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A network of protein interactions that centre around the Cdc42 RhoGAP Rich1 and organize apical polarity in MDCK epithelial cells is identified. Rich1 and Amot maintain tight junctions (TJ) integrity by the coordinate regulation of Cdc42 and by linking specific components of the TJ to intracellular protein trafficking.

Research was conducted to characterize the unc-73 gene product from Caenorhabditis elegans as it relates to guided cell and growth cone migrations. Results showed that unc-73 affected several cell migrations in C. elegans and influenced pioneer and non-pioneer growth cone and cell migrations. They also indicated that the unc-73 peptide was capable of activating Rac and inducing actin reorganization characteristic of membrane ruffling.

Highlights • A new mathematical formulation is proposed to solve the multiple depot vehicle scheduling problem (MDVSP). • A new decomposition of the formulation is proposed that can be solved using column generation. • Column generation requires less time to solve the new decomposition than to solve the existing set partitioning formulation. • Two new heuristics are proposed that use the new decomposition. • The new heuristics perform better than the existing heuristics in terms of the solution quality and time. Abstract The multiple depot vehicle scheduling problem (MDVSP) with a single vehicle type considers the assignment of timetabled trips to homogeneous vehicles that are stationed at different depots. The assignment of trips to a vehicle also provides a schedule for a vehicle. The objective is to minimise the total cost due to waiting and travelling empty while covering all the trips. In this paper, we propose a new formulation for the MDVSP (termed as the inventory formulation) that uses assignment arcs in a multi-commodity time-space network flow formulation. A general way to solve this multi-commodity network flow problem is to decompose the problem for each commodity (in this case, for each depot). However, we apply Dantzig–Wolfe decomposition to the inventory formulation by decomposing it for each trip. Column generation is used to solve the linear relaxation of the trip-based decomposition. Column generation requires less time to solve the new trip-based decomposition than the existing depot-based decompositions. To obtain a good-quality integer solution to the MDVSP, we propose a solution framework that solves the linear relaxation of the MDVSP iteratively. At each iteration, schedules for certain vehicles in the fleet are finalised. The iterations continue until all the trips receive an allocation. Three different heuristics are proposed based on the solution framework. The computational experiments suggest that the new heuristics provide better quality solutions than the existing heuristics. For instances with a large number of trips, the new heuristics provide solutions in less time than that required by the existing heuristics. [ABSTRACT FROM AUTHOR]

A novel modification of piperlongumine is designed, bearing a cyclic sulphonamide (sultam) and its synthesis is described. For the first time herein we report the synthesis and biological evaluation of the natural product derived cyclic sulfonamides using Grubbs second generation catalyst (Grubbs II) via ring closing metathesis approach. Synthesis of a series of piperlongumine derived sultams is done in a moderate to good yield using Wittig reaction, Ring-Closing Metathesis (RCM) and, amide synthesis by using mixed anhydride, approach. All synthesized compounds were evaluated for anticancer activity and some demonstrated dose dependent reduction in HeLa cell growth. Of these 7, 10 and 14 significantly reduced the cell growth. Consequently their calculated GI 50 values were found to be 0.1 or <0.1 μM. [ABSTRACT FROM AUTHOR]

A study was undertaken to investigate the biological activity of the mammalian Grb2, a subset of the SH2 domain-containing proteins of protein-tyrosine kinases, to relate it to the genetic analysis of an SH2/SH3 adaptor. The mammalian Grb2 was believed to bind phosphoproteins, docking proteins and cytoplasmic tyrosine kinases. Results revealed that Grb2 manifested multiple activities in normal and oncogenic signaling pathways. It was suggested that the Grb2 signaling pathway regulated cell differentiation in the early embryonic development.

Abstract: A practical and metal free method for methylthiolation of imidazo[1,2-a]pyridines and other imidazo-fused heterocycles using DMSO–POCl3 complex is reported. The reactions are carried out at room temperature that give the corresponding methylthiolated products in good to excellent yield. Further, its application to indole has been demonstrated. [Copyright &y& Elsevier]

Abstract: Asymmetric multicomponent reactions of optically active phenyl dihydrofuran, keto ester or N-tosyl imino ester, and allylsilane provided functionalized phenyl tetrahydrofurans with multiple stereogenic centers diastereoselectively. Cleavage of the resulting substituted tetrahydrofurans readily provided acyclic derivatives with three contiguous asymmetric centers via an acyloxycarbenium ion intermediate. Ring closing olefin metathesis, using Grubbs catalyst, afforded functionalized cyclopentene derivatives in optically active form. A one-pot tandem tetrahydrofuran ring cleavage followed by ring closing olefin metathesis also provided functionalized cyclopentenes in good yield. [Copyright &y& Elsevier]

The anti-tumor synthel:ic triterpenoid 2-cyano-3, 12-di- oxooleana-1,9-dien-28-oic acid (CDDO)-imidazolide (CDDO- Im) ectopically activates the transforming growth factor ~3 (TGF~)-Smad pathway and extends the duration of signaling by an undefined mechanism. Here we show that CDDO-Im- dependent persistence of Sniad2 phosphorylation is independent of Smad2 phosphatase activity and correlates with delayed TGFI3 receptor degradation md trafficking. Altered TGF~ trafficking parallels the dispersal of EEA1-positive endosomes from the perinuclear region of CDDO-Im-treated cells. The effect of CDI)O-Im on the EEA1 compartment led to an analysis of the cytoskeleton, and we observed that CDDO-Im alters microtubule dynamics by disrupting the microtubule-capping protein, Clip-170. Interestingly, biotinylated triterpenoid was found to localize to the polarity complex at the leading edge of migrating cells. Furthermore, CDDO-Im disrupted the localization of IQGAP1, PKC~ Par6, and TGFI3 receptors from the leading edge of migrating cells and inhibited TGF~-dependent cell migration. Thus, the synthetic triterpenoid CDDO-Im interferes with TGFIJ receptor trafficking and turnover and disrupts cell migration by severing the link between members of the polarity complex and the microtubule network. [ABSTRACT FROM AUTHOR]

Abstract: Structure-based design, synthesis, and biological evaluation of a series of dihydroquinazoline-derived β-secretase inhibitors incorporating thiazole and pyrazole-derived P2-ligands are described. We have identified inhibitor 4f which has shown potent enzyme inhibitory (K i =13nM) and cellular (IC50 =21nM in neuroblastoma cells) assays. A model of 4f was created based upon the X-ray structure of 3a-bound β-secretase. The model suggested possible interactions in the active site. [Copyright &y& Elsevier]

Abstract: Structure-based design, synthesis, and biological evaluation of a series of peptidomimetic β-secretase inhibitors incorporating hydroxyethylamine isosteres are described. We have identified inhibitor 24 which has shown exceedingly potent activity in memapsin 2 enzyme inhibitory (K i 1.8nM) and cellular (IC50 =1nM in Chinese hamster ovary cells) assays. Inhibitor 24 has also shown very impressive in vivo properties (up to 65% reduction of plasma Aβ) in transgenic mice. The X-ray structure of protein-ligand complex of memapsin 2 revealed critical interactions in the memapsin 2 active site. [Copyright &y& Elsevier]