X-ray structure of a pentameric ligand-gated ion channel in an apparently open conformation

Pentameric ligand-gated ion channels from the Cys-loop family mediate fast chemo-electrical transduction, but the mechanisms of ion permeation and gating of these membrane proteins remain elusive. Here we present the X-ray structure at 2.9 A resolution of the bacterial Gloeobacter violaceus pentameric ligand-gated ion channel homologue (GLIC) at pH 4.6 in an apparently open conformation. This cationic channel is known to be permanently activated by protons. The structure is arranged as a funnel-shaped transmembrane pore widely open on the outer side and lined by hydrophobic residues. On the inner side, a 5 A constriction matches with rings of hydrophilic residues that are likely to contribute to the ionic selectivity. Structural comparison with ELIC, a bacterial homologue from Erwinia chrysanthemi solved in a presumed closed conformation, shows a wider pore where the narrow hydrophobic constriction found in ELIC is removed. Comparative analysis of GLIC and ELIC reveals, in concert, a rotation of each extracellular beta-sandwich domain as a rigid body, interface rearrangements, and a reorganization of the transmembrane domain, involving a tilt of the M2 and M3 alpha-helices away from the pore axis. These data are consistent with a model of pore opening based on both quaternary twist and tertiary deformation.     

A Criterion Based on the Mahalanobis Distance for Cluster Analysis with Subsampling

A two-level data set consists of entities of a higher level (say populations), each one being composed of several units of the lower level (say individuals). Observations are made at the individual level, whereas population characteristics are aggregated from individual data. Cluster analysis with subsampling of populations is a cluster analysis based on individual data that aims at clustering populations rather than individuals. In this article, we extend existing optimality criteria for cluster analysis with subsampling of populations to deal with situations where population characteristics are not the mean of individual data. A new criterion that depends on the Mahalanobis distance is also defined. The criteria are compared using simulated examples and an ecological data set of tree species in a tropical rain forest.     

The U/Th production ratio and the age of the Milky Way from meteorites and Galactic halo stars

Some heavy elements (with atomic number A > 69) are produced by the 'rapid' (r)-process of nucleosynthesis, where lighter elements are bombarded with a massive flux of neutrons. Although this is characteristic of supernovae and neutron star mergers, uncertainties in where the r-process occurs persist because stellar models are too crude to allow precise quantification of this phenomenon. As a result, there are many uncertainties and assumptions in the models used to calculate the production ratios of actinides (like uranium-238 and thorium-232). Current estimates of the U/Th production ratio range from approximately 0.4 to 0.7. Here I show that the U/Th abundance ratio in meteorites can be used, in conjunction with observations of low-metallicity stars in the halo of the Milky Way, to determine the U/Th production ratio very precisely (0.57(+0.037)(-0.031). This value can be used in future studies to constrain the possible nuclear mass formulae used in r-process calculations, to help determine the source of Galactic cosmic rays, and to date circumstellar grains. I also estimate the age of the Milky Way (14.5(+2.8)(-2.2)Gyr in a way that is independent of the uncertainties associated with fluctuations in the microwave background or models of stellar evolution.     

Essential role for the p110delta phosphoinositide 3-kinase in the allergic response

Inflammatory substances released by mast cells induce and maintain the allergic response. Mast cell differentiation and activation are regulated, respectively, by stem cell factor (SCF; also known as Kit ligand) and by allergen in complex with allergen-specific immunoglobulin E (IgE). Activated SCF receptors and high-affinity receptors for IgE (FcvarepsilonRI) engage phosphoinositide 3-kinases (PI(3)Ks) to generate intracellular lipid second messenger signals. Here, we report that genetic or pharmacological inactivation of the p110delta isoform of PI(3)K in mast cells leads to defective SCF-mediated in vitro proliferation, adhesion and migration, and to impaired allergen-IgE-induced degranulation and cytokine release. Inactivation of p110delta protects mice against anaphylactic allergic responses. These results identify p110delta as a new target for therapeutic intervention in allergy and mast-cell-related pathologies.     

Genome evolution in yeasts

Identifying the mechanisms of eukaryotic genome evolution by comparative genomics is often complicated by the multiplicity of events that have taken place throughout the history of individual lineages, leaving only distorted and superimposed traces in the genome of each living organism. The hemiascomycete yeasts, with their compact genomes, similar lifestyle and distinct sexual and physiological properties, provide a unique opportunity to explore such mechanisms. We present here the complete, assembled genome sequences of four yeast species, selected to represent a broad evolutionary range within a single eukaryotic phylum, that after analysis proved to be molecularly as diverse as the entire phylum of chordates. A total of approximately 24,200 novel genes were identified, the translation products of which were classified together with Saccharomyces cerevisiae proteins into about 4,700 families, forming the basis for interspecific comparisons. Analysis of chromosome maps and genome redundancies reveal that the different yeast lineages have evolved through a marked interplay between several distinct molecular mechanisms, including tandem gene repeat formation, segmental duplication, a massive genome duplication and extensive gene loss.     

Heterozygous mutations of the kinesin KIF21A in congenital fibrosis of the extraocular muscles type 1 (CFEOM1)

Congenital fibrosis of the extraocular muscles type 1 (CFEOM1; OMIM #135700) is an autosomal dominant strabismus disorder associated with defects of the oculomotor nerve. We show that individuals with CFEOM1 harbor heterozygous missense mutations in a kinesin motor protein encoded by KIF21A. We identified six different mutations in 44 of 45 probands. The primary mutational hotspots are in the stalk domain, highlighting an important new role for KIF21A and its stalk in the formation of the oculomotor axis.