The decreased expression of Beclin-1 correlates with progression to esophageal adenocarcinoma: the role of deoxycholic acid

Beclin-1 has a central role in the regulation of autophagy. Barrett's esophagus (BE) is associated with a significantly increased risk for the development of esophageal adenocarcinoma (EAC). In the current study, we evaluated the role of Beclin-1 and autophagy in the EAC. Biopsies obtained from patients with BE and EAC, tissues from a rat model of BE and EAC, and esophageal cell lines were evaluated for the expression of Beclin-1 by immunohistochemistry, immunoblotting, or RT-PCR. Since reflux of bile acids is important in EAC, we also evaluated the effect of exposure to deoxycholic acid (DCA) on autophagy and Beclin-1 expression. Beclin-1 expression was high in squamous epithelium and nondysplastic BE, whereas its expression was low in dysplastic BE and EAC. The same pattern of expression was observed in rat tissues and in esophageal cell lines. Normal esophageal epithelium and HET-1A cells (derived from normal squamous epithelium) show high levels of Beclin-1, but lower levels of Beclin-1 were found in BE and EAC cell lines (CP-A, CP-C, and OE33). Acute exposure to DCA led to increased Beclin-1 expression and increased autophagy as evaluated by electron microscopy and counting percentage of GFP-LC3-positive BE cells with punctate pattern. In contrast, chronic exposure to DCA did not result in the alteration of Beclin-1 levels or autophagy. In summary, these data suggest that autophagy is initially activated in response to bile acids, but chronic exposure to bile acids leads to decreased Beclin-1 expression and autophagy resistance.     

Molecular basis for regulation of Src by the docking protein p130Cas

The docking protein p130Cas (Cas) becomes tyrosine-phosphorylated in its central substrate domain in response to extracellular stimuli such as integrin-mediated cell adhesion, and transmits signals through interactions with various intracellular signaling molecules such as the adaptor protein Crk. Src-family kinases (SFKs) bind a specific site in the carboxyl-terminal region of Cas and subsequently SFKs phosphorylate progressively the substrate domain in Cas. In this study crystallography, mutagenesis and binding assays were used to understand the molecular basis for Cas interactions with SFKs. Tyrosine phosphorylation regulates binding of Cas to SFKs, and the primary site for this phosphorylation, Y762, has been proposed. A phosphorylated peptide corresponding to Cas residues 759MEDpYDYVHL767 containing the key phosphotyrosine was crystallized in complex with the SH3-SH2 domain of the SFK Lck. The results provide the first structural data for this protein-protein interaction. The motif in Cas 762pYDYV binds to the SH2 domain in a mode that mimics high-affinity ligands, involving dual contacts of Y762 and V765 with conserved residues in SFK SH2 domains. In addition, Y764 is in position to make an electrostatic contact after phosphorylation with a conserved SFK arginine that mediates interactions with other high-affinity SH2 binders. These new molecular data suggest that Cas may regulate activity of Src as a competing ligand to displace intramolecular interactions that occur in SFKs (between the C-terminal tail and the SH2 domain) and restrain and down-regulate the kinase in an inactive form.     

Logical Cell Formation in FMS, Using Flexibility-Based Criteria

Flexible manufacturing systems often are organized into a cellular architecture for ease of operation. The formation of these cells sometimes has been treated as an extension of the conventional cell-formation problem. This paper argues that, owing to the existence of flexible routing and transfer capabilities, the cell-formation problem in FMSs should be treated as quite distinct from that in conventional manufacturing systems and shows that a flexibility-based procedure is apt for overcoming the deficiencies of earlier forays into this area. Manufacturing cell flexibility is defined as a composite of three flexibility measures: producibility,processivity , and transferability. The problem of cell formation is modeled as flexibility maximization, and a procedure is developed for the simultaneous formation of machine cells and part families, while heuristically maximizing within-cell flexibility.     

Key to Indian genera of the familyChalcididae [Hym.: Chalcidoidea]

The Indian chalcid wasps of the familyChalcididae now comprise 30 genera including 4 new records. An illustrated key to the identification of these 30 genera is provided along with relevant subfamilies and tribes. Synonyms of the genera are also provided.

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Résumé Les chalicidens de l'Inde de la famille desChalcididae comprennent maintenant 30 genres incluant 4 nouveaux. Une clé dichotomique pour l'identification de ces 30 genres est présentée en mentionnant les sous-familles et les tribus. Les synonymes de ces genres sont signalés.