TMC-95A analogues with endocyclic biphenyl ether group as proteasome inhibitors

TMC-95A, a cyclic tripeptide metabolite of Apiospora montagnei, is a potent competitive inhibitor of proteasome. Based on the X-ray structure of its complex with yeast proteasome, the synthetically challenging structure of this natural product was simplified in a first generation of analogues by replacing the highly oxidized side-chain biaryl system with a phenyl-oxindole group. In the present study, the TMC-95 biaryl group was substituted with a biphenyl ether with retainment of significant proteasome inhibition. Because of the facile synthetic access of tripeptides containing in i, i+2 positions residues of the isodityrosine type, this new generation of TMC-95 analogues may represent promising lead structures for further optimization of affinity and selectivity of proteasome inhibitors.     

VSQual: a visual system to assist DNA sequencing quality control

A lack of pliant software tools that support small- to medium-scale DNA sequencing efforts is a major hindrance for recording and using laboratory workflow information to monitor the overall quality of data production. Here we describe VSQual, a set of Perl programs intended to provide simple and powerful tools to check several quality features of the sequencing data generated by automated DNA sequencing machines. The core program of VSQual is a flexible Perl-based pipeline, designed to be accessible and useful for both programmers and non-programmers. This pipeline directs the processing steps and can be easily customized for laboratory needs. Basically, the raw DNA sequencing trace files are processed by Phred and Cross_match, then the outputs are parsed, reformatted into Web-based graphical reports, and added to a Web site structure. The result is a set of real time sequencing reports easily accessible and understood by common laboratory people. These reports facilitate the monitoring of DNA sequencing as well as the management of laboratory workflow, significantly reducing operational costs and ensuring high quality and scientifically reliable results.     

The human cytotrophoblastic cell, a mononuclear chameleon

The human placenta represents an abundant; easily accessible and unlimited study material (at birth a human placenta provides about 500 g of trophoblast). Cytotrophoblastic cells (CTB) are one constituent of the human placenta and represent epithelial cells with fascinating properties: They are able to fuse to form syncytia, can behave like immotile polarized epithelial cells, can phenocopy stromal fibroblasts or endothelial cells or undergo a mesenchymal-like transformation that converts them into non proliferative and highly invasive cells. Like a chameleon, CTB are thus able to adapt to their immediate environment by phenocopying their neighbor cells. This review describes the different routes that CTB follow during their differentiation pathways, the regulation of these at the molecular level, it gives also an overview of the pathologies associated with faulty pathways and describes the usual phenotypic markers used to identify the different CTB subsets. This review is intended to stimulate investigators not acquainted with the field of placental biology to use CTB as a model to study important biological functions in vitro, such as cell fusion, cell invasion and cell transformation.     

Entamoeba histolytica: mechanism of decrease of virulence of axenic cultures maintained for prolonged periods

Intraportal injection of non-virulent E. histolytica (derived from prolonged axenic culture of virulent E. histolytica) strain HM1-IMSS in normal hamsters results in no liver lesions and disappearance of the parasites 48-72 h after injection. Viability of non-virulent E. histolytica after 2 h of in vitro incubation in either fresh or decomplemented hamster serum is the same as control virulent E. histolytica (50-90%). In hamsters made leukopenic, or both leukopenic+hypocomplementemic, or hypocomplementemic+sephadex microspheres (to produce focal liver ischemia) intraportally injected non-virulent E. histolytica cause no lesions and disappear after 24 h. In addition, neither hypocomplementemia nor immunosuppression with cyclosporin A prolonged the survival of non-virulent E. histolytica. Methyl prednisolone treatment of hamsters resulted in survival of large numbers of non-virulent E. histolytica in the liver, with little inflammation and minimal tissue damage, for up to 7 days. Inflammatory cells (macrophages) would appear to be chiefly responsible for elimination of non-virulent E. histolytica. Parallel experiments with E. dispar suggest a different mechanism for its non-pathogenicity.     

Phylogenetic relationships ofBacteria based on comparative sequence analysis of elongation factor Tu and ATP-synthase β-subunit genes

Comparative sequence analyses were performed on 14 genes encoding bacterial elongation factors EF-Tu and 7 genes encoding the -subunit of bacterial F₁F₀ type ATP-synthases. The corresponding predicted amino acid sequences were compared with published primary structures of homologous molecules. Phylogenetic trees were reconstructed from both data sets of aligned protein sequences and from an equivalent selection of 16S rRNA sequences by applying distance matrix and maximum parsimony methods. The EF-Tu data were in very good agreement with the rRNA data, although the resolution within the EF-Tu tree was reduced at certain phylogenetic levels. The resolution power of the ATPase -subunit sequence data were more reduced than those of the EF-Tu data. In comparison with the 16S rRNA tree there are minor differences in the order of adjacent branchings within the ATPase -subunit tree.     

Structure and conservation of the periplasmic targeting factor Tic22 protein from plants and cyanobacteria

Mitochondria and chloroplasts are of endosymbiotic origin. Their integration into cells entailed the development of protein translocons, partially by recycling bacterial proteins. We demonstrate the evolutionary conservation of the translocon component Tic22 between cyanobacteria and chloroplasts. Tic22 in Anabaena sp. PCC 7120 is essential. The protein is localized in the thylakoids and in the periplasm and can be functionally replaced by a plant orthologue. Tic22 physically interacts with the outer envelope biogenesis factor Omp85 in vitro and in vivo, the latter exemplified by immunoprecipitation after chemical cross-linking. The physical interaction together with the phenotype of a tic22 mutant comparable with the one of the omp85 mutant indicates a concerted function of both proteins. The three-dimensional structure allows the definition of conserved hydrophobic pockets comparable with those of ClpS or BamB. The results presented suggest a function of Tic22 in outer membrane biogenesis.     

Induction of glycolate oxidase by SO2 in Nicotiana tabacum

In contrast to the inhibitory action of sulfite on glycolate oxidase, the specific activity of the enzyme in tobacco leaves exposed to SO₂ for 18 hr increases in proportion to the SO₂ concentration. This increase is strongly reduced by pretreatment with cycloheximide. As a consequence of induced de novo synthesis of glycolate oxidase the glycolate content of the leaves is markedly reduced after 18 hr exposure to SO₂.     

Juvenile Galápagos Pelicans Increase Their Foraging Success by Copying Adult Behaviour

Social learning is the building block of culture and traditions in humans and nonhuman animals, and its study has a long history. Most investigations have addressed either the causation or the function of social learning. Though much is known about the underlying mechanisms of social learning, demonstrations of its adaptive value in a natural setting are lacking. Here we show that juvenile brown pelicans (Pelecanus occidentalis) can increase their foraging efficiency by copying adult diving behaviour, suggesting that social learning helps juveniles to find profitable food patches. Our findings demonstrate the potential fitness consequences of behavioural copying and thus highlight the possible adaptive importance of social learning.