Anthrax toxins cooperatively inhibit endocytic recycling by the Rab11/Sec15 exocyst

Bacillus anthracis is the causative agent of anthrax in humans and other mammals. In lethal systemic anthrax, proliferating bacilli secrete large quantities of the toxins lethal factor (LF) and oedema factor (EF), leading to widespread vascular leakage and shock. Whereas host targets of LF (mitogen-activated protein-kinase kinases) and EF (cAMP-dependent processes) have been implicated in the initial phase of anthrax, less is understood about toxin action during the final stage of infection. Here we use Drosophila melanogaster to identify the Rab11/Sec15 exocyst, which acts at the last step of endocytic recycling, as a novel target of both EF and LF. EF reduces levels of apically localized Rab11 and indirectly blocks vesicle formation by its binding partner and effector Sec15 (Sec15-GFP), whereas LF acts more directly to reduce Sec15-GFP vesicles. Convergent effects of EF and LF on Rab11/Sec15 inhibit expression of and signalling by the Notch ligand Delta and reduce DE-cadherin levels at adherens junctions. In human endothelial cells, the two toxins act in a conserved fashion to block formation of Sec15 vesicles, inhibit Notch signalling, and reduce cadherin expression at adherens junctions. This coordinated disruption of the Rab11/Sec15 exocyst by anthrax toxins may contribute to toxin-dependent barrier disruption and vascular dysfunction during B. anthracis infection.     

Additional deletion in sex-determining region of human Y chromosome resolves paradox of X,t(Y;22) female

Whether a human embryo develops as a male or a female is determined by the presence of the Y chromosome. The sex-determining function lies entirely in interval 1A, inasmuch as most XX individuals with descended testes and normal male external genitalia carry this small region of the Y chromosome. We have localized an essential part of the sex-determining function to a portion of interval 1A, on the basis of the discovery of a female with a reciprocal Y;22 translocation and part of 1A deleted at the translocation breakpoint. Recently, a paradox has arisen with the report of four partially masculinized XX individuals who carry only a portion of interval 1A--a portion that does not overlap the deletion in the X,t(Y;22) female. These recent findings imply that the sex-determining function lies in the portion of 1A present in the four XX intersexes and not in the portion deleted in the X,t(Y;22) female. To explain the X,t(Y;22) individual, it was proposed that she was female because of a chromosomal position effect or delayed development of the gonadal soma. Here we report that the X,t(Y;22) female has a deletion of a second portion of interval 1A--a portion corresponding closely to that present in the XX intersexes. This resolves the apparent contradiction. Nonetheless, phenotype-genotype correlations suggest that two or more genetic elements in interval 1A may contribute to the sex-determining function of the Y chromosome. The X,t(Y;22) female lacks the ZFY gene but does not exhibit the complex phenotype known as Turner's syndrome, arguing against the hypothesis that ZFY is the Turner's syndrome gene on the Y chromosome.     

Boundary lubrication under water

Boundary lubrication, in which the rubbing surfaces are coated with molecular monolayers, has been studied extensively for over half a century. Such monolayers generally consist of amphiphilic surfactants anchored by their polar headgroups; sliding occurs at the interface between the layers, greatly reducing friction and especially wear of the underlying substrates. This process, widespread in engineering applications, is also predicted to occur in biological lubrication via phospholipid films, though few systematic studies on friction between surfactant layers in aqueous environments have been carried out. Here we show that the frictional stress between two sliding surfaces bearing surfactant monolayers may decrease, when immersed in water, to as little as one per cent or less of its value in air (or oil). We attribute this to the shift of the slip plane from between the surfactant layers, to the surfactant/substrate interface. The low friction would then be due to the fluid hydration layers surrounding the polar head groups attached to the substrate. These results may have implications for future technological and biomedical applications.