The gamma-subunit of the coatomer complex binds Cdc42 to mediate transformation

The Ras-related GTP-binding protein Cdc42 is implicated in a variety of biological activities including the establishment of cell polarity in yeast, the regulation of cell morphology, motility and cell-cycle progression in mammalian cells and the induction of malignant transformation. We identified a Cdc42 mutant (Cdc42F28L) which binds GTP in the absence of a guanine nucleotide exchange factor, but still hydrolyses GTP with a turnover number identical to that for wild-type Cdc42. Expression of this mutant in NIH 3T3 fibroblasts causes cellular transformation, mimicking many of the characteristics of cells transformed by the Dbl oncoprotein, a known guanine nucleotide exchange factor for Cdc42. Here we searched for new Cdc42 targets in an effort to understand how Cdc42 mediates cellular transformation. We identified the gamma-subunit of the coatomer complex (gammaCOP) as a specific binding partner for activated Cdc42. The binding of Cdc42 to gammaCOP is essential for a transforming signal distinct from those elicited by Ras.     

A scaling law for slow earthquakes

Recently, a series of unusual earthquake phenomena have been discovered, including deep episodic tremor, low-frequency earthquakes, very-low-frequency earthquakes, slow slip events and silent earthquakes. Each of these has been demonstrated to arise from shear slip, just as do regular earthquakes, but with longer characteristic durations and radiating much less seismic energy. Here we show that these slow events follow a simple, unified scaling relationship that clearly differentiates their behaviour from that of regular earthquakes. We find that their seismic moment is proportional to the characteristic duration and their moment rate function is constant, with a spectral high-frequency decay of f(-1). This scaling and spectral behaviour demonstrates that they can be thought of as different manifestations of the same phenomena and that they comprise a new earthquake category. The observed scale dependence of rupture velocity for these events can be explained by either a constant low-stress drop model or a diffusional constant-slip model. This new scaling law unifies a diverse class of slow seismic events and may lead to a better understanding of the plate subduction process and large earthquake generation.     

Warming trends in Asia amplified by brown cloud solar absorption

Atmospheric brown clouds are mostly the result of biomass burning and fossil fuel consumption. They consist of a mixture of light-absorbing and light-scattering aerosols and therefore contribute to atmospheric solar heating and surface cooling. The sum of the two climate forcing terms-the net aerosol forcing effect-is thought to be negative and may have masked as much as half of the global warming attributed to the recent rapid rise in greenhouse gases. There is, however, at least a fourfold uncertainty in the aerosol forcing effect. Atmospheric solar heating is a significant source of the uncertainty, because current estimates are largely derived from model studies. Here we use three lightweight unmanned aerial vehicles that were vertically stacked between 0.5 and 3 km over the polluted Indian Ocean. These unmanned aerial vehicles deployed miniaturized instruments measuring aerosol concentrations, soot amount and solar fluxes. During 18 flight missions the three unmanned aerial vehicles were flown with a horizontal separation of tens of metres or less and a temporal separation of less than ten seconds, which made it possible to measure the atmospheric solar heating rates directly. We found that atmospheric brown clouds enhanced lower atmospheric solar heating by about 50 per cent. Our general circulation model simulations, which take into account the recently observed widespread occurrence of vertically extended atmospheric brown clouds over the Indian Ocean and Asia, suggest that atmospheric brown clouds contribute as much as the recent increase in anthropogenic greenhouse gases to regional lower atmospheric warming trends. We propose that the combined warming trend of 0.25 K per decade may be sufficient to account for the observed retreat of the Himalayan glaciers.     

Anaphase initiation is regulated by antagonistic ubiquitination and deubiquitination activities

The spindle checkpoint prevents chromosome mis-segregation by delaying sister chromatid separation until all chromosomes have achieved bipolar attachment to the mitotic spindle. Its operation is essential for accurate chromosome segregation, whereas its dysregulation can contribute to birth defects and tumorigenesis. The target of the spindle checkpoint is the anaphase-promoting complex (APC), a ubiquitin ligase that promotes sister chromatid separation and progression to anaphase. Using a short hairpin RNA screen targeting components of the ubiquitin-proteasome pathway in human cells, we identified the deubiquitinating enzyme USP44 (ubiquitin-specific protease 44) as a critical regulator of the spindle checkpoint. USP44 is not required for the initial recognition of unattached kinetochores and the subsequent recruitment of checkpoint components. Instead, it prevents the premature activation of the APC by stabilizing the APC-inhibitory Mad2-Cdc20 complex. USP44 deubiquitinates the APC coactivator Cdc20 both in vitro and in vivo, and thereby directly counteracts the APC-driven disassembly of Mad2-Cdc20 complexes (discussed in an accompanying paper). Our findings suggest that a dynamic balance of ubiquitination by the APC and deubiquitination by USP44 contributes to the generation of the switch-like transition controlling anaphase entry, analogous to the way that phosphorylation and dephosphorylation of Cdk1 by Wee1 and Cdc25 controls entry into mitosis.     

Parallel bacterial evolution within multiple patients identifies candidate pathogenicity genes

Bacterial pathogens evolve during the infection of their human host(1-8), but separating adaptive and neutral mutations remains challenging(9-11). Here we identify bacterial genes under adaptive evolution by tracking recurrent patterns of mutations in the same pathogenic strain during the infection of multiple individuals. We conducted a retrospective study of a Burkholderia dolosa outbreak among subjects with cystic fibrosis, sequencing the genomes of 112 isolates collected from 14 individuals over 16 years. We find that 17 bacterial genes acquired nonsynonymous mutations in multiple individuals, which indicates parallel adaptive evolution. Mutations in these genes affect important pathogenic phenotypes, including antibiotic resistance and bacterial membrane composition and implicate oxygen-dependent regulation as paramount in lung infections. Several genes have not previously been implicated in pathogenesis and may represent new therapeutic targets. The identification of parallel molecular evolution as a pathogen spreads among multiple individuals points to the key selection forces it experiences within human hosts.     

Meta-analysis of genome-wide association studies of asthma in ethnically diverse North American populations

Asthma is a common disease with a complex risk architecture including both genetic and environmental factors. We performed a meta-analysis of North American genome-wide association studies of asthma in 5,416 individuals with asthma (cases) including individuals of European American, African American or African Caribbean, and Latino ancestry, with replication in an additional 12,649 individuals from the same ethnic groups. We identified five susceptibility loci. Four were at previously reported loci on 17q21, near IL1RL1, TSLP and IL33, but we report for the first time, to our knowledge, that these loci are associated with asthma risk in three ethnic groups. In addition, we identified a new asthma susceptibility locus at PYHIN1, with the association being specific to individuals of African descent (P = 3.9 × 10(-9)). These results suggest that some asthma susceptibility loci are robust to differences in ancestry when sufficiently large samples sizes are investigated, and that ancestry-specific associations also contribute to the complex genetic architecture of asthma.