A Gly/Ala switch contributes to high affinity binding of benzoxazinone-based non-peptide oxytocin receptor antagonists

Non-peptide antagonists of the oxytocin receptor (OTR) have been developed to prevent pre-term labour. The benzoxazinone-based antagonists L-371,257 and L-372,662 display pronounced species-dependent pharmacology with respect to selectivity for the OTR over the V(1a) vasopressin receptor. Examination of receptor sequences from different species identified Ala(318) in helix 7 of the human OTR as a candidate discriminator required for high affinity binding. The mutant receptor [A318G]OTR was engineered and characterised using ligands representing many different chemical classes. Of all the ligands investigated, only the benzoxazinone-based antagonists had decreased affinity for [A318G]OTR. Molecular modelling revealed that Ala(318) provides a direct hydrophobic contact with a methoxy group of L-371,257 and L-372,662.     

Crystal structure of the kainate receptor GluR5 ligand-binding core in complex with (S)-glutamate

The X-ray structure of the ligand-binding core of the kainate receptor GluR5 (GluR5-S1S2) in complex with (S)-glutamate was determined to 1.95 A resolution. The overall GluR5-S1S2 structure comprises two domains and is similar to the related AMPA receptor GluR2-S1S2J. (S)-glutamate binds as in GluR2-S1S2J. Distinct features are observed for Ser741, which stabilizes a highly coordinated network of water molecules and forms an interdomain bridge. The GluR5 complex exhibits a high degree of domain closure (26 degrees) relative to apo GluR2-S1S2J. In addition, GluR5-S1S2 forms a novel dimer interface with a different arrangement of the two protomers compared to GluR2-S1S2J.     

Structure of the house dust mite allergen Der f 2: implications for function and molecular basis of IgE cross-reactivity

The X-ray structure of the group 2 major allergen from Dermatophagoides farinae (Der f 2) was determined to 1.83 A resolution. The overall Der f 2 structure comprises a single domain of immunoglobulin fold with two anti-parallel beta-sheets. A large hydrophobic cavity is formed in the interior of Der f 2. Structural comparisons to distantly related proteins suggest a role in lipid binding. Immunoglobulin E (IgE) cross-reactivity between group 2 house dust mite major allergens can be explained by conserved surface areas representing IgE binding epitopes.     

Diuretic factors and second messengers stimulate secretion of the organic cation TEA by the Malpighian tubules of Drosophila melanogaster

This study showed that four factors which stimulate transepithelial fluid secretion and inorganic ion transport across the main segment of the Malpighian tubules of Drosophila melanogaster also stimulate transepithelial secretion of the prototypical organic cation tetraethylammonium (TEA). TEA fluxes across the Malpighian tubules and gut were measured using a TEA-selective self-referencing (TEA-SeR) microelectrode. TEA flux across isolated Malpighian tubules was also measured using a TEA-selective microelectrode positioned in droplets of fluid secreted by tubules set up in a modified Ramsay assay. TEA flux was stimulated by the intracellular second messengers cAMP and cGMP, which increase the lumen-positive transepithelial potential (TEP), and also by tyramine and leucokinin-I (LK-I), which decrease TEP. The largest increase was measured in response to 1 micromol l-1 LK-I which increased transepithelial TEA flux by 72%. TEA flux in the lower tubule was stimulated slightly (13%) by 1 micromol l-1 tyramine but not by any of the other factors. TEA flux across the midgut was unaffected by cAMP, cGMP or tyramine. This is the first study to demonstrate the effects of insect diuretic factors and second messengers on excretion of organic cations.     

The role of CD1d in the immune response against Listeria infection

To address the role of CD1d in mucosal immune regulation in bacterial infection, we infected CD1d KO mice with Listeria monocytogenes (Lm). A higher systemic bacterial burden associated with inflammatory lymphocytic infiltrations within the intestine was found in CD1d KO compared with wild type (WT) mice. Lm induced strong IFN-gamma mRNA expression in the liver of WT and the intestine of CD1d KO mice, thus demonstrating the dual, opposing immune activities of IFN-gamma in Lm infection that is dependent on CD1d and/or NKT cells. Analysis of hepatic T cell population demonstrated a reduction of NK1.1(+)TCRbeta+ cells in both mice, followed by recovery only in WT mice. Last, the proportion of alpha4beta1 integrin on lung lymphocytes from CD1d KO was dramatically increased compared with WT mice. Thus, the absence of CD1d resulted in increased susceptibility towards Listeria infection, induced changes in NKT cells, and increased trafficking of alpha4beta1 molecule to inflamed lung.     

