Importin-9 wraps around the H2A-H2B core to act as nuclear importer and histone chaperone.

We report the crystal structure of nuclear import receptor Importin-9 bound to its cargo, the histones H2A-H2B. Importin-9 wraps around the core, globular region of H2A-H2B to form an extensive interface. The nature of this interface coupled with quantitative analysis of deletion mutants of H2A-H2B suggests that the NLS-like sequences in the H2A-H2B tails play a minor role in import. Importin-9•H2A-H2B is reminiscent of interactions between histones and histone chaperones in that it precludes H2A-H2B interactions with DNA and H3-H4 as seen in the nucleosome. Like many histone chaperones, which prevent inappropriate non-nucleosomal interactions, Importin-9 also sequesters H2A-H2B from DNA. Importin-9 appears to act as a storage chaperone for H2A-H2B while escorting it to the nucleus. Surprisingly, RanGTP does not dissociate Importin-9•H2A-H2B but assembles into a RanGTP•Importin-9•H2A-H2B complex. The presence of Ran in the complex, however, modulates Imp9-H2A-H2B interactions to facilitate its dissociation by DNA and assembly into a nucleosome

Mutations in the Human naked cuticle Homolog NKD1 Found in Colorectal Cancer Alter Wnt/Dvl/β-Catenin Signaling

BACKGROUND:Mutation of Wnt signal antagonists Apc or Axin activates beta-catenin signaling in many cancers including the majority of human colorectal adenocarcinomas. The phenotype of apc or axin mutation in the fruit fly Drosophila melanogaster is strikingly similar to that caused by mutation in the segment-polarity gene, naked cuticle (nkd). Nkd inhibits Wnt signaling by binding to the Dishevelled (Dsh/Dvl) family of scaffold proteins that link Wnt receptor activation to beta-catenin accumulation and TCF-dependent transcription, but human NKD genes have yet to be directly implicated in cancer. METHODOLOGY/PRINCIPAL FINDINGS:We identify for the first time mutations in NKD1--one of two human nkd homologs--in a subset of DNA mismatch repair-deficient colorectal tumors that are not known to harbor mutations in other Wnt-pathway genes. The mutant Nkd1 proteins are defective at inhibiting Wnt signaling; in addition, the mutant Nkd1 proteins stabilize beta-catenin and promote cell proliferation, in part due to a reduced ability of each mutant Nkd1 protein to bind and destabilize Dvl proteins. CONCLUSIONS/SIGNIFICANCE:Our data raise the hypothesis that specific NKD1 mutations promote Wnt-dependent tumorigenesis in a subset of DNA mismatch-repair-deficient colorectal adenocarcinomas and possibly other Wnt-signal driven human cancers

The role of hubs and economies of scale in network expansion

Freight distribution often operates on the basis of consolidation, which is achieved through the use of hub facilities that allow for economies of scale. Freight networks need to be expanded to meet future demand, to cater for new markets, and to accommodate trends in global supply chains, for which strategic decisions need to be made. These decisions mainly entail the number and location of new hubs to be established. As network expansions require significant capital, striking a balance between the benefits afforded by the new hubs and the expansion costs is crucial. This paper investigates a hub network expansion problem where the configuration of the resulting network is determined by the trade-off between the fixed costs of locating new hubs and new links, as well as routing costs of shipping commodities, and the cost reductions achieved through economies of scale, without imposing a predetermined network structure. This paper also describes a mixed integer programming formulation of the problem and a Benders decomposition algorithm that uses several enhancement techniques to efficiently solve the model to optimality. The application of the algorithm on a real-life case study arising in the expansion of the Indonesian freight transport network yields several managerial insights. In particular, expanding the network with additional hubs and links can yield substantial cost savings, averaging at 47.6%, although at the expense of an increase in the length of the commodity paths. Failing to operate the network at the selected level of economies of scale can result in an increase in the routing costs by up to 58.8%. Expanding the network with no additional hubs leads to a rise in total costs of up to 20.9%. Finally, lower economies of scale leads to an increase in the length of commodity paths, with the routing cost being identified as the most sensitive parameter

