An antifungal agent inhibits an aminoacyl-tRNA synthetase by trapping tRNA in the editing site

Aminoacyl-transfer RNA (tRNA) synthetases, which catalyze the attachment of the correct amino acid to its corresponding tRNA during translation of the genetic code, are proven antimicrobial drug targets. We show that the broad-spectrum antifungal 5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (AN2690), in development for the treatment of onychomycosis, inhibits yeast cytoplasmic leucyl-tRNA synthetase by formation of a stable tRNA(Leu)-AN2690 adduct in the editing site of the enzyme. Adduct formation is mediated through the boron atom of AN2690 and the 2'- and 3'-oxygen atoms of tRNA's3'-terminal adenosine. The trapping of enzyme-bound tRNA(Leu) in the editing site prevents catalytic turnover, thus inhibiting synthesis of leucyl-tRNA(Leu) and consequentially blocking protein synthesis. This result establishes the editing site as a bona fide target for aminoacyl-tRNA synthetase inhibitors.     

Habitat split and the global decline of amphibians

The worldwide decline in amphibians has been attributed to several causes, especially habitat loss and disease. We identified a further factor, namely "habitat split"-defined as human-induced disconnection between habitats used by different life history stages of a species-which forces forest-associated amphibians with aquatic larvae to make risky breeding migrations between suitable aquatic and terrestrial habitats. In the Brazilian Atlantic Forest, we found that habitat split negatively affects the richness of species with aquatic larvae but not the richness of species with terrestrial development (the latter can complete their life cycle inside forest remnants). This mechanism helps to explain why species with aquatic larvae have the highest incidence of population decline. These findings reinforce the need for the conservation and restoration of riparian vegetation.     

Lysosomal glycosphingolipid recognition by NKT cells

NKT cells represent a distinct lineage of T cells that coexpress a conserved alphabeta T cell receptor (TCR) and natural killer (NK) receptors. Although the TCR of NKT cells is characteristically autoreactive to CD1d, a lipid-presenting molecule, endogenous ligands for these cells have not been identified. We show that a lysosomal glycosphingolipid of previously unknown function, isoglobotrihexosylceramide (iGb3), is recognized both by mouse and human NKT cells. Impaired generation of lysosomal iGb3 in mice lacking beta-hexosaminidase b results in severe NKT cell deficiency, suggesting that this lipid also mediates development of NKT cells in the mouse. We suggest that expression of iGb3 in peripheral tissues may be involved in controlling NKT cell responses to infections and malignancy and in autoimmunity.     

The mosquito genome--a breakthrough for public health

The Anopheles gambiae genome sequence will accelerate identification of new insect vector target genes leading to improved strategies for malaria control.     

High-resolution NMR spectroscopy with a portable single-sided sensor

We report construction of a portable nuclear magnetic resonance sensor with a single-sided open probe design. The resulting magnetic field inhomogeneity is compensated by a pulse sequence that takes advantage of parallel inhomogeneity in the applied radio frequency field. We can thereby acquire fluorine-19 spectra of liquid fluorocarbons with 8 parts per million resolution, surmounting the long-standing obstacle of obtaining chemical shift information with open probe instruments.     

The mutational landscape of head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma (HNSCC) is a common, morbid, and frequently lethal malignancy. To uncover its mutational spectrum, we analyzed whole-exome sequencing data from 74 tumor-normal pairs. The majority exhibited a mutational profile consistent with tobacco exposure; human papillomavirus was detectable by sequencing DNA from infected tumors. In addition to identifying previously known HNSCC genes (TP53, CDKN2A, PTEN, PIK3CA, and HRAS), our analysis revealed many genes not previously implicated in this malignancy. At least 30% of cases harbored mutations in genes that regulate squamous differentiation (for example, NOTCH1, IRF6, and TP63), implicating its dysregulation as a major driver of HNSCC carcinogenesis. More generally, the results indicate the ability of large-scale sequencing to reveal fundamental tumorigenic mechanisms.     

Catalytic conversion of biomass to monofunctional hydrocarbons and targeted liquid-fuel classes

It is imperative to develop more efficient processes for conversion of biomass to liquid fuels, such that the cost of these fuels would be competitive with the cost of fuels derived from petroleum. We report a catalytic approach for the conversion of carbohydrates to specific classes of hydrocarbons for use as liquid transportation fuels, based on the integration of several flow reactors operated in a cascade mode, where the effluent from the one reactor is simply fed to the next reactor. This approach can be tuned for production of branched hydrocarbons and aromatic compounds in gasoline, or longer-chain, less highly branched hydrocarbons in diesel and jet fuels. The liquid organic effluent from the first flow reactor contains monofunctional compounds, such as alcohols, ketones, carboxylic acids, and heterocycles, that can also be used to provide reactive intermediates for fine chemicals and polymers markets.     

Relativistic spin precession in the double pulsar

The double pulsar PSR J0737-3039A/B consists of two neutron stars in a highly relativistic orbit that displays a roughly 30-second eclipse when pulsar A passes behind pulsar B. Describing this eclipse of pulsar A as due to absorption occurring in the magnetosphere of pulsar B, we successfully used a simple geometric model to characterize the observed changing eclipse morphology and to measure the relativistic precession of pulsar B's spin axis around the total orbital angular momentum. This provides a test of general relativity and alternative theories of gravity in the strong-field regime. Our measured relativistic spin precession rate of 4.77 degrees (-0 degrees .65)(+0 degrees .66) per year (68% confidence level) is consistent with that predicted by general relativity within an uncertainty of 13%.