tuberculosis, is the greatest single infectious cause of mortality worldwide, killing roughly two million people annually. Estimates indicate that one-third of the world population is infected with latent M. tuberculosis. The synergy between tuberculosis and the AIDS epidemic, and the surge of multidrug-resistant clinical isolates of M. tuberculosis have reaffirmed tuberculosis as a primary public health threat. However, new antitubercular drugs with new mechanisms of action have not been developed in over thirty years. Here we report a series of compounds containing a nitroimidazopyran nucleus that possess antitubercular activity. After activation by a mechanism dependent on M. tuberculosis F420 cofactor, nitroimidazopyrans inhibited the synthesis of protein and cell wall lipid. In contrast to current antitubercular drugs, nitroimidazopyrans exhibited bactericidal activity against both replicating and static M. tuberculosis. Lead compound PA-824 showed potent bactericidal activity against multidrugresistant M. tuberculosis and promising oral activity in animal infection models. We conclude that nitroimidazopyrans offer the practical qualities of a small molecule with the potential for the treatment of tuberculosis.     

Discovery of abundant hydrothermal venting on the ultraslow-spreading Gakkel ridge in the Arctic Ocean

Submarine hydrothermal venting along mid-ocean ridges is an important contributor to ridge thermal structure, and the global distribution of such vents has implications for heat and mass fluxes from the Earth's crust and mantle and for the biogeography of vent-endemic organisms. Previous studies have predicted that the incidence of hydrothermal venting would be extremely low on ultraslow-spreading ridges (ridges with full spreading rates <2 cm x yr(-1)-which make up 25 per cent of the global ridge length), and that such vent systems would be hosted in ultramafic in addition to volcanic rocks. Here we present evidence for active hydrothermal venting on the Gakkel ridge, which is the slowest spreading (0.6-1.3 cm x yr(-1)) and least explored mid-ocean ridge. On the basis of water column profiles of light scattering, temperature and manganese concentration along 1,100 km of the rift valley, we identify hydrothermal plumes dispersing from at least nine to twelve discrete vent sites. Our discovery of such abundant venting, and its apparent localization near volcanic centres, requires a reassessment of the geologic conditions that control hydrothermal circulation on ultraslow-spreading ridges.     

Imaging of Titan from the Cassini spacecraft

Titan, the largest moon of Saturn, is the only satellite in the Solar System with a substantial atmosphere. The atmosphere is poorly understood and obscures the surface, leading to intense speculation about Titan's nature. Here we present observations of Titan from the imaging science experiment onboard the Cassini spacecraft that address some of these issues. The images reveal intricate surface albedo features that suggest aeolian, tectonic and fluvial processes; they also show a few circular features that could be impact structures. These observations imply that substantial surface modification has occurred over Titan's history. We have not directly detected liquids on the surface to date. Convective clouds are found to be common near the south pole, and the motion of mid-latitude clouds consistently indicates eastward winds, from which we infer that the troposphere is rotating faster than the surface. A detached haze at an altitude of 500 km is 150-200 km higher than that observed by Voyager, and more tenuous haze layers are also resolved.