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.     

Abundant gene conversion between arms of palindromes in human and ape Y chromosomes

Eight palindromes comprise one-quarter of the euchromatic DNA of the male-specific region of the human Y chromosome, the MSY. They contain many testis-specific genes and typically exhibit 99.97% intra-palindromic (arm-to-arm) sequence identity. This high degree of identity could be interpreted as evidence that the palindromes arose through duplication events that occurred about 100,000 years ago. Using comparative sequencing in great apes, we demonstrate here that at least six of these MSY palindromes predate the divergence of the human and chimpanzee lineages, which occurred about 5 million years ago. The arms of these palindromes must have subsequently engaged in gene conversion, driving the paired arms to evolve in concert. Indeed, analysis of MSY palindrome sequence variation in existing human populations provides evidence of recurrent arm-to-arm gene conversion in our species. We conclude that during recent evolution, an average of approximately 600 nucleotides per newborn male have undergone Y-Y gene conversion, which has had an important role in the evolution of multi-copy testis gene families in the MSY.     

Fertility assumptions for the 2002-based national population projections

One of the key components of national population projections is the assumed level of fertility, which determines the number of future births in the projections. Assumptions are made in terms of the average number of children women will have over their lifetime. For the 2002-based projections this average is assumed to ultimately be 1.75 for England and for Wales, 1.60 for Scotland, and 1.80 for Northern Ireland, leading to a United Kingdom assumption of 1.74. This article explains how these overall assumptions, which are the same as assumed in the 2000-based and interim 2001-based projections, are derived. It also explains why these levels are higher than current 'period' indicators of fertility. Finally, information on more detailed age specific fertility rates, and implications for family size distributions, is given.     

Higher qualifications,first-birth timing,and further childbearing in England and Wales

This article examines how strong the association is between the obtaining of higher educational qualifications and later entry to motherhood, and how these are associated with levels and pace of second and subsequent childbearing. Data from the ONS Longitudinal Study are used to estimate these associations for women born in England and Wales between 1954 and 1958. Average age of entry to motherhood is found to be five years later for women with higher qualifications than for those without. Increasing age of motherhood is always associated with a lower likelihood of going on to have another child, but the decline with age is less pronounced for women with a higher qualification. Moreover, for any given age of childbearing, mothers with a higher qualification are more likely than those without to have another child, and are more likely to do so quickly.     

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.