Nucleophosmin leukemogenic mutant activates Wnt signaling during zebrafish development

Nucleophosmin (NPM1) is a ubiquitous multifunctional phosphoprotein with both oncogenic and tumor suppressor functions. Mutations of the NPM1 gene are the most frequent genetic alterations in acute myeloid leukemia (AML) and result in the expression of a mutant protein with aberrant cytoplasmic localization, NPMc+. Although NPMc+ causes myeloproliferation and AML in animal models, its mechanism of action remains largely unknown. Here we report that NPMc+ activates canonical Wnt signaling during the early phases of zebrafish development and determines a Wnt-dependent increase in the number of progenitor cells during primitive hematopoiesis. Coherently, the canonical Wnt pathway is active in AML blasts bearing NPMc+ and depletion of the mutant protein in the patient derived OCI-AML3 cell line leads to a decrease in the levels of active \u3b2-catenin and of Wnt target genes. Our results reveal a novel function of NPMc+ and provide insight into the molecular pathogenesis of AML bearing NPM1 mutations

The Tumor Suppressor PRDM5 Regulates Wnt Signaling at Early Stages of Zebrafish Development

PRDM genes are a family of transcriptional regulators that modulate cellular processes such as differentiation, cell growth and apoptosis. Some family members are involved in tissue or organ maturation, and are differentially expressed in specific phases of embryonic development. PRDM5 is a recently identified family member that functions as a transcriptional repressor and behaves as a putative tumor suppressor in different types of cancer. Using gene expression profiling, we found that transcriptional targets of PRDM5 in human U2OS cells include critical genes involved in developmental processes, and specifically in regulating wnt signaling. We therefore assessed PRDM5 function in vivo by performing loss-of-function and gain-of-function experiments in zebrafish embryos. Depletion of prdm5 resulted in impairment of morphogenetic movements during gastrulation and increased the occurrence of the masterblind phenotype in axin+/− embryos, characterized by the loss of eyes and telencephalon. Overexpression of PRDM5 mRNA had opposite effects on the development of anterior neural structures, and resulted in embryos with a shorter body axis due to posterior truncation, a bigger head and abnormal somites. In situ hybridization experiments aimed at analyzing the integrity of wnt pathways during gastrulation at the level of the prechordal plate revealed inhibition of non canonical PCP wnt signaling in embryos overexpressing PRDM5, and over-activation of wnt/β-catenin signaling in embryos lacking Prdm5. Our data demonstrate that PRDM5 regulates the expression of components of both canonical and non canonical wnt pathways and negatively modulates wnt signaling in vivo

High-level waste canister storage final design, installation, and testing. Topical report

This report is a description of the West Valley Demonstration Project`s radioactive waste storage facility, the Chemical Process Cell (CPC). This facility is currently being used to temporarily store vitrified waste in stainless steel canisters. These canisters are stacked two-high in a seismically designed rack system within the cell. Approximately 300 canisters will be produced during the Project`s vitrification campaign which began in June 1996. Following the completion of waste vitrification and solidification, these canisters will be transferred via rail or truck to a federal repository (when available) for permanent storage. All operations in the CPC are conducted remotely using various handling systems and equipment. Areas adjacent to or surrounding the cell provide capabilities for viewing, ventilation, and equipment/component access

Analysis of trapping effects on the forward current-voltage characteristics of al-implanted 4H-SiC p-i-n Diodes

The forward current-voltage characteristics (IF-VF) of aluminum (Al)-implanted 4H-SiC p-i-n diodes are investigated by means of a numerical simulation study that takes into account both intrinsic and doping-induced deep defects, namely, the Z1/2 and EH6/7 centers inside the drift region and an electrically active trap concentration inside the anode region due to the Al+ ion implantation process. From the experimental results, the fundamental electric parameters of several samples were extracted at different regions of diode operation and used for comparison. The modeling analysis reveals that Z1/2 and EH6/7 centers reduce the effective carrier lifetimes and increase the recombination rate in the drift region determining the slope of the IF curve in the recombination and diffusion regimes. In addition, a defect density that becomes comparable to the epilayer doping concentration introduces an apparent shunt resistance effect at low-medium biases and at the same time has a noticeable impact on the diode series resistance at voltages higher than 2.7 V. A detrimental effect on the series resistance is also observed in dependence of the trap concentration in the anode region that increases the diode's internal resistance as a consequence of the carrier mobility decrease. Above the IF curve knee, the diode current is largely dominated by the electron injection into the anode since the concentration of free holes for conduction is strongly limited in turn by the incomplete activation of the ion-implanted impurities and the trap activity