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Galaxies in the early Universe that are bright at submillimetre wavelengths (submillimetre-bright galaxies) are forming stars at a rate roughly 1,000 times higher than the Milky Way. A large fraction of the new stars form in the central kiloparsec of the galaxy.sup.1-3, a region that is comparable in size to the massive, quiescent galaxies found at the peak of cosmic star-formation history.sup.4 and the cores of present-day giant elliptical galaxies. The physical and kinematic properties inside these compact starburst cores are poorly understood because probing them at relevant spatial scales requires extremely high angular resolution. Here we report observations with a linear resolution of 550 parsecs of gas and dust in an unlensed, submillimetre-bright galaxy at a redshift of z = 4.3, when the Universe was less than two billion years old. We resolve the spatial and kinematic structure of the molecular gas inside the heavily dust-obscured core and show that the underlying gas disk is clumpy and rotationally supported (that is, its rotation velocity is larger than the velocity dispersion). Our analysis of the molecular gas mass per unit area suggests that the starburst disk is gravitationally unstable, which implies that the self-gravity of the gas is stronger than the differential rotation of the disk and the internal pressure due to stellar-radiation feedback. As a result of the gravitational instability in the disk, the molecular gas would be consumed by star formation on a timescale of 100 million years, which is comparable to gas depletion times in merging starburst galaxies.sup.5.The molecular gas in the inner kiloparsec of a submillimetre-bright galaxy is clumpy and gravitationally unstable, collapsing to form stars at a rate that will deplete the gas in about 100 million years., Author(s): K. Tadaki [sup.1] , D. Iono [sup.1] [sup.2] , M. S. Yun [sup.3] , I. Aretxaga [sup.4] , B. Hatsukade [sup.5] , D. H. Hughes [sup.4] , S. Ikarashi [...]

Author(s): J. A. Stevens (corresponding author) [1]; R. J. Ivison [1]; J. S. Dunlop [2]; Ian R. Smail [3]; W. J. Percival [2]; D. H. Hughes [4]; H. J. A. [...]

Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed approximately 19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated approximately 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with disease-IRGM for Crohn's disease, HLA for Crohn's disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetes-although in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases.

Macrophages interact with other cells and components of the extracellular environment by means of adhesion receptors. Adhesion to artificial substrata in vitro facilitates isolation of macrophages, and has been used to generate antibodies that inhibit their migration in vivo. Unlike other cell types, macrophages attach to tissue culture plastic in the absence of divalent cations. Here we use an adhesion assay exploiting this property to isolate a rat monoclonal antibody, 2F8, which totally inhibits divalent cation-independent adhesion of murine macrophages to tissue culture plastic in the presence of fetal calf serum. Immunoprecipitation from macrophages and stably transfected Chinese hamster ovary cells revealed that the antigen recognized by monoclonal 2F8 is identical to murine macrophage scavenger receptor. We propose a novel function for this molecule, previously described as an endocytic receptor, thus providing a mechanism for mononuclear phagocyte recruitment to and retention in ligand-rich tissues such as in atherosclerotic lesions.

Intracellular signalling from receptor tyrosine kinases in mammalian cells involves the activation of a signal cascade which includes p21ras and the protein kinases p74raf-1, MAP kinase kinase and MAP kinases. In the yeasts Schizosaccharomyces pombe and Saccharomyces cerevisiae the response to mating pheromones requires the Spk1 and KSS1/FUS3 kinases, which have sequence homology to vertebrate MAP kinases. The recent cloning of complementary DNAs for mammalian and frog MAP kinase kinases has shown that they are homologous to the S. pombe Byr1 (ref. 17) and S. cerevisiae STE7 (ref. 18) kinases, which have been proposed to function upstream of Spk1 and KSS1/FUS3, respectively. We have investigated whether these apparently similar kinase pathways are functionally conserved between vertebrates and S. pombe. We report here that expression of mammalian MAP kinase kinase alone fails to complement a byr1 mutant of S. pombe. When coexpressed with Raf kinase, however, MAP kinase kinase is activated by phosphorylation and the mating defect of the byr1 mutant is rescued. This suggests that the pathways are functionally homologous and that Raf kinase may directly phosphorylate and activate MAP kinase kinase.

A mutation at codon 717 of the beta-amyloid precursor protein gene has been found to cosegregate with familial Alzheimer's disease in a single family. This mutation has been reported in a further five out of approximately 100 families multiply affected by Alzheimer's disease. We have identified another family, F19, in which we have detected linkage between the beta-amyloid precursor protein gene and Alzheimer's disease. Direct sequencing of exon 17 in affected individuals from this family has revealed a base change producing a Val----Gly substitution, also at codon 717. The occurrence of a second allelic variant at codon 717 linked to the Alzheimer's phenotype supports the hypothesis that they are pathogenic mutations.

The ras proto-oncogene products are plasma membrane-bound, guanine nucleotide-binding proteins implicated in signal transduction across the plasma membrane. But the signal(s) that activates the ras pathway(s) is not known. In the budding yeast Saccharomyces cerevisiae, the CDC25 gene product acts upstream of Ras proteins, but it has not been clear whether CDC25 function is unique to the S. cerevisiae ras pathway. Here we report that the ste6 gene of fission yeast Schizosaccharomyces pombe is a homologue of CDC25: the ste6 gene product and the CDC25 gene product have significant amino-acid similarity in their C-terminal regions. Like the S. pombe ras1 gene, ste6 is essential for mating. Epistatic interactions indicate that the ste6 gene functions upstream of ras1. We propose that ste6 and CDC25 activate Ras protein through a common mechanism, perhaps by promoting GDP-GTP exchange, even though it seems that the function of Ras protein in budding yeast differs from that in fission yeast. Homologues of ste6 and CDC25 could regulate ras activity in other eukaryotic cells.

Evidence of myc gene transduction by feline leukaemia virus in several spontaneous lymphoid tumours of cats suggests that recombinant viruses carrying oncogenes may be much more involved in oncogenesis in natural conditions than previously recognized.