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

Pre-Absorbed Immunoproteomics: A Novel Method for the Detection of Streptococcus suis Surface Proteins

Streptococcus suis serotype 2 (SS2) is a zoonotic pathogen that can cause infections in pigs and humans. Bacterial surface proteins are often investigated as potential vaccine candidates and biomarkers of virulence. In this study, a novel method for identifying bacterial surface proteins is presented, which combines immunoproteomic and immunoserologic techniques. Critical to the success of this new method is an improved procedure for generating two-dimensional electrophoresis gel profiles of S. suis proteins. The S. suis surface proteins identified in this study include muramidase-released protein precursor (MRP) and an ABC transporter protein, while MRP is thought to be one of the main virulence factors in SS2 located on the bacterial surface. Herein, we demonstrate that the ABC transporter protein can bind to HEp-2 cells, which strongly suggests that this protein is located on the bacterial cell surface and may be involved in pathogenesis. An immunofluorescence assay confirmed that the ABC transporter is localized to the bacterial outer surface. This new method may prove to be a useful tool for identifying surface proteins, and aid in the development of new vaccine subunits and disease diagnostics

Generation of integration-free neural progenitor cells from cells in human urine

Human neural stem cells hold great promise for research and therapy in neural disease. We describe the generation of integration-free and expandable human neural progenitor cells (NPCs). We combined an episomal system to deliver reprogramming factors with a chemically defined culture medium to reprogram epithelial-like cells from human urine into NPCs (hUiNPCs). These transgene-free hUiNPCs can self-renew and can differentiate into multiple functional neuronal subtypes and glial cells in vitro. Although functional in vivo analysis is still needed, we report that the cells survive and differentiate upon transplant into newborn rat brain.postprin

Multi‑μJ harmonic emission energy from laser‑driven plasma

We report on simultaneous efficiency and divergence measurements for harmonics from solid targets generated by the relativistic oscillating mirror mechanism. For a value of the normalized vector potential of aL≃1.5aL≃1.5, we demonstrate the generation of 30 μJ high-harmonic radiation in a 17±317±3 mrad divergence cone. This corresponds to a conversion efficiency of ≳≳ 10−4 in the 17–80 nm range into a well-confined beam. Presuming phase-locked harmonics, our results predict unprecedented levels of average power for a single attosecond pulse in the generated pulse train. Results of PIC simulations raise the prospect of attaining efficiencies of a few percent at higher laser intensities

Ti-2-Containing 18-Tungsto-2-Arsenate(III) Monolacunary Host and the Incorporation of a Phenylantimony(III) Guest

The novel Ti-2-containing, sandwich-type 18-tungsto-2-arsenate(III) [ ((TiO)-O-IV)(2) (alpha-(AsW9O33)-W-III)(2)](14-) (1) was successfully synthesized by the reaction of [TiO](2+) species with [alpha-(AsW9O33)-W-III](9-). The monolacunary polyanion 1 is solution-stable, and a further reaction with 1 equiv of phenylantimony(III) dichloride resulted in [C6H5SbIII((TiO)-O-IV)(2)(alpha-(AsW9O33)-W-III)(2)](12-) (2). Both polyanions 1 and 2 were structurally characterized in the solid state and solution. Electrochemical studies were also performed on both polyanions

Synthesis, structure, electrochemistry and magnetism of cobalt-, nickel- and zinc-containing [M-4(OH)(3)(H2O)(2)(alpha-SiW10O36.5)(2)](13-) (M = Co2+, Ni2+, and Zn2+)

Interaction of the trilacunary 9-tungstosilicate [A-alpha-SiW9O34](10-) with cobalt(ii), nickel(ii) and zinc(ii) ions in pH 9 aqueous medium at room temperature led to the formation of the respective M-4-containing heteropolytungstates [M-4(OH)(3)(H2O)(2)(alpha-SiW10O36.5)(2)](13-) (M = Co2+ (1), Ni2+ (2), and Zn2+ (3)). Polyanions 1-3 were characterized in the solid state by single-crystal XRD, FT-IR spectroscopy, and thermogravimetric and elemental analyses. Electrochemical studies showed that the Co2+ ions in 1 can be oxidized to Co3+ and the CVs of the W-VI centers of the polyanions feature well-defined and chemically reversible reduction waves. Magnetic measurements on 1 and 2 showed paramagnetism with complex ferromagnetic and antiferromagnetic interactions. A model was presented for extracting the exchange constants for the magnetic exchange interaction

Molecular Interaction between a Gadolinium-Polyoxometalate and Human Serum Albumin

Polyoxometalates (POMs) show promising antibacterial, antiviral (particularly anti-HIV), antitumor, and anticancer activities, but the mechanism of these potential therapeutic effects remains to be elucidated at the molecular level. The interaction between the Gd-containing tungstosilicate [Gd(beta(2)-SiW(11)O(39))(2)](13-) and human serum albumin (HSA) was studied by several techniques. Fluorescence spectroscopy showed an energy transfer between the single tryptophan residue of HSA and the POM. Circular dichroism led to the conclusion that the POM significantly altered the secondary structure of HSA. Isothermal titration calorimetry revealed an enthalpy-driven binding reaction between HSA and the POM, resulting in the formation of a 1:1 complex. ((C) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009