Synthesis and evaluation of novel tricyclic benzo[4.5]cyclohepta[1.2]pyridine derivatives as NMDA/NR2B antagonists

A novel series of annulated tricyclic compounds was synthesized and evaluated as NMDA/NR2B antagonists. Structure–activity development was directed towards in vitro optimization of NR2B activity and selectivity over the hERG K⁺ channel. Preferred compounds were subsequently evaluated for selectivity in an α₁-adrenergic receptor binding counter-screen and a cell-based assay of NR2B activity.     

Synthesis,initial SAR and biological evaluation of 1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-amine derived inhibitors of IκB kinase

A new series of tricyclic-based inhibitors of IKK have been derived from an earlier lead compound. The synthesis and structure–activity relationships (SAR) are described. Compound 4k inhibited TNF production in rats stimulated with LPS.     

Genetic control of wheat quality: interactions between chromosomal regions determining protein content and composition, dough rheology, and sponge and dough baking properties

While the genetic control of wheat processing characteristics such as dough rheology is well understood, limited information is available concerning the genetic control of baking parameters, particularly sponge and dough (S&D) baking. In this study, a quantitative trait loci (QTL) analysis was performed using a population of doubled haploid lines derived from a cross between Australian cultivars Kukri × Janz grown at sites across different Australian wheat production zones (Queensland in 2001 and 2002 and Southern and Northern New South Wales in 2003) in order to examine the genetic control of protein content, protein expression, dough rheology and sponge and dough baking performance. The study highlighted the inconsistent genetic control of protein content across the test sites, with only two loci (3A and 7A) showing QTL at three of the five sites. Dough rheology QTL were highly consistent across the 5 sites, with major effects associated with the Glu-B1 and Glu-D1 loci. The Glu-D1 5 + 10 allele had consistent effects on S&D properties across sites; however, there was no evidence for a positive effect of the high dough strength Glu-B1-al allele at Glu-B1. A second locus on 5D had positive effects on S&D baking at three of five sites. This study demonstrated that dough rheology measurements were poor predictors of S&D quality. In the absence of robust predictive tests, high heritability values for S&D demonstrate that direct selection is the current best option for achieving genetic gain in this product category. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Optimization of CCR4 antagonists: side-chain exploration

The design, synthesis, and activity of novel and selective small molecule antagonists of the CC chemokine receptor-4 (CCR4) are presented. Compound 8c was efficacious in a murine allergic inflammation model (ED(50) 30 mg/kg).     

Optimal allocation of Red List assessments to guide conservation of biodiversity in a rapidly changing world

The IUCN Red List is the most extensive source of conservation status assessments for species worldwide, but important gaps in coverage remain. Here, we demonstrate the use of a spatial prioritization approach to efficiently prioritize species assessments to achieve increased and up‐to‐date coverage efficiently. We focus on freshwater fishes, which constitute a significant portion of vertebrate diversity, although comprehensive assessments are available for only 46% of species. We used marxan to identify ecoregions for future assessments that maximize the coverage of species while accounting for anthropogenic stress. We identified a set of priority regions that would help assess one‐third (ca 4000 species) of all freshwater fishes in need of assessment by 2020. Such assessments could be achieved without increasing current investment levels. Our approach is suitable for any taxon and can help ensure that species threat assessments are sufficiently complete to guide global conservation efforts in a rapidly changing world.     

Predicting the ecological impacts of a new freshwater invader: functional responses and prey selectivity of the ‘killer shrimp’, Dikerogammarus villosus,compared to the native Gammarus pulex

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