Quantification of endothelin receptor subtypes in peripheral tissues reveals downregulation of ET(A) receptors in ET(B)-deficient mice

We have previously shown that in homozygous endothelin (ET)(B)-/- deficient mice, ET(A) receptor density is significantly downregulated in the brain by 45%. In these mice, plasma ET-1 levels are elevated. Our aim was to use quantitative autoradiography to establish the distribution of ET receptor subtypes in peripheral tissues from wild-type mice and to measure the density of the ET(A) subtype in ET(B)-/- knockout animals. Our second aim was to test whether deletion of ET(B) receptors, which is associated with elevated plasma levels of ET-1, would also reduce ET(A) expression in the periphery. In longitudinal sections from wild-type mice, the highest densities of ET(A) receptors localized to major organs including the ventricle of the heart, lung, and liver parenchyma. High densities of ET(A) receptors were detected in the smooth muscle layer of the vasculature such as intrarenal vessels as well as the smooth muscle layer and epithelial cells of the gastrointestinal tract. In these tissues, the ET(A) subtype was more abundant, representing between 60% and 100% of the ET receptors. ET(B) receptors predominated in the medulla of kidney, with high densities also localizing to glomeruli within the cortex and to the sinusoids from the liver. Lower densities of ET(B) receptors were also present in the lung, heart, liver, and the smooth muscle layer of the gastrointestinal tract. In ET(B)-/- knockout mice, ET(B) receptors were not detected as expected by either ligand binding or immunocytochemistry. The pattern of ET(A) receptor distribution in the ET(B)-/- knockout mice was similar to the controls, but the density of ET(A) receptors was significantly reduced in the lung by 39%. Diminished responses to the endogenous agonist after repeated stimulation are an important feature of G-protein signaling, preventing potential damage to the overstimulated cell, and it is likely that downregulation occurs in response to higher circulating levels of ET-1.     

Colitis induced by proteinase-activated receptor-2 agonists is mediated by a neurogenic mechanism

Proteinase-activated receptor-2 (PAR2) activation induces colonic inflammation by an unknown mechanism. We hypothesized that PAR2 agonists administered intracolonically in mice induce inflammation via a neurogenic mechanism. Pretreatment of mice with neurokinin-1 and calcitonin-gene-related peptide (CGRP) receptor antagonists or with capsaicin showed attenuated PAR2-agonist-induced colitis. Immunohistochemistry demonstrated a differential expression of a marker for the type-1 CGRP receptor during the time course of PAR2-agonist-induced colitis, further suggesting a role for CGRP. We conclude that PAR2-agonist-induced intestinal inflammation involves the release of neuropeptides, which by acting on their receptors cause inflammation. These results implicate PAR2 as an important mediator of intestinal neurogenic inflammation.     

Hemispheric dissociation in access to the human semantic system

Patient studies suggest that speech and environmental sounds are differentially processed by the left and right hemispheres. Here, using functional imaging in normal subjects, we compared semantic processing of spoken words to equivalent processing of environmental sounds, after controlling for low-level perceptual differences. Words enhanced activation in left anterior and posterior superior temporal regions, while environmental sounds enhanced activation in a right posterior superior temporal region. This left/right dissociation was unchanged by different attentional/working memory contexts, but it was specific to tasks requiring semantic analysis. While semantic processing involves widely distributed networks in both hemispheres, our results support the hypothesis of a dual access route specific for verbal and nonverbal material, respectively.     

River Red Gum (Eucalyptus camaldulensis Dehnh.) organic matter as a carbon source in the lower Darling River,Australia

The Darling River, in New South Wales, Australia, is a large semi-arid system with a highly variable flow regime, characterised by unpredictable events of flooding and drought. In large lowland rivers like the Darling, lateral (river-floodplain) interactions can greatly influence both physical and biological components of the system. The floodplain and riparian zone of the Darling River is dominated by River Red Gum (RRG), Eucalyptus camaldulensis. The large amount of organic matter they produce accumulates on the floodplain and on benches within the channel, and is subject to alternate periods of flooding and drying as a result of highly variable flows. This paper examines the effect of alternate periods of flooding and drying on the processing of E. camaldulensis organic matter. Results of the 6-month in situ field study, together with results from laboratory experiments comparing dissolved organic carbon (DOC) release from various RRG litter types, suggest that RRG leaves provide the most bio-available source of carbon to the system, while bark may be more important as a habitat for invertebrates and other fauna. Laboratory experiments exploring the effect of drying and re-flooding on litter breakdown and release of DOC suggested that the majority of DOC was released from RRG leaves in the first 24 h of inundation. Also, upon drying and re-flooding of the leaves, a smaller but significant release of DOC occurred. However, an alternative wet/dry cycle did not affect weight loss of the leaf litter. Results of the field and lab experiments suggest that RRG leaves represent an important source of carbon to the Darling River, with inputs being influenced by the highly variable flow regime.     

Novel 3-O-carbamoyl erythromycin A derivatives (carbamolides) with activity against resistant staphylococcal and streptococcal isolates

A novel series of 3-O-carbamoyl erythromycin A derived analogs, labeled carbamolides, with activity versus resistant bacterial isolates of staphylococci (including macrolide and oxazolidinone resistant strains) and streptococci are reported. An (R)-2-aryl substituent on a pyrrolidine carbamate appeared to be critical for achieving potency against resistant strains. Crystal structures showed a distinct aromatic interaction between the (R)-2-aryl (3-pyridyl for 4d) substituent on the pyrrolidine and G2484 (G2505, Escherichia coli) of the Deinococcus radiodurans 50S ribosome (3.2 Å resolution).     

Cover,not caging,influences chronic physiological stress in a ground‐nesting bird

Predator exclosures (‘nest cages’) around nests are increasingly used to enhance hatching success of declining ground‐nesting birds. However, such exclosures are contentious and have been suggested to have detrimental effects on the species which they aim to protect. This study examines whether exclosures increase physiological stress of incubating birds, a hitherto unrecognised and untested potential drawback of exclosures. Red‐capped plover Charadrius ruficapillus hatching success was radically altered and significantly higher for nests with exclosures (96.2%) compared with those without (6.8%). Chronic physiological stress in parents (as measured by the heterophil/lymphocyte [H/L] ratio in blood) did not vary between nests with and without exclosures, or between the sexes. However the absence of vegetative cover at the nest site was associated with a 62.7% elevation in H/L ratio, indicating that incubating birds which place their nests in the open are subject to increased levels of chronic stress. The results from this study demonstrate the fundamental importance of predation for the nesting success of this species and confirm that chronic stress levels are not a detrimental side effect of exclosure use.