Spirocyclic ureas: Orally bioavailable 11β-HSD1 inhibitors identified by computer-aided drug design

Structure-guided drug design led to the identification of a class of spirocyclic ureas which potently inhibit human 11β-HSD1 in vitro. Lead compound 10j was shown to be orally bioavailable in three species, distributed into adipose tissue in the mouse, and its (R) isomer 10j2 was efficacious in a primate pharmacodynamic model.     

Expression, purification and structural analysis of the Pyrococcus abyssi RNA binding protein PAB1135

Background

Epistatic interactions of multiple single nucleotide polymorphisms (SNPs) are now believed to affect individual susceptibility to common diseases. The detection of such interactions, however, is a challenging task in large scale association studies. Ant colony optimization (ACO) algorithms have been shown to be useful in detecting epistatic interactions.

Findings

AntEpiSeeker, a new two-stage ant colony optimization algorithm, has been developed for detecting epistasis in a case-control design. Based on some practical epistatic models, AntEpiSeeker has performed very well.

Conclusions

AntEpiSeeker is a powerful and efficient tool for large-scale association studies and can be downloaded from http://nce.ads.uga.edu/~romdhane/AntEpiSeeker/index.html.     

Complete genome sequence of Acetohalobium arabaticum type strain (Z-7288)

Veillonella parvula (Veillon and Zuber 1898) Prévot 1933 is the type species of the genus Veillonella in the family Veillonellaceae within the order Clostridiales. The species V. parvula is of interest because it is frequently isolated from dental plaque in the human oral cavity and can cause opportunistic infections. The species is strictly anaerobic and grows as small cocci which usually occur in pairs. Veillonellae are characterized by their unusual metabolism which is centered on the activity of the enzyme methylmalonyl-CoA decarboxylase. Strain Te3(T), the type strain of the species, was isolated from the human intestinal tract. Here we describe the features of this organism, together with the complete genome sequence, and annotation. This is the first complete genome sequence of a member of the large clostridial family Veillonellaceae, and the 2,132,142 bp long single replicon genome with its 1,859 protein-coding and 61 RNA genes is part of the Genomic Encyclopedia of Bacteria and Archaea project.     

Complete genome sequence of Archaeoglobus profundus type strain (AV18)

Archaeoglobus profundus (Burggraf et al. 1990) is a hyperthermophilic archaeon in the euryarchaeal class Archaeoglobi, which is currently represented by the single family Archaeoglobaceae, containing six validly named species and two strains ascribed to the genus 'Geoglobus' which is taxonomically challenged as the corresponding type species has no validly published name. All members were isolated from marine hydrothermal habitats and are obligate anaerobes. Here we describe the features of the organism, together with the complete genome sequence and annotation. This is the second completed genome sequence of a member of the class Archaeoglobi. The 1,563,423 bp genome with its 1,858 protein-coding and 52 RNA genes is a part of the Genomic Encyclopedia of Bacteria and Archaea project.     

Complete genome sequence of Nakamurella multipartita type strain (Y-104)

Nakamurella multipartita (Yoshimi et al. 1996) Tao et al. 2004 is the type species of the monospecific genus Nakamurella in the actinobacterial suborder Frankineae. The nonmotile, coccus-shaped strain was isolated from activated sludge acclimated with sugar-containing synthetic wastewater, and is capable of accumulating large amounts of polysaccharides in its cells. Here we describe the features of the organism, together with the complete genome sequence and annotation. This is the first complete genome sequence of a member of the family Nakamurellaceae. The 6,060,298 bp long single replicon genome with its 5415 protein-coding and 56 RNA genes is part of the Genomic Encyclopedia of Bacteria and Archaea project.     

Complete genome sequence of Streptosporangium roseum type strain (NI 9100)

Streptosporangium roseum Crauch 1955 is the type strain of the species which is the type species of the genus Streptosporangium. The 'pinkish coiled Streptomyces-like organism with a spore case' was isolated from vegetable garden soil in 1955. Here we describe the features of this organism, together with the complete genome sequence and annotation. This is the first completed genome sequence of a member of the family Streptosporangiaceae, and the second largest microbial genome sequence ever deciphered. The 10,369,518 bp long genome with its 9421 protein-coding and 80 RNA genes is a part of the Genomic Encyclopedia of Bacteria and Archaea project.     

Complete genome sequence of Desulfarculus baarsii type strain (2st14)

Desulfarculus baarsii (Widdel 1981) Kuever et al. 2006 is the type and only species of the genus Desulfarculus, which represents the family Desulfarculaceae and the order Desulfarculales. This species is a mesophilic sulfate-reducing bacterium with the capability to oxidize acetate and fatty acids of up to 18 carbon atoms completely to CO(2). The acetyl-CoA/CODH (Wood-Ljungdahl) pathway is used by this species for the complete oxidation of carbon sources and autotrophic growth on formate. The type strain 2st14(T) was isolated from a ditch sediment collected near the University of Konstanz, Germany. This is the first completed genome sequence of a member of the order Desulfarculales. The 3,655,731 bp long single replicon genome with its 3,303 protein-coding and 52 RNA genes is a part of the Genomic Encyclopedia of Bacteria and Archaea project.     

The C terminus of c-Src inhibits breast tumor cell growth by a kinase-independent mechanism

Overexpression or increased activity of cellular Src (c-Src) is frequently detected in human breast cancer, implicating involvement of c-Src in the etiology of breast carcinomas. Curiously, overexpression of c-Src in tissue culture cells results in a weakly or non-transforming phenotype, indicating that it alone is not sufficient for oncogenesis. However, the protein has been demonstrated to potentiate mitogenic signals from transmembrane receptors. This report investigates the requirement for c-Src in breast cancer as a transducer and integrator of anchorage-dependent and -independent growth signals by utilizing the Src family pharmacological inhibitors, PP1 and PP2, or stable overexpression of the catalytically inactive c-Src mutant (K- c-Src). Both methods of inhibiting endogenous c-Src diminished formation of soft agar colonies and tumors in nude mice. The majority of the dominant-negative activity of K- c-Src was mapped to the Src homology 2 (SH2) domain and C-terminal half of the molecule, but not to the Unique domain, Src homology 3 (SH3) domain, or the N-terminal half of K- c-Src. Further analysis of the C terminus revealed that its ability to inhibit growth localized to the N-terminal lobe (N-lobe) of the catalytic region. These results underscore the requirement for c-Src to maintain the oncogenic phenotype of breast cancer cells and suggest that c-Src may be manipulated to inhibit cell growth by the direct disruption of its catalytic activity or the introduction of either the SH2 domain or the N-lobe of K- c-Src.     

Optimization of alpha-acylaminoketone ecdysone agonists for control of gene expression

Fifteen new alpha-acylaminoketones were prepared by four different routes in an initial effort to optimize the potency of these compounds as ecdysone agonists. The compounds were assayed in mammalian cells expressing the ecdysone receptors from Bombyx mori (BmEcR) and Choristoneura fumiferana (CfEcR) for their ability to cause expression of a reporter gene downstream of an ecdysone response element. A new alpha-acylaminoketone was identified which had activity equal to that of the standard dibenzoylhydrazine ecdysone agonist GS()-E in the assay based on CfEcR.