Structure-Activity relationships of 2-substituted 5,7-Diarylcyclopenteno[1,2-b]pyridine-6-carboxylic acids as a novel class of endothelin receptor antagonists

Synthesis and structure-activity relationships of 2-substituted-5,7-diarylcyclopenteno[1,2-b]pyridine-6-carboxylic acids, a novel class of endothelin receptor antagonists, were described. Derivatization of a lead structure 1 (IC(50)=2.4nM, 170-fold selectivity) by incorporating a substituent such as an alkyl, alkoxy, alkylthio, or alkylamino group into the 2-position of the cyclopenteno[1,2-b]pyridine skeleton was achieved via the key intermediate 8. Introduction of an alkyl group led to the identification of potent ET(A)/ET(B) mixed receptor antagonists, a butyl (2d: IC(50)=0.21nM, 52-fold selectivity) and an isobutyl (2f: IC(50)=0.32nM, 26-fold selectivity) analogue. In contrast, installment of a primary amino group resulted in ET(A) selective antagonists, a propylamino 2p (IC(50)=0.12nM, 520-fold selectivity) and an isopropylamino 2q (IC(50)=0.10nM, 420-fold selectivity) analogue. These results suggested that a substituent at the 2-position of the 5,7-diarylcyclopenteno[1,2-b]pyridine-6-carboxylic acids played a key role in the binding affinity for both ET(A) and ET(B) receptors.     

Massive spawning behavior of the triplespine deepwater cardinalfish <Emphasis Type="Italic">Sphyraenops bairdianus</Emphasis> Poey, 1861 observed on an offshore sea mount in the West Mariana Ridge

Using a hydrographic echo sounder, we encountered an animal aggregation on a sea mount summit (350 m deep) at the West Mariana Ridge (14°07’ N, 142°48′ E). The aggregation suddenly ascended from the summit at civil dawn, and we were able to capture the ascending aggregation at the next dawn using a large midwater trawl net. Hundreds of fishes captured were determined to be Sphyraenops bairdianus (Poey, 1861). Hydrated eggs in the ovary were histologically confirmed, indicating that this species performed a massive spawning associated with an offshore sea mount and sunrise.     

Catalytic versatility of Bacillus pumilus beta-xylosidase: glycosyl transfer and hydrolysis promoted with alpha- and beta-D-xylosyl fluoride

Bacillus pumilus beta-xylosidase, an enzyme considered restricted to hydrolyzing a narrow range of beta-D-xylosidic substrates with inversion of configuration, was found to catalyze different stereochemical, essentially irreversible, glycosylation reactions with alpha- and beta-D-xylopyranosyl fluoride. The enzyme promoted the hydrolysis of beta-D-xylopyranosyl fluoride at a high rate, V = 6.25 mumol min-1 mg-1 at 0 degrees C, in a reaction that obeyed Michaelis-Menten kinetics. In contrast, its action upon alpha-D-xylopyranosyl fluoride was slow and characterized by an unusual relation between the rate of fluoride release and the substrate concentration, suggesting the possible need for two substrate molecules to be bound at the active center in order for reaction to occur. Moreover, 1H NMR spectra of a digest of alpha-D-xylosyl fluoride showed the substrate to be specifically converted to alpha-D-xylose by the enzyme. The observed retention of configuration is not consistent with direct hydrolysis by this "inverting" enzyme but is strongly indicative of the occurrence of two successive inverting reactions: xylosyl transfer from alpha-D-xylosyl fluoride to form a beta-D-xylosidic product, followed by hydrolysis of the latter to produce alpha-D-xylose. The transient intermediate product formed enzymically from alpha-D-xylosyl fluoride in the presence of [14C]xylose was isolated and shown by its specific radioactivity and 1H NMR spectrum as well as by methylation and enzymic analyses to be 4-O-beta-D-xylopyranosyl-D-xylopyranose containing one [14C]xylose residue.(ABSTRACT TRUNCATED AT 250 WORDS)     