Effects of ethylenediaminetetraacetic acid and sodium hypochlorite on the bond strength of bonding agents to pulp chamber lateral walls

Barutcugil, Cagatay/0000-0002-5321-2299; harorli, osman tolga/0000-0001-6828-5063WOS: 000342263000004Background/purpose: The purposes of this in vitro study were to determine the microtensile bond strengths of four different dentin adhesive materials placed in pulp chamber walls, and to test the effects of 5% sodium hypochlorite (NaOCl) and 17% ethylenediaminetetraacetic acid (EDTA) pretreatments on resin dentin bond strengths. Materials and methods: Recently extracted human third molars were selected. The teeth were divided into four groups. Specimens in each group were treated as follows: irrigated with distilled water; irrigated with EDTA for 5 minutes; irrigated with sodium hypochlorite for 5 minutes; and irrigated with EDTA for 5 minutes followed by NaOCl. for 5 minutes. Treated specimens were dried, bonded with a total-etching adhesive, two self-etching adhesives, or a one-bottle self-etching adhesive system. After the bonding procedure and composite restoration, teeth were sectioned, and 15 dentin sticks were obtained. Microtensile testing was performed, and scanning electron micrographs were taken of each irrigated group. Results: In the control group, the one-bottle self-etching adhesive system showed statistically higher bond strength values. EDTA irrigation did not affect the bond strength except for the total-etching adhesive. NaOCl significantly reduced the bond strengths of all adhesives. The EDTA and NaOCl combination did not show a statistically significant reduction in bond strengths of the adhesives to pulpal dentin. Conclusion: There was a reduction in bond strengths of all adhesive systems used to test pulp chamber lateral walls after endodontic irrigation solutions were used. Copyright (C) 2012, Association for Dental Sciences of the Republic of China. Published by Elsevier Taiwan LLC. All rights reserved

Push-Out Bond Strength Between Composite Core Buildup and Fiber-Reinforced Posts After Different Surface Treatments

Objective: The aim of this study was to evaluate the effects of different surface treatments on the pushout bond strength of fiber-reinforced posts to composite resin cores. Materials and methods: Twenty-five translucent glass fiber posts were divided into five groups according to surface treatment methods as follows: an untreated control group, a group coated with silicated alumina particles (Co-Jet system, 3M ESPE, St. Paul, MN), and three groups undergoing surface preparation with erbium: yttrium-aluminum-garnet (Er:YAG) laser under three different power settings (150, 300, and 450 mJ at 10 Hz for 60 sec at 100 mu s duration). After surface treatment, fiber posts were built up to a dual cure composite resin core. All of the specimens were set and sectioned perpendicularly along the long axis of the post using a saw. Two discs (thickness of 2 mm) were obtained from each post-core sample; finally, each group consisted of 10 samples. For artificial aging, the specimens were stored in water (37 degrees C) for 24 h and subjected to thermal cycling (5000 cycles, 5-55 degrees C, and 30 sec dwell time). Pushout tests were performed using a universal testing machine at a crosshead speed of 0.5 mm/min. The pushout pressure values were measured in MPa and analyzed using one way analysis of variance (ANOVA) and Tukey's honestly significant difference (HSD) post-hoc test (p < 0.05). Fiber post surface images were obtained using a scanning electron microscope (SEM). Results: The bond strength values ranged between 14,949 and 23,879 MPa. The lowest values were observed in the groups treated with the Er:YAG laser at 150 mJ. Irradiation by the Er:YAG laser at 450 mJ affected the bond strength significantly (p < 0.05). After Co-Jet sandblasting, the bond strength increased relatively (19,184 MPa). Conclusions: Er:YAG laser irradiation enhanced the bond strength of fiberre-inforced posts to composite resin cores depending upon the power applied; Co-Jet sandblasting also increased the bond strength

