Mutations in Ran system affected telomere silencing in Saccharomyces cerevisiae

The Ran GTPase system regulates the direction and timing of several cellular events, such as nuclear-cytosolic transport, centrosome formation, and nuclear envelope assembly in telophase. To gain insight into the Ran system\u27s involvement in chromatin formation, we investigated gene silencing at the telomere in several mutants of the budding yeast Saccharomyces cerevisiae, which had defects in genes involved in the Ran system. A mutation of the RanGAP gene, rna1-1, caused reduced silencing at the telomere, and partial disruption of the nuclear Ran binding factor, yrb2-Δ2, increased this silencing. The reduced telomere silencing in rna1-1 cells was suppressed by a high dosage of the SIR3 gene or the SIT4 gene. Furthermore, hyperphosphorylated Sir3 protein accumulated in the rna1-1 mutant. These results suggest that RanGAP is required for the heterochromatin structure at the telomere in budding yeast. © 2007 Elsevier Inc. All rights reserved

The properties of residual water molecules in ionic liquids : a comparison between direct and inverse Kirkwood-Buff approaches

We study the properties of residual water molecules at different mole fractions in dialkylimidazolium based ionic liquids (ILs), namely 1-ethyl-3-methylimidazolium tetrafluoroborate (EMIM/BF4) and 1-butyl-3-methylimidazolium tetrafluoroborate (BMIM/BF4) by means of atomistic molecular dynamics (MD) simulations. The corresponding Kirkwood-Buff (KB) integrals for the water-ion and ion-ion correlation behavior are calculated by a direct evaluation of the radial distribution functions. These are compared to the corresponding KB integrals derived by an inverse approach based on experimental data. Our results reveal a quantitative agreement between both approaches, which paves a way towards a more reliable comparison between simulation and experimental results. The simulation outcomes highlight that water even at intermediate mole fractions has a negligible influence on the ion distribution in the solution. Further analysis on the local/bulk partition coefficients and the partial structure factors reveal that water molecules at low mole fractions mainly remain in the monomeric state. A non-linear increase of higher order water clusters can be found at larger water concentrations. For both ILs, a higher water coordination number around the cations can be observed, which reveals that mainly the cations are responsible for water pairing mechanisms at higher mole fractions. Our results also provide more detailed insights in the properties of dialkylimidazolium based ILs with hydrophobic side chains and their effects on water binding

ACTN1 Mutations Cause Congenital Macrothrombocytopenia

Congenital macrothrombocytopenia (CMTP) is a heterogeneous group of rare platelet disorders characterized by a congenital reduction of platelet counts and abnormally large platelets, for which CMTP-causing mutations are only found in approximately half the cases. We herein performed whole-exome sequencing and targeted Sanger sequencing to identify mutations that cause CMTP, in which a dominant mode of transmission had been suspected but for which no known responsible mutations have been documented. In 13 Japanese CMTP-affected pedigrees, we identified six (46%) affected by ACTN1 variants cosegregating with CMTP. In the entire cohort, ACNT1 variants accounted for 5.5% of the dominant forms of CMTP cases and represented the fourth most common cause in Japanese individuals. Individuals with ACTN1 variants presented with moderate macrothrombocytopenia with anisocytosis but were either asymptomatic or had only a modest bleeding tendency. ACTN1 encodes α-actinin-1, a member of the actin-crosslinking protein superfamily that participates in the organization of the cytoskeleton. In vitro transfection experiments in Chinese hamster ovary cells demonstrated that altered α-actinin-1 disrupted the normal actin-based cytoskeletal structure. Moreover, transduction of mouse fetal liver-derived megakaryocytes with disease-associated ACTN1 variants caused a disorganized actin-based cytoskeleton in megakaryocytes, resulting in the production of abnormally large proplatelet tips, which were reduced in number. Our findings provide an insight into the pathogenesis of CMTP