Killing activity of neutrophils is mediated through activation of proteases by K+ flux

According to the hitherto accepted view, neutrophils kill ingested microorganisms by subjecting them to high concentrations of highly toxic reactive oxygen species (ROS) and bringing about myeloperoxidase-catalysed halogenation. We show here that this simple scheme, which for many years has served as a satisfactory working hypothesis, is inadequate. We find that mice made deficient in neutrophil-granule proteases but normal in respect of superoxide production and iodinating capacity, are unable to resist staphylococcal and candidal infections. We also show that activation provokes the influx of an enormous concentration of ROS into the endocytic vacuole. The resulting accumulation of anionic charge is compensated for by a surge of K+ ions that cross the membrane in a pH-dependent manner. The consequent rise in ionic strength engenders the release of cationic granule proteins, including elastase and cathepsin G, from the anionic sulphated proteoglycan matrix. We show that it is the proteases, thus activated, that are primarily responsible for the destruction of the bacteria.     

CFTR channel opening by ATP-driven tight dimerization of its nucleotide-binding domains

ABC (ATP-binding cassette) proteins constitute a large family of membrane proteins that actively transport a broad range of substrates. Cystic fibrosis transmembrane conductance regulator (CFTR), the protein dysfunctional in cystic fibrosis, is unique among ABC proteins in that its transmembrane domains comprise an ion channel. Opening and closing of the pore have been linked to ATP binding and hydrolysis at CFTR's two nucleotide-binding domains, NBD1 and NBD2 (see, for example, refs 1, 2). Isolated NBDs of prokaryotic ABC proteins dimerize upon binding ATP, and hydrolysis of the ATP causes dimer dissociation. Here, using single-channel recording methods on intact CFTR molecules, we directly follow opening and closing of the channel gates, and relate these occurrences to ATP-mediated events in the NBDs. We find that energetic coupling between two CFTR residues, expected to lie on opposite sides of its predicted NBD1-NBD2 dimer interface, changes in concert with channel gating status. The two monitored side chains are independent of each other in closed channels but become coupled as the channels open. The results directly link ATP-driven tight dimerization of CFTR's cytoplasmic nucleotide-binding domains to opening of the ion channel in the transmembrane domains. This establishes a molecular mechanism, involving dynamic restructuring of the NBD dimer interface, that is probably common to all members of the ABC protein superfamily.     

First births by age and education in Britain, France and Norway

Progressively later starting of childbearing has been a feature of cohort change in fertility across Europe and elsewhere over recent decades. Growing differences in the age patterns of childbearing between the Anglo-American and continental European countries, however, have also been found. The present study uses large linked-record databases in Britain, France and Norway to analyse these differences in more detail, focussing on age at entry to motherhood (first childbearing) by level of educational attainment among women born in the 1950s and in the 1960s. The shift between these two cohorts towards a later pattern of first childbearing in Britain was confined to women with secondary school qualifications and above. For women born in the 1960s, the peak age for risk of first childbearing among those with secondary school qualifications grew to be between seven and eleven years later than among women without secondary school qualifications. In France and Norway, the peak ages for risk of first childbearing shifted more uniformly across education levels between the two cohorts. For these 1950s and 1960s cohorts, improvements in women's educational levels also occurred more uniformly in France and Norway, moving more women into education categories characterised by later patterns of first childbearing.     

Transiting circumbinary planets Kepler-34 b and Kepler-35 b

Most Sun-like stars in the Galaxy reside in gravitationally bound pairs of stars (binaries). Although long anticipated, the existence of a 'circumbinary planet' orbiting such a pair of normal stars was not definitively established until the discovery of the planet transiting (that is, passing in front of) Kepler-16. Questions remained, however, about the prevalence of circumbinary planets and their range of orbital and physical properties. Here we report two additional transiting circumbinary planets: Kepler-34 (AB)b and Kepler-35 (AB)b, referred to here as Kepler-34 b and Kepler-35 b, respectively. Each is a low-density gas-giant planet on an orbit closely aligned with that of its parent stars. Kepler-34 b orbits two Sun-like stars every 289?days, whereas Kepler-35 b orbits a pair of smaller stars (89% and 81% of the Sun's mass) every 131?days. The planets experience large multi-periodic variations in incident stellar radiation arising from the orbital motion of the stars. The observed rate of circumbinary planets in our sample implies that more than ～1% of close binary stars have giant planets in nearly coplanar orbits, yielding a Galactic population of at least several million.     

Towards an Understanding of Rich Picture Interpretation

Systemic Practice and Action Research - This paper considers the value of the Rich Picture (RP) as a means to capture data from multiple groups exploring a question, problem or issue. RPs emerge...     

The European dimension for the mouse genome mutagenesis program

The European Mouse Mutagenesis Consortium is the European initiative contributing to the international effort on functional annotation of the mouse genome. Its objectives are to establish and integrate mutagenesis platforms, gene expression resources, phenotyping units, storage and distribution centers and bioinformatics resources. The combined efforts will accelerate our understanding of gene function and of human health and disease.