Phylogeography study of Ammodytes personatus in Northwestern Pacific: Pleistocene isolation, temperature and current conducted secondary contact

To assess the role of historical process and contemporary factors in shaping population structures in Northwestern Pacific, mitochondrial control region sequences were analyzed to characterize the phylogeography and population structure of the Japanese sand lance Ammodytes personatus. A total of 429 individuals sampled from 17 populations through the species' range are sequenced. Two distinct lineages are detected, which might have been divergent in the Sea of Japan and Pacific costal waters of Japanese Island, during the low sea level. Significant genetic structure is revealed between the Kuroshio and Oyashio Currents. However, significant genetic structure is also detected in the Sea of Japan, contracting expected homogenization hypothesis in Tsushima Current. The haplotype frequency of lineages in both sides of Japanese Island and significant genetic structure between north and south groups revealed that the distribution of lineage B and north group were highly limited by the annual sea temperature. The lack of lineage B in Qingdao population with low sea temperature reflects the sea temperature barrier. Lack of genetic structure in the south group and north group populations indicated that ocean currents within groups facilitated the dispersal of A. personatus.     

Genetic diversity in the mtDNA control region and population structure in the small yellow croaker <Emphasis Type="Italic">Larimichthys polyactis</Emphasis>

The genetic diversity and population genetic structure of the small yellow croaker (Larimichthys polyactis) were investigated. One hundred and fourteen individuals were sampled from 8 localities of the Yellow Sea and the northern East China Sea. Genetic variation in DNA sequences were examined from the first hypervariable region (HVR-1) of the mitochondrial DNA control region. High levels of haplotype diversity (h = 0.98 ± 0.87%) in the HVR-1 region were detected, indicating a high level of genetic diverstiy. A total of 84 polymorphic sites were found, and 87 haplotypes were defined. The pairwise nucleotide differences between samples ranged from 3.83 ± 2.19 to 6.56 ± 3.25. The demographic history of L. polyactis was examined by using neutrality tests and mismatch distribution analysis, which indicated a Pleistocene population expansion at about 49,300–197,000 years. The star burst structure of the minimum spanning tree also suggestted a very recent origin for most haplotypes. Hierarchical molecular variance analysis (AMOVA) and conventional population Fst comparisons revealed no significant genetic structure throughout the examined range, which is inconsistent with previous findings based on the morphological and ecological studies. Long-term dispersal and high gene flow likely have contributed to the genetically homogeneous population structure of the species. The knowledge on genetic diversity and genetic structure will be crucial to establish appropriate fishery management stocks for the species.     

Effects of muscle metaboreceptor stimulation on cutaneous blood flow from glabrous and nonglabrous skin in mildly heated humans.

Given differences in sympathetic innervation to glabrous and nonglabrous skin, we tested the hypothesis that muscle metaboreceptor regulation of cutaneous vascular conductance (CVC) differs between these skin regions. Subjects (n = 21) performed isometric handgrip exercise (IHG; 50% maximal voluntary contraction for 60 s), followed by 2 min of postexercise ischemia. Throughout IHG and postexercise ischemia, CVC was measured from glabrous (palm) and nonglabrous (forearm and chest) regions contralateral to the exercising arm. These procedures were conducted after the subjects had been exposed to an ambient temperature of 35 degrees C and a relative humidity of 50% for 60 min. These thermal conditions were intended to cause slight increases in cutaneous blood flow via sympathetic withdrawal. Esophageal, sublingual, and mean skin temperatures did not change markedly during IHG or postexercise ischemia. During IHG, forearm CVC did not change, chest CVC increased slightly, and palm CVC decreased substantially (from 100 to 34.8 +/- 3.5%; P = 0.001). During muscle metaboreceptor stimulation due to postexercise ischemia, CVC from nonglabrous regions returned to preexercise baselines, whereas CVC at the palm remained below preexercise baseline (68.2 +/- 4.2%; P = 0.001 relative to preexercise baseline). These results indicate that in mildly heated humans muscle metaboreflex stimulation is capable of modulating CVC in glabrous, but not in nonglabrous, skin.