A single positively selected West Nile viral mutation confers increased virogenesis in American crows

West Nile virus (WNV), first recognized in North America in 1999, has been responsible for the largest arboviral epiornitic and epidemic of human encephalitis in recorded history. Despite the well-described epidemiological patterns of WNV in North America, the basis for the emergence of WNV-associated avian pathology, particularly in the American crow (AMCR) sentinel species, and the large scale of the North American epidemic and epiornitic is uncertain. We report here that the introduction of a T249P amino acid substitution in the NS3 helicase (found in North American WNV) in a low-virulence strain was sufficient to generate a phenotype highly virulent to AMCRs. Furthermore, comparative sequence analyses of full-length WNV genomes demonstrated that the same site (NS3-249) was subject to adaptive evolution. These phenotypic and evolutionary results provide compelling evidence for the positive selection of a mutation encoding increased viremia potential and virulence in the AMCR sentinel bird species.     

Submarine hot springs and the origin of life

The discovery of hydrothermal vents at oceanic ridge crests and the appreciation of their importance in the element balance of the oceans is one of the main recent advances in marine geochemistry. It is likely that vents were present in the oceans of the primitive Earth because the process of hydrothermal circulation probably began early in the Earth's history. Here we examine the popular hypothesis that life arose in these vents. This proposal, however, is based on a number of misunderstandings concerning the organic chemistry involved. An example is the suggestion that organic compounds were destroyed on the surface of the early Earth by the impact of asteroids and comets, but at the same time assuming that organic syntheses can occur in hydrothermal vents. The high temperatures in the vents would not allow synthesis of organic compounds, but would decompose them, unless the exposure time at vent temperatures was short. Even if the essential organic molecules were available in the hot hydrothermal waters, the subsequent steps of polymerization and the conversion of these polymers into the first organisms would not occur as the vent waters were quenched to the colder temperatures of the primitive oceans.     

PTC124 targets genetic disorders caused by nonsense mutations

Nonsense mutations promote premature translational termination and cause anywhere from 5-70% of the individual cases of most inherited diseases. Studies on nonsense-mediated cystic fibrosis have indicated that boosting specific protein synthesis from <1% to as little as 5% of normal levels may greatly reduce the severity or eliminate the principal manifestations of disease. To address the need for a drug capable of suppressing premature termination, we identified PTC124-a new chemical entity that selectively induces ribosomal readthrough of premature but not normal termination codons. PTC124 activity, optimized using nonsense-containing reporters, promoted dystrophin production in primary muscle cells from humans and mdx mice expressing dystrophin nonsense alleles, and rescued striated muscle function in mdx mice within 2-8 weeks of drug exposure. PTC124 was well tolerated in animals at plasma exposures substantially in excess of those required for nonsense suppression. The selectivity of PTC124 for premature termination codons, its well characterized activity profile, oral bioavailability and pharmacological properties indicate that this drug may have broad clinical potential for the treatment of a large group of genetic disorders with limited or no therapeutic options.     

Low beta diversity of herbivorous insects in tropical forests

Recent advances in understanding insect communities in tropical forests have contributed little to our knowledge of large-scale patterns of insect diversity, because incomplete taxonomic knowledge of many tropical species hinders the mapping of their distribution records. This impedes an understanding of global biodiversity patterns and explains why tropical insects are under-represented in conservation biology. Our study of approximately 500 species from three herbivorous guilds feeding on foliage (caterpillars, Lepidoptera), wood (ambrosia beetles, Coleoptera) and fruit (fruitflies, Diptera) found a low rate of change in species composition (beta diversity) across 75,000 square kilometres of contiguous lowland rainforest in Papua New Guinea, as most species were widely distributed. For caterpillars feeding on large plant genera, most species fed on multiple host species, so that even locally restricted plant species did not support endemic herbivores. Large plant genera represented a continuously distributed resource easily colonized by moths and butterflies over hundreds of kilometres. Low beta diversity was also documented in groups with differing host specificity (fruitflies and ambrosia beetles), suggesting that dispersal limitation does not have a substantial role in shaping the distribution of insect species in New Guinea lowland rainforests. Similar patterns of low beta diversity can be expected in other tropical lowland rainforests, as they are typically situated in the extensive low basins of major tropical rivers similar to the Sepik-Ramu region of New Guinea studied here.     

A SNARE-adaptor interaction is a new mode of cargo recognition in clathrin-coated vesicles

Soluble NSF attachment protein receptors (SNAREs) are type II transmembrane proteins that have critical roles in providing the specificity and energy for transport-vesicle fusion and must therefore be correctly partitioned between vesicle and organelle membranes. Like all other cargo, SNAREs need to be sorted into the forming vesicles by direct interaction with components of the vesicles' coats. Here we characterize the molecular details governing the sorting of a SNARE into clathrin-coated vesicles, namely the direct recognition of the three-helical bundle H(abc) domain of the mouse SNARE Vti1b by the human clathrin adaptor epsinR (EPNR, also known as CLINT1). Structures of each domain and of their complex show that this interaction (dissociation constant 22 muM) is mediated by surface patches composed of approximately 15 residues each, the topographies of which are dependent on each domain's overall fold. Disruption of the interface with point mutations abolishes the interaction in vitro and causes Vti1b to become relocalized to late endosomes and lysosomes. This new class of highly specific, surface-surface interaction between the clathrin coat component and the cargo is distinct from the widely observed binding of short, linear cargo motifs by the assembly polypeptide (AP) complex and GGA adaptors and is therefore not vulnerable to competition from standard motif-containing cargoes for incorporation into clathrin-coated vesicles. We propose that conceptually similar but mechanistically different interactions will direct the post-Golgi trafficking of many SNAREs.