The color differences of direct esthetic restorative materials after setting and compared with a shade guide

harorli, osman tolga/0000-0001-6828-5063; Barutcugil, Cagatay/0000-0002-5321-2299; BAYINDIR, FUNDA/0000-0001-5699-2879WOS: 000291844800019PubMed: 21628688Background. The authors conducted a study to evaluate esthetic restorative materials' color differences after setting and color matching between set materials and a shade guide. Materials and Methods. The authors evaluated 13 resin-based composites, one silorane-based composite, two polyacid-modified resin composites and one conventional glass ionomer cement. They measured the color parameters of the samples, which were 8 millimeters in diameter and 1 5 mm in thickness, before and after they were set according to the Commission International de l'Eclairage (CIE) L*a*b* color scale relative to standard illumination against a white background by means of a dental colorimeter. They also compared the final colors of the restorative materials with a shade guide. Results. Color difference values for each restorative material ranged from 3.25 to 14.04. With the exception of Fuji IX (GC, Tokyo), Filtek P60 (3M ESPE) and Te-Econom (Ivoclar Vivadent), the restorative materials exhibited a perceptible color change after setting. Color difference values between the set materials and the shade guide tabs ranged from 1.86 to 11.83. With the exception of Filtek Supreme XT (3M ESPE) and Fuji IX, the materials exhibited a perceptible difference. Conclusion. Most of the materials tested exhibited a significant color change after polymerization and did not match the shade guide tab after undergoing light curing.Ataturk University Research FundAtaturk University [2003/158]This study was supported partially by Ataturk University Research Fund (project 2003/158)

Temporal competition between differentiation programs determines cell fate choice

Multipotent differentiation, where cells adopt one of several possible fates, occurs in diverse systems ranging from bacteria to mammals. This decision-making process is driven by multiple differentiation programs that operate simultaneously in the cell. How these programs interact to govern cell fate choice is poorly understood. To investigate this issue, we simultaneously measured activities of the competing sporulation and competence programs in single Bacillus subtilis cells. This approach revealed that these competing differentiation programs progress independently without cross-regulation before the decision point. Cells seem to arrive at a fate choice through differences in the relative timing between the two programs. To test this proposed dynamic mechanism, we altered the relative timing by engineering artificial cross-regulation between the sporulation and competence circuits. Results suggest a simple model that does not require a checkpoint or intricate cross-regulation before cellular decision-making. Rather, cell fate choice appears to be the outcome of a 'molecular race' between differentiation programs that compete in time, providing a simple dynamic mechanism for decision-making

An Unconventional Nuclear Localization Motif Is Crucial for Function of the Drosophila Wnt/Wingless Antagonist Naked Cuticle

Wnt/β-catenin signals orchestrate cell fate and behavior throughout the animal kingdom. Aberrant Wnt signaling impacts nearly the entire spectrum of human disease, including birth defects, cancer, and osteoporosis. If Wnt signaling is to be effectively manipulated for therapeutic advantage, we first must understand how Wnt signals are normally controlled. Naked cuticle (Nkd) is a novel and evolutionarily conserved inducible antagonist of Wnt/β-catenin signaling that is crucial for segmentation in the model genetic organism, the fruit fly Drosophila melanogaster. Nkd can bind and inhibit the Wnt signal transducer Dishevelled (Dsh), but the mechanism by which Nkd limits Wnt signaling in the fly embryo is not understood. Here we show that nkd mutants exhibit elevated levels of the β-catenin homolog Armadillo but no alteration in Dsh abundance or distribution. In the fly embryo, Nkd and Dsh are predominantly cytoplasmic, although a recent report suggests that vertebrate Dsh requires nuclear localization for activity in gain-of-function assays. While Dsh-binding regions of Nkd contribute to its activity, we identify a conserved 30-amino-acid motif, separable from Dsh-binding regions, that is essential for Nkd function and nuclear localization. Replacement of the 30-aa motif with a conventional nuclear localization sequence rescued a small fraction of nkd mutant animals to adulthood. Our studies suggest that Nkd targets Dsh-dependent signal transduction steps in both cytoplasmic and nuclear compartments of cells receiving the Wnt signal