Numerical prediction of cavitation erosion in cavitating flow

In this study bubble behavior in cavitating flow is analyzed and prediction of cavitation erosion in 2D cavitating flow around ClarkY 11.7 % hydrofoil at several cavitation is performed by impact pressure induced by bubble collapse. Our numerical method predicts that the impact energy is small if variation of cavitating flow is small and that the position of peak impact energy moves downstream with the decrease in cavitation number until the maximum sheet cavity length becomes larger than chord length. When the maximum sheet cavity length becomes larger than chord length, there are not obvious peak values and relatively weak erosion occurs. And it is found that high impact pressures are mainly induced by bubbles in a cloud and in the vicinity of sheet cavity termination during a cloud collapse. Therefore large impact energy occurs when the cloud cavity collapses near the hydrofoil, the sheet cavity termination is on the hydrofoil and the number of bubble is large in these cavities.http://deepblue.lib.umich.edu/bitstream/2027.42/84264/1/CAV2009-final67.pd

New Insight into Intrachromosomal Deletions Induced by Chrysotile in the gpt delta Transgenic Mutation Assay

BACKGROUND: Genotoxicity is often a prerequisite to the development of malignancy. Considerable evidence has shown that exposure to asbestos fibers results in the generation of chromosomal aberrations and multilocus mutations using various in vitro approaches. However, there is less evidence to demonstrate the contribution of deletions to the mutagenicity of asbestos fibers in vivo. OBJECTIVES: In the present study, we investigated the mutant fractions and the patterns induced by chrysotile fibers in gpt delta transgenic mouse primary embryo fibroblasts (MEFs) and compared the results obtained with hydrogen peroxide (H(2)O(2)) in an attempt to illustrate the role of oxyradicals in fiber mutagenesis. RESULTS: Chrysotile fibers induced a dose-dependent increase in mutation yield at the redBA/gam loci in transgenic MEF cells. The number of λ mutants losing both redBA and gam loci induced by chrysotiles at a dose of 1 μg/cm(2) increased by > 5-fold relative to nontreated controls (p < 0.005). Mutation spectra analyses showed that the ratio of λ mutants losing the redBA/gam region induced by chrysotiles was similar to those induced by equitoxic doses of H(2)O(2). Moreover, treatment with catalase abrogated the accumulation of γ-H2AX, a biomarker of DNA double-strand breaks, induced by chrysotile fibers. CONCLUSIONS: Our results provide novel information on the frequencies and types of mutations induced by asbestos fibers in the gpt delta transgenic mouse mutagenic assay, which shows great promise for evaluating fiber/particle mutagenicity in vivo

Escherichia coli YafP protein modulates DNA damaging property of the nitroaromatic compounds

Escherichia coli SOS functions constitute a multifaceted response to DNA damage. We undertook to study the role of yafP, a SOS gene with unknown function. yafP is part of an operon also containing the dinB gene coding for DNA Polymerase IV (PolIV). Our phylogenetic analysis showed that the gene content of this operon is variable but that the dinB and the yafP genes are conserved in the majority of E. coli natural isolates. Therefore, we studied if these proteins are functionally linked. Using a murine septicaemia model, we showed that YafP activity reduced the bacterial fitness in the absence of PolIV. Similarly, YafP increased cytotoxicity of two DNA damaging nitroaromatic compounds, 4-nitroquinoline-1-oxide (NQO) and nitrofurazone, in the absence of PolIV. The fact that PolIV counterbalances YafP-induced cytotoxicity could explain why these two genes are transcriptionally linked. We also studied the involvement of YafP in genotoxic-stress induced mutagenesis and found that PolIV and YafP reduced NQO-induced mutagenicity. The YafP antimutator activity was independent of the PolIV activity. Given that YafP was annotated as a putative acetyltransferase, it could be that YafP participates in the metabolic transformation of genotoxic compounds, hence modulating the balance between their mutagenicity and cytotoxicity

Selective disruption of the DNA polymerase III α–β complex by the umuD gene products

DNA polymerase III (DNA pol III) efficiently replicates the Escherichia coli genome, but it cannot bypass DNA damage. Instead, translesion synthesis (TLS) DNA polymerases are employed to replicate past damaged DNA; however, the exchange of replicative for TLS polymerases is not understood. The umuD gene products, which are up-regulated during the SOS response, were previously shown to bind to the α, β and ε subunits of DNA pol III. Full-length UmuD inhibits DNA replication and prevents mutagenic TLS, while the cleaved form UmuD′ facilitates mutagenesis. We show that α possesses two UmuD binding sites: at the N-terminus (residues 1–280) and the C-terminus (residues 956–975). The C-terminal site favors UmuD over UmuD′. We also find that UmuD, but not UmuD′, disrupts the α–β complex. We propose that the interaction between α and UmuD contributes to the transition between replicative and TLS polymerases by removing α from the β clamp

Antistaphylococcal activity of DNA-interactive pyrrolobenzodiazepine (PBD) dimers and PBD-biaryl conjugates

