2-Arylbenzoxazoles as CETP inhibitors: raising HDL-C in cynoCETP transgenic mice

We describe structure-activity studies leading to the discovery of 2-arylbenzoxazole 3, the first in a series to raise serum high-density lipoprotein cholesterol levels in transgenic mice. Replacement of the 4-piperidinyloxy moiety with piperazinyl provided a more synthetically tractable lead, which upon optimization resulted in compound 4, an excellent inhibitor of cholesteryl ester transfer protein function with good pharmacokinetic properties and in vivo efficacy.     

Evolution and taxonomy of the wild species of the genus Ovis (Mammalia,Artiodactyla, Bovidae)

New insights for the systematic and evolution of the wild sheep are provided by molecular phylogenies inferred from Maximum parsimony, Bayesian, Maximum likelihood, and Neighbor-Joining methods. The phylogeny of the wild sheep was based on cytochrome b sequences of 290 samples representative of most of the sub-species described in the genus Ovis. The result was confirmed by a combined tree based on cytochrome b and nuclear sequences for 79 Ovis samples representative of the robust clades established with mitochondrial data. Urial and mouflon, which are either considered as a single or two separate species, form two monophyletic groups (O. orientalis and O. vignei). Their hybrids appear in one or the other group, independently from their geographic origin. The European mouflon O. musimon is clearly in the O. orientalis clade. The others species, O. dalli, O. canadensis, O. nivicola, and O. ammon are monophyletic. The results support an Asiatic origin of the genus Ovis, followed by a migration to North America through North-Eastern Asia and the Bering Strait and a diversification of the genus in Eurasia less than 3 million years ago. Our results show that the evolution of the genus Ovis is a striking example of successive speciation events occurring along the migration routes propagating from the ancestral area.     

Synthesis and characterization of Sn(IV) complexes of lower rim 1,3-diacid derivative of calix[4]arene and their protective effects on tissue oxidative stress and essential metal concentration in lead exposed male Wistar rats

The two Sn(IV) complexes synthesized using calix[4]arene-1,3-di-acid derivative were characterized by analytical, (1)H, (13)C and (119)Sn NMR, matrix assisted laser desorption ionization mass, and (119)Sn Mossbauer techniques and found that the complexes are tetranuclear possessing structurally two different types of tin centers. These complexes were evaluated for their protective value against blood and tissue oxidative stress in lead exposed male albino rats of Wistar strain. The results suggest that the two tin complexes significantly protect changes in lead induced biochemical variables indicative of heme synthesis pathway and exhibit only moderate effect on tissue oxidative stress. The beneficial effects could be attributed mainly to the ability of Sn(IV) complexes in preventing absorption of lead to the target sites/tissues.     

Complete Genome Sequences of Corynebacterium pseudotuberculosis Strains 3/99-5 and 42/02-A, Isolated from Sheep in Scotland and Australia, Respectively

Here, we report the whole-genome sequences of two ovine-pathogenic Corynebacterium pseudotuberculosis isolates: strain 3/99-5, which represents the first C. pseudotuberculosis genome originating from the United Kingdom, and 42/02-A, the second from Australia. These genome sequences will contribute to the objective of determining the global pan-genome of this bacterium.     

FRS2 PTB domain conformation regulates interactions with divergent neurotrophic receptors

Membrane-anchored adaptor proteins FRS2alpha/beta (also known as SNT-1/2) mediate signaling of fibroblast growth factor receptors (FGFRs) and neurotrophin receptors (TRKs) through their N-terminal phosphotyrosine binding (PTB) domains. The FRS2 PTB domain recognizes tyrosine-phosphorylated TRKs at an NPXpY (where pY is phosphotyrosine) motif, whereas its constitutive association with FGFR involves a receptor juxtamembrane region lacking Tyr and Asn residues. Here we show by isothermal titration calorimetry that the FRS2alpha PTB domain binding to peptides derived from TRKs or FGFR is thermodynamically different. TRK binding is largely enthalpy-driven, whereas the FGFR interaction is governed by a favorable entropic contribution to the free energy of binding. Furthermore, our NMR spectral analysis suggests that disruption of an unstructured region C-terminal to the PTB domain alters local conformation and dynamics of the residues at the ligand-binding site, and that structural disruption of the beta8-strand directly weakens the PTB domain association with the FGFR ligand. Together, our new findings support a molecular mechanism by which conformational dynamics of the FRS2alpha PTB domain dictates its association with either fibroblast growth factor or neurotrophin receptors in neuronal development.