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Utrecht, Netherlands

Moldovan G.-L.,Dana-Farber Cancer Institute | Dejsuphong D.,Dana-Farber Cancer Institute | Petalcorin M.I.R.,Cancer Research UK Research Institute | Hofmann K.,Bioinformatics Group | And 3 more authors.
Molecular Cell | Year: 2012

Inappropriate homologous recombination (HR) causes genomic instability and cancer. In yeast, the UvrD family helicase Srs2 is recruited to sites of DNA replication by SUMO-modified PCNA, where it acts to restrict HR by disassembling toxic RAD51 nucleofilaments. How human cells control recombination at replication forks is unknown. Here, we report that the protein PARI, containing a UvrD-like helicase domain, is a PCNA-interacting partner required for preservation of genome stability in human and DT40 chicken cells. Using cell-based and biochemical assays, we show that PARI restricts unscheduled recombination by interfering with the formation of RAD51-DNA HR structures. Finally, we show that PARI knockdown suppresses the genomic instability of Fanconi Anemia/BRCA pathway-deficient cells. Thus, we propose that PARI is a long sought-after factor that suppresses inappropriate recombination events at mammalian replication forks. © 2012 Elsevier Inc.

Goodyer E.,Bioinformatics Group | Gunderson M.,University of Wisconsin - Madison | Dailey S.H.,University of Wisconsin - Madison
Journal of Voice | Year: 2010

During phonation, energy is transferred from the subglottal airflow through the air/mucosa interface that results in the propagation of the mucosal wave in the vocal fold. The vocal fold is soft, and the subglottal mucosa is stiff. We hypothesize that it is highly improbable that there is a rigid boundary between the tissue structures, with a sudden drop in stiffness; and that a gradual change would be more likely to support the efficient transfer of energy from the airflow to the mucosal wave. Our objective was to test this hypothesis by quantifying the change in mucosa stiffness with respect to anatomical position. In this initial study, using five pig larynges, a series of point-specific measurements of mucosa stiffness were taken in a line from the midpoint of the vocal fold toward the trachea. A modified linear skin rheometer adapted for laryngeal elasticity measurement applied shear stress to a series of seven positions at 2-mm intervals starting from the midmembranous vocal fold medial surface. A sinusoidal shear force of 1 g was applied at each point, and resultant displacement curve logged. Using a regression algorithm, the stiffness of the tissue was derived in units of grams force per millimeter displacement. Five readings were taken at each position. The results indicate that there is a linear increase in stiffness with respect to position, increasing as the measurements are taken further from the vocal fold. There is a gradual change in stiffness of the subglottal mucosa of a pig larynx. © 2010 The Voice Foundation.

Polachi N.,Bharathidasan University | Nagaraja P.,Bioinformatics Group | Subramaniyan B.,Bharathidasan University | Mathan G.,Bharathidasan University
Asian Journal of Pharmaceutical and Clinical Research | Year: 2015

Objective: The aim was to study the inhibitory effect of n-butanol fraction of Butea monosperma floral extracts (NBF-BMFE) against HCT116 cells. Moreover, the drug-likeness properties and in silico evaluation of their active compounds toward glycogen synthase kinase-3β (GSK-3β)/Axin and β-catenin/T-Cell factor-4 (Tcf-4) complex proteins. Methods: The three-dimensional protein structures were incurred from RCSB protein data bank, and their active site amino acids predicted using CASTp server. Similarly, the NBE-BMFE phytochemicals were retrieved from PubChem Database then their absorption, distribution, metabolism, excretion, and toxicity (ADMET)-related descriptors were calculated by using the admetSAR along with ACD/i-lab software. The docking analysis was performed by using AutoDock 4.2. Concurrently, the NBF-BMFE were experimentally characterized by using liquid chromatography/mass spectrometry (LC/MS) besides their anticancer activity was assessed against HCT-116 human colon cancer cells. Results: The docking studies results showed that the NBF-BMFE phytochemicals showed good hydrogen bond interaction against GSK-3β/Axin (4B7T) and β-catenin/Tcf-4 (1JPW) complex proteins. Moreover, the in silico results of ADMET factors were also satisfying correspondingly. The LC/MS results revealed that the NBF-BMFE contains isocoreopsin, butrin and isobutrin as major compounds, and it has significant anticancer activity (˃100 μM) against HCT-116 human colon cancer cells. Conclusion: Overall our results concluded that all the NBF-BMFE had significant inhibitory effect on HCT-116 cells plus good binding interaction with 4B7T and 1JPW, in specific isocoreopsin, butein and butin showed promising agents to develop as potent drug molecules against colorectal cancer. © 2015, Asian Journal of Pharmaceutical and Clinical Research. All rights reserved.

Kreck B.,University of Kiel | Marnellos G.,CA Technologies | Richter J.,University of Kiel | Krueger F.,Bioinformatics Group | And 2 more authors.
Bioinformatics | Year: 2012

Bisulfite sequencing, a combination of bisulfite treatment and high-throughput sequencing, has proved to be a valuable method for measuring DNA methylation at single base resolution. Here, we present B-SOLANA, an approach for the analysis of two-base encoding (colorspace) bisulfite sequencing data on the SOLiD platform of Life Technologies. It includes the alignment of bisulfite sequences and the determination of methylation levels in CpG as well as non-CpG sequence contexts. B-SOLANA enables a fast and accurate analysis of large raw sequence datasets. © The Author(s) 2011. Published by Oxford University Press. All rights reserved.

Schofield P.N.,University of Cambridge | Schofield P.N.,The Jackson Laboratory | Gkoutos G.V.,University of Cambridge | Gruenberger M.,University of Cambridge | And 2 more authors.
DMM Disease Models and Mechanisms | Year: 2010

A major challenge of the post-genomic era is coding phenotype data from humans and model organisms such as the mouse, to permit the meaningful translation of phenotype descriptions between species. This ability is essential if we are to facilitate phenotype-driven gene function discovery and empower comparative pathobiology. Here, we review the current state of the art for phenotype and disease description in mice and humans, and discuss ways in which the semantic gap between coding systems might be bridged to facilitate the discovery and exploitation of new mouse models of human diseases. © 2010. Published by The Company of Biologists Ltd.

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