Objectives: pyrrolobenzodiazepine (PBD) dimers, tethered through inert propyldioxy or pentyldioxy linkers, possess potent bactericidal activity against a range of Gram-positive bacteria by virtue of their capacity to cross-link duplex DNA in sequence-selective fashion. Here we attempt to improve the antibacterial activity and cytotoxicity profile of PBD-containing conjugates by extension of dimer linkers and replacement of one PBD unit with phenyl-substituted or benzo-fused heterocycles that facilitate non-covalent interactions with duplex DNA.Methods: DNase I footprinting was used to identify high-affinity DNA binding sites. A staphylococcal gene microarray was used to assess epidemic methicillin-resistant Staphylococcus aureus 16 phenotypes induced by PBD conjugates. Molecular dynamics simulations were employed to investigate the accommodation of compounds within the DNA helix.Results: increasing the length of the linker in PBD dimers led to a progressive reduction in antibacterial activity, but not in their cytotoxic capacity. Complex patterns of DNA binding were noted for extended PBD dimers. Modelling of DNA strand cross-linking by PBD dimers indicated distortion of the helix. A majority (26 of 43) of PBD-biaryl conjugates possessed potent antibacterial activity with little or no helical distortion and a more favourable cytotoxicity profile. Bactericidal activity of PBD-biaryl conjugates was determined by inability to excise covalently bound drug molecules from bacterial duplex DNA.Conclusions: PBD-biaryl conjugates have a superior antibacterial profile compared with PBD dimers such as ELB-21. We have identified six PBD-biaryl conjugates as potential drug development candidate

Epigenetic perturbations in the pathogenesis of mustard toxicity; hypothesis and preliminary results

Among the most readily available chemical warfare agents, sulfur mustard (SM), also known as mustard gas, has been the most widely used chemical weapon. SM causes debilitating effects that can leave an exposed individual incapacitated for days to months; therefore delayed SM toxicity is of much greater importance than its ability to cause lethality. Although not fully understood, acute toxicity of SM is related to reactive oxygen and nitrogen species, oxidative stress, DNA damage, poly(ADP-ribose) polymerase (PARP) activation and energy depletion within the affected cell. Therefore several antioxidants and PARP inhibitors show beneficial effects against acute SM toxicity. The delayed toxicity of SM however, currently has no clear mechanistic explanation. One third of the 100,000 Iranian casualties are still suffering from the detrimental effects of SM in spite of the extensive treatment. We, therefore, made an attempt whether epigenetic aberrations may contribute to pathogenesis of mustard poisoning. Preliminary evidence reveals that mechlorethamine (a nitrogen mustard derivative) exposure may not only cause oxidative stress, DNA damage, but epigenetic perturbations as well. Epigenetic refers to the study of changes that influence the phenotype without causing alteration of the genotype. It involves changes in the properties of a cell that are inherited but do not involve a change in DNA sequence. It is now known that in addition to mutations, epimutations contribute to a variety of human diseases. Under light of preliminary results, the current hypothesis will focus on epigenetic regulations to clarify mustard toxicity and the use of drugs to correct possible epigenetic defects

The Association between OGG1 Ser326Cys Polymorphism and Lung Cancer Susceptibility: A Meta-Analysis of 27 Studies

Background: Numerous studies have investigated association of OGG1 Ser326Cys polymorphism with lung cancer susceptibility; however, the findings are inconsistent. Therefore, we performed a meta-analysis based on 27 publications encompass 9663 cases and 11348 controls to comprehensively evaluate such associations. Methods: We searched publications from MEDLINE and EMBASE which were assessing the associations between OGG1 Ser326Cys polymorphism and lung cancer risk. We calculated pooled odds ratio (OR) and 95 % confidence interval (CI) by using either fixed-effects or random-effects model. We used genotype based mRNA expression data from HapMap for SNP rs1052133 in normal cell lines among 270 subjects with four different ethnicities. Results: The results showed that individuals carrying the Cys/Cys genotype did not have significantly increased risk for lung cancer (OR = 1.15, 95 % CI = 0.98–1.36) when compared with the Ser/Ser genotype; similarly, no significant association was found in recessive, dominant or heterozygous co-dominant model (Ser/Cys vs. Cys/Cys). However, markedly increased risks were found in relatively large sample size (Ser/Ser vs. Cys/Cys: OR = 1.29, 95 % CI = 1.13–1.48, and recessive model: OR = 1.19, 95 % CI = 1.07–1.32). As to histological types, we found the Cys/Cys was associated with adenocarcinoma risk (Ser/Ser vs. Cys/Cys: OR = 1.32, 95 % CI = 1.12–1.56; Ser/Cys vs. Cys/Cys: OR = 1.19, 95 % CI = 1.04–1.37, and recessive model OR = 1.23, 95 % CI = 1.08–1.40). No significant difference of OGG1 mRNA expression was found among genotypes between differen