The early Miocene onset of a ventilated circulation regime in the Arctic Ocean

Deep-water formation in the northern North Atlantic Ocean and the Arctic Ocean is a key driver of the global thermohaline circulation and hence also of global climate. Deciphering the history of the circulation regime in the Arctic Ocean has long been prevented by the lack of data from cores of Cenozoic sediments from the Arctic's deep-sea floor. Similarly, the timing of the opening of a connection between the northern North Atlantic and the Arctic Ocean, permitting deep-water exchange, has been poorly constrained. This situation changed when the first drill cores were recovered from the central Arctic Ocean. Here we use these cores to show that the transition from poorly oxygenated to fully oxygenated ('ventilated') conditions in the Arctic Ocean occurred during the later part of early Miocene times. We attribute this pronounced change in ventilation regime to the opening of the Fram Strait. A palaeo-geographic and palaeo-bathymetric reconstruction of the Arctic Ocean, together with a physical oceanographic analysis of the evolving strait and sill conditions in the Fram Strait, suggests that the Arctic Ocean went from an oxygen-poor 'lake stage', to a transitional 'estuarine sea' phase with variable ventilation, and finally to the fully ventilated 'ocean' phase 17.5 Myr ago. The timing of this palaeo-oceanographic change coincides with the onset of the middle Miocene climatic optimum, although it remains unclear if there is a causal relationship between these two events.     

A sequence-based variation map of 8.27 million SNPs in inbred mouse strains

A dense map of genetic variation in the laboratory mouse genome will provide insights into the evolutionary history of the species and lead to an improved understanding of the relationship between inter-strain genotypic and phenotypic differences. Here we resequence the genomes of four wild-derived and eleven classical strains. We identify 8.27 million high-quality single nucleotide polymorphisms (SNPs) densely distributed across the genome, and determine the locations of the high (divergent subspecies ancestry) and low (common subspecies ancestry) SNP-rate intervals for every pairwise combination of classical strains. Using these data, we generate a genome-wide haplotype map containing 40,898 segments, each with an average of three distinct ancestral haplotypes. For the haplotypes in the classical strains that are unequivocally assigned ancestry, the genetic contributions of the Mus musculus subspecies--M. m. domesticus, M. m. musculus, M. m. castaneus and the hybrid M. m. molossinus--are 68%, 6%, 3% and 10%, respectively; the remaining 13% of haplotypes are of unknown ancestral origin. The considerable regional redundancy of the SNP data will facilitate imputation of the majority of these genotypes in less-densely typed classical inbred strains to provide a complete view of variation in additional strains.     

Gadd45a promotes epigenetic gene activation by repair-mediated DNA demethylation

DNA methylation is an epigenetic modification that is essential for gene silencing and genome stability in many organisms. Although methyltransferases that promote DNA methylation are well characterized, the molecular mechanism underlying active DNA demethylation is poorly understood and controversial. Here we show that Gadd45a (growth arrest and DNA-damage-inducible protein 45 alpha), a nuclear protein involved in maintenance of genomic stability, DNA repair and suppression of cell growth, has a key role in active DNA demethylation. Gadd45a overexpression activates methylation-silenced reporter plasmids and promotes global DNA demethylation. Gadd45a knockdown silences gene expression and leads to DNA hypermethylation. During active demethylation of oct4 in Xenopus laevis oocytes, Gadd45a is specifically recruited to the site of demethylation. Active demethylation occurs by DNA repair and Gadd45a interacts with and requires the DNA repair endonuclease XPG. We conclude that Gadd45a relieves epigenetic gene silencing by promoting DNA repair, which erases methylation marks.     

Crystal structure of a human membrane protein involved in cysteinyl leukotriene biosynthesis

The cysteinyl leukotrienes, namely leukotriene (LT)C4 and its metabolites LTD4 and LTE4, the components of slow-reacting substance of anaphylaxis, are lipid mediators of smooth muscle constriction and inflammation, particularly implicated in bronchial asthma. LTC4 synthase (LTC4S), the pivotal enzyme for the biosynthesis of LTC4 (ref. 10), is an 18-kDa integral nuclear membrane protein that belongs to a superfamily of membrane-associated proteins in eicosanoid and glutathione metabolism that includes 5-lipoxygenase-activating protein, microsomal glutathione S-transferases (MGSTs), and microsomal prostaglandin E synthase 1 (ref. 13). LTC4S conjugates glutathione to LTA4, the endogenous substrate derived from arachidonic acid through the 5-lipoxygenase pathway. In contrast with MGST2 and MGST3 (refs 15, 16), LTC4S does not conjugate glutathione to xenobiotics. Here we show the atomic structure of human LTC4S in a complex with glutathione at 3.3 A resolution by X-ray crystallography and provide insights into the high substrate specificity for glutathione and LTA4 that distinguishes LTC4S from other MGSTs. The LTC4S monomer has four transmembrane alpha-helices and forms a threefold symmetric trimer as a unit with functional domains across each interface. Glutathione resides in a U-shaped conformation within an interface between adjacent monomers, and this binding is stabilized by a loop structure at the top of the interface. LTA4 would fit into the interface so that Arg 104 of one monomer activates glutathione to provide the thiolate anion that attacks C6 of LTA4 to form a thioether bond, and Arg 31 in the neighbouring monomer donates a proton to form a hydroxyl group at C5, resulting in 5(S)-hydroxy-6(R)-S-glutathionyl-7,9-trans-11,14-cis-eicosatetraenoic acid (LTC4). These findings provide a structural basis for the development of LTC4S inhibitors for a proinflammatory pathway mediated by three cysteinyl leukotriene ligands whose stability and potency are different and by multiple cysteinyl leukotriene receptors whose functions may be non-redundant.     

A real-time transaction service for grid computing

A real-time transaction service aims at ensuring the consistency of real-time and transactional Grid applications. This paper proposes an efficient real-time transaction service (RTYS). It provides abilities to discover qualified services, i.e., participants, to execute specified sub-transactions, coordinate realtime Grid transactions, calculate deadline and assign priority for scheduling concurrent transactions. The service discovery adopts the two-level registry mechanism to adapt to transient Grid services. The coordination algorithm invokes multiple functional alternative services for each sub-transaction so that it remarkably improves the successful ratio of real-time transactions. The experiment result shows that the RTIS can well coordinate real-time transactions for Grid service environment and shield users from the complex process.