Staphylocoagulase is a prototype for the mechanism of cofactor-induced zymogen activation

Many bacterial pathogens secrete proteins that activate host trypsinogen-like enzyme precursors, most notably the proenzymes of the blood coagulation and fibrinolysis systems. Staphylococcus aureus, an important human pathogen implicated in sepsis and endocarditis, secretes the cofactor staphylocoagulase, which activates prothrombin, without the usual proteolytic cleavages, to directly initiate blood clotting. Here we present the 2.2 A crystal structures of human alpha-thrombin and prethrombin-2 bound to a fully active staphylocoagulase variant. The cofactor consists of two domains, each with three-helix bundles; this is a novel fold that is distinct from known serine proteinase activators, particularly the streptococcal plasminogen activator streptokinase. The staphylocoagulase fold is conserved in other bacterial plasma-protein-binding factors and extracellular-matrix-binding factors. Kinetic studies confirm the importance of isoleucine 1 and valine 2 at the amino terminus of staphylocoagulase for zymogen activation. In addition to making contacts with the 148 loop and (pro)exosite I of prethrombin-2, staphylocoagulase inserts its N-terminal peptide into the activation pocket of bound prethrombin-2, allosterically inducing functional catalytic machinery. These investigations demonstrate unambiguously the validity of the zymogen-activation mechanism known as 'molecular sexuality'.     

PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes

DNA microarrays can be used to identify gene expression changes characteristic of human disease. This is challenging, however, when relevant differences are subtle at the level of individual genes. We introduce an analytical strategy, Gene Set Enrichment Analysis, designed to detect modest but coordinate changes in the expression of groups of functionally related genes. Using this approach, we identify a set of genes involved in oxidative phosphorylation whose expression is coordinately decreased in human diabetic muscle. Expression of these genes is high at sites of insulin-mediated glucose disposal, activated by PGC-1alpha and correlated with total-body aerobic capacity. Our results associate this gene set with clinically important variation in human metabolism and illustrate the value of pathway relationships in the analysis of genomic profiling experiments.     

Phylogeography: English elm is a 2,000-year-old Roman clone

The outbreak of Dutch elm disease in the 1970s ravaged European elm populations, killing more than 25 million trees in Britain alone; the greatest impact was on Ulmus procera, otherwise known as the English elm. Here we use molecular and historical information to show that this elm derives from a single clone that the Romans transported from Italy to the Iberian peninsula, and from there to Britain, for the purpose of supporting and training vines. Its highly efficient vegetative reproduction and its inability to set seeds have preserved this clone unaltered for 2,000 years as the core of the English elm population--and the preponderance of this susceptible variety may have favoured a rapid spread of the disease.     

Identification of protein pheromones that promote aggressive behaviour

Mice use pheromones, compounds emitted and detected by members of the same species, as cues to regulate social behaviours such as pup suckling, aggression and mating. Neurons that detect pheromones are thought to reside in at least two separate organs within the nasal cavity: the vomeronasal organ (VNO) and the main olfactory epithelium (MOE). Each pheromone ligand is thought to activate a dedicated subset of these sensory neurons. However, the nature of the pheromone cues and the identity of the responding neurons that regulate specific social behaviours are largely unknown. Here we show, by direct activation of sensory neurons and analysis of behaviour, that at least two chemically distinct ligands are sufficient to promote male-male aggression and stimulate VNO neurons. We have purified and analysed one of these classes of ligand and found its specific aggression-promoting activity to be dependent on the presence of the protein component of the major urinary protein (MUP) complex, which is known to comprise specialized lipocalin proteins bound to small organic molecules. Using calcium imaging of dissociated vomeronasal neurons (VNs), we have determined that the MUP protein activates a sensory neuron subfamily characterized by the expression of the G-protein Galpha(o) subunit (also known as Gnao) and Vmn2r putative pheromone receptors (V2Rs). Genomic analysis indicates species-specific co-expansions of MUPs and V2Rs, as would be expected among pheromone-signalling components. Finally, we show that the aggressive behaviour induced by the MUPs occurs exclusively through VNO neuronal circuits. Our results substantiate the idea of MUP proteins as pheromone ligands that mediate male-male aggression through the accessory olfactory neural pathway.     

New models of collaboration in genome-wide association studies: the Genetic Association Information Network

The Genetic Association Information Network (GAIN) is a public-private partnership established to investigate the genetic basis of common diseases through a series of collaborative genome-wide association studies. GAIN has used new approaches for project selection, data deposition and distribution, collaborative analysis, publication and protection from premature intellectual property claims. These demonstrate a new commitment to shared scientific knowledge that should facilitate rapid advances in understanding the genetics of complex diseases.     

Genome sequence, comparative analysis and haplotype structure of the domestic dog

Here we report a high-quality draft genome sequence of the domestic dog (Canis familiaris), together with a dense map of single nucleotide polymorphisms (SNPs) across breeds. The dog is of particular interest because it provides important evolutionary information and because existing breeds show great phenotypic diversity for morphological, physiological and behavioural traits. We use sequence comparison with the primate and rodent lineages to shed light on the structure and evolution of genomes and genes. Notably, the majority of the most highly conserved non-coding sequences in mammalian genomes are clustered near a small subset of genes with important roles in development. Analysis of SNPs reveals long-range haplotypes across the entire dog genome, and defines the nature of genetic diversity within and across breeds. The current SNP map now makes it possible for genome-wide association studies to identify genes responsible for diseases and traits, with important consequences for human and companion animal health.     

Life cycles and host–parasitoid relationships of five species of Leucospis wasps in Argentina (Hymenoptera: Leucospidae)

The genus Leucospis Fabricius is comprised of parasitoid wasps relatively uncommon in nature. Their immature stages develop on aculeate Hymenoptera, in particular solitary bees, but hosts are known for only around 25 Leucospis species (about 20% of 115–120 world species), so the true relationship of this family with bees is largely unknown. Here we report on individuals of five species of Leucospis wasps which emerged from nests of different bee and wasp species during distinct sampling periods during a trap-nesting programme, in two contrasting areas: agro-ecosystems and natural habitats in the Pampean region. Some of these nests were parasitised by L. cayennensis Westwood, L. coxalis Kirby, L. egaia Walker, L. pulchriceps Cameron and L. signifera Bou?ek. Our results expand the available information of host species for L. cayennensis, L. coxalis, L. egaia and L. pulchriceps and represent the first record of hosts associated with L. signifera. The hosts were only bee species of the genera Centris, Tetrapedia (family Apidae) and Megachile (Megachilidae). These species were more abundant in the natural reserve than in agro-ecosystems, suggesting that anthropogenic activities could negatively affect their populations. Most nests were attacked in one (43.7%) or two (40.7%) cells, but the remaining nests (16.5%) had more (up to seven cells). However, the position of the attacked cells was variable, suggesting that females of Leucospis species oviposit in recently built cells, and that the hatching of larvae is delayed, or that the first larval stage waits until the host larva reaches a sufficient size to attack.