Role of carnivores in the accumulation of the Sterkfontein Member 4 hominid assemblage: a taphonomic reassessment of the complete hominid fossil sample (1936-1999)

New taphonomic data on the Sterkfontein Member 4 (South Africa) fossil hominid assemblage are presented. The previous estimate of hominid individuals represented in the deposit (45) is increased to 87. New minimum numbers of hominid skeletal elements are provided, and incidences of bone surface damage inflicted by prehistoric biological agents are summarized. The hominid sample from Member 4 is composed predominately of gnathic remains and has a paucity of postcrania. This dearth of postcrania limits, to some extent, inferences about the formation of the Sterkfontein assemblage. However, carnivore tooth marks on some fossil specimens and an overall broad similarity in patterns of skeletal part representation between Sterkfontein and primate bone assemblages created by extant carnivores suggest that carnivores did have some involvement in the accumulation of the fossil hominid assemblage. Thus, this study provides support for the “carnivore‐collecting hypothesis” of Brain (Brain [ 1981 ] The Hunters or the Hunted? Chicago: University of Chicago Press), which implicates large carnivores as prominent collecting agents of hominid body parts in Sterkfontein Member 4. Evidence of bone surface damage is, however, too scant to make confident inferences about specific carnivore taxon/taxa involved in hominid bone collection at the site. Am J Phys Anthropol, 2004. © 2004 Wiley‐Liss, Inc.     

Binding of arachidonic acid to myeloid-related proteins (S100A8/A9) enhances phagocytic NADPH oxidase activation

Activation of the O(2)(-) generating NADPH oxidase of phagocytes results from the assembly of the membrane-bound flavocytochrome b(558) with cytosolic proteins, p67(phox), p47(phox), and Rac. However, it has been recently reported that the arachidonic acid- and calcium-binding heterodimer S100A8/A9, abundant in neutrophil cytosol, influences the activation process. In a semi-recombinant system comprising neutrophil membranes, recombinant proteins, p67(phox), p47(phox), GTPgamma S-loaded Rac2, and arachidonic acid (AA), both the rate and the extent of the oxidase activation were increased by S100A8/A9, provided it was preloaded with AA. Binding of [(14)C]AA to S100A8/A9 was potentiated by recombinant cytosolic phox proteins and GTPgammaS, suggesting the formation of a complex, comprising oxidase activating proteins and S100A8/A9, with a greater affinity for AA. The rate constant of oxidase activation was not increased by AA-loaded S100A8/A9, whereas the maximal oxidase activity elicited was twice as high. AA-loaded S100A8/A9 increases oxidase activation probably by decreasing the deactivation rate.     

Restoration principles applied to cultural landscapes

Restoration models and practise to date have been applied mainly to ecosystems. More recently, there has been a focus on the “landscape perspective” of ecosystem restoration in order to improve nature conservation and management effectiveness.

Here, we clarify some of the differences between ecosystem- and landscape-oriented restoration, and propose four components that should be considered in planning and conceptualising: (a) landscape composition and configuration; (b) traditional land management techniques; (c) linear and point features; and (d) other heritage features. We further discuss the concept of reference landscapes, and the contrasts between restoration and rehabilitation. Spatial approaches to restoration are explored, comparing small areas with complete restoration (“museum landscapes”) from large areas with rehabilitation of landscape physiognomy or point and linear features. The linkages with nature conservation and the sustainable use and management of natural resources are examined in the context of a rapidly changing world.     

Personality-dependent dispersal: characterization, ontogeny and consequences for spatially structured populations

Dispersal is one of the most fundamental components of ecology, and affects processes as diverse as population growth, metapopulation dynamics, gene flow and adaptation. Although the act of moving from one habitat to another entails major costs to the disperser, empirical and theoretical studies suggest that these costs can be reduced by having morphological, physiological or behavioural specializations for dispersal. A few recent studies on different systems showed that individuals exhibit personality-dependent dispersal, meaning that dispersal tendency is associated with boldness, sociability or aggressiveness. Indeed, in several species, dispersers not only develop behavioural differences at the onset of dispersal, but display these behavioural characteristics through their life cycle. While personality-dependent dispersal has been demonstrated in only a few species, we believe that it is a widespread phenomenon with important ecological consequences. Here, we review the evidence for behavioural differences between dispersers and residents, to what extent they constitute personalities. We also examine how a link between personality traits and dispersal behaviours can be produced and how personality-dependent dispersal affects the dynamics of metapopulations and biological invasions. Finally, we suggest future research directions for population biologists, behavioural ecologists and conservation biologists such as how the direction and the strength of the relationship between personality traits and dispersal vary with ecological contexts.