Structural basis for synthesis of inflammatory mediators by human leukotriene C4 synthase

Cysteinyl leukotrienes are key mediators in inflammation and have an important role in acute and chronic inflammatory diseases of the cardiovascular and respiratory systems, in particular bronchial asthma. In the biosynthesis of cysteinyl leukotrienes, conversion of arachidonic acid forms the unstable epoxide leukotriene A4 (LTA4). This intermediate is conjugated with glutathione (GSH) to produce leukotriene C4 (LTC4) in a reaction catalysed by LTC4 synthase: this reaction is the key step in cysteinyl leukotriene formation. Here we present the crystal structure of the human LTC4 synthase in its apo and GSH-complexed forms to 2.00 and 2.15 A resolution, respectively. The structure reveals a homotrimer, where each monomer is composed of four transmembrane segments. The structure of the enzyme in complex with substrate reveals that the active site enforces a horseshoe-shaped conformation on GSH, and effectively positions the thiol group for activation by a nearby arginine at the membrane-enzyme interface. In addition, the structure provides a model for how the omega-end of the lipophilic co-substrate is pinned at one end of a hydrophobic cleft, providing a molecular 'ruler' to align the reactive epoxide at the thiol of glutathione. This provides new structural insights into the mechanism of LTC4 formation, and also suggests that the observed binding and activation of GSH might be common for a family of homologous proteins important for inflammatory and detoxification responses.     

Pneumococcal genome sequencing tracks a vaccine escape variant formed through a multi-fragment recombination event

Streptococcus pneumoniae ('pneumococcus') causes an estimated 14.5 million cases of serious disease and 826,000 deaths annually in children under 5 years of age(1). The highly effective introduction of the PCV7 pneumococcal vaccine in 2000 in the United States(2,3) provided an unprecedented opportunity to investigate the response of an important pathogen to widespread, vaccine-induced selective pressure. Here, we use array-based sequencing of 62 isolates from a US national monitoring program to study five independent instances of vaccine escape recombination(4), showing the simultaneous transfer of multiple and often large (up to at least 44 kb) DNA fragments. We show that one such new strain quickly became established, spreading from east to west across the United States. These observations clarify the roles of recombination and selection in the population genomics of pneumococcus and provide proof of principle of the considerable value of combining genomic and epidemiological information in the surveillance and enhanced understanding of infectious diseases.     

Aristotle’s Difficult Relationship With Modern Economic Theory

This paper reviews Aristotle’s problematic relationship with modern economic theory. It argues that in terms of value and income distribution theory, Aristotle should probably be seen as a precursor to neither classical nor neoclassical economic thought. Indeed, there are strong arguments to be made that Aristotle’s views are completely at odds with all modern economic theory, since, among other things, he was not necessarily concerned with flexible market prices, opposed the use of money to acquire more money, and did not think that the unintended consequences of human activity were generally beneficial. The paper argues however, that this interpretation goes too far. The Benthamite neoclassical theory of choice can be seen as a dumbing down of Aristotle’s theory, applicable to animals, not humans. Adam Smith and Karl Marx were deeply influenced by Aristotle’s work and both started their main economic works with Aristotle: Smith ultimately rejecting, and Marx ultimately developing Aristotle’s views of the use of money to acquire more money. Possibilities for the future development of a new Aristotelian Economics are explored.     

Aquatic Oligochaeta (Annelida: Lumbriculidae, Haplotaxidae, Naididae, Tubificidae) of Utah

Thirty-six species of aquatic Oligochaeta (Lumbriculidae, Haplotaxidae, Naididae, Tubificidae) are now known form Utah. Aquatic habitats in 27 counties were sampled, with 32 oligochaete species identified. An additional 4 species were added from other published investigations. The majority of species are cosmopolitan and occur in other areas of North America. Nais barbata, N. alpina, and N. pardalis are reported from the western United States for the first time. Ilyodrilus frantzi was found to be a major component of the oliogochaete fauna in the Great Basin lentic environment. The North American distribution of Telmatodrilus vejdovskyi is extended significantly eastward. Tow undetermined species of Tubificidae are discussed.     

Phospholipase Cgamma1 controls surface expression of TRPC3 through an intermolecular PH domain

Many ion channels are regulated by lipids, but prominent motifs for lipid binding have not been identified in most ion channels. Recently, we reported that phospholipase Cgamma1 (PLC-gamma1) binds to and regulates TRPC3 channels, components of agonist-induced Ca2+ entry into cells. This interaction requires a domain in PLC-gamma1 that includes a partial pleckstrin homology (PH) domain-a consensus lipid-binding and protein-binding sequence. We have developed a gestalt algorithm to detect hitherto 'invisible' PH and PH-like domains, and now report that the partial PH domain of PLC-gamma1 interacts with a complementary partial PH-like domain in TRPC3 to elicit lipid binding and cell-surface expression of TRPC3. Our findings imply a far greater abundance of PH domains than previously appreciated, and suggest that intermolecular PH-like domains represent a widespread signalling mode.